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	DB00250
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 O=S(=O)(c1ccc(N)cc1)c2ccc(N)cc2
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
Y (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]

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 (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),^[5] then with of dapsone independently by Ernest Fourneau^[6] in France and Gladwin Buttle^[7] in United-Kingdom.^[8]

Mechanism

As an antibacterial, dapsone inhibits bacterial synthesis of dihydrofolic acid, via competition with para-aminobenzoate for the active site of dihydropteroate synthetase.^[9] 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,^[10] 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.^[11]

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.^{[12][13][14][15][16]}

Myeloperoxidase inhibition has also been suggested as a neuron-sparing mechanism for reducing inflammation in neurodegenerative diseases such as Alzheimer's disease and stroke.^[17]

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

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:^[18]

Indication

As well as being used in leprosy, dapsone can also be used to treat mucous membrane pemphigoid,^[19] (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.^[20]

Dapsone is also used to treat Brown recluse spider bites.^[21] In presumed cases of brown recluse spider bites, dapsone is often used effectively, but clinical trials do not demonstrate similar effectiveness;^[22] however, dapsone may be effective at treating many "spider bites" because many such cases are actually misdiagnosed microbial infections.^[23]

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).^[24] 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.^[25] In December 2008, a 5% dapsone gel called Aczone was introduced to the prescription market as a topical treatment for moderate to severe acne.. Preliminary reports suggest that topical dapsone is a safe and moderately effective acne treatment.^[26]

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 30-, 60-, & 90 gram tubes. In normal use, 0.5 grams (or "a pea sized amount") should be administered to the face per application twice a day.

Adverse effects

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%.^[27]

Effects on the blood

The most prominent side-effects of this drug are dose-related hemolysis (which may lead to hemolytic anemia) and methemoglobinemia.^[28] About 20% of patients treated with dapsone suffer hemolysis ^[29] 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.^[30][31] Agranulocytosis occurs rarely when dapsone is used alone but more frequently in combination regimens for malaria prophylaxis.^[32] Abnormalities in white blood cell formation, including aplastic anemia, are rare, yet are the cause of the majority of deaths attributable to dapsone therapy.^[33][34][35]

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 metabolized by the Cytochrome P450 system, specifically isozymes CYP2D6, CYP2B6, CYP3A4, and CYP2C19.^[36] Dapsone metabolites produced by the cytochrome P450 2C19 isozyme are associated with the methemoglobinemia side effect of the drug.

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.^[37]

Dapsone reaction

Hypersensitivity reactions occur in some patients. This reaction may be more frequent in patients receiving multiple-drug therapy.^[38][39][40]

The reaction always involves a rash and may also include fever, jaundice, and eosinophilia.^{[41][42][43][44][45]} In general, these symptoms will occur within the first six weeks of therapy or not at all, and may be ameliorated by corticosteroid therapy.^[20]

Specific considerations

Certain patients are at higher risks of adverse effects when using dapsone. Some specific issues that should be considered are:^[20]

• 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

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.

References

External links

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