News, Views & Reviews. Repurposing of Drugs for Dermatologic Applications: Five Key Medications
November 2014 | Volume 13 | Issue 11 | Feature | 1413 | Copyright © 2014
Brandon L. Adler BA and Adam J. Friedman MD
No abstract available
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Dermatologists and other physicians frequently prescribe medications off-label for the treatment of cutaneous disease.1,2 Off-label prescribing refers to prescription of a drug in a way that diverges from FDA-approved use. It may represent first-line therapy, be incorporated into treatment guidelines, or serve solely as a last resort.3 The ability to prescribe off-label empowers physicians to innovate within the scope of clinical practice, especially when standard treatments fail.3 This may offer considerable benefits for patient care. Off-label prescribing avoids the expenses of running clinical trials and obtaining FDA approval for a new indication, which provide pharmaceutical companies with little motivation to seek new approvals for existing medications. In addition, the low incidence and prevalence rates of many dermatologic conditions do not always support extensive research.1 On the other hand, although off-label prescribing is legal and common, there are concerns regarding safety and efficacy that may need to be addressed, as well as issues of cost to the healthcare system.3,4
The field of dermatology is in a unique position to repurpose existing therapies for cutaneous conditions, given the broad variety of pathophysiologic processes affecting the skin. This review covers five medications that have been adapted for novel off-label use within dermatology. We include a brief history of each drug, followed by mechanisms of action, current use in dermatologic practice, and adverse effect profiles.
First synthesized in 1908 during experiments on dye chemistry,5 dapsone is a sulfone drug that possesses both antimicrobial and anti-inflammatory activities. However, dapsone’s medical applications were not discovered for nearly 30 years, when it was shown to possess antistreptococcal activity in mice.6 About a decade later sulfones were implemented for leprosy7 and dermatitis herpetiformis,8 paving the way for further dermatologic applications.
Like sulfonamide antibiotics, dapsone acts bacteriostatically via competitive inhibition of dihydropteroate synthetase (competing with para-aminobenzoic acid for the enzyme active site), thereby decreasing downstream production of folic acid.9 Its anti- inflammatory mechanism is much more complex and enables translation of dapsone to numerous neutrophil-mediated and autoimmune processes.10 These effects are varied and incompletely characterized, but foremost among them is reversible inhibition of myeloperoxidase, preventing cellular damage by hypochlorous acid produced by both neutrophils and eosinophils.11
Dapsone is ideally suited for broad off-label use in dermatology because of its combination antimicrobial-antiprotozoal effects, formidable anti-inflammatory activity, long-term (even lifelong) safety, steroid-sparing properties, and low cost.12 Currently, dapsone is only approved by the FDA for dermatitis herpetiformis and as a component of leprosy multidrug therapy. Its off-label uses in dermatology stretch much further: dapsone is recommended as first-line therapy for acropustulosis infantilis, 13 cicatricial pemphigoid,14 erythema elevatum diutinum,15 IgA pemphigus,16 linear IgA dermatosis,17 prurigo pigmentosa, 18 recurrent neutrophilic dermatosis of the dorsal hands,19 and subcorneal pustulosis.13 It may be employed as adjunctive therapy in a number of diseases, and reports of use exist for many other conditions, with variable results.10,20,21 Dosing of dapsone for chronic inflammatory dermatoses is highly individualized, generally beginning at 50-100 mg daily; if treatment goal is not attained after 4-6 weeks, the dose may be titrated up to 150-300 mg daily, according to patient tolerability.12
The most common adverse effects associated with dapsone include methemoglobinemia and hemolysis.10 Severe anemia may occur in persons with glucose-6-phosphate dehydrogenase deficiency. Accordingly, all patients should be screened for this enzyme deficiency prior to initiation of therapy. Cimetidine, by acting as a cytochrome P450 inhibitor, has been shown to reduce methemoglobin formation and may increase adherence among patients receiving more than 200 mg daily.22
The first phenothiazine compound was synthesized in 1883 during chemical dye experiments, but no medicinal use was found for this class of drugs until 1952, when exciting results were reported on the use of chlorpromazine for psychosis. This spurred a series of experiments on the emerging class of tricyclic antidepressants, resulting in the creation of doxepin in the early 1960s.23
Tricyclic antidepressants such as doxepin act primarily by inhibiting reuptake of serotonin and norepinephrine, increasing the synaptic concentrations of those neurotransmitters. However, there are numerous off-target effects that occur with use of this class of drugs, mediated largely via muscarinic and histamine receptors.24 Doxepin has 56 times the affinity of hydroxyzine and nearly 800 times that of diphenhydramine for the H1 receptor.25
Pruritus is a very common dermatologic complaint. Given doxepin’s well known activity at histamine H1 receptors, topical doxepin formulations are FDA-approved for pruritus secondary to eczematous dermatitis. Doxepin has found more extensive use as a systemic agent prescribed to patients suffering from psychodermatoses, especially neurotic excoriations, as