Dapsone in dermatology and beyond

Abstract

Dapsone (4,4'-diaminodiphenylsulfone) is an aniline derivative belonging to the group of synthetic sulfones. In 1937 against the background of sulfonamide era the microbial activity of dapsone has been discovered. Shortly thereafter, the use of dapsone to treat non-pathogen-caused diseases revealed alternate antiinflammatory mechanisms that initially were elucidated by inflammatory animal models. Thus, dapsone clearly has dual functions of both: antimicrobial/antiprotozoal effects and anti-inflammatory features similarly to non-steroidal anti-inflammatory drugs. The latter capabilities primarily were used in treating chronic inflammatory disorders. Dapsone has been investigated predominantly by in vitro methods aiming to get more insights into the effect of dapsone to inflammatory effector cells, cytokines, and/or mediators, such as cellular toxic oxygen metabolism, myoloperoxidase-/halogenid system, adhesion molecules, chemotaxis, membrane-associated phospholipids, prostaglandins, leukotrienes, interleukin-8, tumor necrosis factor α, lymphocyte functions, and tumor growth. Moreover, attention has been paid to mechanisms by which dapsone mediates effects in more complex settings like impact of lifespan, stroke, glioblastoma, or as anticonvulsive agent. Additionally, there are some dermatological investigations in human being using dapsone and its metabolites (e.g., leukotriene B4-induced chemotaxis, ultraviolet-induced erythema). It could be established that dapsone metabolites by their own have anti-inflammatory properties. Pharmacology and mechanisms of action are determining factors for clinical use of dapsone chiefly in neutrophilic and/or eosinophilic dermatoses and in chronic disorders outside the field of dermatology. The steroid-sparing effect of dapsone is useful for numerous clinical entities. Future avenues of investigations will provide more information on this fascinating and essential agent.

Fig. 1

Structural formula of dapsone (4,4′diaminodiphenylsulfone)

Fig. 2

The two major metabolic pathways of dapsone (MADDS monoacetyldapsone, DDS-NOH dapsone hydroxylamine)

Fig. 3

Dapsone metabolism in human PMN and mononuclear cells after activation by phorbol myristate acetate (PMA) and oxidation path by NaOCl (according to Uetrecht et al. [156])

Fig. 4

The effect of dapsone on the extracellular superoxide (O₂ ⁻) release induced by N-formyl-l-methionyl-l-leucyl-l-phenyalanine (fMLP), C5a and phorbol myristate acetate (PMA). Neutrophils (1 × 10⁶ cells mL⁻¹) were preincubated with or without dapsone at the concentrations indicated for 30 min and then stimulated with fMLP (1 μmol L⁻¹) (a), C5a (100 nmol L⁻¹) (b) or PMA (100 nmol L⁻¹) (c). After addition of cytochrome C (20 μmol L⁻¹), the reduction of absorbance at 550 nm in the absence (ΔOD₅₅₀[SOD]) was measured for 5 min using a single-beam spectrophotometer. SOD-inhibitable cytochrome C reduction corresponded to ΔOD₅₅₀–ΔOD₅₅₀[SOD]. The data shown are representative of three to four separate experiments with similar results. Dapsone suppressed the extracellular O₂ ⁻ production induced by fMLP and C5a but not by PMA. (according to Suda et al. [148])

Fig. 5

The effect of dapsone on neutrophils. Dapsone suppressed intra- and extracellular production of superoxide (O₂ ⁻) and elastase release triggered by FLMP and physiological agonist C5a, but not by PMA. Both FMLP and C5a signaled the above pathways by inducing calcium influx, but PMA functions bypassed calcium influx. Dapsone was capable of antagonizing the induction of calcium influx (FMLP: N-formyl-l-methionyl-l-leucyl-l-phenyalanine, PMA phorbol myristate acetate, PKC protein kinase C, NADPH Nicotinamide adenosine dinucleotide phosphate) (according to Suda et al. [148]

Fig. 6

Survival curves of Ceanorhabditis elegans (n = 129) treated with dapsone (2 mmol) during their entire life time compared with worms that were untreated. (according to Cho et al. [26])

Fig. 7

Suppression of ultraviolet (UV)-induced erythema with topical applied dapsone (1 % solved in acetone, 48 h after UV exposition) (right forearm), control: left forearm (UV source: UVB erythemal effective Hg-lamp VITALUX/OSRAM GmbH, Germany)

Fig. 8

Photoallergic reaction by dapsone in a female patient with linear IgA dermatosis (a), Photo-patch test (5 J/cm² UVA/Philips TL09) with dapsone and the two main metabolites of dapsone (b), (according to Stöckel et al. [145])

Fig. 9

Chemical structure of dapsone hydroxylamine

Fig. 10

Chemical structure of chlorodapsone

Fig. 11

Chemical structure of a nitroderivative of dapsone