Dapsone: modes of action, toxicity and possible strategies for increasing patient tolerance

Coleman, Michael D.

doi:10.1111/j.1365-2133.1993.tb00476.x

Cited by 186 publications

(140 citation statements)

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“…Specifically, DDS is a principal drug in a multidrug regimen recommended by the World Health Organization for the treatment of leprosy (1)(2)(3)(4). DDS acts as an antibiotic in a manner similar to sulphonamides by inhibiting bacterial synthesis of dihydrofolic acid through competition with para-aminobenzoic acid (PABA) for the active site of dihydropteroate synthetase (DHPS) (5). In addition to its antibacterial activity, DDS has been reported to be involved in other cellular processes that occur in eukaryotic cells, such as inflammation, migration, and apoptosis (6).…”

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confidence: 99%

DDS, 4,4′-diaminodiphenylsulfone, extends organismic lifespan

Cho

Park

Keam

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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DDS, 4,4′-diaminodiphenylsulfone, is the most common drug prescribed to treat Hansen disease patients. In addition to its antibacterial activity, DDS has been reported to be involved in other cellular processes that occur in eukaryotic cells. Because DDS treatment significantly enhances the antioxidant activity in humans, we examined its effect on lifespan extension. Here we show that DDS extends organismic lifespan using Caenorhabditis elegans as a model system. DDS treatment caused a delay in aging and decreased the levels of a mitochondrial complex. The oxygen consumption rate was also significantly lowered. Consistent with these data, paraquat treatment evoked less reactive oxygen species in DDS-treated worms, and these worms were less sensitive to paraquat. Interestingly enough, all of the molecular events caused by DDS treatment were consistently reproduced in mice treated with DDS for 3 mo and in the C2C12 muscle cell line. Structural prediction identified pyruvate kinase (PK) as a protein target of DDS. Indeed, DDS bound and inhibited PK in vitro and inhibited it in vivo, and a PK mutation conferred extended lifespan of C. elegans. Supplement of pyruvate to the media protected C2C12 cells from apoptosis caused by paraquat. Our findings establish the significance of DDS in lowering reactive oxygen species generation and extending the lifespan, which renders the rationale to examining the possible effect of DDS on human lifespan extension.F irst synthesized a century ago, 4,4′-diaminodiphenylsulfone (DDS) is a drug still used to treat many skin diseases. Specifically, DDS is a principal drug in a multidrug regimen recommended by the World Health Organization for the treatment of leprosy (1-4). DDS acts as an antibiotic in a manner similar to sulphonamides by inhibiting bacterial synthesis of dihydrofolic acid through competition with para-aminobenzoic acid (PABA) for the active site of dihydropteroate synthetase (DHPS) (5). In addition to its antibacterial activity, DDS has been reported to be involved in other cellular processes that occur in eukaryotic cells, such as inflammation, migration, and apoptosis (6). However, there has been controversy over the issue of whether DDS acts as a pro-oxidant (especially when a higher dose of DDS is used rather than a standard dose) or antioxidant (7-9). Most studies on the pro-oxidant effects of DDS have been based on its use at high concentrations. For example, in human dermal fibroblasts, a high dose of DDS (1.5 mM) induced oxidative stress and glutathione depletion (10), but in rat livers, DDS administration at a dose of 30 mg/kg body weight resulted in oxidative stress (11). Therefore, the debate regarding the nature of DDS as a pro-oxidant or antioxidant appears to reflect the dosage effect. Another interesting observation is that Hansen disease patients in Korea, who usually have taken DDS for several decades, had a longer lifespan in spite of their socioeconomical disadvantages (12). This finding prompted us to examine whether and how DDS treatment extends an...

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confidence: 99%

DDS, 4,4′-diaminodiphenylsulfone, extends organismic lifespan

Cho

Park

Keam

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…The mecha nisms through which dap so ne produ ces hemoly sis are varied and inclu de for ma tion of hap tens, immu no com ple xes, free radi cals and adsorption of hema tic pro teins. 13 When there is sus pi cion of hemoly sis, dap so ne should be dis con ti nued. In such cases, the main the ra peu tic alter na ti ves are glu co corti coids, aza thio pri ne, metho tre xa te, tetracy cli nes, eryth romy cin and cyclos po ri ne.…”

Section: Discussionmentioning

confidence: 99%

Dermatose por IgA e IgG linear: relato de caso com boa resposta terapêutica à dapsona e ao micofenolato mofetil

Passos

Rabelo

Matsuo

et al. 2011

An. Bras. Dermatol.

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Abstract:A 21-year-old female presenting linear IgA and IgG disease initially responded well to dapsone therapy. However, the treatment with dapsone was withdrawn due to severe anemia induced by malaria, which led to worsening of the clinical picture. Although prednisone and methylprednisolone were tried, the patient responded only to the association of dapsone and mycophenolate mofetil. Keywords: Dapsone; Immunoglobulin A; Immunoglobulin G; Receptors, IgGResumo: Relata-se o caso de pacien te femi ni na, de 21 anos, com der ma to se por IgA e IgG linear. Inicialmente, a res pos ta clí ni ca foi favo rá vel à dap so na. Após a inter rup ção desta medi ca ção, por crise de ane mia sin to má ti ca, pre ci pi ta da por malá ria, houve piora da doen ça, ape sar da uti li za ção da pred ni so na e pul so te ra pia com metilpred ni so lo na. A rein tro du ção da dap so na, asso cia da ao mico fe no la to mofe til, pos si bi li tou o con tro le da enfermi da de. ©2011 by Anais Brasileiros de Dermatologia INTRO DUC TIONLinear IgA der ma to sis (LAD) is defi ned as an acqui red autoim mu ne bul lous disea se, cha rac te ri zed by linear depo si tion of IgA along the base ment membra ne zone (BMZ). 1,2 Despite the dif fi cul ties in dis tinguis hing sube pi der mal bul lous disea ses, as of 1979 LAD has been dif fe ren tia ted from her pe ti form der mati tis. Since then, bul lous disea ses with sube pi der mal clea va ge and linear depo si tion of IgA along the BMZ have been auto ma ti cally clas si fied as LAD. 3,4 In 1998, Honokik and cols demons tra ted the pre sen ce of IgG against cir cu la ting epi der mal anti gens in LAD patients. 5 Subsequent reports cor ro bo ra te the findings of this group. 3,[6][7][8] The pre sen ce of simul ta neous linear depo si tion of IgA and IgG was fun da men tal for the con cep tion of a new cli ni cal-patho lo gi cal entity, IgA and IgG linear der ma to sis (LAGD). 9,10 However, the mag ni tu de and cli ni cal rele van ce of this clas si fi ca tion remain con trover sial, as there seems to be no dif fe ren ces in the derma to lo gi cal pre sen ta tion and the ra peu tic spec trum of both disea ses. The rea son for such simi la rity has been attri bu ted to the fact that IgA is an anti body with very hete ro ge neous tar get anti gens, against seve ral BM com po nents. A pos si ble mecha nism of inter mo le cu lar expan sion of epi to pes could be res pon si ble for the autoim mu nity exten sion of BP180 anti gen to the

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“…However, the risks of serious side effects hindered the widespread use of dapsone in the treatment of acne [9]. A topical formulation of dapsone 5% gel was approved for the treatment of acne [10,11].…”

Section: Introductionmentioning

confidence: 99%