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Dapsone in dermatology and beyond.

Wozel G, Blasum C - Arch. Dermatol. Res. (2013)

Bottom Line: Thus, dapsone clearly has dual functions of both: antimicrobial/antiprotozoal effects and anti-inflammatory features similarly to non-steroidal anti-inflammatory drugs.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.The steroid-sparing effect of dapsone is useful for numerous clinical entities.

View Article: PubMed Central - PubMed

Affiliation: Study Centre for Clinical Trials, Dermatology, Gesellschaft für Wissens- und Technologietransfer der Technischen Universität Dresden mbH, Blasewitzer Str. 43, 01307, Dresden, Germany, Gkatharina.bluemlein@uniklinikum-dresden.de.

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.

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Related in: MedlinePlus

The two major metabolic pathways of dapsone (MADDS monoacetyldapsone, DDS-NOH dapsone hydroxylamine)
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Related In: Results  -  Collection


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Fig2: The two major metabolic pathways of dapsone (MADDS monoacetyldapsone, DDS-NOH dapsone hydroxylamine)

Mentions: Chemically, dapsone is an aniline derivative. As a sulfone, it shows the structure of a sulphur atom linking to two carbon atoms (Fig. 1). Solubility of dapsone varies over a wide range depending on the solvent used (e.g. water, 0.2 mg/mL vs. methanol, 52 mg/mL). Following oral administration, dapsone is almost completely absorbed from the gut with bioavailability exceeding 86 %. Peak serum concentrations are attained within 2–8 h. After ingestion of a single 50–300 mg dose of dapsone, maximum serum concentrations range from 0.63 to 4.82 mg/L [2, 165, 181]. Under steady-state conditions, 100 mg/day (the dose most frequently used) results in serum concentrations of 3.26 mg/L (maximum) and 1.95 mg/L (after 24 h) [2, 41, 181]. These dapsone serum concentrations attained in vivo must be kept in mind when interpreting the results of in vitro investigations (see below). After absorption, dapsone undergoes enterohepatic circulation. It is metabolized by the liver but also by activated polymorphonuclear leukocytes (PMN) and mononuclear cells [152, 156]. In the liver, dapsone is metabolized primarily through acetylation by N-acetyltransferase to monoacteyldapsone (MADDS), and through hydroxylation by cytochrome P-450 enzymes, resulting in the generation of dapsone hydroxylamine (DDS-NOH) (Fig. 2). In fact, administration of dapsone has been utilized to determine the acetylation phenotype (rapid vs. slow acetylator). In terms of both efficacy and induction of adverse effects, the most important issue is the generation of DDS-NOH. This metabolic pathway also occurs in lesional skin of inflammatory dermatoses and is thought to be mediated by activated PMN [156]. Dapsone is distributed to virtually all organs. Dapsone is retained in skin, muscle, kidneys, and liver. Trace concentrations of the drug may be presented in these tissues up to 3 weeks after discontinuation of dapsone treatment. The drug is also distributed into sweat, saliva, sputum, tears, and bile. Dapsone is 50–90 % bound to plasma proteins, whereas MADDS is almost completely bound to plasma proteins. It crosses the blood–brain barrier and placenta and is detectable in breast milk [20, 137]. Cases have been reported where dapsone therapy of the mother resulted in neonatal haemolysis and cyanosis [105]. Approximately 20 % of dapsone is excreted as unchanged drug via urine, whereas 70–85 % is eliminated as water-soluble metabolites after conjugation with glucuronic acid. This step is mediated by uridine diphosphate (UDP)-glucuronosyltransferase. Additionally, a small amount might be excreted in faeces including some yet unidentified metabolites. The complex metabolic pathway of dapsone has been reviewed in detail several times [156, 159, 164, 165, 178, 181].Fig. 1


Dapsone in dermatology and beyond.

Wozel G, Blasum C - Arch. Dermatol. Res. (2013)

The two major metabolic pathways of dapsone (MADDS monoacetyldapsone, DDS-NOH dapsone hydroxylamine)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3927068&req=5

Fig2: The two major metabolic pathways of dapsone (MADDS monoacetyldapsone, DDS-NOH dapsone hydroxylamine)
Mentions: Chemically, dapsone is an aniline derivative. As a sulfone, it shows the structure of a sulphur atom linking to two carbon atoms (Fig. 1). Solubility of dapsone varies over a wide range depending on the solvent used (e.g. water, 0.2 mg/mL vs. methanol, 52 mg/mL). Following oral administration, dapsone is almost completely absorbed from the gut with bioavailability exceeding 86 %. Peak serum concentrations are attained within 2–8 h. After ingestion of a single 50–300 mg dose of dapsone, maximum serum concentrations range from 0.63 to 4.82 mg/L [2, 165, 181]. Under steady-state conditions, 100 mg/day (the dose most frequently used) results in serum concentrations of 3.26 mg/L (maximum) and 1.95 mg/L (after 24 h) [2, 41, 181]. These dapsone serum concentrations attained in vivo must be kept in mind when interpreting the results of in vitro investigations (see below). After absorption, dapsone undergoes enterohepatic circulation. It is metabolized by the liver but also by activated polymorphonuclear leukocytes (PMN) and mononuclear cells [152, 156]. In the liver, dapsone is metabolized primarily through acetylation by N-acetyltransferase to monoacteyldapsone (MADDS), and through hydroxylation by cytochrome P-450 enzymes, resulting in the generation of dapsone hydroxylamine (DDS-NOH) (Fig. 2). In fact, administration of dapsone has been utilized to determine the acetylation phenotype (rapid vs. slow acetylator). In terms of both efficacy and induction of adverse effects, the most important issue is the generation of DDS-NOH. This metabolic pathway also occurs in lesional skin of inflammatory dermatoses and is thought to be mediated by activated PMN [156]. Dapsone is distributed to virtually all organs. Dapsone is retained in skin, muscle, kidneys, and liver. Trace concentrations of the drug may be presented in these tissues up to 3 weeks after discontinuation of dapsone treatment. The drug is also distributed into sweat, saliva, sputum, tears, and bile. Dapsone is 50–90 % bound to plasma proteins, whereas MADDS is almost completely bound to plasma proteins. It crosses the blood–brain barrier and placenta and is detectable in breast milk [20, 137]. Cases have been reported where dapsone therapy of the mother resulted in neonatal haemolysis and cyanosis [105]. Approximately 20 % of dapsone is excreted as unchanged drug via urine, whereas 70–85 % is eliminated as water-soluble metabolites after conjugation with glucuronic acid. This step is mediated by uridine diphosphate (UDP)-glucuronosyltransferase. Additionally, a small amount might be excreted in faeces including some yet unidentified metabolites. The complex metabolic pathway of dapsone has been reviewed in detail several times [156, 159, 164, 165, 178, 181].Fig. 1

Bottom Line: Thus, dapsone clearly has dual functions of both: antimicrobial/antiprotozoal effects and anti-inflammatory features similarly to non-steroidal anti-inflammatory drugs.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.The steroid-sparing effect of dapsone is useful for numerous clinical entities.

View Article: PubMed Central - PubMed

Affiliation: Study Centre for Clinical Trials, Dermatology, Gesellschaft für Wissens- und Technologietransfer der Technischen Universität Dresden mbH, Blasewitzer Str. 43, 01307, Dresden, Germany, Gkatharina.bluemlein@uniklinikum-dresden.de.

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.

Show MeSH
Related in: MedlinePlus