Hexachlorophene

Abstract

Sulfur has antifungal, antibacterial, and keratolytic activity. In the past, its use was widespread in dermatological disorders such as acne vulgaris, rosacea, seborrheic dermatitis, dandruff, pityriasis versicolor, scabies, and warts. Adverse events associated with topically applied sulfur are rare and mainly involve mild application site reactions. Sulfur, used alone or in combination with agents such as sodium sulfacetamide or salicylic acid, has demonstrated efficacy in the treatment of many dermatological conditions.

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Introduction

Sulfur is a yellow, non-metallic element with medicinal properties. The use of sulfur as a therapeutic agent dates back nearly 70 years. However, in recent years it has received little attention. In dermatology, sulfur has been employed in the treatment of many diseases, including acne vulgaris, rosacea, seborrheic dermatitis, dandruff, pityriasis versicolor, scabies, and warts (1).

Properties

In addition to keratolytic activity, sulfur has mild antifungal and antibacterial activity. However, its precise mechanism of action is unknown. When applied to skin, sulfur is thought to interact with cysteine, present in the stratum corneum, to form hydrogen sulfide (2). Hydrogen sulfide can break down keratin, thus demonstrating sulfur's keratolytic activity. Pentathionic acid, which is toxic to fungi, is also formed by cutaneous bacteria as well as keratinocytes from topically applied sulfur (2). In addition, the keratolytic effects may promote fungal shedding from the stratum corneum (1). Sulfur has an inhibitory effect on the growth of Propionibacterium acnes as well as Sarcoptes scabiei, some Streptococci, and Staphylococcus aureus (3-5). This suggested antibacterial activity purportedly results from the inactivation of sulfhydryl groups contained in bacterial enzyme systems (5). Although data is sparse, sulfur may have an effect on Demodex mites (6). However, the role of Demodex in the pathogenesis of rosacea is unclear (7-12).

Pharmacology

The pharmacokinetics of topically applied sulfur has not been fully characterized. Sulfur penetrates skin and is detectable in the epidermis within two hours and throughout skin within eight hours after application (5). However, 24 hours after application there are no detectable levels of sulfur remaining in the skin (5). Absorption into the systemic circulation reportedly occurred after application of a 25% sulfur ointment to abraded animal skin, but did not occur when applied to intact skin (5).

It has previously been reported that sulfur is comedogenic in the rabbit ear model as well as on the human back (13). However, another study re-examined the comedogenic potential of sulfur (14). This double-blind, randomized study involved the application of test solutions containing 5% sulfur to comedone-free skin of healthy volunteers with or without active acne. These patches were replaced three times per week for six weeks. At the end of the study, it was concluded that there was no trend or correlation between the presence or absence of sulfur in the formulation and appearance of comedones (14).

Sulfur Combined with Sodium Sulfacetamide

Sodium sulfacetamide is a sulfonamide agent with antibacterial activity. It acts as a competitive antagonist to paraaminobenzoic acid (PABA), an essential component for bacterial growth (34). Sodium sulfacetamide has demonstrated activity against P. acnes (15).

When combined with sulfur in dermatologic preparations, the keratolytic and antibacterial effects make sodium sulfacetamide an effective topical treatment for acne vulgaris, rosacea, and seborrheic dermatitis. It is especially beneficial in the treatment of acne vulgaris since no sensitivity is observed, the response is consistent, and long-term patient compliance is obtained, as the formulation is cosmetically appealing (16). Sulfur with sodium sulfacetamide lotion is able to effectively ameliorate seborrhea and acne lesions without excessive erythema or peeling (16). The combination of sulfur and sodium sulfacetamide is available as a lotion, topical suspension, and cleanser (3,4,17).

Diseases/Disorders Treated with Sulfur

Acne Vulgaris

In clinical trials, lotions containing sulfur 5% with sodium sulfacetamide 10% have been found to be very effective in reducing the number of inflammatory lesions and comedones, as well as reducing seborrhea. Few adverse events were noted and were generally transient and mild, including dryness and itching (15,18,19). Table I (15,18-20) summarizes the results of clinical trials investigating the treatment of acne vulgaris with sulfur. One trial evaluated a polythionic acid preparation in the therapy of acne vulgaris (20). Patients were treated with the preparation in strengths of 2.5. 3.25 or 5%, with or without concomitant therapy with vitamin A, injections of acne vaccine and/or roentgen therapy. After an average of 3 months of treatment, 90 out of 141 patients (64%) benefited from treatment (20).

Other topical and oral acne medications, such as tretinoin, benzoyl peroxide, azelaic acid, antibiotics and retinoids are effective, but have numerous adverse events such as irritation, UV hypersensitivity and toxicity (15). Notably, in women with adult-onset acne, the scaling and erythema associated with other acne treatments are quite unwanted. In addition, systemic antibiotics and retinoids carry significant risk/benefit considerations, such as potential reactions with other medications and systemic toxicity (18).

Rosacea

Rosacea is a common inflammatory facial skin disorder. Since it is chronic in nature, long-term maintenance therapy in addition to avoidance of flare factors (e.g., sunlight, temperature extremes, and alcohol), are necessary to effectively control rosacea. Topical formulations of sulfur are beneficial in this disease (Table II) (2,21-24).

One double-blind study compared the effectiveness of a sulfur 5%/sodium sulfacetamide 10% lotion and metronidazole 0.75% gel in the treatment of adults with moderate rosacea (2). After six weeks of treatment, the sulfur with sodium sulfacetamide formulation was found to significantly improve erythema (p=0.017), papulopustules (p=0.011) and overall severity score (p=0.002), as well as reduce the number of pustules as compared to metronidazole 0.75% topical gel (2).

Another study compared a 10% sulfur cream to systemic tetracycline (23). At the end of treatment, the only difference between the two groups was in the total number of papules and pustules. The sulfur cream produced a greater reduction in the inflammatory components of rosacea than the antibiotic treatment (23). Also, there was no difference in the relapse rate within six months (23).

Sulfur with sodium sulfacetamide as a cleanser has also been shown to be effective in rosacea. An investigator-blinded, randomized study evaluated the efficacy of sodium sulfacetamide 10%/sulfur 5% cleanser either alone or in combination with metronidazole 0.75% gel (24). A reduction in the overall severity of rosacea was noted after eight weeks for both groups, indicating that the cleanser was effective as a monotherapy as well as in combination with metronidazole (24).

Since oral antibiotic use can be complicated by adverse events, such as bacterial or fungal superinfection, gastrointestinal intolerance and phototoxicity (25), as well as the reported patient preference (21), topical preparations containing sulfur are highly desirable therapeutic agents in the treatment of rosacea.

Seborrheic Dermatitis, Dandruff and Pityriasis Versicolor

Seborrheic dermatitis, dandruff and pityriasis versicolor are common chronic infections of the skin caused by yeasts of the genus Malassezia. Sulfur reduces the itching and flaking associated with seborrheic dermatitis and dandruff (5), as well as having a possible antifungal effect against the Malassezia yeasts (26). Sulfur is often used in combination with salicylic acid for the treatment of these conditions, as they have a synergistic keratolytic action (1).

Trials evaluating the effectiveness of sulfur preparations in seborrheic dermatitis and dandruff, and pityriasis versicolor are detailed in Tables III (20,27) and IV (26), respectively. There was a low incidence of adverse events noted, and these generally included a mild burning sensation and/or dry skin.

Other Diseases/Disorders

There are reports regarding the efficacy of sulfur in other dermatological diseases. Sulfur has been effective in the treatment of scabies, since topically applied sulfur is toxic to the scabies mite (S. scabiei) (2,5). The United States Centers for Disease Control and Prevention (CDC) recommends a 6% sulfur ointment applied daily for three days in the treatment of scabies (5).

A sulfur preparation has also been shown to be effective in the treatment of plane warts. Four patients with plane warts were treated with a preparation containing 2% sulfur, 6% laureth-4 and 37% alcohol in a gel base (28). With twice daily application of the gel for an average of two months, three patients had excellent results, and the fourth showed improvement (28).

Conclusion

The obvious efficacy and safety of sulfur has been demonstrated in many trials. Although it has been overshadowed by new oral and topical agents in the treatment of many dermatological diseases, sulfur is still a useful therapeutic modality today.

This manuscript was supported in part by Medicis Pharmaceutical Corporation.

References

1. Lin AN, Reimer RJ, Carter DM. Sulfur revisited. J Am Acad Dermatol 1988; 18: 553-558.

2. Lebwohl MG, et al. The comparative efficacy of sodium sulfacetamide 10%/Sulfur 5% (Sulfacet-R[R]) lotion and metronidazole 0.75% (MetroGel[R]) in the treatment of rosacea. J Geriatr Dermatol 1995; 3: 183-185.

3. Plexion[TM] Cleanser, Plexion[TM] TS Topical Suspension (sodium sulfacetamide 10% and sulfur 5%) [package insert]. Scottsdale, AZ: Medicis, The Dermatology Company; 2000.

4. Plexion SCT[TM] (sodium sulfacetamide 10% and sulfur 5%) [package insert]. Scottsdale, AZ: Medicis, The Dermatology Company; 2001.

5. Sulfur. In: AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharamacists, Inc; 2003: 3426-3428.

6. Ayres S. Jr. Demodex folliculorum as a pathogen. Cutis 1986; 37: 441.

7. Erbagci Z, Ozgoztasi O. The significance of Demodex folliculorum density in rosacea. Int J Dermatol 1998; 37: 421-425.

8. Burns DA. Follicle mites and their role in disease. Clin Exp Dermatol 1992; 17: 152-155.

9. Forton F, Seys B. Density of Demodex folliculorum in rosacea: a case-control study using standardized skin-surface biopsy. Br J Dermatol 1993; 128: 650-659.

10. Roihu T. Kariniemi AL. Demodex mites in acne rosacea. J Cutan Pathol 1998; 25: 550-552.

11. Robinson TWE. Demodex folliculorum and rosacea. A clinical and histological study. Arch Dermatol 1965; 92: 542-544.

12. Sibenge S, Gawkrodger DJ. Rosacea: a study of clinical patterns, blood flow, and the role of Demodex folliculorum. J Am Acad Dermatol 1992; 26: 590-593.

13. Mills OH Jr. Kligman AM. Is sulphur helpful or harmful in acne vulgaris? Br J Dermatol 1972; 86: 620-627.

14. Strauss JS, et al. A reexamination of the potential comedogenicity of sulfur. Arch Dermatol 1978; 114: 1340-1342.

15. Tarimci N, Sener S, Kilinc T. Topical sodium sulfacetamide/sulfur lotion. J Clin Pharm Ther 1997; 22: 301.

16. Olansky S. Old drug--in a new system--revisited. Cutis 1977; 19: 852-854.

17. Rosanil[TM] Cleanser (Sodium sulfacetamide 10% and sulfur 5%) [package insert]. Fort Worth, TX: Galderma Laboratories; 2002.

18. Breneman DL, Ariano MC. Successful treatment of acne vulgaris in women with a new topical sodium sulfacetamide/sulfur lotion. Int J Dermatol 1993; 32:365-367.

19. Olansky S. Re-evaluation of sulfacetamide as a topical agent in the treatment of pustular acne. Cutis 1967; 3: 611-614.

20. Finnerud CW, Riddell JM Jr. Polythionic acid in the therapy of acne vulgaris and seborrheic dermatitis. Arch Dermatol Syph 1951; 63: 373-375.

21. Sauder DN, et al. The treatment of rosacea: the safety and efficacy of sodium sulfacetamide 10% and sulfur 5% lotion (Novacet) is demonstrated in a double-blind study. J Dermatol Treat 1997; 8: 79-85.

22. Davis GF, Glazer SD, Medansky RS. Successful treatment of rosacea with a novel formulation of sodium sulfacetamide 10% and sulfur 5% (Novacet,) topical lotion. J Geriatr Dermatol 1994; 2: 140-144.

23. Blom I, Hornmark AM. Topical treatment with sulfur 10 percent for rosacea. Acta Derm Venereol 1984; 64: 358-359.

24. Data on file at Medicis, The Dermatology Company.

25. Del Rosso JQ. A status report on the medical management of rosacea: focus on topical therapies. Cutis 2002; 70: 271-275.

26. Bamford JTM. Treatment of tinea versicolor with sulfur-salicylic shampoo. J Am Acad Dermatol 1983; 8: 211-213.

27. Leyden JJ, et al. Effects of sulfur and salicylic acid in a shampoo base in the treatment of dandruff: a double-blind study using corneocyte counts and clinical grading. Cutis 1987; 39: 557-561.

28. Thomas JRI, Daniel Su WP. The treatment of plane warts. Arch Dermatol 1982; 118: 626.

ADITYA K GUPTA MD PHD FRCP(C) (1,2), KARYN NICOL HBMSC (2)

1. DIVISION OF DERMATOLOGY, DEPARTMENT OF MEDICINE, SUNNYBROOK AND WOMEN'S COLLEGE HEALTH SCIENCE CENTER (SUNNYBROOK SITE) AND THE UNIVERSITY OF TORONTO, TORONTO, ONTARIO, CANADA

2. MEDIPROBE RESEARCH INC., LONDON, ONTARIO, CANADA

ADDRESS FOR CORRESPONDENCE:

Dr. Aditya K Gupta

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