Acne vulgaris, a disorder of the pilosebaceous apparatus, is the most common skin disorder of the second and third decades of life. Although the disorder has for years been a perplexing enigma to patients and physicians alike, recent scientific advances have finally suppressed much of its mystique and mythology, allowing a rational and highly successful approach to therapy.
The tendency to develop acne is often familial and is thought to be inherited as an autosomal dominant trait. However, because of the high incidence of this disorder, its exact genetic pattern remains indeterminate. Hereditary influences can easily be appreciated by taking histories and looking for scars among firstorder relatives, yet, except for Nierman's study snowing 98 per cent concordance of acne in identical twins, controlled data are lacking.1 Acne is therefore probably a polygenetic disorder in which the clinical expression represents the sum of many genes.2
Although the basic cause of acne remains unknown, considerable data on its pathogenesis accumulated in recent years allow a rational and therapeutically successful approach to this disorder. A clear understanding of its physiologic basis can simplify one's therapeutic approach and thus produce results far better than have heretofore been attainable.
Acne usually begins at puberty as a result of androgenic stimulation of the sebaceous glands. These glands, holocrine in nature, are devoid of motor innervation and depend solely on androgenic stimulation. Recent studies have demonstrated that circulating testosterone is taken up by the sebaceous gland and converted by the enzyme 5-alphareductase to dihydrotestosterone, the tissue androgen that causes hypertrophy of the sebaceous gland and the increased production of sebum associated with this disorder.3 This does not imply a hormonal imbalance, merely a normal physiologic phenomenon that sets the stage for the subsequent changes seen in acne.
Acne is a disease of the sebaceous follicle. It is initiated by an altered keratinization process of the follicular canal that results in obstruction of the pilosebaceous unit. The cause of this abnormality of keratinization is unknown, although patients with a predisposition to acne appear to have a tendency for irritation to the follicular wall by free fatty acids.4,5 When the normal flow of sebum onto the skin surface is obstructed by follicular hyperkeratosis, comedones are formed, initiating the process of acne.
In terms of pathogenesis, two types of comedones are formed: open comedones (blackheads) and closed comedones (whiteheads).6 Open comedones (blackheads), though unsightly, are easily managed and rarely create problems in acne. They consist of epithelium-lined sacs, filled with keratin and lipid, with a widely dilated orifice. The contents of open comedones easily escape to the skin surface; follicular disruption and inflammation therefore rarely occur, except when they are deliberately or inadvertently traumatized by the patient.
It is the whitehead, or closed comedo, that is responsible for the problems seen in acne. These lesions are small, skin-colored, slightly elevated papules just beneath the skin surface (their visualization may be enhanced by a slight stretching of the overlying skin). The closed comedo has a microscopic opening that keeps its contents from escaping. It continues to form keratin and some sebum and, when the follicular wall ruptures, acts as a miniature time bomb and expels sebum into the surrounding dermis, initiating the inflammatory process seen in this disorder.4,6
Sebum is made up of a mixture of triglycerides, wax esters, squalene, and sterol esters. Free fatty acids, particularly those with short chains (C8 to Cu), are believed to play an important role in comedogenesis and the formation of inflammatory lesions.7 Their release appears to be the result of hydrolysis of triglycerides within the pilosebaceous follicles (to diglycerides, monoglycerides, and finally glycerol) by lipases, with release of physiologically active molecules of free fatty acid along each step of the process. Ordinarily harmless bacteria, the anaerobic Corynebacterium acnes, appear to be the major source of lipolytic enzymes within the pilosebaceous follicle.8-10
Acne usually presents as a variety of lesions in which the comedo, when seen, is pathognomonic. In its mildest form it is limited to open comedones (blackheads) and closed comedones (whiteheads). As the disorder increases in severity, patients may develop papules, pustules, nodules, or cysts. The term cyst is actually a misnomer; it denotes a large nodular lesion that has undergone suppuration and thus resembles an inflamed cyst.
The primary sites of acne are the face, chest, back, and shoulders. There is often a seasonal variation, the disorder being least active in summer and most severe in the winter. As acne lesions resolve, they are frequently followed by temporary postinflammatory redness and hyperpigmentation. Although patients commonly regard these as active lesions and potential scars, the discoloration gradually subsides once the condition is controlled. In the more severe pustular and cystic forms of acne, sheaths of epithelium from remaining follicular walls tend to encapsulate the inflammatory areas, with subsequent fibrous contraction and eventual cicatricial formation.6 The scars usually present as sharply punched-out pits or as hypertrophic and keloid scars. The severity of the scarring depends on the depth and intensity of the inflammation and the patient's susceptibility to cicatrization.
Although the basic cause of acne is unknown, considerable data on its pathogenesis accumulated in recent years allow a much more rational and successful therapeutic approach to this disorder. Acne should therefore never be dismissed as being of no consequence, with mere reassurance that the patient will outgrow it. It is a grievous injustice to regard acne as evanescent or untreatable, for the psychologic scars and trauma are often deeper and more disastrous than the blemishes displayed on the cutaneous surface alone. Only those who are personally afflicted or who have had a share in this dramatic metamorphosis can fully appreciate the psychologic as well as physical transformation that proper therapy can initiate.
There is no single treatment of acne vulgaris. Therapy must be individualized, with appropriate variations and modifications as the degree or severity of the disorder fluctuates. The success of therapy depends on prevention of follicular hyperkeratosis; reduction of C. acnes and free fatty acids; and the elimination of comedones and the papules, pustules, cysts, and nodules that result therefrom. This can be achieved by proper selection of available medications, coupled with cooperation by the patient and the knowledge, continued interest, and enthusiasm of the physician and his staff, usually within six to 12 weeks of treatment. Once this has been accomplished, therapy must be faithfully continued for as long as the tendency towards acne persists. Unfortunately, as with so many long-term programs, patients occasionally develop a false sense of security and tend to modify their therapy, often with regrettable effects.
Recent controlled studies refute the value of dietary restrictions imposed upon acne patients. For years the elimination of various foods - such as chocolate and cola drinks, sweets, milk, ice cream, fatty foods, and shellfish - dominated the futile approaches to acne control. The misconception that iodine is injurious to patients with acne originated from the concept that iodides administered orally as medication occasionally initiate papulopustular acneiform eruptions. A large-scale epidemiologic investigation of over 1,000 North Carolina high-school students revealed that dietary iodine exerts no influence on either the incidence or the severity of acne.11 The concept that chocolate exerts an adverse effect on acne has also been challenged. In a carefully controlled double-blind study, it was found that this too failed to affect either the course of acne vulgaris or the composition of sebum.12 For patients who attest to flares following ingestion of certain foods, it is judicious to eliminate the suspicious agents until their true influence can be appropriately and individually assessed.
Appropriate topical therapy is essential to the successful management of acne. For years therapy consisted of various cleansing agents, abrasives, astringents, and exfoliants designed to remove blackheads and lipids on the skin surface. Contrary to previously held concepts, there is little evidence to support the reputed beneficial effect of such preparations. Not only are they ineffective, but, owing to their tendency toward dryness and chapping, they often inhibit the effective use of potent topical agents.
Of the available topical agents, those that have had the greatest popularity include sulfur, resorcinol, salicylic acid, benzoyl peroxide, and vitamin A acid (tretinoin). Sulfur, salicylic acid, and resorcinol have been used in concentrations of 1 to 5 per cent, 2 to 8 per cent, and 1 to 10 per cent. Although the mode of action is uncertain, their efficacy is limited and appears to be related to their capacity to produce erythema and desquamation. They tend to help dry and peel existing comedones, papules, and pustules, but they fail to limit the formation of closed comedones (whiteheads) and the lesions that result from them. Benzoyl peroxide and vitamin A acid, although potentially irritating, have been shown to be highly effective topical agents for the treatment of acne.
Benzoyl peroxide is currently available in lotion form (Benoxyl,® Oxy-5,® Persadox,® Vanoxide,® Loroxide®) or in the more potent and penetrating gel formulations (Benzagel,® Desquam-X,® PanOxyl,® Persa-Gel®). These preparations offer more than a form of epidermal irritation. They cause a fine desquamation, help reduce the level of free fatty acids, and appear to be bacteriostatic for C. acnes.13-14 The preparations should be applied to the entire involved area. Spotting acne lotions on active lesions is inadequate and will not prevent the development of new lesions. A relatively low incidence of allergic contact dermatitis (1 to 2.5 per cent), however, suggests caution in the use of these preparations.15
For years, vitamin A has been administered orally to patients with acne vulgaris in the hope of reducing hyperkeratosis of the sebaceous follicle. Unfortunately, therapeutic effect requires dosage in the toxic range of 400,000 to 700,000 units a day. In an effort to find a way of delivering a substantial dose of this drug to the target area without exacting the penalty of systemic toxicity, the use of tretinoin (topical vitamin A acid) in the therapy of acne vulgaris was proposed in 1969. 16 Available as Aberel® or Retin- A,® in swabs or liquid (0.05 per cent), or as Retin- A® creams (0.05 or 0.1 per cent) and Retin-A® gel (0.025 per cent), tretinoin seems to have several beneficial effects on the skin of patients with acne vulgaris. Included among these benefits are an increased cell turnover within the pilosebaceous ducts and a decreased cohesiveness of epidermal cells, due to a reduction in the number of desmosomes. This stimulates dehiscence of horny cells, with resulting thinning of the horny layer, decreased comedo formation, sloughing and expulsion of existing comedones from their sebaceous follicles, and reduction of inflammatory lesions arising from comedones.16,17
It is unfortunate that vitamin A acid, perhaps the single most effective topical remedy for acne, is very irritating and therefore not universally successful. Because of its known capacity to cause severe irritation and peeling, topical vitamin A acid therapy should be initiated conservatively, on an alternate-day or, occasionally, an every-third-day regimen, preferably with the less irritating gel or cream preparations. Patients should be instructed to wash with a mild soap, no more than two or three times a day, and to wait at least 30 minutes after washing (to ensure that the skin is completely dry) before application of vitamin A acid. If prolonged sun exposure is anticipated, patients must be cautioned to use a protective sun screen.
Systemic antibiotics suppress C. acnes and inhibit bacterial lipases, causing a reduction in the concentration of free fatty acids (the primary irritant of sebum). For years, broadspectrum antibiotics have been invaluable in the treatment of inflammatory pustules, nodules, and cystic lesions. Today, however, the use of systemic antibiotics can be decreased and often eliminated with the growth of experience and sophistication in the use of effective topical agents.18 Since little or no improvement can be expected with noninflammatory lesions (comedones), antibiotics are unnecessary in patients in whom these lesions appear as the sole manifestation of their acne problem.
When antibiotics are considered necessary, tetracycline, the antibiotic most frequently prescribed, is effective, inexpensive, and relatively free of side effects.19,20 Erythromycin, clindamycin, and minocycline also are beneficial when inflammatory and pustular lesions fail to respond to oral doses of tetracycline. Of these, erythromycin is the least expensive and has the fewest complications. Minocycline appears to have merit in patients unresponsive to tetracycline or erythromycin therapy, although caution must be exercised, since this tetracycline derivative appears to have an affinity for the central nervous system, with a resulting high incidence of headaches and dizziness. The use of sulfone (diaminodiphenylsulfone) has been suggested for the management of very severe, resistant, nodulocystic, and conglobate acne. This preparation should be used only with extreme caution, with full awareness of the risk of hemolytic anemia, cyanosis, and methemoglobinemia. Penicillin and its derivatives appear to be ineffective in the treatment of acne. Sulfa drugs have been used, but clinical results are not as favorable as those with the broadspectrum antibiotics.
Tetracycline therapy generally begins with a dosage of 500-1,000 mg. a day. This is gradually decreased to the lowest optimal level, usually to a dosage of 250 mg. per day or every other day, until clinical improvement allows its discontinuation. The capacity for tetracycline to bind to certain types of cells and to intracellular organelles is well documented; however, it takes several weeks to develop an effective level of tetracycline in the skin.21 Antibiotic treatment, therefore, should be used for a minimum of three to four weeks before results are appreciable. Tetracyclines are incompletely absorbed from the gastrointestinal tract and may be impaired by food, iron supplements, milk, aluminum hydroxide gel, and calcium-magnesium salts. To assure optimal absorption, patients should be instructed to take this medication on an empty stomach, preferably one hour before or two hours after mealtime.
Low dosage of tetracycline may be continued for many months with relatively few side effects.19 The most frequent complication of antibiotic therapy in female patients is vaginal moniliasis. This complication, less frequently seen in young adolescents, is proportionally more common in women who take oral contraceptives concomitantly with their systemic antibiotics. Patients taking tetracycline occasionally manifest gastrointestinal irritation (epigastric distress, anorexia, nausea, or vomiting) after ingestion of tetracycline or its derivatives. Enteric symptoms (cramps and diarrhea) are believed to result from alteration of normal intestinal flora, with overgrowth of yeasts and resistant bacteria. Complications based upon antigen-antibody mechanisms (urticaria, angioneurotic edema, erythema multiforme, and fixed eruptions), although reported, are relatively rare.
The incidence of photoreactivity to oral tetracycline is unknown but appears to be extremely low, except in the case of demethylchlortetracycline (Declomycin®), in which photosensitivity appears to develop in about 20 per cent of cases. Recent reports also describe unusual porphyrialike photosensitivity with bullae on the hands of patients on tetracycline therapy.22 Occasionally, patients on long-term tetracycline therapy may develop a gram-negative folliculitis due to Klebsiella or Proteus overgrowth.23,24 This complication is manifested by a pustular folliculitis along the ala nasi or by deep nodulocystic lesions of the face.
The possibility of tetracycline staining of teeth precludes its use for children under 12 years of age and for women after the first trimester of pregnancy. The deposition of the drug in the teeth is thought to be the result of its chelating properties, with the formation of a tetracyclinecalcium orthophosphate complex. In time, exposure to light results in slow oxidation, with a change in color of affected teeth from yellow to brown or gray. The ingestion of outdated tetracycline may cause severe toxicity. It is particularly dangerous in patients who use "leftover" medication and who start and stop therapy on their own without proper medical guidance.
It is desirable to avoid oral or systemic therapy in the treatment of skin diseases if an equally potent topical agent can be used. Recent investigarions have shown that topical tetracycline, topical erythromycin, and topical clindamycin, when used in appropriate vehicles, can inhibit the growth of C. acnes and produce a decrease in comedones, papules, and pustules in acne patients. Although studies are incomplete and these products are not yet available commercially, it appears that topical antibiotics may to a great degree replace oral antibiotic therapy in the near future.25-27
Although success in the management of acne vulgaris can be achieved by the use of topical vitamin A acid or !benzoyl peroxide alone, the therapeutic effect is substantially increased by the use of the two agents in combination. Although vitamin A acid, when used alone, can be very irritating to the skin, benzoyl peroxide appears to toughen the epidermis against this cutaneous reaction. When the two agents are used in combination (one in the morning and one at night), there is less irritation than when vitamin A acid is used alone, the use of systemic antibiotics is decreased and often eliminated, and dramatic therapeutic effects are achieved in a relatively short time in a high percentage of patients, even those with severe pustulocystic forms of this disorder.21 Better clinical results may yet be achieved as newer forms of vitamin A acid, benzoyl peroxide, and topical antibiotics are introduced and as experience and sophistication in the use of these agents, alone and in combination, are developed.18
Although acne is not listed among the manufacturers' indications for use of anovulatory drugs, these preparations have been useful in the treatment of women over 16 years of age with severe, recalcitrant, pustulocystic acne, producing good results but not without a certain element of potential risk. Anovulatory drugs suppress the androgenic stimulation of sebum production and, when adequate amounts of estrogen are used, are beneficial in 50 to 70 per cent of patients. It is important to weigh the risks and benefits when the use of estrogens is contemplated in the treatment of acne. Side effects to be considered include nausea, weight gain, monilial vaginitis, chloasma, hypertension, and thromboembolic phenomena. I prefer to restrict the use of estrogens to those few female patients, over 16 years of age, with severe recalcitrant pustulocystic acne or to those who elect a course of anovulatory drugs for reasons other than their acne. Estrogens should never be prescribed in males, since the dose required for sebum suppression will produce feminizing side effects; nor should they be administered to patients under the age of 16, when possible bone growth inhibition is a consideration.
If estrogen is used, it should contain a minimum of 80-100 /*g. of ethinylestradiol or its 3-methyl ether derivative (mestranol). This amount is present in Enovid-E,® Ovulen,® Ortho-Novum,® and Norinyl®; it is not present in Ovral,® Demulen,® or Enovid.® Although sebum production occasionally decreases during the first or second cycle of drug administration, it usually takes three or four cycles (12 to 16 weeks) for a maximum effect to be achieved.28 In two-thirds of patients, a temporary acne flare may occur during the first two cycles of therapy. Patients should be forewarned of this possibility and reassured that this effect is only temporary.27,28
Acne surgery - the mechanical removal of comedones, pustules, and cysts - though time consuming, is extremely important for the rapid involution of individual acne lesions. This procedure is helpful only when properly done. The removal of open comedones does not materially influence the course of acne. However, it is desirable that they be removed for cosmetic purposes. Closed comedones should be removed to prevent their rupture and spilling of their inflammatory contents into the surrounding dermis. The procedure may be assisted by nicking the surface of the lesion with a sharp needle and expressing the contents with a comedo extractor. When improperly performed, inaccurate placement of the comedo extractor or overzealous manipulation may cause damage and irritation to the overlying skin or rupture of the comedo wall, with escape of sebum and further formation of inflammatory lesions.
INTRALESIONAL ACNE THERAPY
When cystic lesions are drained, a slightly larger incision is occasionally necessary. Whenever possible, a small-gauge sterile needle is preferred over a scalpel blade in an effort to minimize potential scarring. Intralesional corticosteroid injection usually results in rapid involution of nodular and cystic lesions. The injection of 0.1-0.3 ml. of triamcinolone acetonide (in a concentration of 2.510.0 mg. /ml.) is recommended. With proper use of intralesional corticosteroid injection, incision and drainage of lesions is rarely required and scars can frequently be avoided. Extreme caution should be exercised, however, since atrophy of the skin may occur when the injection is high in the dermis, particularly when the amount or concentration of steroid is excessive. Fortunately, this atrophy disappears spontaneously within six months to one year.
The value of artificial ultraviolet light is debatable. Its major effect is to give the patient a feeling of wellbeing, mild erythema, desquamation, and a resultant tan, which helps to conceal acne lesions. The risk of overexposure and conjunctival inflammation from failure to shield the eyes suggests the use of caution and the limitations of this as a method of home therapy.
X-ray, once widely used in the treatment of acne, has generally been abandoned as more effective forms of therapy have been developed. Superficial x-ray has been shown to reduce the size of sebaceous glands; however, acne often recurs when the glands regenerate after three to four months.
Cryotherapy appears to be helpful in the hands of some dermatologists. Erythema and desquamation may be produced by carbon dioxide "slush," made by powdered dry ice and acetone, applied by lightly brushing the skin with this mixture on a piece of gauze held in a clamp. Involution of isolated persistent acne lesions may also be accelerated by local application of solid carbon dioxide, dipped in acetone, or of liquid nitrogen, on a simple cotton applicator, applied carefully to individual lesions. This technique effectively hastens involution of small pustular lesions; more vigorous application of liquid nitrogen (15 to 30 seconds or more) appears to help the resolution of cystic lesions and keloidal scars, particularly those measuring 1.0-1.5 cm. in diameter or less.
Acne scars may improve spontaneously to a surprising degree over a period of two to three years, but often the patient's final appearance is less than desirable. Topical chemotherapy with 20 to 30 per cent trichloroacetic acid appears to help some patients with persistent pitting. Dermabrasion, popular in the past, still offers hope for improvement in those with residual scarring and persistent nodular lesions. It is important to note that, following dermabrasion, people who pigment easily occasionally develop hyperpigmentation, which may be more unattractive than the original scars. Other possible complications of dermabrasion include infection, further scarring, occasional hypopigmentation, and an incapacity to tan properly over treated areas. Medical-grade liquid silicone (dimethyl polysiloxane) has been found to be of value in the correction and reconstruction of deep pits and atrophic scars. It is currently available only under investigational-drug status, and the number of physicians now authorized to use it is strictly limited.29 Although some controversy still exists, it appears that this preparation may prove to be safe and effective for the correction of atrophic acne scars. Dermabrasion and liquid silicone should be used only in selected cases, by a dermatologist or plastic surgeon familiar with their techniques and potential consequences.
Occasionally, infants develop an eruption that resembles the acne vulgaris seen in adolescents. While the cause of acne neonatorum is not clearly defined, it appears to develop as a result of hormonal stimulation of sebaceous glands that have not yet involuted to their childhood state of immaturity. Although testosterone synthesis occurs in the fetal testis and adrenal gland between the ninth and 15th weeks of intrauterine life, steroid synthesis in the fetal ovary is relatively limited. This disparity may explain the apparent higher incidence of acne neonatorum in male infants.30-32
Acne neonatorum frequently develops during the first three months, but it may occur at any time during the first three years of life. Lesions characteristically present as erythematous comedones, papules, or pustules, although cystic and deepseated nodules have been noted. They are usually confined to the cheeks; occasionally, the chin and forehead may also be involved. In contrast to adolescent acne, however, the chest and back are not affected.
The course of neonatal acne may vary considerably. Most cases disappear within the first year of life; although some cases may clear spontaneously in one or two months, others reportedly have persisted for up to 11 years. Infants with acne neonatorum generally have no evidence of sexual precocity; those with persistent involvement, however, should be investigated for evidence of precocity or abnormal virilization. If endocrine abnormality is suspected, 17-ketosteroid excretion should be examined. During the first few weeks of life, this may be elevated. A level of 0.5 mg. in a 24-hour urine after two weeks of age, therefore, should be considered excessive, suggesting further investigation for gonadal or adrenal cortex hyperfunction.
Acne neonatorum should be differentiated from milia of the newborn, a disorder manifested by numerous 1-2-mm. white or yellowish- white follicular papules. Milia of the newborn usually occurs on the face - particularly the nose, cheeks, chin, and forehead - as a normal phenomenon in up to 40 per cent of infants during the first few years of life. Occasionally, lesions may also be noted on the upper trunk, limbs, or mucous membranes. When seen on the hard palate, these temporary retention cysts are termed Epstein's pearls; similar lesions also may occur on the gums. Histologically, the skin lesions represent keratinous cysts of the pilosebaceous apparatus. They usually disappear spontaneously during the first few weeks of life.
In mild cases of acne neonatorum, therapy is often unnecessary; daily cleansing with soap and water may be all that is required. Exogenous oils, such as baby oils and lotions, may aggravate this disorder and should be avoided. Occasionally, mild keratolytic agents containing 3 to 5 per cent sulfur, salicylic acid, or resorcinol may be helpful. In more severe cases, benzoyl peroxide preparations may be utilized. Management should be determined by the degree of peeling or irritation and by individual tolerance to these agents.
1. Niermann, H. Bericht über 230 Zwillinge mit Hautkrankheiten. Z. Menscht. Vererb. Konstit-Lehre 34 (1958), 483-487.
2. Kligman, A. M. An overview of acne. J. Invest. Dermatol. 62 (1974), 268-287.
3. Strauss, J. S., Kligman, A. M., and Pochi, P. E. The effect of androgens and estrogens on human sebaceous glands. J. Invest. Dermatol. 39 (1962), 139-155.
4. Van Scott, E. J.. and McCardle, R. C. Keratinization of the duct of the sebaceous gland and growth cycle of the hair follicle in the histogenesis of acne in human skin. J. Invest. Dermatol. 27 (1956), 405-429.
5. Plewig, G. Follicular keratinization. J. Invest. Dermatol. 62 (1974), 308-315.
6. Strauss, J. S., and Kligman, A. M. The pathologic dynamics of acne vulgaris. Arch. Dermatol. 82 (1960), 729-790.
7. Kellum, R. E. Acne vulgaris - studies in pathogenesis: Relative irritancy of free fatty acids from C2 to C16. Arch. Dermatol. 97 (1968). 722-726.
8. Kellum, R. E., Strangfeld. K., and Ray. L. F. Acne vulgaris - studies in pathogenesis: Triglyceride hydrolysis by Corynebacterium acnes in vitro. Arch. Dermatol. 101 (1970), 41-47.
9. Marples, R. R., et. al. The role of aerobic microflora in the genesis of fatty acids in human surface lipids. J. Invest. Dermatol. 55 (1970), 173-178.
10. Shalita, A. R. Genesis of free fatty acids. J. Invest. Dermatol. 62 (1974). 332-335.
11. Hitch, J. M., and Greenburg. B. G. Adolescent acne and dietary odine. Arch. Dermatol. 84 (1961), 898-911.
12. Fulton. J. E.. Jr.. Plewig, G.. and Kligman, A. M. The effect of chocolate on acne vulgaris. J.A.M.A. 210 (1969). 2071-2074.
13. Fulton. J. E-. Jr., Farzad-Bakeshandeh. A., and Bradley, S. Studies on the mechanism of the action of topical benzoyl peroxide and vitamin A acid in acne vulgaris. J. Cutan. Pathol. 1 (1974), 194.
14. Anderson. A. S.. et al. Improved reduction of cutaneous bacteria and free fatty acids with new benzoyl peroxide gel. CuVs 16 (1975). 307-310.
15. Eaglstein, W. H. Allergic contact dermatitis to benzoyl peroxide - Report of cases. Aren. Dermatol. 97 (1968), 527.
16. Kligman. A. M.. Fulton. J. E.. Jr.. and Plewig, G. Topical vitamin A acid in acne vulgaris. Arch. Dermatol. 99 (1969). 469-476.
17. Strauss, J. S., Pochi, P. E., and Downing. D. T. Acne perspectives. J. Invest. Dermatol. 62 (1974), 321-325.
18. Hurwitz. S. The combined effect of vitamin A acid and benzoyl peroxide in the treatment of acne. Cutis 17 (1976), 585-590.
19. Committee on Drugs. The treatment of acne with antibiotics. Pediatrics 48 (1971), 663-665.
20. Clendenning, W. E. Complications of tetracycline therapy. Arch. Dermatol. 91 (1965). 628-632.
21. Freinkel, R. K., et. al. The effect of tetracycline on the composition of sebum in acne vulgaris. N. Engl. J. Med. 273 (1965), 850-854.
22. Epstein, J. H., et. al. Porphyria-like cutaneous changes induced by tetracycline. Arch. Dermatol. 112 (1976), 661-666.
23. Fulton, J. E.. Jr., et. al. Gram-negative folliculitis in acne vulgaris. Arch. Dermatol. 98 (1968), 349-353.
24. Leyden, J., et. al. Gram-negative folliculitis - A complication of antibiotic therapy in acne vulgaris. Br. J. Dermatol. 88 (1973). 533-538.
25. Fulton, J. E., Jr., and Pablo, G. Topical antibacterial therapy for acne. Arch. Dermatol. 110 (1974). 83-86.
26. Resh. W., and Stoughton, R. B. Topical antibiotics in acne vulgaris: Clinical response and suppression of C. acnes in open comedones. Arch. Dermatol. 112 (1976). 182-184.
27. Strauss. J. S., Kligman, A. M., and Pochi, P. E. The effect of androgens and estrogens on human sebaceous glands. J. Invest. Dermatol. 39 (1962). 139-155.
28. Strauss. J. S., and Pochi. P. E. Effect of cyclic progestin-estrogen therapy on sebum and acne in women J.A.M.A. 190 (1964). 815-819.
29. Rees. T. D. The current status of silicone fluid in plastic and reconstructive surgery. J. Dermatol. Surg. 2 (1976). 34-38.
30. Hellier. F. I. Acneiform eruptions in infancy. Br. J. Dermatol. 66 (1964). 25-30.
31. Ginnis. F. L, Hall. W. K., and Tolman. M. M. Acne neonatorum. Arch. Dermatol. 66 (1952), 717721.
32. Pochi, P. E.. and Strauss, J. S. Endocrinologie control of the development and activity of the human sebaceous gland. J. Invest. Dermatol. 62 (1974), 191-201.