Sulfur Introduction Sulfur is a keratolytic agent and scabicide.

. Uses Acne Topical sulfur preparations are used principally for the symptomatic treatment of acne vulgaris. Although the drug may relieve plugging and rupturing of follicles, ease the evacuation of comedones, and promote peeling of the skin, some clinicians believe that topical sulfur may also promote the formation of new comedones. Sulfur generally has been shown to be more effective than a placebo vehicle in decreasing the number of comedones and other lesions in patients with acne. Although several studies have shown a combination of sulfur and ben oyl pero!ide to be more effective than either drug alone in the treatment of acne, other studies have shown no substantial difference between sulfur, ben oyl pero!ide, or combined therapy. "ombined therapy with #$ sulfur and %.#$ ben oyl pero!ide generally is considered effective in the topical treatment of acne vulgaris& however, there is some evidence that the cutaneous to!icity 'i.e., hypersensitivity( of ben oyl pero!ide is enhanced by sulfur. Sulfur ')$( is commonly used in combination with resorcinol '*$ resorcinol or +$ resorcinol monoacetate( for the treatment of acne. "ombined sulfur,resorcinol therapy generally has been shown to be more effective than a placebo vehicle in decreasing the number of comedones and other lesions in patients with acne, and some clinicians believe that resorcinol enhances the activity of sulfur. The efficacy of sulfur compared with other forms of therapy 'e.g., ben oyl pero!ide, topical anti,infectives, retinoic acid( in the treatment of acne vulgaris has not been fully determined using well,designed, controlled studies. Scabies Topical #,-.$ sulfur ointment 'in a petrolatum base& no longer commercially available in the US( has been used for the treatment of scabies. /ecause sulfur ointment is messy, malodorous, tends to stain, and can produce an irritant dermatitis, its use has largely been supplanted by permethrin, lindane, or other scabicides for most patients. 0any clinicians and the US "enters for 1isease "ontrol and 2revention '"1"( consider permethrin #$ to be the scabicide of choice because of its safety and efficacy profile relative to other available agents, particularly lindane.-.+, -.3, -.#, -.4, -.%, --- 5ecommendations for alternative therapy differ among various clinicians.-.+, -.3, -.4, -.% The "1" and others recommend sulfur 4$ ointment-.*, -.3 or lindane -$ as preferred alternative scabicides,-.-, -.+, -.3 and cost and convenience considerations may factor into the choice for certain patients.-.*, -.3, -.# "rotamiton -.$-.+, -.% or oral ivermectin *.. mcg6kg as a single dose also have been suggested as alternative scabicides.-.+, -.% The "1" and other clinicians currently recommend permethrin #$ as preferred therapy for scabies in infants and young children and in pregnant and lactating women because of its low percutaneous absorption and relative topical safety.-.+, -.3 Some clinicians also consider sulfur #,-.$ ointment a scabicide of choice in such patients,-.7 although systemic to!icity has been reported in several infants receiving such therapy at high doses. 'See "autions8 Adverse 9ffects.( :orwegian scabies is a particularly severe and highly infectious form of scabies that presents as crusted, hyperkeratotic, scaling pla;ues, which may be generali ed or locali ed to the hands and feet.-.*, -.+, -.7, --+ In this condition, the patient is infested with large numbers 'thousands to millions( of Sarcoptes mites.-.*, -.), -.7, --+ In less than -.$ of patients with scabies, nodular scabies may develop, which is characteri ed by intensely pruritic nodules that persist for months after effective scabies therapy&-.+, --. mites seldom are identified in these nodules.--. <or further information on the management of :orwegian and nodular scabies, see Uses8 Scabies in 2ermethrin )38.3.-*. The "1" states that patients with human immunodeficiency virus '=I>( infections who have uncomplicated scabies should receive the same treatment as those without =I> infection.-.3 2atients with =I> infection and other immunocompromised patients are at increased risk of developing :orwegian scabies,-.+, -.3, --+ and the

"1" recommends that such patients be managed in consultation with an e!pert.-.3 <or further information on the management of scabies in patients with =I> infection, see Uses8 Scabies in 2ermethrin )38.3.-*. ?ther Uses Sulfur 'e.g., *,#$( is used topically for its keratolytic effect alone or, usually, in combination with salicylic acid 'e.g., *$( for controlling dandruff. Sulfur, alone or in combination with salicylic acid, generally has been shown to be more effective than a placebo vehicle in controlling dandruff, producing a decrease in corneocyte counts in some studies. Sulfur has also been used topically in combination with salicylic acid for controlling seborrheic dermatitis. Sulfur has been used topically for the symptomatic treatment of many other dermatologic conditions 'e.g., fungal infections(, but other treatments are usually preferred. 2recipitated sulfur also has been available in combination with oral la!ative products, but there has been no ob@ective evidence that systemic sulfur may be useful in the treatment of any disease. 1osage and Administration Acne Sulfur, in the form of -,)$ creams, @ellies, lotions, or soaps, is applied topically for the treatment of acne vulgaris. In these topical products, precipitated or colloidal sulfur usually is used and usually is available in combination with topical anti,infectives, detergents, and6or other keratolytics. The higher concentrations of sulfur produce a more intense keratolytic effect& a concentration of at least *$ sulfur generally is re;uired for effectiveness. Sulfur is contained in some acne cleansers but because contact with the skin is only brief, the value of sulfur in these products is ;uestionable. In acne vulgaris, the fre;uency with which topical preparations are applied should be determined by the severity of the acne and patient response. Aenerally, preparations intended to be applied and left on the skin are applied to thoroughly cleansed skin, covering the entire affected area with a thin layer of the preparation -,+ times daily or as directed by a physician. To avoid e!cessive drying, therapy generally is initiated with a single application daily and then the fre;uency is increased gradually if necessary. Scabies <or the treatment of scabies, a thin layer of a #,-.$ precipitated sulfur ointment 'in a petrolatum base( has been applied uniformly and gently massaged into all skin surfaces 'entire trunk and e!tremities( from the neck to the toes 'including the soles of the feet(& the "1" and others currently recommend a 4$ ointment as the preferred concentration. This treatment has been repeated on each of *,+ successive days. Usually, a bath has been taken before each application of the ointment and *3 hours after the last treatment in order to remove the drug. In an adult, +. g of the ointment usually has been sufficient for one application& children have received a proportionately smaller amount. All clothing and bed linen that may have been contaminated by a patient with scabies should be decontaminated 'dry,cleaned or either machine,washed or machine,dried using the hot cycle( or removed from body contact for at least %* hours following treatment to avoid reinfestation or transmission of scabies.-.3 <umigation of living areas is not necessary in these cases.-.3 0any e!perts recommend particular attention to thorough cleaning of areas inhabited by patients with :orwegian scabies because of the large numbers of mites infesting these patients.-.*, -.+ The "1" recommends that scabies epidemics in institutional settings 'e.g., nursing homes, hospitals, residential facilities and communities( be managed in consultation with an e!pert.-.3 "ontrol of such epidemics re;uires treatment of the entire population at risk.-.*, -.3, --* 2ermethrin has been recommended as a scabicide of choice in institutional outbreaks&--* other clinicians recommend either permethrin or lindane.-.* 1andruff <or relief of itching and scalp flaking associated with dandruff, *,#$ sulfur alone or, most often, in combination with salicylic acid, usually is used as a lotion shampoo. The lotion should be applied to wet hair and massaged vigorously into the scalp& the scalp then is rinsed thoroughly and application of the lotion and rinsing is repeated. The lotion usually is used as a shampoo twice weekly. "autions Adverse 9ffects Bhen used in appropriate dosage, topically applied sulfur preparations have a low order of to!icity. Topical preparations containing *,#$ sulfur generally are well tolerated. Cocal irritation of the skin, eyes, or respiratory

tract may occur and, therefore, contact with the eyes should be avoided. Allergic reactions to sulfur occur rarely. 5epeated applications may cause dermatitis, sometimes severe 'e.g., dermatitis venenata(. In concentrations greater than -#$, sulfur is very irritating to the skin however, commercially available preparations contain up to )$ of sulfur. Sulfur ointment stains clothing, bedding, and metal, including @ewelry. Systemic to!icity 'e.g., headache, vomiting, muscle cramps, di iness, collapse( has reportedly occurred following topical application of precipitated sulfur powder or sulfur ointment to patients with ec ema, but symptoms resolved within several hours. Topical application of a -.$ sulfur ointment 'no longer commercially available in the US( for + days on infants with scabies reportedly caused systemic to!icity and several deaths. There have been no reports of systemic to!icity to date following topical application of preparations containing *,#$ sulfur, and such concentrations are generally considered safe for topical use. 2recautions and "ontraindications Topical preparations containing sulfur are intended for e!ternal use only. Topical sulfur,containing preparations should not be used near the eyes& if contact with the eye's( occurs, the affected eye's( should be rinsed thoroughly with water. If topical sulfur,containing preparations are used for self,medication and the condition worsens or persists after regular use as directed, a physician should be consulted. If e!cessive skin irritation develops or increases during self,medication with a topical sulfur,containing preparation, the drug should be discontinued and a physician or pharmacist consulted. "ombination topical preparations containing sulfur and resorcinol should not be used for self,medication of large areas of the body or of areas with broken skin. Bhen used for self,medication of acne, topical sulfur,containing preparations generally should not be used concurrently with other topical acne medications unless otherwise directed by a physician. 2ediatric 2recautions Topical preparations containing sulfur should not be used in children younger than * years of age e!cept under the direction and supervision of a physician. 2harmacology Topically applied sulfur is a keratolytic agent. Sulfur has keratoplastic activity at low concentrations, correcting abnormal keratini ation, and keratolytic activity at high concentrations, causing peeling of skin& these effects apparently result from the same action of the drug. <ollowing topical application of a #$ sulfur ointment 'no longer commercially available in the US( on hairless mouse skin for a 3,week period, there was increasing edema during the first week, followed by thickening of the prickle cell layer. This reaction was ma!imal at * weeks and resulted in nonadherent cells in the stratum corneum& these cells retained their nuclei. Bhen a *.$ sulfur ointment 'no longer commercially available in the US( was used, similar but more severe reactions occurred. A 3.$ ointment 'no longer commercially available in the US( caused almost complete loss of the stratum corneum at 3 weeks, and intercellular and intracellular edema with resultant separation of epidermis from dermis. Thus, at lower concentrations, sulfur causes epidermal in@ury which is followed by repair. Bhen sulfur concentrations greater than #$ are applied topically, in@ury e!ceeds the reparative process, and peeling 'keratolytic effect( occurs in severity proportionate to the sulfur concentration. Although the mechanism of sulfurDs keratolytic action has not been determined, this action may depend on formation of hydrogen sulfide when the drug comes in contact with skin& the production of the characteristic odor of rotten eggs when sulfur comes in contact with skin results from hydrogen sulfide formation. =ydrogen sulfide may be formed within the epidermis by sulfur reacting with cysteine. Topically applied sulfur has mild antifungal and antibacterial activity. It has been suggested that when applied topically to the skin, sulfur forms hydrogen sulfide and6or polythionic acid, which may e!ert germicidal activity. In vitro studies indicate that sulfur has little if any fungistatic or fungicidal activity. Therefore, sulfurDs antifungal activity probably results largely from its keratolytic action, causing shedding of fungal spores and hyphae embedded within the stratum corneum. In vitro, sulfur has been shown to have some antibacterial activity& the drug has a potent inhibitory effect against some streptococci, a moderate inhibitory effect against Staphylococcus aureus, and no activity against gram,negative bacteria. It has been suggested that the drugDs antibacterial activity may partly result from inactivation of sulfhydryl groups contained in bacterial en yme systems, since the antibacterial effect of the drug has reportedly been neutrali ed by addition of cysteine and other sulfhydryl,

containing compounds to the culture medium. Topically applied sulfur is reportedly to!ic to the parasitic arthropod Sarcoptes scabiei. The e!act mechanism's( of action of sulfur in the treatment of acne is not fully understood but is presumed to involve the drugDs keratolytic and antibacterial effects. Although some studies indicate that sulfur may also be comedogenic, other studies have been unable to substantiate this effect and the drug generally is considered effective in the topical treatment of acne. Bhen administered orally, sulfur reportedly has a la!ative or cathartic effect. 2harmacokinetics The absorption, distribution, and elimination of sulfur following topical application have not been fully characteri ed. Topically applied sulfur reportedly penetrates the skin and is detectable in the epidermis within * hours after application and throughout the skin within about ) hours& the drug is not detectable in skin *3 hours after application. 2ercutaneous absorption of the drug into systemic circulation reportedly occurred following topical application of a *#$ sulfur ointment to abraded skin of animals but did not occur when the drug was applied to intact skin. "hemistry and Stability "hemistry Sulfur is a keratolytic agent. Sulfur is a naturally occurring element found in the free state in deposits in the US and Sicily. Sulfur also is distributed widely and abundantly in nature as sulfides and sulfates of metals. Two official 'US2( forms of sulfur, precipitated sulfur and sublimed sulfur, of at least 77.#$ purity 'on an anhydrous basis(, are used in topical preparations. 2recipitated sulfur 'milk of sulfur(, made by boiling sulfur with lime and precipitating the filtered solution with hydrochloric acid, occurs as a very fine, pale yellow, amorphous or microcrystalline powder. Sublimed sulfur 'abric, flowers of sulfur(, made by cooling and condensing sulfur vapors in a chamber, occurs as a fine, yellow, crystalline powder having a faint odor and taste. 2recipitated sulfur is practically insoluble in water, very slightly soluble in alcohol, and slightly soluble in olive oil. Sublimed sulfur is practically insoluble in water and in alcohol and sparingly soluble in olive oil. The particles of precipitated sulfur are finer than those of sublimed sulfur and, therefore, are preferred for dermatologic preparations. Sulfur also is available as ground roll sulfur 'flour of sulfur( which has different physical properties than sublimed sulfur. "ommercially available topical preparations also may contain sulfur in the form of colloidal sulfur or washed sulfur. "olloidal sulfur contains the drug as a colloidal comple! in which minute particles of sulfur are stabili ed in an a;ueous medium containing a colloid such as egg albumin or gelatin. Bashed sulfur, made by washing sublimed sulfur with ammoniated water, occurs as a fine, yellow, crystalline powder. Stability 2reparations containing sulfur may react with metals including silver and copper, resulting in discoloration of the metal. 2reparations containing sulfur should be stored in well,closed containers. Preparations "olloidal Sulfur 2owder "olloidal Sulfur "ombinations Topical "ream )$ with 5escorcinol *$ /ensulfoidE, 'with alcohol -.$( 2oythress Cotion Shampoo #$ with 5esorcinol *$ SulforcinE, 'with S1 alcohol 3. --.4#$( =ealthpoint #$ with Salicylic Acid +$ Aen1erm 0etedE Improved,

0A *-%E 0edicated Tar,<ree

Shampoo, Triton 2recipitated Sulfur 2owder Topical "ake +$ #$ -.$

Sulfo,CoE Soap, 0ed, 1erm Sulpho,CacE 0edicated Soap, 1oak SAStidE Soap, Stiefel Sulfur Soap, Stiefel

Cotion

3$

Ci;uimatE, 'with alcohol **$& light and medium shades( Summers Sulfo,CoE, 0ed, 1erm

2recipitated Sulfur "ombinations Topical "ake #$ with Salicylic Acid +$ , Stiefel "ream Cotion

Salicylic Acid and Sulfur Soap

)$ with 5esorcinol *$ AcnomelE, 'with alcohol --$ w 6w( 0enley F Games *$ with /en oyl 2ero!ide #$ Sulfo!ylE Cotion 5egular, 'with propylene glycol( Stiefel #$ with /en oyl 2ero!ide -.$ Sulfo!ylE Cotion Strong, 'with propylene glycol( Stiefel #$ with 5esorcinol *$ 5e amidE, 'with S1 alcohol 3. *).#$( Summers #$ with Sulfacetamide Sodium :ovacetE, -.$ Aen1erm Sodium Sulfacetamide and Sulfur Cotion, Alades =ope Sulfacet,5E, 'with parabens, propylene glycol, and inc o!ide& regular and tint,free( 1ermik

Sublimed Sulfur 2owder Topical "ream #$ 1oak Cotion Shampoo *$ *$

Sulpho,CacE Acne 0edication, <ostrilE, 'with parabens( Bestwood,S;uibb SulfoamE 0edicated Antidandruff, 1oak

Sublimed Sulfur "ombinations Topical "leansing *$ and Salicylic Acid -.#$ 2erno!E Scrub "leanser, 'lemon Suspension and regular( Bestwood,S;uibb "ream Cotion +$ with 5escorcinol *$ "learasilE Adult "areE, 2rocter F Aamble *$ and Salicylic Acid -.#$ S;uibb 2erno!E, Bestwood,

Shampoo

*$ with "oal Tar ..#$ and SebutoneE, 'cream or lotion( Salicylic Acid *$ Bestwood,S;uibb *$ with Salicylic Acid *$ S;uibb Sebule!E, Bestwood,

Sebule!E with "onditioners, 'with propylene glycol( Bestwood,S;uibb