Limits...
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.

Show MeSH

Related in: MedlinePlus

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]
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3927068&req=5

Fig5: 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]

Mentions: Historically, Japanese authors were the first in 1983 to attribute an oxygen-radical scavenging ability to dapsone [112–115, 121, 161]. In the works of this group, dapsone was shown to effectively lower the concentrations of H2O2 and of OH− as well as the activity of chemiluminescence when these parameters were studied during the process of oxidative activation PMN. However, dapsone did not alter the concentration of O2−. Experiments by van Baar et al. [unpublished data] confirmed these findings. Furthermore, the Japanese authors were able to demonstrate an effect of dapsone to reduce the concentrations of extracellular ROS as well as that of singulett ¹O2. In these experiments the xanthine/xanthine oxidase system had been tested in the absence of both PMN and superoxide dismutase (SOD). Accordingly, the ROS—but not O2−-lowering effect of dapsone, is unlikely to be mediated by an interaction of dapsone and SOD. In contrast to these conclusions it was claimed by later publications that dapsone actually suppressed N-formyl-methionyl-leucyl-phenylalanine (FLMP)-induced production of extracellular O2− [43]. More recent studies by Suda et al. [148] yielded comparable data with those of Debol et al. [43]. Suda et al. utilized human PMN, stimulated by FLMP, C5a and PMA and evaluated any influence of dapsone on the generation of extracellular O2− (using a cytochrome C reductase assay), intracellular O2− (using flow cytometry), the generation of elastase and on cytosolic free ionized calcium. They found dapsone to cause dose-dependant, sizeable reductions of intracellular O2− (after induction by FLMP and C5a) and of extracellular O2− (Fig. 4a–c). Stikingly, in these experiments, dapsone appeared to exert little or no effect on PMA-stimulated O2− production. The authors demonstrated an influx of calcium into cells in response to FLMP. In contrast, PMA failed to mobilize calcium. Dapsone was seen to inhibit calcium influx in response to FLMP or C5a. Similarly, dapsone was able to inhibit any generation of elastase in the presence of FLMP and C5a. Given that PMA failed to cause an influx of calcium, one may conclude that dapsone exerts some direct effect on the intracellular concentrations of free ionized calcium when the latter was induced by signalling mechanisms [148]. With respect to the O2− production and the effects of dapsone in PMN the authors suggested a pathway which is shown in Fig. 5. The FLMP-induced calcium influx in PMN and its suppression by dapsone were confirmed by other laboratories [43].Fig. 4


Dapsone in dermatology and beyond.

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

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]
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig5: 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]
Mentions: Historically, Japanese authors were the first in 1983 to attribute an oxygen-radical scavenging ability to dapsone [112–115, 121, 161]. In the works of this group, dapsone was shown to effectively lower the concentrations of H2O2 and of OH− as well as the activity of chemiluminescence when these parameters were studied during the process of oxidative activation PMN. However, dapsone did not alter the concentration of O2−. Experiments by van Baar et al. [unpublished data] confirmed these findings. Furthermore, the Japanese authors were able to demonstrate an effect of dapsone to reduce the concentrations of extracellular ROS as well as that of singulett ¹O2. In these experiments the xanthine/xanthine oxidase system had been tested in the absence of both PMN and superoxide dismutase (SOD). Accordingly, the ROS—but not O2−-lowering effect of dapsone, is unlikely to be mediated by an interaction of dapsone and SOD. In contrast to these conclusions it was claimed by later publications that dapsone actually suppressed N-formyl-methionyl-leucyl-phenylalanine (FLMP)-induced production of extracellular O2− [43]. More recent studies by Suda et al. [148] yielded comparable data with those of Debol et al. [43]. Suda et al. utilized human PMN, stimulated by FLMP, C5a and PMA and evaluated any influence of dapsone on the generation of extracellular O2− (using a cytochrome C reductase assay), intracellular O2− (using flow cytometry), the generation of elastase and on cytosolic free ionized calcium. They found dapsone to cause dose-dependant, sizeable reductions of intracellular O2− (after induction by FLMP and C5a) and of extracellular O2− (Fig. 4a–c). Stikingly, in these experiments, dapsone appeared to exert little or no effect on PMA-stimulated O2− production. The authors demonstrated an influx of calcium into cells in response to FLMP. In contrast, PMA failed to mobilize calcium. Dapsone was seen to inhibit calcium influx in response to FLMP or C5a. Similarly, dapsone was able to inhibit any generation of elastase in the presence of FLMP and C5a. Given that PMA failed to cause an influx of calcium, one may conclude that dapsone exerts some direct effect on the intracellular concentrations of free ionized calcium when the latter was induced by signalling mechanisms [148]. With respect to the O2− production and the effects of dapsone in PMN the authors suggested a pathway which is shown in Fig. 5. The FLMP-induced calcium influx in PMN and its suppression by dapsone were confirmed by other laboratories [43].Fig. 4

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