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Topical Therapy for Nail InfectionsYeast and bacterial infections of the nails are usually the result of microscopic damage to the nail plates. The nails will have either a white, thin discoloration at the tip of the nail that starts to extend toward the cuticle, or may have a greenish-black color to the nail. A mixture of 4% thymol in alcohol used twice daily until the affected area has grown out is excellent for this condition. Thymol is an antibacterial and antifungal, and alcohol also reduces moisture in skin folds and cuticles.

For treatment of onychomycosis, penetration of the topical antifungal agent through the nail plate from the surface of the nail and diffusion of the systemic antifungal drug through the nail bed may increase the total amount of antifungal activity at the site of infection. Results from an initial study in patients with onychomycosis suggest that this approach can enhance the overall efficacy of therapy. Using a combination of antifungal drugs in this manner may potentially reduce the duration of therapy and allow a reduction in dose of the oral agent, which may reduce systemic adverse effects. Physicians may also consider combining topical antifungal therapy with topical urea. Urea degrades protein, including keratin — a major component of the nail plate. Potentially, urea can soften the nail plate, making it more porous and penetrable to topical antifungal drugs. Urea ointment (40 to 55%) can be applied to the nail twice daily for two weeks. Then, topical formulations such as clotrimazole 2% and ibuprofen 2% in DMSO USP (“apply to affected nails BID for 6 weeks”) or butenafine 2% and tea tree oil 5% cream can be applied to the affected nail.

A randomized, double-blind, placebo-controlled study examined the clinical efficacy and tolerability of 2% butenafine hydrochloride and 5% Melaleuca alternifolia (tea tree) oil incorporated into a cream base to manage toenail onychomycosis. Sixty outpatients (39 M, 21 F) aged 18-80 years (mean 29.6) with 6 to 36 months duration of disease were randomized to two groups (40 active therapy and 20 placebo). After 16 weeks, 80% of patients using medicated cream were cured, as opposed to none in the placebo group. Four patients in the active treatment group experienced subjective mild inflammation without discontinuing treatment. During follow-up, no relapse occurred in cured patients and no improvement was seen in medication-resistant and placebo participants.

Audrey Kunin, M.D. http://www.dermadoctor.com/article_Nail-Fungus_57.html (accessed January 2012)
http://www.medscape.com/viewarticle/452687_8 (accessed January 2012)
Timothy J. Scott, DPM, FACFAS, Clarion, PA
Trop Med Int Health. 1999 Apr;4(4):284-7.
Treatment of toenail onychomycosis with 2% butenafine and 5% Melaleuca alternifolia (tea tree) oil in cream.
to access the PubMed abstract of this article.

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A recent large prospective study has shown that onychomycosis is among the most significant predictors of foot ulcer. If left untreated, toenails can become thick, causing pressure and irritation, and thus act as a trigger for more severe complications. In the treatment of onychomycosis, compliance and drug interactions are important considerations, as diabetic patients frequently take concomitant medications.

Am J Clin Dermatol. 2009;10(4):211-20.
Toenail onychomycosis in diabetic patients: issues and management.
Mayser P, Freund V, Budihardja D.
to access the PubMed abstract of this article.

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Study participants were treated with a solution of 1% fluconazole and 20% urea in a mixture of ethanol and water, applied once daily at bedtime. The response to this local therapy was appreciable.

J Dermatolog Treat. 2005 Feb;16(1):52-5.
Combination of fluconazole and urea in a nail lacquer for treating onychomycosis.
Baran R, Coquard F.
to access the PubMed abstract of this article.

Studies have shown that antifungal agents can be of benefit in treating onychomycosis in patient populations that include the elderly, children, and immunocompromised individuals (e.g., transplant patients, Down’s patients, HIV patients, and diabetics). The treatment modality in special patient populations should take into account the clinical presentation of onychomycosis, causative organism, patient and physician preference, concomitant medications that the patient is taking, and the potential for adverse events associated with antifungal therapy.

J Cutan Med Surg. 2004 Jan-Feb;8(1):25-30. Epub 2004 Jan 23.
Treatment of onychomycosis: pros and cons of antifungal agents.
Gupta AK, Ryder JE, Skinner AR.
to access the PubMed abstract of this article.

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Chemical nail destruction with a combination of urea and bifonazole, followed by treatment with an antifungal ointment, can be used when the nail is markedly thickened. Non-comparative trials have shown cure rates close to 70% at three months when the matrix is not involved, and 40% with matrix involvement.

Prescrire Int. 2009 Feb;18(99):26-30.
Fungal nail infections: diagnosis and management.
to access the PubMed abstract of this article.

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Fungal infections of the feet are commonly associated with dry, cracked skin surrounding the plantar surface and heel fissures. Hyperkeratosis can have various etiologies, and chronic conditions are often quite difficult to treat. Moccasin tinea pedis is typically resistant to topical antifungal therapy when used as sole therapy, because the scale on the plantar surface of the foot impedes or limits the absorption of the antifungal agent. However, one study showed a 100% cure rate was achieved in 12 patients with confirmed moccasin tinea pedis who were treated with topical 40% urea cream and antifungal cream concomitantly for 2 to 3 weeks.

Cutis 2004 May;73(5):355-7
The use of 40% urea cream in the treatment of moccasin tinea pedis.
to access the PubMed abstract

The following article concludes: “Topical non-steroidal anti-inflammatory drugs are effective in relieving pain in acute and chronic conditions.”BMJ. 1998 Jan 31;316(7128):333-8
Quantitative systematic review of topically applied non-steroidal anti-inflammatory drugs.
to access the PubMed abstract of this article.

Free full text article available at bmj.com: http://bmj.bmjjournals.com/cgi/content/full/316/7128/333

The following article reports “The systemic concentrations of ketoprofen have also been found to be 100 fold lower compared to tissue concentrations below the application site in patients undergoing knee joint surgery. Topically applied ketoprofen thus provides high local concentration below the site of application but lower systemic exposure.”

Pharm Res. 1996 Jan;13(1):168-72
Percutaneous absorption of ketoprofen from different anatomical sites in man.
Click here to access the PubMed abstract of this article.

Various synergistic combinations are used for antifungal therapy. Research points to the practicality “of using ibuprofen, alone or in combination with azoles, in the treatment of candidosis, particularly when applied topically, taking advantage of the drug’s antifungal and anti-inflammatory properties.”J Med Microbiol 2000 Sep;49(9):831-40
Antifungal activity of ibuprofen alone and in combination with fluconazole against Candida species.
Click here to access the PubMed abstract of this article.

Neuropathic pain includes a variety of conditions such as diabetic neuropathy, phantom limb pain, reflex sympathetic dystrophy (RSD or Complex Regional Pain Syndrome), and pain caused by blunt trauma or crushing injuries. Symptoms of neuropathic pain may not be evident for weeks to months after the injury. Optimal treatment may involve not only the use of traditional analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) and opioids, but may also include medications that possess pain-relieving properties, including some antidepressants, anticonvulsants, antiarrhythmics, anesthetics, antiviral agents, and NMDA antagonists. “Combination therapy is frequently the only effective approach for managing the complex array of chemical mediators and other contributors to the individual pain experience.”"As topical formulations are developed, they provide hope for more effective drug combinations, with fewer systemic adverse drug effects and drug-drug interactions.”1 For example, research has shown that topically applied ketoprofen provides a high local concentration of drug below the site of application but decreases systemic exposure and significantly reduces the risk of gastrointestinal upset or bleeding. When properly compounded into an appropriate base, tissue concentrations of ketoprofen were found to be 100-fold greater below the application site (knee) compared to systemic concentrations. Sever disease is the most common cause of heel pain in pre-pubertal children. A case report described the use of topical ketoprofen 10% gel as an adjunct to physical therapy to relieve pain and inflammation.

Advanced Studies in Medicine 2003 July;3(7A):S639
Pharmaceutical Research (1996) 13: 1; 168-172
Phys Ther. 2006 Mar;86(3):424-33
Ketoprofen gel as an adjunct to physical therapist management of a child with Sever disease.
Click here to access the PubMed abstract of this article.

Neuropathy Foot Cream

The following testimonial appeared in the December 1999 issue of Neuropathy News, a patient newsletter:

“My local [compounding pharmacist] has created a cream to help alleviate the pain of foot neuropathy. It reduces the burning and sharp, needle-like pain. All you need is a very thin coat. The directions call for using it four times a day, but I find it particularly helpful at night. [The formulation contains] 2% amitriptyline and 2% baclofen in a transdermal gel.”
“Compounding pharmacists have the unique training and ability to create medications that address the individual needs of patients. One of the most helpful products they use are transdermal gels that allow for the passage of medication directly through the tissue into the area of pain. Many of the medications typically prescribed for neuropathy patients such as amitriptyline, lidocaine, mexilitene, ketamine and [gabapentin] can cause significant side effects when taken orally. Transdermal gel minimizes systemic side effects and maximizes local pain relief. Compounding pharmacists have many resources that offer relief from neuropathic pain.”

In Diabetes Interviews, January 2000, Neil A. Burrell, DPM, CDE, of Beaumont, Texas, writes “We have a very high success rate using amitriptyline and baclofen mixed in a gel component. This compound is applied to the feet three times per day, and offers immediate relief… [For] recalcitrant neuropathic pain, many times we use a combination of tramadol, gabapentin and amitriptyline.”

At our compounding pharmacy, we work together with physicians and patients to prepare formulations containing the medications and doses that are most appropriate to meet each patient’s specific needs. Let us know how we can be of service.

Arginine Transdermal

Diabetes Care, January 2004; 27(1):284-5
Improvement of Temperature and Flow in Feet of Subjects with Diabetes With Use of a Transdermal Preparation of L-Arginine – A pilot study
Click here for the full article.

Topical doxepin could be an alternative and relatively safe treatment in alleviating neuropathic pain in the diabetic patient, especially when the use of systemic treatment is contraindicated. In the following case study, the soles of the patient’s feet were treated with topical doxepin 5% twice daily for four weeks. The patient responded dramatically with loss of the severe burning sensation and no side effects reported.

Wounds 15(8):272-276, 2003. © 2003 Health Management Publications, Inc.
Burning Feet Due to Diabetic Neuropathy
Click here for the full article.

Resistant warts and molluscum contagiosum have been treated successfully with compounded topical medications, avoiding discomfort associated with freezing, scraping, electrocautery and laser therapy.Therapy with 10% KOH was found to be effective and safe in the treatment of molluscum contagiosum (MC) in children, although a stinging sensation was reported by most children during the trial and some developed hyper- or hypopigmentation after treatment at the site of the lesions.

Pediatr Dermatol. 1999 May-Jun;16(3):228-31.
Treatment of molluscum contagiosum with potassium hydroxide: a clinical approach in 35 children.
Romiti R et al.
Click here to access the PubMed abstract of this article.

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In an attempt to reduce the side effects (stinging sensation & hyper- or hypopigmentation) found with use of 10% KOH, a new trial of 20 children used a less concentrated KOH solution (5%) for treatment of molluscum contagiosum (MC). The 5% KOH aqueous solution proved to be as effective as and less irritating than 10% KOH, and spared children from more aggressive physical modalities of treatment.

Pediatr Dermatol. 2000 Nov-Dec;17(6):495.
Evaluation of the effectiveness of 5% potassium hydroxide for the treatment of molluscum contagiosum.
Romiti R, Ribeiro AP, Romiti N.
Click here to access the PubMed abstract of this article.

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These studies showed that 5% imiquimod cream and 10% KOH solution are equally effective in treating molluscum contagiosum, although KOH has a faster onset of action.

Ann Dermatol. 2010 May;22(2):156-62. Epub 2010 May 17.
An open, randomized, comparative clinical and histological study of imiquimod 5% cream versus 10% potassium hydroxide solution in the treatment of molluscum contagiosum.
Seo SH, Chin HW, Jeong DW, Sung HW.
Click here to access the PubMed abstract of this article.

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Indian J Dermatol Venereol Leprol. 2008 Nov-Dec;74(6):614-8.
An open, nonrandomized, comparative study of imiquimod 5% cream versus 10% potassium hydroxide solution in the treatment of molluscum contagiosum.
Metkar A, Pande S, Khopkar U.
Click here to access the PubMed abstract of this article.

Treatment of Fingernail Lichen PlanusNail lichen planus most commonly occurs during the fifth and sixth decade of life and can be notoriously recalcitrant to many forms of treatment. Prevost and English of the University of Pittsburgh Department of Dermatology reported a case of successful treatment of destructive inflammatory lichen planus of the nails with combined topical therapy of tazarotene gel and clobetasol gel, without the occurrence of potential adverse affects of systemic treatments.

J Drugs Dermatol. 2007 Feb;6(2):202-4.
Palliative treatment of fingernail lichen planus.
Click here to access the PubMed abstract of this article.

Although surgical excision is the most popular method for removing nails, the use of concentrated urea plasters applied under occlusion may be superior. The use of urea plasters has inherent advantages – they are inexpensive, several nails can be treated in one session, and the procedure is essentially painless. Various synergistic combinations and topical medications with penetrant enhancers can be compounded for antifungal therapy. Topical medications usually have a lower adverse drug-reaction profile than systemic medications.

Cutis. 1980 Jun;25(6):609-12
Urea ointment in the nonsurgical avulsion of nail dystrophies–a reappraisal.
Click here to access the PubMed abstract of this article.

Cutis. 1980 Apr;25(4):397, 405
Combination urea and salicyclic acid ointment nail avulsion in nondystrophic nails: a follow-up observation.
Click here to access the PubMed abstract of this article.

JAMA 1979 Apr 13;241(15):1559, 1563
Urea plasters alternative to surgery for nail removal.
PMID: 430701 (No abstract available)

Clin Exp Dermatol 1982 May;7(3):273-6
The treatment of fungus and yeast infections of nails by the method of “chemical removal”.
PMID: 7105479 (No abstract available)

Management of onychomycosis, a fungal infection of the fingernails and toenails, usually consists of systemic antifungal medications, topical therapy (e.g., urea ointment, desiccating solutions, keratolytics, vital dyes), or surgical intervention (e.g., nail plate avulsion, laser therapy). Topical prescription antifungal preparations, containing the active ingredient of your choice, may be less likely to cause the serious systemic side effects that can occur with oral antifungal therapy and can provide a more economical alternative, as lower doses are needed when the medication is applied topically at the site. Penetrant enhancers can be included in the preparation to improve the effectiveness of topical antifungals.

Trop Med Int Health 1999 Apr;4(4):284-7
Treatment of toenail onychomycosis with 2% butenafine and 5% Melaleuca alternifolia (tea tree) oil in cream.
Click here to access the PubMed abstract of this article.

The primary objective of a current multicenter, randomized controlled trial conducted by the Department of Health Sciences, University of York, UK is to compare the clinical effectiveness of two common treatments for verrucae: cryotherapy using liquid nitrogen versus salicylic acid. The primary outcome is complete clearance of all verrucae as observed on digital photographs taken at 12 weeks.The EVERT (effective verruca treatments) trial protocol: a randomised controlled trial to evaluate cryotherapy versus salicylic acid for the treatment of verrucae
E Sarah Cockayne and The EVERT Trial Team

http://trialsjournal.com/content/11/1/12
Accessed May 9, 2011

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Topical 5-fluorouracil (5-FU) 5% with tape occlusion produced complete eradication of all plantar warts within 12 weeks of treatment in 19 of 20 patients. It was concluded that use of topical 5% 5-fluorouracil cream for plantar warts is safe, efficacious, and accepted by the patient.

J Drugs Dermatol. 2006 May;5(5):418-24.
Topical 5% 5-fluorouracil cream in the treatment of plantar warts: a prospective, randomized, and controlled clinical study.
Click here to access the PubMed abstract of this article.

A medical record review was conducted by the Podiatry Division, Department of Orthopedics, Cabrini Medical Center, New York, NY to determine the clinical outcome and average time to resolution of verruca plantaris (plantar warts) in 20 patients treated with twice-daily applications of topical fluorouracil (5-FU) combined with topical 17% and 40% salicylic acid. Twice-daily application of topical fluorouracil and salicylic acid is a safe and effective treatment for verruca plantaris.

J Am Podiatr Med Assoc. 2005 Jul-Aug;95(4):366-9.
Treatment of verruca plantaris with a combination of topical fluorouracil and salicylic acid.
Click here to access the PubMed abstract of this article.

Phys Ther. 2002 Dec;82(12):1184-91
Treatment of plantar verrucae using 2% sodium salicylate iontophoresis.
Click here to access the PubMed abstract of this article.

Cantharidin in a collodion vehicle has been used by dermatologists as a treatment for molluscum contagiosum and warts since the 1950s. Cantharidin lost FDA approval in 1962 because its manufacturers failed to submit data attesting to cantharidin’s efficacy. However, in 1999, the FDA included cantharidin on its “Bulk Substances List” of drugs which although not available as commercial products, were approved for compounding on a customized basis for individual patients.

Because of cantharidin’s potential for toxicity, the FDA has proposed that cantharidin should be limited to “topical use in the professional office setting only.” Severe blistering can result from improper use, and ingestion, especially by children, can be fatal. Treatment of mucous membranes is contraindicated and placement of cantharidin near the eyes and eyelids should be avoided to prevent scleral erosion.

Caution: The treatment of plantar warts with cantharidin is NOT recommended and may have a higher rate of significant complications including lymphangitis and refractory lymphedema.

Arch Dermatol. 2001;137:1357-1360
Cantharidin revisited: a blistering defense of an ancient medicine.
Click here to access the PubMed abstract

J Am Acad Dermatol. 2000;43:503-507
Childhood molluscum contagiosum: experience with cantharidin therapy in 300 patients.
Click here to access the PubMed abstract

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Squaric Acid Dibutylester (SADBE) for Cutaneous Warts in Children

Warts are a common pediatric skin infection and clearance may be enhanced by contact sensitizers, such as squaric acid dibutylester (SADBE). Contact immunotherapy with SADBE is relatively safe and an effective alternative in the management of multiple and resistant cutaneous warts in children.

J Am Acad Dermatol. 2000 May;42(5 Pt 1):803-8
Squaric acid immunotherapy for warts in children.
Click here to access the PubMed abstract

Pediatr Dermatol. 2000 Jul-Aug;17(4):315-8
Use of squaric acid dibutylester (SADBE) for cutaneous warts in children.
Click here to access the PubMed abstract

J Am Acad Dermatol. 1999 Oct;41(4):595-9
Contact immunotherapy with squaric acid dibutylester for the treatment of recalcitrant warts.
Click here to access the PubMed abstract

Wounds and pressure sores may heal more quickly if treated with topical phenytoin. Medications which improve capillary blood flow can be added to a compounded medication to enhance circulation at the wound margins and promote healing of the injured area.Topical Phenytoin for Wound Healing

The stimulatory effect of orally administered phenytoin on gingival tissue prompted its assessment in wound healing. Phenytoin may promote wound healing by a number of mechanisms, including stimulation of fibroblast proliferation, facilitation of collagen deposition, glucocorticoid antagonism, and antibacterial activity. Phenytoin has been used topically in the healing of pressure sores, venous stasis and diabetic ulcers, traumatic wounds, skin autograft donor sites, and burns.

Rhodes et al compared the healing of stage II decubitus ulcers with topically applied phenytoin and two other standard topical treatment procedures in 47 patients in a long-term care setting. Ulcers were examined for the presence of healthy granulation tissue, reduction in surface dimensions, and time to healing. Topical phenytoin therapy resulted in a shorter time to complete healing and formation of granulation tissue when compared with DuoDerm dressings or triple antibiotic ointment applications. The mean time to healing in the phenytoin group was 35.3 +/- 14.3 days compared with 51.8 +/- 19.6 and 53.8 +/- 8.5 days for the DuoDerm and triple antibiotic ointment groups, respectively. Healthy granulation tissue in the phenytoin group appeared within 2 to 7 days in all subjects, compared to 6 to 21 days in the standard treatment groups. The phenytoin-treated group showed no detectable serum phenytoin concentrations.

Anstead et al. described a patient with a massive grade IV pressure ulcer that was unresponsive to conventional treatment, yet responded rapidly to treatment with topical phenytoin. Song and Cheng reported phenytoin improved wound breaking strength in normal and radiation-impaired wounds. The results of their study indicated that topical phenytoin accelerated normal and irradiation-impaired wound healing by increasing the number of wound macrophages and improving the macrophage function. Pendse et al evaluated the effectiveness of topical phenytoin in healing chronic skin ulcers in a controlled trial of 75 inpatients. At the end of the fourth week, 29 of 40 phenytoin-treated ulcers had healed completely versus 10 of 35 controls. They concluded: “topical phenytoin appears to be an effective, inexpensive, and widely available therapeutic agent in wound healing.”

The effectiveness of topical phenytoin as a wound healing agent was compared with that of OpSite and a conventional topical antibiotic dressing (Soframycin) in a controlled study of 60 patients with partial-thickness skin autograft donor sites on the lower extremities. Mean pain scores were lower and mean time to complete healing (complete epithelialization) was best in the phenytoin-treated group (6.2 +/- 1.6 days). Topical phenytoin compared very favorably with, and in some aspects was superior to, occlusive dressings.

The efficacy of topical phenytoin in the treatment of diabetic foot ulcers was evaluated in a controlled inpatient study. Fifty patients were treated with topical phenytoin, and 50 patients received dry sterile occlusive dressings. Both groups improved, but the ulcers treated with topical phenytoin healed more rapidly. Mean time to complete healing was 21 days with phenytoin and 45 days with control.

No study reported any significant adverse effects secondary to topical phenytoin therapy.

Ann Pharmacother 2001 Jun;35(6):675-81
Topical phenytoin treatment of stage II decubitus ulcers in the elderly.
Click here to access the PubMed abstract of this article.

Biochem Pharmacol 1999 May 15;57(10):1085-94
Role of phenytoin in wound healing–a wound pharmacology perspective.
Click here to access the PubMed abstract of this article.

Ann Pharmacother 1996 Jul-Aug;30(7-8):768-75
Phenytoin in wound healing.
Click here to access the PubMed abstract of this article.

Int J Dermatol 1993 Mar;32(3):214-7
Topical phenytoin in wound healing.
Click here to access the PubMed abstract of this article.

Chung Hua I Hsueh Tsa Chih 1997 Jan;77(1):54-7
[The effect of systemic and local irradiation on wound macrophages and the repair promoting action of phenytoin sodium]
Click here to access the PubMed abstract of this article.

Burns 1993 Aug;19(4):306-10
Topical phenytoin in the treatment of split-thickness skin autograft donor sites: a comparative study with polyurethane membrane drape and conventional dressing.
Click here to access the PubMed abstract of this article

Diabetes Care 1991 Oct;14(10):909-11
Topical phenytoin in diabetic foot ulcers.
Click here to access the PubMed abstract of this article

Iontophoresis facilitates delivery of medications into the tissues beneath the skin by electronic transport of ionized drugs in solution. Acetic acid iontophoresis is effective in the treatment of heel pain. Iontophoresis of dexamethasone for plantar fasciitis should be considered when more immediate results are needed. Iontophoresis has also been used to successfully treat plantar hyperhidrosis.Phonophoresis is a technique that combines topical drug therapy with ultrasound to achieve therapeutic drug concentrations in muscle and other tissues beneath the skin. Ultrasound gels can be formulated to contain medications such as anti-inflammatories and/or anesthetics.

J Am Podiatr Med Assoc. 1999 May;89(5):251-7
Management of heel pain syndrome with acetic acid iontophoresis.
Click here to access the PubMed abstract of this article.

Am J Sports Med 1997 May-Jun;25(3):312-6
Treatment of plantar fasciitis by iontophoresis of 0.4% dexamethasone. A randomized, double-blind, placebo-controlled study.Click here to access the PubMed abstract of this article.

The following list is just a few of the preparations that we can compound for podiatry. We work together with prescriber and patient to solve problems, and all formulations are customized per prescription to meet the unique needs of each patient. Therapeutic results depend not only on the selection of drug, but also the use of a proper base and preparation technique. Please contact our compounding pharmacist to discuss the dosage form, strength, and medication or combination that is most appropriate for your patient.

• Clotrimazole in DMSO solution
• Dexamethasone iontophoresis solution
• Fluconazole/Ibuprofen topical gel
• Ketamine/Gabapentin transdermal gel
• Ketoprofen 10% topical gel
• KOH solution – 5% and 10%
• Phenytoin topical
• Urea 40% ointment