Dapsone: Wikis

  
  

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Dapsone
Systematic (IUPAC) name
4-[(4-aminobenzene)sulfonyl]aniline
Identifiers
CAS number 80-08-0
ATC code D10AX05 J04BA02
PubChem 2955
DrugBank APRD00345
ChemSpider 2849
Chemical data
Formula C 12H12N2O2S 
Mol. mass 248.302 gmol-1
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 70 to 80%
Protein binding 70 to 90%
Metabolism Hepatic (mostly CYP2E1-mediated)
Half life 20 to 30 hours
Excretion Renal
Therapeutic considerations
Pregnancy cat. B2(AU) C(US)
Legal status ℞-only (U.S.), POM (UK)
Routes Oral
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Dapsone (diamino-diphenyl sulfone) is a pharmacological medication most commonly used in combination with rifampicin and clofazimine as multidrug therapy (MDT) for the treatment of Mycobacterium leprae infections (leprosy). It is also used to treat Pneumocystis carinii pneumonia (PCP) caused by Pneumocystis jiroveci (formerly P. carinii). Dapsone is used in combination with pyrimethamine in the treatment of malaria.[1][2]

Contents

History

In the early 20th century the German chemist Paul Ehrlich was developing theories of selective toxicity based largely on the ability of certain dyes to kill microbes. Gerhard Domagk, who would later win a Nobel Prize for his efforts, made a major breakthrough in 1932 with the discovery of the antibacterial prontosil red. Further investigation into the active chemicals involved led to the discoveries both of dapsone and of the antibacterial sulfonamides. [3]

Mechanism

As an antibacterial, dapsone inhibits bacterial synthesis of dihydrofolic acid.[4] Though structurally distinct from dapsone, the sulfonamide group of antibacterial drugs also work in this way.

When used for the treatment of skin conditions in which bacteria do not have a role, the mechanism or action of dapsone is less well understood. In presumed cases of brown recluse spider bites, dapsone is often used effectively, but clinical trials do not demonstrate similar effectiveness[5]; however, dapsone may be effective at treating many "spider bites" because many such cases are actually misdiagnosed microbial infections.[6]

Dapsone has anti-inflammatory and immunomodulatory effects.[7] Dapsone blocks myeloperoxidase, which has been suggested to be its mechanism of action in treating dermatitis herpetiformis.[8] Myeloperoxidase inhibition has also been suggested as a mechanism for a neuron-sparing effect in inflammatory neurodegenerative diseases such as Alzheimer disease and stroke [9]

Although dapsone is not a steroid, and it is anti-inflammatory, it does not fit the usual definition of an NSAID since it does not block cyclo-oxygenase as most NSAIDs do as their primary mechanism.

Synthesis

Dapsone was first synthesized by Fromm and Wittmann in 1908. 4,4'-Dinitrodiphenyl sulfide was oxidized to the sulfone in a solution of potassium dichromate, glacial acetic acid, and sulfuric acid. The nitro- groups on the sulfone was reduced with tin and concentrated hydrochloric acid, and the free base was obtained by treatment with an alkali:[10]

Synthesis of dapsone.png

Indication

As well as being used in leprosy, dapsone can also be used to treat mucous membrane pemphigoid,[11] an autoimmune blistering disease of skin and mucous membranes, dermatitis herpetiformis and Linear immunoglobulin A dermatosis both blistering skin diseases which are effectively treated with a long-time treatment with dapsone, as well as other skin conditions including lichen planus.

It is also sometimes used to prevent Pneumocystis pneumonia (PCP) in people who are immunosuppressed and to treat idiopathic thrombocytopenic purpura.

It is used prophylactically to prevent Pneumocystis pneumonia and toxoplasmosis in patients unable to tolerate trimethoprim with sulfamethoxazole.[12]

Dapsone is also used to treat Brown recluse spider bites.[13]

In December 2008, a 5% dapsone gel called Aczone was introduced to the prescription market as a treatment for moderate to severe acne.[1]

Administration

Dapsone is administered orally as a 100 mg tablet or alternatively as 25 mg tablets.

To deal with dapsone-resistant leprosy cases, multidrug therapy was introduced by WHO in 1981; dapsone is administered along with rifampin and clofazimine or other antileprotic drugs.

Adverse effects

Effects on the blood

The most prominent side effects of this drug are dose-related hemolysis (which may lead to hemolytic anemia) and methemoglobinemia.[14] Agranulocytosis occurs rarely when dapsone is used alone but more frequently in combination regimens for malaria prophylaxis.[15] Abnormalities in white blood cell formation, including aplastic anaemia, are rare but the cause of the majority of deaths due to dapsone therapy.[16][17][18]

Effects on the liver

Toxic hepatitis and cholestatic jaundice have been reported by the manufacturer. Jaundice may also occur as part of the dapsone reaction or dapsone syndrome (see below). Dapsone is also known to inhibit the Cytochrome P450 system.

Other adverse effects

Other adverse effects include nausea, headache, and rash, which are common, and insomnia, psychosis and peripheral neuropathy. Effects on the lung occur rarely and may be serious though are generally reversible.[19]

Dapsone reaction

Hypersensitivity reactions occur in some patients. This reaction may be more frequent in patients receiving multiple drug therapy.[20][21][22]

The reaction always involves a rash and may also include fever, jaundice, and eosinophilia.[23][24][25][26][27] These symptoms will generally occur within the first six weeks of therapy or not at all, and may be ameliorated by corticosteroid therapy.[12]

Specific considerations

Certain patients are at higher risks of adverse effects when using dapsone. Some specific issues which should be considered are:[12]

  • Related to allergy:
    • Sulfonamide allergy is associated with dapsone allergy

References

  1. ^ Croft, AM (Nov 2007). "Malaria: prevention in travellers". Clinical evidence 2007. PMID 19450348.   edit
  2. ^ Alkadi, H. O. (2007). "Antimalarial drug toxicity: a review". Chemotherapy 53 (6): 385–391. doi:10.1159/000109767. ISSN 0009-3157. PMID 17934257.   edit
  3. ^ "Leprosy | 14 History of dapsone and dyes". http://www.itg.be/itg/DistanceLearning/LectureNotesVandenEndenE/22_Leprosyp14.htm. Retrieved 2009-02-24.  
  4. ^ "Medscape.com". http://www.medscape.com/viewarticle/440403_5. Retrieved 2009-02-24.  
  5. ^ Elston DM, Miller SD, Young RJ 3rd, Eggers J, McGlasson D, Schmidt WH, Bush A. Comparison of colchicine, dapsone, triamcinolone, and diphenhydramine therapy for the treatment of brown recluse spider envenomation: a double-blind, controlled study in a rabbit model. Arch Dermatol 2005; 141(5):595-7.
  6. ^ Vetter R, Bush S (2002). "The diagnosis of brown recluse spider bite is overused for dermonecrotic wounds of uncertain etiology". Ann Emerg Med 39 (5): 544–6. doi:10.1067/mem.2002.123594. PMID 11973562.  
  7. ^ Begon E, Chosidow O, Wolkenstein P (December 2004). "[Disulone]" (in French). Ann Dermatol Venereol 131 (12): 1062–73. PMID 15692440.  
  8. ^ Uetrecht JP (1995). "Myeloperoxidase as a generator of drug free radicals". Biochem. Soc. Symp. 61: 163–70. PMID 8660393.  
  9. ^ Diaz-Ruiz A, Zavala C, Montes S, et al. (November 2008). "Antioxidant, antiinflammatory and antiapoptotic effects of dapsone in a model of brain ischemia/reperfusion in rats". J. Neurosci. Res. 86 (15): 3410–9. doi:10.1002/jnr.21775. PMID 18615706.  
  10. ^ E. Fromm, J. Wittmann (1908). "Derivate des p-Nitrothiophenols". Ber. 41: 2264. doi:10.1002/cber.190804102131.  
  11. ^ Rogers RS, Seehafer JR, Perry HO (February 1982). "Treatment of cicatricial (benign mucous membrane) pemphigoid with dapsone". J. Am. Acad. Dermatol. 6 (2): 215–23. doi:10.1016/S0190-9622(82)70014-3. PMID 7037880.  
  12. ^ a b c Rossi S, ed. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
  13. ^ Rees RS, Altenbern DP, Lynch JB, King LE (November 1985). "Brown recluse spider bites. A comparison of early surgical excision versus dapsone and delayed surgical excision". Ann. Surg. 202 (5): 659–63. doi:10.1097/00000658-198511000-00020. PMID 4051613.  
  14. ^ Jopling WH. Side-effects of antileprosy drugs in common use. Lepr Rev 1983; 54: 261–70.
  15. ^ Firkin FC, Mariani AF. Agranulocytosis due to dapsone. Med J Aust 1977; 2: 247–51.
  16. ^ Foucauld J, et al. Dapsone and aplastic anemia. Ann Intern Med 1985; 102: 139.
  17. ^ Meyerson MA, Cohen PR. Dapsone-induced aplastic anaemia in a woman with bullous systemic lupus erythematosus. Mayo Clin Proc 1994; 69: 1159–62.
  18. ^ Björkman A, Phillips-Howard PA. Adverse reactions to sulfa drugs: implications for malaria chemotherapy. Bull WHO 1991; 69: 297–304.
  19. ^ Jaffuel D, et al. Eosinophilic pneumonia induced by dapsone. BMJ 1998; 317: 181.
  20. ^ Richardus JH, Smith TC. Increased incidence in leprosy of hypersensitivity reactions to dapsone after introduction of multidrug therapy. Lepr Rev 1989; 60: 267–73.
  21. ^ Kumar RH, et al. Dapsone syndrome—a five year retrospective analysis. Indian J Lepr 1998; 70: 271–6.
  22. ^ Rao PN, Lakshmi TSS. Increase in the incidence of dapsone hypersensitivity syndrome—an appraisal. Lepr Rev 2001; 72: 57–62.
  23. ^ Joseph MS. Hypersensitivity reaction to dapsone. Lepr Rev 1985; 56: 315–20.
  24. ^ Jamrozik K. Dapsone syndrome occurring in two brothers. Lepr Rev 1986; 57: 57–62.
  25. ^ Hortaleza AR, et al. Dapsone syndrome in a Filipino man. Lepr Rev 1995; 66: 307–13.
  26. ^ Tomecki KJ, Catalano CJ. Dapsone hypersensitivity: the sulfone syndrome revisited. Arch Dermatol 1981; 117: 38–9.
  27. ^ Kromann NP, et al. The dapsone syndrome. Arch Dermatol 1982; 118: 531–2.

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