Dapsone in dermatology and beyond
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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.
KeywordsDapsone Antiinflammatory mechanisms of action Adverse effects Therapeutic strategies Use in dermatology Non-dermatological disorders
Acquired immunodeficiency syndrome
Area under curve
- C. elegans
Complete blood count
Central nervous system
Complement component 5a
CXC chemokine receptor
- CYP 450/2E1
Delayed type hypersensitivity
Endotoxin activated autologous serum
Epidermal growth factor/epidermal growth factor receptor
Fluorescence-activated cell sorter
Food and drug administration
Half-maximal inhibitory concentration
Idiopathic thrombocytopenic purpura
Leukocyte-derived chemotactic factor
Leukocyte function antigen
- LTB4 /LTC4
Mouse ear swelling test
Messenger ribonucleic acid
Mammalian target of rapamycin
Reduced nicotinamide adenine dinucleotide phosphate
Non-steroidal anti-inflammatory drug
National Institute of Health Stroke Scale
Peripheral blood mononuclear cell
Phorbol myristate acetate
Reactive oxygen species
Tumor necrosis factor α
Vascular endothelial growth factor/VEGF receptor
Dapsone was first synthesized in 1908 . At that time, dapsone was not envisioned as a therapeutic agent, but was the result of pure chemical science ambition. Sulfone research in medicine started in 1937, when two groups in England and France were the first to investigate dapsone as an antimicrobial agent in the framework of sulfonamide research [22, 43, 59]. In this context, it is remarkable that certain congeners, but not the so-called parent sulfone dapsone, were the first sulfones used to treat gonorrhea [18, 123]. Later, introduction into the therapy of non-infectious diseases was not the result of systematic research, but virtually driven by fortune [170, 173].
Concerning the mechanisms of action, dapsone is characterized by dual function. It combines both antimicrobial/antiprotozoal properties and anti-inflammatory effects resembling those of non-steroidal anti-inflammatory drugs. In past decades, especially the hematological adverse effects of dapsone have induced intense efforts to develop substituted sulfones with improved risk–benefit-ratio. A parallel goal of research was the synthesis of parenteral application modalities. Interestingly, however, still today the oral application of dapsone constitutes the only sulfone used in systemic therapy.
The changeful history of dapsone has been covered in detail in the literature [47, 165, 170]. Therefore, this issue has been omitted from this survey. Rather, this paper will focus on the mechanisms of action of dapsone and consider important indications in dermatology and beyond as well as therapeutic consequences. In order to understand the mechanisms of action of sulfone and its adverse effects, knowledge of its pharmacology and metabolism in human beings and in inflammatory cells is mandatory.
Chemistry and pharmacology
Controls in cell-free settings using purified myeloperoxidase and H2O2 confirmed these findings. In contrast, adding catalase or sodium azide, respectively, led to a dose-dependent inhibition of the oxidation of dapsone. The authors were not able to demonstrate a presumptive alternative enzymatic pathway of hydroxylation of dapsone through the prostaglandin pathway, as classic inhibitors like acetylsalicylic acid or indometacin did not induce a decrease of oxidation. Dapsone metabolism in human mononuclear cells has been demonstrated to be quite similar .
When dapsone is administered, there is equilibrium between acetylation and deacetylation. Thus, there is the possibility that PMN in peripheral blood are exposed both to dapsone and its metabolites. These metabolites like DDS-NOH have been shown to be pharmacologically active. However, they have been made responsible not only for anti-inflammatory mechanisms (e.g., inhibition of chemotaxis) but also for a number of side effects. To date, this has been clearly documented for DDS-NOH . Interestingly, Khan et al.  recently demonstrated that human keratinocytes which had been stimulated by various cytokines like tumor necrosis factor α (TNF-α), interleukin 1β (Il-1β), and interferon γ (INF-γ) can produce DDS-NOH as well.
As an antimicrobial agent, dapsone is bacteriostatic in action. It inhibits the synthesis of dihydrofolic acid through by competing with para-aminobenzoic acid for the active site of dihydropteroate synthetase [35, 41], thus resembling the action of sulphonamides. Sulfones were found to suppress the growth of various pathogenic bacteria such as streptococci, staphylococci, pneumococci, mycobacteria, and other strains. The mechanism of action of topical dapsone in the treatment of acne vulgaris may result from a combination of both antiinflammatory and antimicrobial effects. In vitro, dapsone has some antibacterial activity against Propionibacterium acnes. Owing to its antimicrobial activities, dapsone is clearly playing a role in the treatment of certain infectious diseases (see section “Indications”) .
Anti-inflammatory mechanisms of action
Investigations of dapsone in common animal inflammatory models
A single dose studies
Capstick and Lewis
Kaolin-induced oedema (rat)
Lewis et al.
Zymosan-induced oedema (rat)
Gemmel et al.
Reverse passive Arthus-type reaction (rat)
UV erythema (guinea pig)
Lewis et al.
B multiple dose studies
Reverse passive Arthus-type reaction (guinea pig)
Ruzicka et al.
Aktive Arthus-type reaktion (guinea pig)
Thompson and Souhami
Cotton wool pellet granuloma (rat)
Capstick and Lewis
Lewis et al.
Cotton wool pellet granuloma (rat)
Adjuvant arthritis (rat)
Capstick and Lewis
Lewis et al.
Hypervitaminosis A (rabbit)
Arachidonic acid-induced mouse ear swelling test (AA-MEST)
0.1; 1; 5; 10 %
Topically and systemically
Hence, it is difficult to draw reliable conclusions regarding the mechanisms of action of dapsone in sulfone-sensitive diseases. In this respect, several factors have to be considered. Amongst others, the inflammation models used are only poorly characterised on phenotypic and genotypic levels. Often, dapsone-concentrations applied were considerably exceeding those achieved under therapy. Apart from that, single dose application cannot be readily compared with repeated doses. Finally, testing conditions varied substantially (e.g. pre-therapeutic vs. post-therapeutic application of the sulfone). Despite these limitations, dapsone can be attributed an anti-inflammatory potential that—cum grano salis—equals that of classic NSAID’s. In the following, the impact of dapsone on isolated proinflammatory signal transduction pathways and on more complex disease processes is described in detail.
Reactive oxygen species
The role of dapsone in the generation of reactive oxygen species (ROS) has also been studied in non-phagocytizing cells . These authors utilized diploid fibroblasts obtained from human newborns. The cells were stimulated by paraquat, a herbicide. Paraquat is a known inducer of oxidative stress. Its effect involves the membrane-bound NADPH oxidase and the production of superoxide anion. The intracellular mitochondrial complex may also participate in this process. In the experiments, dapsone—applied in different concentrations—leads to a reduction of the expression of NADPH oxidase 4. Cho et al.  found an inhibition of paraquat-inducible proteinkinase C, of the mitochondrial complex, and they showed a reduced production of cytosolic and mitochondrial superoxide anion. Moreover, they showed that dapsone as parent compound does not possess a scavenger function for ROS. In summary, results of these studies repeatedly disclosed that dapsone possesses substantial antioxidative properties that can be attributed in large parts to an inhibition of ROS production. This calls earlier studies into question that had ascribed dapsone with direct scavenger function . Apart from this, this experimental study shows for the first time that experimentally stimulated cells without phagocytic properties are capable of producing ROS. In another experiment, the same group examined the mitochondrial complex V of Caenorhabditis elegans (C. elegans) and detected a drop in protein levels in dapsone-treated animals. Again, dapsone inhibited paraquat-induced release of H2O2. Finally, the authors could reproduce the same effect in mammalian muscle cells (male BALB/c mice and C2C12 cells) . These findings confirmed that not only stimulated inflammatory cells can generate ROS that are being down regulated by dapsone.
MPO mediates the transformation of H2O2 via halogenation
Adhesion molecules/cellular adhesion
Leukocyte function antigen (LFA-1) (CD 11 a/CD 18), Mac-1 (CD 11b/CD 18) and p 150, 95 (CD 11 c/CD 18) are important members of the β2-integrin family of adhesion molecules. The effects of dapsone on Mac-1-mediated adherence of neutrophils of healthy persons were examined by Booth et al. . They observed a dose-dependent inhibition of adherence, but only when cells were stimulated with either FMLP or PMA. Adherence of unstimulated cells remained unchanged under the influence of dapsone. Addition of integrin- β2-antibodies proved that adherence was indeed integrin-mediated. Yet it is not clear whether these findings are of relevance in patients treated with dapsone as the concentrations used exceed those under therapy by a factor of 10–100. Heidenbluth et al. [unpublished data] confirmed the ability of dapsone to interfere with the function of integrins. They examined the expression of leukocyte integrins LFA1, Mac-1 and p 150, 95 in various cell populations under the influence of dapsone (20, 100 and 200 μg/mL). Fluorescence–activated cell sorter (FACS) analysis was performed in human whole blood, in isolated PMN and in the macrophage cell line U937. Stimulation with PMA induced an increased expression of CD11 a, b, c and CD18 both in PMN and in U937 cells. Dapsone inhibited the expression of β2-integrins CD11a, CD11c and CD18 in PMN only marginally, but significantly in U937-cells (CD11c). This effect was not dose dependent. Thuong-Nguyen et al.  showed that dapsone inhibited adherence of neutrophils to IgA and IgG from sera of patients with IgA-linear dermatosis and bullous pemphigoid in a dose-dependent manner. Other investigators established an inhibition of adhesion of TNF-α- or platelet activating factor (PAF)-activated PMN of healthy donors by dapsone . This group used a frozen section adhesion assay of healthy skin under incubation with IFN-γ and observed an inhibition of neutrophil adhesion to epidermal cells in a concentration range from 0.1 to 80 μg/mL dapsone. They could also verify that dapsone down regulates the expression of CD11b on activated neutrophils.
In vitro, dapsone possesses a protective effect on elastase inhibitor capacity of α-1-protease inhibitor (AIP), thereby showing similar properties as the physiologic antioxidant ceruloplasmine. Once more, this AIP-protective effect has been linked to the potent suppression of ROS-production and to the inhibition of the MPO-halide-system . As the dapsone concentrations used in this study resemble that attained in vivo, this action might be useful in the therapy of diseases with AIP dysfunction.
The impact of dapsone on chemotaxis has been studied with partly conflicting results. A pilot study utilized various chemotaxins and found a selective inhibition by dapsone in concentrations resembling those under therapy only when FMLP was used as stimulus, but not when leukocyte-derived chemotactic factor (LDCT) and C5a were applied . Moreover, species- and cell dependency could be observed; PMN of guinea pigs and monocytes did not show inhibition of chemotaxis. Booth et al.  examined chemotaxis and random migration by agarose-technique using FMLP and IL-8 as stimuli. Dapsone was added in concentrations of 30, 100 and 300 μg/mL. Again, a dose-dependent inhibitory effect of dapsone on chemotaxis of human neutrophils could be observed (FMLP: 30 μg dapsone/mL: 24 % inhibition, 300 μg dapsone/mL: 62 % inhibition, IL-8: 100 μg dapsone/mL: 24 % inhibition, 300 μg dapsone/mL: 61 % inhibition). Once more, random migration was also inhibited by dapsone. In vivo studies produced inconsistent results. A short-term study with rabbits and guinea pigs which were fed dapsone for 3 days showed no influence of dapsone on chemotaxis of PMN . A1h E. coli activated autologous serum even showed that dapsone induces an increase in chemotaxis in healthy individuals and in leprosy patients . In a human in vivo study in healthy volunteers, leukotriene B4 (LTB4) was applied epidermally to induce chemotaxis as described by Lammers et al. . In this setting, Salomon demonstrated that 100 mg dapsone/day does not inhibit LTB4-induced chemotaxis . This is in consistency with earlier findings that dapsone therapy does not induce inhibition of LTB4-induced chemotaxis in the skin of patients with acne [Prendiville et al., unpublished data]. Further studies with differentially activated sera again came to nothing [54, 55, 110, 131]. In conclusion, dapsone inhibits chemotaxis, but only when certain stimuli are applied. Thus, the statement that dapsone inhibits chemotaxis per se can no longer be sustained.
Membrane-associated phospholipid metabolism
Cell activation produces a process of enzymatically mediated signal transduction which leads to liberation of arachidonic acid which on her part is source of biologically active mediators of the cyclooxygenase (COX)- and lipoxygenase (LOX) pathway. The influence of dapsone on choline phosphotransferase (ChPhTF) and methyltransferase I and II (MTF) was examined using PMN, lymphocytes and erythrocytes of healthy donors . The investigators found a cell-specific inhibitory effect of dapsone. MTF-activity in lymphocytes and PMN was inhibited slightly by high dapsone concentrations, but not that of erythrocytes. Conversely, erythrocytes showed a significant drop of ChPhTF-activity in contrast to PMN and lymphocytes where there was no significant influence. Venom-induced inflammation following the bite of the brown recluse spider (loxosceles reclusa) has been linked to an activation of membrane phospholipids. The venom incorporates a variety of enzymes (e.g. phospholipase D, esterases, and hyaluronidase) that are believed to provoke cutaneous and even systemic effects (viscero-cutaneous loxoscelism). Using a model of cultivated human keratinocytes, venom-induced activation of membrane phospholipids could be confirmed . Whether the well-known therapeutic efficacy of dapsone in the therapy of brown recluse spider bites can be attributed to the aforementioned mechanism remains speculative .
Regarding the inhibition of synthesis and liberation of prostaglandins by dapsone, there is some evidence presented by Ruzicka et al. . Using thin layer chromatography, the authors examined the production of prostaglandin D2 (PGD2) of mast cells that had been gathered from the plasma and peritoneal caves of Sprague–Dawley rats under the influence of dapsone (10−2–10−6 mol/L). Their experiments revealed a dose-dependent inhibition of the production of PGD2 (IC50: 1 mmol with exogenous arachidonic acid (AA)-application, 0.2–0.4 mmol with exclusively endogenous AA). Complete suppression was observed with 6 × 10−3 mol or 6 × 10−2 mol, respectively. Washing the cells following incubation with dapsone completely abolished this effect pointing to a reversible effect. Moreover, dapsone had a marked inhibitory effect on IgE-mediated antigen-stimulated production of PGD2 (IC50: 0.2–0.4 mmol). Interestingly, the liberation of histamine was not inhibited. As the conversion of PGH2 to PGD2 was not influenced by dapsone, the target of dapsone can be assumed to be located before the PGH-PGD-isomerase step. The authors postulate a direct inhibitory effect on COX. A similar dose-dependent inhibitory effect of dapsone on the production of PGD2 and 6-keto prostaglandin F1α (6KF1α) by peritoneal macrophages of mice was described by Bonney et al. . Apart from mast cells and macrophages, human PMN were examined in respect to a possible inhibition of the COX pathway . In contrast to clofazimine, dapsone in concentrations of 5 and 10 μg/mL inhibited both spontaneous and FMLP-induced synthesis of PGE2. There was no difference between the PMN of healthy donors and of leprosy patients. In summary, the inhibitory effect of dapsone on prostaglandin synthesis/liberation is beyond doubt.
IC50 of dapsone for LTB4 and 5-HETE in a cell-free system (5-LOX) and in intact PMN
Cell free (5-LOX) (5 × 106 PMN)
Intakt PMN (5 × 106 PMN)
35.0 ± 4.3
15.0 ± 5.6
59.0 ± 5.1
9.0 ± 7.1
Interleukin 8 (IL-8), a member of the CXC-chemokine family, purportedly plays an important role, especially in neutrophil-mediated inflammation, but has also been shown to affect other cell species as well (e.g. lymphocytes, monocytes, hematopoietic progenitor cells). Signal transduction is mediated via CXCR1 and CXCR2 receptors and is involved in viral infections and tumor progression . Following observations that ROS markedly influence the regulation of IL-8  studies were initiated that examined the effect of dapsone on IL 8 in different settings [44, 80]. In an in vitro model of human whole blood, dapsone in therapeutic concentrations was shown to exert a suppressive effect on lipopolysaccharide (LPS)- induced IL-8 levels , an observation that was confirmed by several study groups. Amongst others, dapsone suppresses bullous-pemphigoid-IgG-induced IL-8-release from keratinocytes at a posttranscriptional level  and is capable of inhibiting IL-8-mRNA expression . Accordingly, dapsone blocks IL-8-induced chemotaxis [16, 65]. Furthermore, IL-8 has been shown to be of importance in neurologic diseases. It is expressed by neurons  and glioblastoma cells have been shown to be affluent sources of IL-8 . As dapsone shows a suppressive effect on seizure disorders  and inhibits the growth of glioblastoma, it is discussed that these effects might be mediated by an inhibitory effect on IL-8 via targeting neutrophils . Lately, the therapeutic application of dapsone in glioblastoma was the object of several studies . However, with the advent of modern molecular-targeted strategies like inhibition of epidermal growth factor receptor, vascular endothelial growth factor, mammalian target of rapamycin (mTOR) and others, the value of dapsone in this field remains doubtful.
Abe et al.  examined the influence of dapsone on TNF-α and other proinflammatory cytokines like IL-1β- and IL-8 in the context of its therapeutic use in lupus erythematosus. This group used PBMC from healthy donors which were stimulated with LPS. Dapsone induced a dose-dependent suppression of TNF-α at mRNA level. With the exception of IL-8, no influence on the levels of other cytokines was found. The effect on IL-8 resembled to that already reported above. It has to be pointed out, however, that the dapsone concentrations used in this study exceed that under therapy.
In comparison to the effect on neutrophils, those on eosinophils have been far less studied. It is likely that overlapping mechanism play a role (e.g. inhibition of lipoxygenase, ROS production). Bozmen et al. examined the influence of dapsone on eosinophil peroxidase . The inhibitory effect of the sulfone on MPO was even stronger than that in neutrophils and associated with a reduced production of toxic hypochlorous acid and other ROS. Consecutively, the effect of eosinophil peroxidase on mast cells was reduced (e.g. liberation of histamine) . The inhibitory effect on eosinophil peroxidase could provide at least in part an explanation of the therapeutic efficacy of dapsone in eosinophil-mediated diseases (e.g. eosinophilic fasciitis).
Complement system, coagulation and fibrinolytic system, cutaneous proteases
In vitro, an inhibitory effect of dapsone on the alternative way of complement activation was detected [Millikan et al., unpublished data]. On the contrary, Katz et al. could not find an influence of dapsone on the classic or alternative activation of complement in patients with dermatitis herpetiformis and in animal experiments . Anecdotal reports document a normalization of initially decreased complement factors in immune complex vasculitis under therapy with dapsone [132, 167]. Certainly, these effects could be the result of an improvement of the disease per se and not necessarily be a result of a specific effect of dapsone on complement factors. Dapsone had no influence on plasminogen activator when epidermal cells were incubated with pemphigus antibodies . Finally, the effect of dapsone on cutaneous proteases was found to be only minor .
Once more, results with regard to lymphocyte function are in part contradictory. Beiguelman and Pisam  described an inhibition of PHA-induced lymphocyte-transformation (LZT) by dapsone. In healthy donors who had taken dapsone in therapeutic doses for 7 days, a significant inhibition of PHA-stimulated LZT could be observed . Other authors could confirm this observation when using other mitogens like concanavalin A and lepromin [5, 99]. The influence of dapsone on delayed type hypersensitivity was examined in a mouse model by Nagata et al. . A daily clinical dose (1CD) of dapsone taken to be equivalent to that used in humans was 1.7 ng/kg of body weight. Up to threefold equivalent doses of dapsone (3CD) exerted no reduction of carrageenan-induced paw edema. On the other hand in mice alimentation with dapsone was followed by an emptying of the paracortical zone of lymph nodes . Interestingly, dapsone loses its antibacterial potency against inoculated mycobacterium (M. leprae) in thymectomized naked mice, in contrast to mice with normal immune system . In comparison with T-lymphocytes, B-lymphocytes are influenced by dapsone to a far lesser extent. In 20 patients with lepra lepromatosa who were treated with dapsone 50 mg/day over 12–24 months, there was no difference in the number of B-lymphocytes when compared with 26 untreated leprosy patients and 25 healthy controls . Dapsone did not influence antibody-producing cells of BALB/c- and C57 BI/6-mice in a plaque-forming cell assay . Furthermore, Thompson and Souhami could not find any changes in antibody production . In contrast to that, Das et al. 1985 [unpublished data] demonstrated a dose-dependent inhibition of the synthesis of rabies—specific IgA- and IgG-antibodies by dapsone. The production of total IgA and IgG was not influenced. The authors attribute the inhibitory effect on specific B cell clones to a reduction of antigen-specific T-helper cell activity. The action of dapsone on Arthus reaction is controversial. Thompson and Souhami  as well as Ruzicka et al.  observed a dose-dependent suppressive effect of dapsone in guinea pigs and rabbits. Sulfoxone, a soluble sulfone, exerted no effect in guinea pigs with C4 deficiency .
Animal studies with liver and spleen immune cells (T- and B-lymphocytes stimulated with concanavalin A and LPS) revealed a dose-dependent effect of dapsone. At lower concentrations (1 μmol), dapsone stimulated B- and T-cell proliferation under the influence of both mitogens, but inhibited B-cell proliferation at higher concentrations (150 μmol). The authors claim an immunostimulating effect of dapsone in lower concentrations but an immunosuppressive in higher concentrations as general principle .
Lifespan of Caenorhabditis elegans
Dapsone delayed the induction of aging and was shown to suppress mitochondrial ROS as well as mRNA of NADPH-oxidase. Typical scavenger-enzymes like superoxide dismutase (SOD), catalase, glutathione peroxidase-/reductase were not influenced by dapsone. As already noted, this contrasts with earlier studies which had postulated a scavenger function of dapsone. More precisely, dapsone seems to inhibit the production of ROS as it has been shown by molecular studies by Cho et al. [26, 28]. Interestingly, these authors have identified muscle pyruvate kinase as the protein target of dapsone in C. elegans. Additional studies in long-term dapsone therapy leprosy patients using a ferric-reducing ability assay demonstrated increased antioxidative capacity in erythrocytes. These mechanisms could be reproduced in mammalian cells . Experimental and clinical results thus confirm studies in human fibroblasts .
Recent research revealed that dapsone can influence functions of the central nerve system [86, 120, 129, 130, 160]. More precisely, it could be shown that dapsone suppresses experimentally induced neurotoxicity . In a pilot study, neuroprotective effects of dapsone could be demonstrated in stroke patients. Patients were given a single 200 mg-dose of dapsone within 12 h following the incident. A follow-up study of 60 days’ duration showed a significant reduction of National Institute of Health Stroke Scale (NIHSS) in comparison with a placebo group . In order to further clarify the protective mechanism of dapsone, animal ischemia–reperfusion studies supplied evidence that dapsone exerts an inhibitory effect on lipid peroxidation, MPO, nitric oxide activity and apoptosis (annexin V, caspase 3 und 9) . Again, this neuroprotective effect of dapsone was attributed to its antioxidative capacities. Anticonvulsive effects of dapsone have been described in earlier studies [4, 70, 78]. In the context of neurologic diseases, Japanese authors have reported successful therapy of steroid-dependent neuro-Sweet-disease that responded to 75 mg dapsone/day  (see 4.10). The neuro-Sweet-disease is characterized by multiple neurologic (e.g. meningitis, encephalitis) and well-known dermatological features (e.g. painful dull red erythematous plaques) in association with HLA-Cw1 or B54.
Following 16 days of inoculation with a continuous sixfold equivalent dose of dapsone, BALB/c-mice-myeloma cells growth showed no difference when compared with animals that had been fed with placebo . In contrast, recent studies generated results pointing to an anti-cancer activity of certain dapsone derivatives [3, 12, 25, 71, 124]. At present, further research in this field is in progress.
Human pharmacology studies
In another human pharmacology study, dapsone was found not to possess antipsoriatic efficacy in the psoriasis plaque test .
Unique characteristics of dapsone
Combination of antimicrobial/antiprotozoal effects (utilized, e.g. in the treatment of opportunistic infections in patients with acquired immunodeficiency syndrome).
Safety of long-term treatment (e.g., life-long use in leprosy, long-term or chronic intermittent therapy of inflammatory dermatoses).
Unique powerful disease-specific antiphlogistic activities (e.g., prompt decrease of pruritus and control of skin lesions in dermatitis herpetiformis; fast amelioration of loxoscelism associated with brown recluse spider bites).
Steroid-sparing effects (e.g., long-term treatment in autoimmune blistering diseases and as an adjuvant treatment in bronchial asthma).
CNS-protective effects (anticonvulsive effects, reduction of stroke-associated tissue damage, inhibition of glioblastoma).
Finally, the pharmacoeconomic benefit due to the low cost of dapsone deserves to be mentioned.
Adverse effects of dapsone
As already mentioned, hydroxylamines of dapsone, above all DDS-NOH, are held responsible for some of its major adverse effects including met-Hb formation, haemolysis and agranulocytosis. As DDS-NOH is inevitably formed during dapsone therapy, all these adverse effects are obligatory and vary only in intensity. These hematologic side effects of dapsone have long been recognized and have been reviewed by various authors [11, 101, 125, 136, 165, 173, 178]. Therefore, they will not be dealt with in detail in this survey. However, it has to be stressed that glucose-6-phosphate dehydrogenase (G6PD)-deficient patients are less susceptible to met-Hb production, but more susceptible to haemolysis. For instance, patients with G6PD-deficient erythrocytes reveal about a twofold increase in sensitivity towards sulfone-induced anaemia. Cyanosis which is usually associated with mild methaemoglobinemia may occur during dapsone treatment. Acute methaemoglobinemia occurs rarely, but may result in dyspnea, anemia, vascular collapse, and in serious courses finally in death. In patients who do not have G6PD deficiency acute methaemoglobinemia should be treated with intravenous methylene blue (1–2 mg/kg given by slow injection). The effect is generally complete within 30 min, but the procedure may need to be readministered if met-Hb reaccumulates.
Rash reportedly occurs in about 30–40 % of AIDS patients receiving dapsone concomitantly with trimethoprim, but less frequently in those receiving dapsone alone. Despite that observation, a substantial proportion of patients who do not tolerate co-trimoxazole are able to tolerate dapsone .
Gastrointestinal effects/hepatic reactions
Isolated abnormalities of liver function tests (e.g., increased bilirubin and/or liver enzymes) without evidence of hepatitis or hepatosis. If any abnormality is detected, the dosage of dapsone should be decreased or the drug should be discontinued until the source is established.
Prehepatic jaundice induced by haemolytic anaemia. Hyperbilirubinemia may occur more often in patients with G6PD-deficiency. All affected patients should be monitored periodically after reduction of dapsone dosage/discontinuation of treatment.
Toxic or cholestatic hepatitis in conjunction with hypersensitivity syndrome (HS). Hepatic coma is indeed the most frequent cause of death in the hypersensitivity syndrome .
Clinical features of hypersensitivity reaction of dapsone (HS)
n Total (n-334)
21 ≤ 28
29 ≤ 35
Immediately after HS onset
Delayed to HS onset
Systemic steroid therapy
Some other adverse effects of dapsone with hitherto unknown mechanisms have been recognized. Fortunately, most of them are really extremely rare (e.g. albuminuria, insomnia, psychosis, changes of electrolytes, atrioventricular block) [41, 165, 177]. Some of these may be partially attributed to anaemia and/or methaemoglobinaemia.
Clinical use of dapsone
Due to its antimycobacterial effects, dapsone is a component of rifampicin-based multiple drug regimes for the treatment of multibacillar and paucibacillary leprosy. Besides rifampicin, the WHO most notably recommends combinations with clofazimine [41, 67]. The antiprotozoal effect of dapsone is used in primary prophylaxis and prevention of recurrence in AIDS patients with pneumocystis jiroveci pneumonia and toxoplasmosis.
Dapsone as first choice of treatment in chronic inflammatory dermatoses
Dapsone used in dermatologic entities as an adjunctive treatment modality
Chronic-idiopathic urticaria/delayed pressure urticariaa
Eosinophilic folliculitis (Ofuji’s disease) 
Lichen ruber pemphigoides 
Reccurent neutrophilic dermatosis of the dorsal hands 
Dapsone used in non-dermatological diseases
With these diseases, dapsone has made its way into the field of non-dermatological disorders. However, many scientific questions have not yet been answered and its definitive status remains to be elucidated.
One topical gel formulation of 5 % dapsone is available on the US market for treating acne vulgaris. Results of two large-scale studies (dapsone: n = 1506; vehicle: n = 1504) show a marginal to moderate reduction of non-inflammatory lesions compared with placebo after a 12-week treatment period (mean change: 32 % dapsone vs 42 % vehicle) . For treatment of acne in adults, adolescents and children 12 years of age or older, a thin layer of dapsone gel should be applied to the cleansed affected areas. Combinations with topical benzoyl peroxide may result in temporary local yellow or orange discoloration of the skin and facial hair .
Dosage of dapsone in chronic inflammatory dermatoses
The dosage of dapsone in nearly all sulfone-sensitive disorders must be individually titrated to determine the minimum daily dose that effectively controls symptoms. Typically, initial dosages in adults range from 50 to 100 mg/day. If the treatment goal is not achieved after 4–6 weeks, a higher dosage may be tried (150–300 mg/day). Administration of higher doses depends on tolerability and the results of laboratory monitoring. When a favourable response is attained, the dosage should then be reduced to the minimum that maintains a satisfactory clinical state.
For administration in children, commercially available tablets of dapsone can be crushed and dissolved, for example, in strawberry syrup. Studies evaluating bioavailability of dapsone after administration of this preparation have not been published. For some indications in childhood, such as infantile acropustulosis or eosinophilic folliculitis, a daily dosage of 2 mg per kilogram of body weight is recommended. Therapy with this dosage, or 4 mg/kg weekly, results in concentrations equivalent to those reached in adults receiving 100 mg/day. In the treatment of immune thrombocytopenia in children, dapsone was used in a similar dose of about 2 mg/kg body weight .
For topical treatment of acne a twice-daily application is recommended.
Conclusions for treating patients with dapsone
Contraindications, baseline-monitoring and follow-up controls
Glucose-6-phosphate dehydrogenase deficiency
Cardiac insufficiency/heart failure
Co-medication with met-Hb-inducing drugs or compounds, respectively
Laboratory evaluation before initiation of dapsone therapy
Complete blood count
Serologic test for hepatitis
Met-Hb generation after a single dapsone dose reaches its maximum after approximately 6 h and, therefore, undergoes a time-dependent process. In the early treatment phase met-Hb should be determined 4–6 h after ingestion of dapsone, because the maximum level of met-Hb in peripheral blood is indicative of real cardiopulmonary risk. For this reason, dapsone intake should be recommended in the evening in patients with activity during the day.
Approximately 14 days after initiation of treatment, determination of met-Hb will estimate the level under steady-state conditions and may also allow evaluation of patients adherence to therapy.
Other met-Hb determinations must be considered at any time if the patient`s condition has changed (e.g., increased dapsone dosage; clinical complaints, co-medication with other drugs, starting of smoking, use of pump water in agricultural regions with potential content of nitrites/anilines).
Met-Hb levels do not need to be checked if clinical conditions of the patient remain stable.
Strategies to reduce hematologic adverse effects
N-hydroxylation of dapsone via the 3A-family of isoenzymes or CYP 2E1 of the hepatic cytochrome P-450 system leads to the production of DDS-NOH, which has been made responsible for haematologic side effects [35, 36, 37, 79, 111, 155]. Against this background, considerable efforts have been made to increase dapsone tolerance. Cytochrome p-450 inhibitors like ketoconazole and cimetidine reduced dapsone-associated formation of met-Hb [32, 33, 34, 128]. Co-administration of cimetidine in dosages of 3 × 400 mg/day reduced met-Hb-levels by 25–30 % in vivo, whereupon this effect surprisingly decreased after 3 months. Coleman recommended to routinely co-administer cimetidine at higher dapsone doses (e.g. 200 mg/day and more) . It has to be borne in mind, however, that DDS-NOH possesses anti-inflammatory effects on its own right. Theoretically, suppressing its production might reduce the therapeutic effects of the parent compound dapsone. This question has not yet been addressed in studies. As another strategy, various antioxidants like ascorbic acid and vitamin E have been examined. Neither a dose of 1000 mg ascorbic acid/day [89, 127, 146] nor 800 mg vitamin E had a significant effect on dapsone-induced haemolysis . Only simultaneous application of ascorbic acid and vitamin E exerted an inhibitory effect on met-Hb formation . The reason for these conflicting results might be attributable to the design of the studies which at that time were not GCP-based (no randomization, blinding or placebo controls). For daily practice, in cases of pronounced haematologic adverse effects, co-administration of cimetidine during the first weeks of treatment can be recommended if there are no alternative treatment modalities.
Potential risk: concomitant use of local anaesthetics
It is well-known that co-medication with other inductors of methaemoglobinaemia as phenacetine and sulphonamides is risky in patients under therapy with dapsone. However, the risk associated with concomitant application of local anaesthetics like benzocaine or lidocaine is often neglected . Cases have been reported where application of local anaesthetics of the amid or ester type as a spray or cream resulted in severe methaemoglobinaemia up to 35 % manifesting right away during surgical procedures. Thus, patients should always carry a dapsone pass and be instructed to present it to their doctors. In elective surgery, dapsone should be stopped a few days earlier. As a precaution, met-Hb levels should be determined before surgery.
Prevention of photosensitivity
Dapsone is able to suppress UV-induced erythema both when applied orally and topically . However, allergic photosensitivity to dapsone cannot be excluded; but apparently, this is an extremely rare event. So far, less than 20 cases have been reported. As photo-patch tests revealed, the characteristic sulfone group of the parent compound and dapsone metabolites is responsible for the allergic reaction . In view of the suppressive effects of dapsone on UV-induced erythema, it might be wise to advise at least skin type I patients to reckon with increased photosensitivity when dapsone therapy is stopped.
Cross-allergy between dapsone and sulfonamides
Several lines of evidence suggest that there is no obligatory cross-reactivity between sulfonamides and other sulfonamide-nonantibiotic drugs including dapsone . FDA-approved label for dapsone states that sulfonamide allergy does “not include as a contraindication for dapsone use”. Currently, absence of cross-reactivity between dapsone and sulfonamides was confirmed and ascribed to the differential chemical structure of these two drugs . In conclusion, dapsone is not contraindicated in patients with sulfonamide-allergy.
Animal reproduction studies with dapsone have not been conducted. Dapsone has been tested in rats and rabbits with concentrations 500- to 800-fold higher than therapeutic levels, when referenced to AUC-value in female patients under therapy with a 5 % dapsone gel. In these studies, dapsone was associated with embryocidal effects . There are, however, no documented noxious effects of dapsone when used in pregnancy . Especially publications about the use of dapsone in the therapy of leprosy suggest that dapsone can be used safely in pregnancy. Multiple case reports about the use of dapsone in a variety of diseases support the assumption of innocuousness. [39, 50, 76, 97, 105, 106, 109, 154, 158]. In any case, the risk of not treating the mother must be weighed up against the risk for the fetus. Dapsone is labelled by US FDA as drug of pregnancy category C. Patients should be informed about the lack of secured data.
In past years much progress in developing molecular-based methods has substantially led to new insights into mechanisms of action of immunosuppressive and/or immunomodulating remedies including biologics. Therefore, to get more detailed information about the mechanisms of action of dapsone, this panel of investigations should be used with dapsone (e.g., pharmacogenetics) in concentrations comparable with therapeutic conditions.
Most of the experimental and clinical studies have been conducted with the parent compound dapsone. Hitherto, the relevance of dapsone metabolites has not been clarified sufficiently. Modern molecular targeted analyses can certainly help to rectify these deficits. This aspect has not yet been addressed at all in the scientific literature.
Experimental clues to a preventive effect of dapsone on neurotoxicity require further clarification, as the proposed mechanisms leave room for speculations.
Observations of a positive effect of dapsone on lifespan in the Caenorhabditis elegans model raise new questions concerning the inhibition of ageing effects of the sulfone in mammalian cells and organisms.
Finally, dapsone has experienced a renaissance as reference molecule in organic chemistry as efforts are made to synthesize biologically active dapsone analogues like sulfoximine [3, 12, 25, 124]. In this context the definition of the anti-cancer activity of dapsone derivatives currently is of special interest.
Despite that bundle of unanswered questions, dapsone remains an indispensable drug for dermatology and a scientifically fascinating remedy. Discovering dapsone congeners which exhibit the positive therapeutic properties of the original drug but lack unwanted side effects appears desirable.
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