Dapsone

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Dapsone
Dapsone.svg
Dapsone3d.png
Systematic (IUPAC) name
4-[(4-aminobenzene)sulfonyl]aniline
Clinical data
Trade namesAczone
AHFS/Drugs.commonograph
MedlinePlusa682128
Pregnancy cat.
Legal status
  • ℞-only (U.S.), POM (UK)
RoutesOral, Topical
Pharmacokinetic data
Bioavailability70 to 80%
Protein binding70 to 90%
MetabolismHepatic (mostly CYP2E1-mediated)
Half-life20 to 30 hours
ExcretionRenal
Identifiers
CAS number80-08-0 YesY
ATC codeD10AX05 J04BA02
PubChemCID 2955
DrugBankDB00250
ChemSpider2849 YesY
UNII8W5C518302 YesY
KEGGD00592 YesY
ChEBICHEBI:4325 YesY
ChEMBLCHEMBL1043 YesY
Chemical data
FormulaC12H12N2O2S 
Mol. mass248.302 gmol-1
 YesY (what is this?)  (verify)
 
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Dapsone
Dapsone.svg
Dapsone3d.png
Systematic (IUPAC) name
4-[(4-aminobenzene)sulfonyl]aniline
Clinical data
Trade namesAczone
AHFS/Drugs.commonograph
MedlinePlusa682128
Pregnancy cat.
Legal status
  • ℞-only (U.S.), POM (UK)
RoutesOral, Topical
Pharmacokinetic data
Bioavailability70 to 80%
Protein binding70 to 90%
MetabolismHepatic (mostly CYP2E1-mediated)
Half-life20 to 30 hours
ExcretionRenal
Identifiers
CAS number80-08-0 YesY
ATC codeD10AX05 J04BA02
PubChemCID 2955
DrugBankDB00250
ChemSpider2849 YesY
UNII8W5C518302 YesY
KEGGD00592 YesY
ChEBICHEBI:4325 YesY
ChEMBLCHEMBL1043 YesY
Chemical data
FormulaC12H12N2O2S 
Mol. mass248.302 gmol-1
 YesY (what is this?)  (verify)

Dapsone (diamino-diphenyl sulfone) is an antibacterial 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 jirovecii (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 in both topical and oral formulations. Topical dapsone is available in a 5% gel formulation that is sold under the brand name Aczone and is produced by Allergan. Oral dapsone is also available but is less commonly used than other sulfonamide antibiotics, many of which have a lower incidence of adverse effects.[4]

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[5]

Medical uses[edit]

As well as being used in leprosy, dapsone can also be used to treat mucous membrane pemphigoid,[6] (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), and other skin conditions including lichen planus. Dapsone is also used in the treatment of pyostomatitis vegetans, an oral manifestation of inflammatory bowel disease, commonly seen in patients with ulcerative colitis.

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

It is used prophylactically to prevent Pneumocystis pneumonia and toxoplasmosis in patients unable to tolerate trimethoprim with sulfamethoxazole.[7]

Dapsone is also used to treat Brown recluse spider bites.[8] In presumed cases of brown recluse spider bites, dapsone is often used effectively, but clinical trials do not demonstrate similar effectiveness;[9] however, dapsone may be effective at treating many "spider bites" because many such cases are actually misdiagnosed microbial infections.[10]

Oral dapsone was one of the first medications used to treat moderate to severe acne vulgaris, and is still occasionally prescribed for the treatment of severe and abnormal acne (e.g. acne conglobata and acne fulminans).[11] Oral dapsone is generally reserved for cases where conventional treatments for severe acne, such as isotretinoin and first-line antibiotics, are found to be ineffective.[12] In December 2008, a 5% dapsone gel called Aczone was introduced to the prescription market as a topical treatment for moderate to severe acne.[1]. Preliminary reports suggest that topical dapsone is a safe and moderately effective acne treatment.[13]

Adverse effects[edit]

The dapsone hypersensitivity syndrome develops in 0.5-3.6% of persons treated with the drug, and is associated with a mortality of 9.9%.[14]

Effects on the blood[edit]

The most prominent side-effects of this drug are dose-related hemolysis (which may lead to hemolytic anemia) and methemoglobinemia.[15] About 20% of patients treated with dapsone suffer hemolysis [16] 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.[17][18] Agranulocytosis occurs rarely when dapsone is used alone but more frequently in combination regimens for malaria prophylaxis.[19] Abnormalities in white blood cell formation, including aplastic anemia, are rare, yet are the cause of the majority of deaths attributable to dapsone therapy.[20][21][22]

Effects on the liver[edit]

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 metabolized by the Cytochrome P450 system, specifically isozymes CYP2D6, CYP2B6, CYP3A4, and CYP2C19.[23] Dapsone metabolites produced by the cytochrome P450 2C19 isozyme are associated with the methemoglobinemia side effect of the drug.

Dermatologic[edit]

When used topically, dapsone can cause mild skin irritation, redness, dry skin, burning and itching. When used together with benzoyl peroxide products, temporary yellow or orange skin discolorations can occur.[24][25]

Other adverse effects[edit]

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.[26]

Dapsone reaction[edit]

Hypersensitivity reactions occur in some patients. This reaction may be more frequent in patients receiving multiple-drug therapy.[27][28][29]

The reaction always involves a rash and may also include fever, jaundice, and eosinophilia.[30][31][32][33][34] In general, these symptoms will occur within the first six weeks of therapy or not at all, and may be ameliorated by corticosteroid therapy.[7]

Mechanism of action[edit]

As an antibacterial, dapsone inhibits bacterial synthesis of dihydrofolic acid, via competition with para-aminobenzoate for the active site of dihydropteroate synthetase.[35] 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,[36] which are thought to come from the drug's blockade of myeloperoxidase. This is thought to be its mechanism of action in treating dermatitis herpetiformis.[37]

As part of the respiratory burst that neutrophils use to kill bacteria, myeloperoxidase converts hydrogen peroxide (H2O2) into hypochlorous acid (HOCl). HOCl is the most potent oxidant generated by neutrophils, and can cause significant tissue damage during inflammation. Dapsone arrests myeloperoxidase in an inactive intermediate form, reversibly inhibiting the enzyme. This prevents accumulation of hypochlorous acid, and reduces tissue damage during inflammation.[38][39][40][41][42]

Myeloperoxidase inhibition has also been suggested as a neuron-sparing mechanism for reducing inflammation in neurodegenerative diseases such as Alzheimer's disease and stroke.[43]

Though dapsone is an anti-inflammatory agent and not a steroid, it does not fit the usual definition of an NSAID. By definition, NSAIDs block cyclo-oxygenase as their primary mechanism of action, which dapsone does not do.

Synthesis[edit]

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 were reduced with tin and concentrated hydrochloric acid, and the free base obtained by treatment with an alkali:[44]

Synthesis of dapsone.png

Administration[edit]

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.

Specific considerations[edit]

Certain patients are at higher risks of adverse effects when using dapsone. Some specific issues that should be considered are:[7]

Patients with Diabetes mellitus have been seen to exhibit unexpectedly low HbA1c results when taking Dapsone, and HbA1c i an unreliable test in states of increased red cell turnover, e.g. a drug induced haemolytic anaemia.

History[edit]

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 (sulfonamidochrysoidine). Further investigation into the involved chemicals opened the way to sulfa drug and sulfone therapy, first with the discovery of sulfanilamide, the active agent of prontosil, by Daniel Bovet and his team at Pasteur Institute (1935),[45] then with of dapsone independently by Ernest Fourneau[46] in France and Gladwin Buttle[47] in United-Kingdom.[48]

References[edit]

  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: 0903. PMC 2943798. PMID 19450348.  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. ^ Zhu, et al., YI; Stiller, MJ (2001). "Dapsone and sulfones in dermatology: overview and update". Journal of the American Academy of Dermatology 45 (3): 420–34. doi:10.1067/mjd.2001.114733. PMID 11511841. 
  5. ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014. 
  6. ^ Rogers RS, Seehafer JR, Perry HO (February 1982). "Treatment of cicatricial (benign mucous membrane) pemphigoid with dapsone". J. Am. Acad. Dermatol. 6 (2): 215–. doi:10.1016/S0190-9622(82)70014-3. PMID 7037880. 
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  17. ^ http://www.who.int/medicines/publications/drugalerts/Alert_117_LapDap.pdf
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External links[edit]