Dapsone

Dapsone

Systematic (IUPAC) name
4-[(4-aminobenzene)sulfonyl]aniline
Clinical data
Trade names	Aczone
AHFS/Drugs.com	monograph
MedlinePlus	a682128
Pregnancy cat.	B2(AU) C(US)
Legal status	℞-only (U.S.), POM (UK)
Routes	Oral
Pharmacokinetic data
Bioavailability	70 to 80%
Protein binding	70 to 90%
Metabolism	Hepatic (mostly CYP2E1-mediated)
Half-life	20 to 30 hours
Excretion	Renal
Identifiers
CAS number	80-08-0 Y
ATC code	D10AX05 J04BA02
PubChem	CID 2955
DrugBank	APRD00345
ChemSpider	2849 Y
UNII	8W5C518302 Y
KEGG	D00592 Y
ChEBI	CHEBI:4325 Y
ChEMBL	CHEMBL1043 Y
Chemical data
Formula	C12H12N2O2S
Mol. mass	248.302 gmol-1
SMILES	eMolecules & PubChem
InChI InChI=1S/C12H12N2O2S/c13-9-1-5-11(6-2-9)17(15,16)12-7-3-10(14)4-8-12/h1-8H,13-14H2 Y Key:MQJKPEGWNLWLTK-UHFFFAOYSA-N Y
N(what is this?)  (verify)

Dapsone (diamino-diphenyl sulfone) is a 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 second-line treatment for prophylaxis (prevention) against Pneumocystis pneumonia (PCP) caused by Pneumocystis jiroveci (formerly P. carinii) in HIV patients in whom CD4 counts are below 200/mm³.^[1]

Dapsone is an odorless white to creamy-white crystalline powder with a slightly bitter taste, used in combination with pyrimethamine in the treatment of malaria.^[2][3] Dapsone is commercially available as a gel 5% topical acne medication and is used as an acne treatment for mild to moderate acne in teens and adults. To treat acne, Dapsone is marketed as Aczone by Allergan. Oral Dapsone may also be prescribed for acne conglobata and acne fulminans, if conventional treatments for extremely severe acne, such as isotretinoin and prednisone, fail to work.

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.^[4]

Mechanism

As an antibacterial, dapsone inhibits bacterial synthesis of dihydrofolic acid, via competition with para-aminobenzoate for the active site of dihydropteroate synthetase.^[5] 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 not well understood.

Dapsone has anti-inflammatory and immunomodulatory effects.^[6] Dapsone blocks myeloperoxidase, which has been suggested to be its mechanism of action in treating dermatitis herpetiformis.^[7] Myeloperoxidase converts hydrogen peroxide (H₂O₂) into hypochlorous acid (HOCl) as part of the respiratory burst in neutrophils to kill bacteria. HOCl is the most toxic and potent oxidant generated by neutrophils, which have potential to cause significant tissue damage in many inflammatory diseases. The respiratory burst uses large quantities of oxygen, and a single neutrophil may produce enough HOCl in one second to destroy 150 bacteria.^[8] In the absence of chloride ions or when there is excess hydrogen peroxide, the myeloperoxidase is converted to its inactive form. Dapsone reversibly inhibits myeloperoxidase activity by promoting the formation of an inactive intermediate of the enzyme, thus preventing the conversion of hydrogen peroxide to hypochlorous acid, an extremely potent neutrophil oxidant.^{[9][10][11][12][13]} Myeloperoxidase inhibition has also been suggested as a mechanism for a neuron-sparing effect in inflammatory neurodegenerative diseases such as Alzheimer disease and stroke ^[14]

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:^[15]

Indication

As well as being used in leprosy, dapsone can also be used to treat mucous membrane pemphigoid,^[16] an autoimmune blistering disease of skin and mucous membranes, dermatitis herpetiformis and Linear immunoglobulin A dermatosis, both blistering skin diseases that 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 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.^[17]

Dapsone is also used to treat Brown recluse spider bites.^[18] In presumed cases of brown recluse spider bites, dapsone is often used effectively, but clinical trials do not demonstrate similar effectiveness;^[19] however, dapsone may be effective at treating many "spider bites" because many such cases are actually misdiagnosed microbial infections.^[20]

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.

Dapsone is administered transdermally (via the skin) as a gel 5% topical acne medication and available in 3-, 30-, and 60-gram tubes. In normal use, 0.5 grams should be administered to the face per application twice a day.

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.^[21] About 20% of patients treated with dapsone suffer hemolysis ^[22] and the side-effect is more common and severe in those with glucose-6-phosphate dehydrogenase deficiency, leading to the dapsone-containing antimalarial combination Lapdap being withdrawn from clinical use.^[23][24] Agranulocytosis occurs rarely when dapsone is used alone but more frequently in combination regimens for malaria prophylaxis.^[25] Abnormalities in white blood cell formation, including aplastic anemia, are rare but the cause of the majority of deaths due to dapsone therapy.^[26][27][28]

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.^[29]

Dapsone reaction

Hypersensitivity reactions occur in some patients. This reaction may be more frequent in patients receiving multiple-drug therapy.^[30][31][32]

The reaction always involves a rash and may also include fever, jaundice, and eosinophilia.^{[33][34][35][36][37]} In general, these symptoms will occur within the first six weeks of therapy or not at all, and may be ameliorated by corticosteroid therapy.^[17]

Specific considerations

Certain patients are at higher risks of adverse effects when using dapsone. Some specific issues that should be considered are:^[17]

• Related to the blood (a full blood count should be obtained prior to initiating therapy):
  • Porphyria
  • Anemia
  • Cardiac disease
  • Pulmonary disease
  • HIV infection
  • G6PD deficiency

• Related to the liver (obtain liver function tests before starting therapy):
  • Liver impairment

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

References

1. ^ Pocket Medicine: The Massachusetts General Hospital Handbook of Internal Medicine, by Sabatine, 3rd Edition
2. ^ Croft, A. M. (Nov 2007). "Malaria: prevention in travellers". Clinical evidence 2007. PMC 2943798. PMID 19450348. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2943798.  edit
3. ^ Alkadi, H. O. (2007). "Antimalarial drug toxicity: a review". Chemotherapy 53 (6): 385–391. doi:10.1159/000109767. ISSN 0009-3157. PMID 17934257.  edit
4. ^ "Leprosy | 14 History of dapsone and dyes". http://www.itg.be/itg/DistanceLearning/LectureNotesVandenEndenE/22_Leprosyp14.htm. Retrieved 2009-02-24. 
5. ^ "Medscape.com". http://www.medscape.com/viewarticle/440403_5. Retrieved 2009-02-24. 
6. ^ Begon E, Chosidow O, Wolkenstein P (December 2004). "[Disulone]" (in French). Ann Dermatol Venereol 131 (12): 1062–73. doi:10.1016/S0151-9638(04)93842-2. PMID 15692440. 
7. ^ Uetrecht JP (1995). "Myeloperoxidase as a generator of drug free radicals". Biochem. Soc. Symp. 61: 163–70. PMID 8660393. 
8. ^ Weiss S. Tissue destruction by neutrophil. N Engl J Med 1989; 320:365-392.
9. ^ Bozeman P, Learn D, Thomas E. Assay of the human leukocyte encymes myeloperoxidase and eosinophil peroxidase. J Immunol Methods 1990; 126:125-133.
10. ^ Bozeman P, Learn D, Thomas E. Inhibition of the human leukocyte enzymes myeloperoxidase and eosinophil peroxidase by dapsone. Biochem Pharmacol 1992; 44:553-563.
11. ^ Stendahl O, Molin L, Lindroth M. Granulocyte-mediated release of histamine from mast cells. Effect of myeloperoxidase and its inhibition by antiinflammatory sulfone compounds. Int Arch Allergy Appl Immunol 1983; 70:277-284.
12. ^ Kettle A, Gedye C, Winterbourn C. Superoxide is an antagonist of antiinflammatory drugs that inhibit hypochlorous acid production by myeloperoxidase. Biochem Pharmacol 1993; 45:2003-2010.
13. ^ Kettle A, Winterbourn C. Mechanism of inhibition of myeloperoxidase by anti-inflammatory drugs. Biochem Pharmacol 1991; 41:1485-1492.
14. ^ 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. 
15. ^ E. Fromm, J. Wittmann (1908). "Derivate des p-Nitrothiophenols". Ber. 41 (2): 2264. doi:10.1002/cber.190804102131. 
16. ^ 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. 
17. ^ ^{a b c} Rossi S, ed. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
18. ^ 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. PMC 1250983. PMID 4051613. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1250983. 
19. ^ 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.
20. ^ 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. 
21. ^ Jopling WH. Side-effects of antileprosy drugs in common use. Lepr Rev 1983; 54: 261–70.
22. ^ Puavilai S, Chutha S, Polnikorn N, et al. (July 1984). "Incidence of anemia in leprosy patients treated with dapsone". J Med Assoc Thai 67 (7): 404–7. PMID 6512448. 
23. ^ http://www.who.int/medicines/publications/drugalerts/Alert_117_LapDap.pdf
24. ^ Luzzatto L (August 2010). "The rise and fall of the antimalarial Lapdap: a lesson in pharmacogenetics". Lancet 376 (9742): 739–41. doi:10.1016/S0140-6736(10)60396-0. PMID 20599264. 
25. ^ Firkin FC, Mariani AF. Agranulocytosis due to dapsone. Med J Aust 1977; 2: 247–51.
26. ^ Foucauld J, et al. Dapsone and aplastic anemia. Ann Intern Med 1985; 102: 139.
27. ^ Meyerson MA, Cohen PR. Dapsone-induced aplastic anaemia in a woman with bullous systemic lupus erythematosus. Mayo Clin Proc 1994; 69: 1159–62.
28. ^ Björkman A, Phillips-Howard PA. Adverse reactions to sulfa drugs: implications for malaria chemotherapy. Bull WHO 1991; 69: 297–304.
29. ^ Jaffuel D, et al. Eosinophilic pneumonia induced by dapsone. BMJ 1998; 317: 181.
30. ^ Richardus JH, Smith TC. Increased incidence in leprosy of hypersensitivity reactions to dapsone after introduction of multidrug therapy. Lepr Rev 1989; 60: 267–73.
31. ^ Kumar RH, et al. Dapsone syndrome—a five year retrospective analysis. Indian J Lepr 1998; 70: 271–6.
32. ^ Rao PN, Lakshmi TSS. Increase in the incidence of dapsone hypersensitivity syndrome—an appraisal. Lepr Rev 2001; 72: 57–62.
33. ^ Joseph MS. Hypersensitivity reaction to dapsone. Lepr Rev 1985; 56: 315–20.
34. ^ Jamrozik K. Dapsone syndrome occurring in two brothers. Lepr Rev 1986; 57: 57–62.
35. ^ Hortaleza AR, et al. Dapsone syndrome in a Filipino man. Lepr Rev 1995; 66: 307–13.
36. ^ Tomecki KJ, Catalano CJ. Dapsone hypersensitivity: the sulfone syndrome revisited. Arch Dermatol 1981; 117: 38–9.
37. ^ Kromann NP, et al. The dapsone syndrome. Arch Dermatol 1982; 118: 531–2.

External links

• MedlinePlus Drug Information
• U.S. National Library of Medicine: Drug Information Portal - Dapsone