Common Name(s): Fruit acids , alpha hydroxy acids , malic acid , lactic acid , glycolic acid , citric acid , tartaric acid , gluconolactone
Fruit acids have been used to treat a range of dermatological conditions, including acne, photoaging, dry skin, psoriasis, actinic keratosis, and melasma. Additionally, they have been investigated as a treatment for fibromyalgia.
For dry skin disorders, alpha hydroxy acid 8% to 10% cream or lotion is applied 2 to 3 times daily to the affected area. If the dry skin persists after 2 weeks, the concentration can be increased by 2% to 4%. Once the skin appears healthy, the frequency can be reduced to every 2 to 3 days. 1 For fibromyalgia, clinical data suggest the use of 3 Super Malic tablets (each containing malic acid 200 mg) twice daily. 2 Dosing for chemical peels involving glycolic acid will depend on a variety of factors, including the condition being treated, patient expectations, patient age, cumulative sun exposure, skin type, area being treated, peeling agent used, concentration of peel agent, frequency of application, quantity applied, and length of time applied. Typically, on the first visit, glycolic acid is applied for approximately 2 to 3 minutes to determine sensitivity and provide guidance for future length of exposure. Intervals between peels are generally 2 to 4 weeks, and 6 to 8 peels are required for most patients. 3 , 4
Hypersensitive individuals and those with irritated skin should use alpha hydroxy acids cautiously. Patients who have undergone recent cosmetic surgeries, patients with open wounds, and those who have used isotretinoin therapy within the last 6 to 12 months should not receive alpha hydroxy acid peels. 5 In patients who have a history of recurrent or active herpes simplex lesions, treatment with an oral antiviral agent should occur before undergoing chemical peels. 4
Information regarding safety and efficacy in pregnancy and lactation is lacking.
Use of isotretinoin causes a reduction in the number and size of pilosebaceous units in the skin and may cause a delay in wound healing and increase the risk of scarring. It is advised that patients wait at least 6 to 12 months after receiving isotretinoin to begin chemical peels. 3 Antimetabolites and corticosteroids may delay wound healing in patients using chemical peels. 3 Use of hormone replacement therapy and oral contraceptives may cause postinflammatory hyperpigmentation in some patients using chemical peels. 3 Following a chemical peel with glycolic acid, there may be an increase in risk of photosensitivity in patients using photosensitizing agents, such as tetracyclines and other photosensitizing agents. 4
In rats, long-term ingestion of malic acid was found to reduce body weight gains and feed consumption when given for a period of 2 years. 8
As the name indicates, these acidic organic compounds are derived primarily from fruit and other natural sources. 1 Specifically, malic acid is derived from apples, glycolic acid (the smallest alpha hydroxy acid) is derived from sugar cane, lactic acid is derived from sour milk, tartaric acid is derived from grapes, and citric acid is derived from citrus fruits. 1 , 4 , 9 , 10 Other sources may be used for commercial production of these acids (eg, starch, glucose, other sugars).
Organic acids, such as lactic acid, have long been used in dermatologic preparations as humectants to improve the moisturization of the top skin layers. In ancient Egypt, it was believed that Cleopatra bathed in spoiled milk, which contains lactic acid. 9 Organic acids have also been used to remove hair from and to tan animal hides. 11 In 1974, alpha hydroxy acids were first used in dermatology for their topical efficacy against severe hyperkeratosis of ichthyosis. 12
Most organic acids can be caustic in sufficiently high concentrations. As agents that modify the keratinization process (see Pharmacology), alpha hydroxy acids may be useful for the treatment of acne and other skin disorders. 13 Because they help debride dead cells from the skin, they have been added to a variety of skin cleansers. People with all types of skin are typically able to tolerate alpha hydroxy acid products, including people with sensitive or darker skin. 5
A number of cosmetic companies are marketing products that contain alpha hydroxy acids for their anti-aging effects on the skin. Removal of top skin layers may enhance the appearance of the skin.
The fruit acids are a group of organic acids that share a common chemical structure consisting of a hydroxyl group positioned at the alpha-carbon position. Consequently, these compounds are often referred to as alpha hydroxy acids. 14 Common fruit acids include lactic, citric, and malic acids. Because of the structural configuration of these acids, they are optically active. Alpha hydroxy acids typically are water-soluble compounds. 9 However, some alpha hydroxy acids, such as mandelic acid and benzylic acid, are more lipophilic, making them more suitable for treating conditions such as oily skin. 10 Gluconolactone, a polyhydroxy acid, contains a ring structure that is hydrolyzed to gluconic acid, which is an alpha hydroxy acid and poly-alpha hydroxy acid. This gives the molecule keratolytic and moisturizing capabilities. The lactone structure masks the acidity of the molecule, and the compound is suitable for patients with sensitive skin. 15 Unlike glycolic acid, gluconolactone pretreatment does not cause an increase in sunburn cells following sun exposure. 10
Uses and PharmacologyAnti-aging/photoaging/actinic keratosis
Alpha hydroxy acids exert a thinning effect on the stratum corneum. Specifically, the acids cause an “ungluing” of cells, causing them to shed instead of maintain their “stickiness.” The thinning effect of the stratum corneum can be noted up to 14 days after treatment discontinuation. 1 , 4 Additionally, they stimulate the synthesis of collagen in the dermis. The overall effect is improvement in wrinkles, elasticity, and skin tone. 1 , 15 Chemical peels with alpha hydroxy acids can be used to treat a variety of dermatological conditions, including acne, rosacea, age spots, melasma, scarring, and wrinkles. 5 These peels cause an increase in dermal perfusion, as noted by marked erythema and vasodilation occurring after treatment. 9 It may take as long as 6 months before patients achieve noticeable results with alpha hydroxy acid peels. Patients typically require 4 to 6 peels over a 4- to 6-month time period. However, the success of these peels is dependent on the severity of the condition being treated.Animal data
In a murine model, the effects of the alpha hydroxy acids glycolic acid and lactic acid were assessed in hairless mice. The mice were randomized to receive either glycolic acid 5% or lactic acid 5% applied to the right side of the back with vehicle applied to the left side of the back daily for 14 days. No differences were noted between the 2 application sites with regards to transepidermal water loss and capacitance (a measure of hydration). Additionally, no difference in epidermal thickness was noted with alpha hydroxy acid treatment, vehicle treatment, or untreated skin. Electron microscopy suggested the stratum corneum was decreased in the areas treated with glycolic and lactic acids as compared with the areas receiving vehicle. An increase in the number and secretion of lamellar bodies was noted in the areas treated with alpha hydroxy acids. 16Clinical data
In 11 healthy subjects, 4 alpha hydroxy acids were tested with regards to their effects on the stratum corneum and skin irritation. There were no differences among the 4 alpha hydroxy acids with regard to transepidermal water loss and erythema following 4 weeks of twice daily application. Following a challenge with sodium lauryl sulfate, all sites experienced an increase in transepidermal water loss; however, lower transepidermal water loss occurred with the sites treated with alpha hydroxy acids compared with those treated with vehicle or those that were untreated. Gluconolactone and tartaric acid yielded the lowest transepidermal water loss values. 17
In a clinical study, the efficacy of alpha hydroxy acids on photoaging was assessed in 17 patients with moderate to severe photoaged skin. Patients were randomly assigned to receive a 25% concentration of a lotion containing lactic acid, glycolic acid, or citric acid, with instructions to apply to 1 forearm and a placebo lotion to the other forearm twice daily. After treatment for an average of 6 months (range, 4 to 8 months), the forearm thickness on the side treated with alpha hydroxy acids increased from 11.5 ± 1.1 mm at baseline to 14.3 ± 1.1 mm (25% increase). The forearm thickness on the placebo side actually decreased from 12.2 ± 0.9 mm to 11.9 ± 0.9 mm, a 2% decrease from baseline. The difference between the treated and placebo forearms was statistically significant ( P < 0.0001) and was discernible by pinching the skin. Histologically, the mean epidermal thickness and papillary dermal thickness were greater on the forearms treated with alpha hydroxy acids compared with the forearms treated with placebo. Regarding ultrastructural findings, forearms treated with alpha hydroxy acids were found to have an epidermal base layer with more uniform basal kertinocyte nuclei, reduced clumping of tonofilaments in the cytoplasm, increased perinuclear localization of the tonofilaments, and formation of microvilli. Transient burning and/or itching were reported with initial treatment with the alpha hydroxy acid lotions but improved or disappeared with continued use. 18
In a 12-week, controlled clinical study, 57 patients with visible signs of photoaging were randomized to receive a polyhydroxy acid preparation containing gluconolactone 4% applied once in the morning and a gluconolactone 10% cream to be applied in the evening, or an alpha hydroxy acid preparation consisting of a glycolic acid 8% cream to be applied in the morning and an 8% cream to be applied each evening. Patients were instructed to apply the creams twice daily for 12 weeks. Both products showed improvements in the skin after approximately 6 and 12 weeks of treatment. All photoaging parameters improved at the 6-week follow-up visit (except for wrinkles) compared with baseline. Following 12 weeks of treatment, statistically significant improvement in all parameters improved in both treatment groups. Alpha hydroxy acid treatment resulted in significantly better improvements in sallowness after 12 weeks of treatment compared with polyhydroxy acid treatment (17% vs 12%, respectively; P < 0.05). Additionally, alpha hydroxy acid therapy was associated with a greater improvement in pinch recoil after 12 weeks of treatment compared with polyhydroxy acid treatment ( P < 0.05). 6 In a prospective, randomized study, 18 patients with actinic keratosis were randomized to apply glycolic acid 70% in combination with a fluorouracil 5% peel to one half of the face and a glycolic acid peel to the other half of the face once weekly for 8 doses. After 6 months, 92% of actinic keratosis lesions were cleared compared with 20% on the side treated with glycolic acid monotherapy. 19Dry skin and ichthyosis
Lactic acid (in concentrations of approximately 1% to 2% in creams or lotions) has been reported to be an effective, naturally occurring skin humectant, having beneficial effects on dry skin and also in severe hyperkeratotic conditions.Animal data
Research reveals no animal data regarding the use of fruit acids for dry skin.Clinical data
Twenty patients with a range of dry skin complications, including xerosis, epidermolytic hyperkeratosis, and ichthyosis, applied either regular or extra-strength alpha hydroxy acid-blend cream to a test site, as well as a non–alpha hydroxy acid moisturizer to another site, for a period of 4 weeks. After 2 weeks of treatment, there were reduced symptoms and improvements in cosmetic appearance; further improvement occurred with continued treatment. The improvements were significant when compared with baseline and with the sites treated with the non–alpha hydroxy acid moisturizer. 20Melasma
Glycolic acid has been investigated for its use in the treatment of melasma. Specifically, glycolic acid reduces the stratum corneum and is able to augment the effect of hydroquinone, the most commonly used treatment for melasma. 21Animal data
Research reveals no data regarding the use of fruit acids for the treatment of melasma.Clinical data
The efficacy of glycolic acid in combination with either hydroquinone or kojic acid for the treatment of melasma was assessed in a clinical study. Thirty-nine patients with melasma applied the 2 formulas to the right and left sides of the face twice daily for 3 months. Patients began to notice benefit with treatment after 4 weeks of application. Fifty-one percent of patients experienced equal reductions in hyperpigmentation with both hydroquinone and kojic acid in combination with glycolic acid. A larger reduction with hydroquinone occurred in 21% of patients, and a larger reduction occurred with kojic acid in 28% of patients. No differences occurred with regard to pigmentation between the 2 treatment groups. 21Acne
Hyperkeratinization appears to play a role in the development of acne and is often the result of decreases in the rate of skin cell sloughing, which itself is due to an increase in the cohesion of cells known as corneocytes. 22 Alpha hydroxy acids may decrease the cohesiveness of corneocytes by weakening intracellular bonding, 23 freeing skin cells and permitting more efficient cell removal and skin cleansing. 24Animal data
Research reveals no animal data regarding the use of fruit acids for acne.Clinical data
One fruit acid component, gluconolactone, has been found to be as effective as benzoyl peroxide in the treatment of acne. 22 In a double-blind trial of 150 patients, a solution of gluconolactone 14% was compared with benzoyl peroxide 5% lotion and a placebo vehicle. Both active treatments reduced the number of inflamed lesions (compared with baseline) during the 12-week study. While there was no difference between active treatments during the first 4 weeks, the benzoyl peroxide was better in reducing the number of inflamed lesions by weeks 8 and 12 than was the alpha hydroxy acid. Both groups were similarly effective in reducing the total number of inflamed and noninflamed lesions, but dryness was reported by more patients treated with benzoyl peroxide. Overall, 50% of the benzoyl peroxide–treated patients reported adverse events compared with 24% of those treated with gluconolactone and 10% of the placebo-treated patients. Dryness, scaling, and burning were the most commonly reported events. 22
In a multicenter, open-label study, the effects of an alpha hydroxy acid cream ( Hyseac AHA ) on mild to moderate acne in combination with other agents and as monotherapy were assessed in 248 patients. All participants used the Hyseac AHA cream (containing arginine glicolate, malic acid, esterified malic acid, Sebomes [sebum reducing agents], phytosfingosine, and piroctone olamine) twice daily for 60 days. Approximately half of the patients used the product as monotherapy and the other half in combination with other pharmacological agents (ie, antibiotics, retinoids, benzoyl peroxide). The overall efficacy was reported to be 64.2% for all patients, with no differences noted between treatment groups (64.8% combination therapy vs 63.3% monotherapy). There were also no differences in the efficacy as related to the type of acne. 25
In a clinical study, 22 patients with acne applied aqueous lactate 5% lotion all over the face twice daily for 1 year. Antibiotic use was permissible during times of acute flare-ups. Efficacy was assessed by counting the number of lesions, comedones, and cysts. Maximal effects on inflammatory lesions were noted between 8 and 24 weeks of therapy, and for comedones, maximal effects were noted between 8 and 30 weeks. Adverse effects reported include temporary prickling sensations occurring on the lesions, irritation, and facial oiliness, which disappeared after the first several days of treatment. Therefore, findings from this study demonstrate safe and effective use of lactate lotion for the prevention of acne lesions. 26
The efficacy of alpha and beta hydroxy acid peels were compared in a split-face, double-blind, randomized study of 20 patients with mild to moderate facial acne. Patients were assigned to apply a glycolic acid 30% peel to 1 side of the face and a salicylic acid 30% peel to the other side of the face. The participants completed 6 treatments, administered every 2 weeks. Both treatment groups experienced significant reductions in acne lesions by the second treatment ( P < 0.05). At the 1-month follow-up visit, a 43% reduction in acne lesions occurred on the glycolic acid side compared with 47% on the salicylic acid side. Following 2 months of treatment, 75% of the sides treated with glycolic acid experienced good or fair improvement compared with 81% on the side treated with salicylic acid. Though not statistically significant, more acne lesions were noted at the 2-month follow-up visit on the glycolic acid side compared with the salicylic acid side. Conversely, the salicylic acid side had fewer acne lesions at the 2-month follow-up visit compared with baseline ( P < 0.01). 7
In another study, lactic acid peels were found to improve skin texture, pigmentation, and appearance after use for 3 months in 7 Indian patients with scarring due to acne. 27Psoriasis
Research reveals no animal data regarding the use of fruit acids for psoriasis.Clinical data
In a double-blind clinical study, 20 patients with scalp psoriasis and seborrhoeic psoriasis applied combinations of a 10% (w/w) glycolic/lactic acid scalp lotion, placebo lotion, and a 0.1% (w/w) betamethasone scalp application on each half side of the face or body twice daily for 8 weeks. Areas treated with alpha hydroxy acid scalp lotion as monotherapy resulted in improvements in all cases. However, when betamethasone was combined with the alpha hydroxy acid lotion, most of the affected sites were healed and resulted in a reduction in the duration of treatment needed by approximately one-half when compared with alpha hydroxy acid lotion or betamethasone application treatment applied as monotherapy. 28Contact dermatitis
Research reveals no animal data regarding the use of fruit acids for contact dermatitis.Clinical data
In a randomized, single-blind study, the ability of fruit acids (ie, malic, citric, lactic acid) to induce contact dermatitis was assessed in 20 healthy volunteers without skin diseases. Fifteen areas on the back were stenciled, and the areas were randomized with regard to application of malic acid 2% (pH 2 and 4), citric acid 5% (pH 2 and 4), lactic acid 20% (pH 2.5 and 4), sodium lauryl sulfate (SLS) 0.5%, and distilled water. A second exposure occurred 3 hours after the first exposure, and application of the test solutions occurred for 4 consecutive days. Application of malic or citric acid twice daily did not cause any significant irritant effects. However, application of lactic acid pH 2.5 caused significant erythema and marked clinical reaction (visual score), but this was not noted with the pH 4 solution. An irritant effect was noted when alternating exposure to 1 of the fruit acids followed by SLS. However, the irritant effect was not as pronounced as it was following alternating exposure to aqua (negative control) and SLS (positive control), suggesting perhaps fruit acids may confer some protection against exposure to SLS. 29Fibromyalgia
It has been hypothesized that patients with fibromyalgia experience muscle pain due to abnormal muscle energy metabolism. Malic acid is involved in generating adenosine triphosphate (ATP) and has been investigated for its use in the management of fibromyalgia in combination with magnesium, which is also believed to play a role in ATP production. 2 , 30Animal data
Research reveals no animal data regarding the use of fruit acids for the management of fibromyalgia.Clinical data
In a randomized, double-blind, placebo-controlled crossover study, 24 patients with fibromyalgia were randomized to receive Super Malic (malic acid 200 mg and magnesium hydroxide 50 mg/tablet) or placebo 3 tablets twice daily for 4 weeks. This was followed by a 2-week washout period, and then patients switched to the other treatment group for an additional 4 weeks. Following this crossover study, 18 patients continued into an open-label study where they increased the dose of Super Malic every 3 to 5 days until they achieved benefit or experienced a treatment-related adverse effect. After 2 months of being in the open-label trial, patients could reintroduce any medication they used prior to study entry. There were no statistically significant differences between the treatment and placebo periods with regard to 3 primary pain/tenderness measurements. However, dose-titrated Super Malic given for a longer duration in the open-label portion of the study resulted in improvements in the pain and tenderness measurements. 2
For dry skin disorders, 1 expert has recommended alpha hydroxy acid 8% to 10% cream or lotion applied 2 to 3 times daily to the affected area(s). If the dry skin persists after 2 weeks, the concentration can be increased by 2% to 4%. Once the skin appears healthy, the frequency can be reduced to every 2 to 3 days. 1
For fibromyalgia, clinical data suggest the use of 3 Super Malic tablets (each containing malic acid 200 mg) twice daily. 2
Dosing for chemical peels involving glycolic acid may depend on factors such as the condition being treated, patient expectations, patient age, cumulative sun exposure, skin type, area(s) being treated, peeling agent(s) used, concentration(s) of peel agent(s), frequency of application, quantity applied, and length of time applied. Typically, on the first visit, glycolic acid is applied for approximately 2 to 3 minutes to determine sensitivity and provide guidance for future length of exposure. Intervals between peels are generally 2 to 4 weeks, and 6 to 8 peels are required for most patients. 3 , 4
In pregnant rats, doses of malic acid up to 350 mg/kg for 10 consecutive days did not appear to exert any negative effect on the mother or the fetus. Similarly, in rabbits, doses of malic acid up to 300 mg/kg for 13 consecutive days did not exert any negative effect on the mother or the fetus. 8 However, information regarding the safe and effective use of alpha hydroxy acids in pregnant and lactating women is lacking.
Use of isotretinoin causes a reduction in the number and size of pilosebaceous units in the skin and may cause a delay in wound healing and cause scarring. It is advised that patients wait at least 6 to 12 months after receiving isotretinoin to begin chemical peels. 3Antimetabolites and corticosteroids
Use of these agents may delay wound healing in patients using chemical peels. 3Hormone replacement therapy and oral contraceptives
Hormone replacement therapy and oral contraceptives may cause postinflammatory hyperpigmentation in some patients who are using chemical peels. 3Tetracyclines and other photosensitizing agents
Following a chemical peel with glycolic acid, there may be an increase in risk of photosensitivity in patients using photosensitizing agents. 4
Depending on the concentrations used, alpha hydroxy acids can cause severe skin irritation, burning, and sloughing. Topical application may also produce skin erythema and is expected to occur with chemical peels. Hypersensitive individuals and those with irritated skin should cautiously use alpha hydroxy acids. 3 , 4 , 6 , 7
In a murine model, rats were fed malic acid 500, 5,000 or 50,000 parts per million for 104 weeks. Reductions in body weight gains and feed consumption occurred in those fed the high dose of malic acid, particularly during the first year. The differences were not as distinct during year 2 of treatment. No differences were noted with hematological, blood, or urine parameters. In a similarly designed study in beagles, no differences were noted with regard to weight changes between beagles who were fed malic acid and those who were fed a control diet. 6
Malic acid was found to moderately irritate the skin of rabbits with a 500 mg application. It was determined to be a strong irritant for guinea pigs. In a clinical study, 1 M malic acid 2 mg/cm 2 was applied to the nasal fold and found to be a skin irritant; however, skin irritation was reduced as the pH of the product increased. Additionally, when malic acid 750 mcg was applied to the conjunctival sac of rabbits, severe ocular irritation resulted. 6
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