Dapsone
|
|
| Systematic (IUPAC) name |
|
4-[(4-aminobenzene)sulfonyl]aniline
|
| Clinical data |
| Trade names |
Aczone |
| AHFS/Drugs.com |
monograph |
| MedlinePlus |
a682128 |
Pregnancy
category |
- AU: B2
- US: C (Risk not ruled out)
|
| Legal status |
|
Routes of
administration |
Oral, Topical |
| Pharmacokinetic data |
| Bioavailability |
70 to 80% |
| Protein binding |
70 to 90% |
| Metabolism |
Hepatic (mostly CYP2E1-mediated) |
| Biological half-life |
20 to 30 hours |
| Excretion |
Renal |
| Identifiers |
| CAS Number |
80-08-0 Y |
| ATC code |
D10AX05 J04BA02 |
| PubChem |
CID 2955 |
| DrugBank |
DB00250 Y |
| ChemSpider |
2849 Y |
| UNII |
8W5C518302 Y |
| KEGG |
D00592 Y |
| ChEBI |
CHEBI:4325 Y |
| ChEMBL |
CHEMBL1043 Y |
| Chemical data |
| Formula |
C12H12N2O2S |
| Molar mass |
248.302 g/mol |
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
|
| (verify) |
Dapsone, also known as diaminodiphenyl sulfone (DDS),[1] is an antibiotic commonly used in combination with rifampicin and clofazimine for the treatment of leprosy.[2] It is a second-line medication for the treatment and prevention of Pneumocystis pneumonia and for the prevention of toxoplasmosis in those who have poor immune function.[2] Additionally, it has been used for acne as well as other skin conditions.[3] Dapsone is available both topically and by mouth.[4]
Severe side effects may include: a decrease in blood cells, red blood cell breakdown especially in those with glucose-6-phosphate dehydrogenase deficiency (G-6-PD), or hypersensitivity.[2] Common side effects include nausea and loss of appetite.[4] Other side effects include liver inflammation and a number of types of skin rashes.[2] While it is not entirely clear the safety of use during pregnancy some physicians recommend that it be continued in those with leprosy.[2] It is of the sulfone class.[2]
Dapsone was first studied as an antibiotic in 1937.[3] Its use for leprosy began in 1945.[3] It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[5] The oral form is available as a generic drug and not very expensive.[2][6]
Contents
- 1 Medical uses
- 2 Adverse effects
- 2.1 Blood
- 2.2 Liver
- 2.3 Skin
- 2.4 Other adverse effects
- 2.5 Dapsone reaction
- 3 Mechanism of action
- 4 Specific considerations
- 5 History
- 6 See also
- 7 References
- 8 External links
Medical uses
Infections
Dapsone is commonly used in combination with rifampicin and clofazimine for the treatment of leprosy.[2] It is also used to both treat and prevent Pneumocystis pneumonia (PCP).[2][7] It is also used for toxoplasmosis in people unable to tolerate trimethoprim with sulfamethoxazole.[7]
Dapsone by mouth was one of the first medications used to treat moderate to severe acne vulgaris, and is still occasionally prescribed for the treatment of severe cases.[8][9] A topical form of dapsone is also effective with potentially less side effects.[10]
It is unclear if the combination with pyrimethamine is useful in the prevention of malaria.[11]
Other
Dermatitis herpetiformis, often in combination with a gluten free diet.[2]
Dapsone may be used to treat brown recluse spider bites that become necrotic.[12]
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%.[13]
Blood
The most prominent side-effects of this drug are dose-related hemolysis (which may lead to hemolytic anemia) and methemoglobinemia.[14] About 20% of patients treated with dapsone suffer hemolysis[15] 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.[16][17] A case of hemolysis in a neonate from dapsone in breast milk has been reported.[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]
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.[23] Dapsone metabolites produced by the cytochrome P450 2C19 isozyme are associated with the methemoglobinemia side effect of the drug.
Skin
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
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
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
As an antibacterial, dapsone inhibits bacterial synthesis of dihydrofolic acid, via competition with para-aminobenzoate for the active site of dihydropteroate synthase.[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 (H
2O
2) 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.
Dapsone is an odorless white to creamy-white crystalline powder with a slightly bitter taste.
Specific considerations
Certain patients are at higher risks of adverse effects when using dapsone. Some specific issues that should be considered are:[7]
- 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):
- Related to allergy:
- Sulfonamide allergy is associated with dapsone allergy
People 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
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),[44] then with of dapsone independently by Ernest Fourneau[45] in France and Gladwin Buttle[46] in United-Kingdom.[47]
First synthesis of Dapsone from 4,4'-Thiodianiline
Fromm & Wittman, 1908
See also
References
- ^ Thomas L. Lemke (2008). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. p. 1142. ISBN 9780781768795.
- ^ a b c d e f g h i j "Dapsone". The American Society of Health-System Pharmacists. Retrieved Jan 12, 2015.
- ^ a b c Zhu, YI; Stiller, MJ; et al. (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.
- ^ a b Joel E. Gallant (2008). Johns Hopkins HIV Guide 2012. Jones & Bartlett Publishers. p. 193. ISBN 9781449619794.
- ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
- ^ Greenwood, David (2008). Antimicrobial Drugs: Chronicle of a Twentieth Century Medical Triumph. Oxford University Press. p. 197. ISBN 9780199534845.
- ^ a b c d Rossi S, ed. (2006). Australian Medicines Handbook. Adelaide. ISBN 0-9757919-2-3.
- ^ Ross, CM (1961). "The treatment of acne vulgaris with dapsone". Br J Dermatol 73 (10): 367–70. doi:10.1111/j.1365-2133.1961.tb14398.x. PMID 14494150.
- ^ "Dapsone and Acne Vulgaris". ScienceOfAcne.com. 2012-10-10. Retrieved 2012-08-17.
- ^ Pickert, A; Raimer, S (June 2009). "An evaluation of dapsone gel 5% in the treatment of acne vulgaris". Expert opinion on pharmacotherapy 10 (9): 1515–21. doi:10.1517/14656560903002097. PMID 19505219.
- ^ Croft, AM (29 November 2007). "Malaria: prevention in travellers.". Clinical evidence 2007. PMC 2943798. PMID 19450348.
- ^ Forks, TP (2000). "Brown recluse spider bites.". J Am Board Fam Pract 13 (6): 415–23. doi:10.3122/15572625-13-6-415. PMID 11117338.
- ^ Zhang FR, Liu, H; Irwanto, A et al. (October 2013). "HLA-B*13:01 and the dapsone hypersensitivity syndrome.". N Engl J Med. 369 (17): 1620–8. doi:10.1056/NEJMoa1213096. PMID 24152261.
- ^ Jopling WH (1983). "Side-effects of antileprosy drugs in common use". Lepr Rev 54 (4): 261–70. PMID 6199637.
- ^ 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.
- ^ "Antimalarial chlorproguanil-dapsone (LapDap™) withdrawn following demonstration of post-treatment haemolytic anaemia in G6PD deficient patients in a Phase III trial of chlorproguanil-dapsone-artesunate (Dacart™) versus artemether-lumefantrine (Coartem®) and confirmation of findings in a comparative trial of LapDap™ versus Dacart ™" (PDF). World Health Organization. 4 March 2008. QSM/MC/IEA.1.
- ^ 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.
- ^ Sanders SW, Zone JJ, Foltz RL, Tolman KG, Rollins DE. (April 1982). "Hemolytic anemia induced by dapsone transmitted through breast milk.". Ann Intern Med. 96 (4): 465–6. doi:10.7326/0003-4819-96-4-465. PMID 7065565.
- ^ Firkin FC, Mariani AF (1977). "Agranulocytosis due to dapsone". Med. J. Aust. 2 (8): 247–51. PMID 909500.
- ^ Foucauld J, Uphouse W, Berenberg J (1985). "Dapsone and aplastic anemia". Ann. Intern. Med. 102 (1): 139. doi:10.7326/0003-4819-102-1-139_2. PMID 3966740.
- ^ Meyerson MA, Cohen PR (1994). "Dapsone-induced aplastic anemia in a woman with bullous systemic lupus erythematosus". Mayo Clin. Proc. 69 (12): 1159–62. doi:10.1016/s0025-6196(12)65768-1. PMID 7967777.
- ^ Björkman A, Phillips-Howard PA (1991). "Adverse reactions to sulfa drugs: implications for malaria chemotherapy". Bull. World Health Organ. 69 (3): 297–304. PMC 2393107. PMID 1893504.
- ^ Ganesan, S; Sahu, R; Walker, LA; Tekwani, BL (April 2010). "Cytochrome P450-dependent toxicity of dapsone in human erythrocytes". J Appl Toxicol 30 (3): 271–5. doi:10.1002/jat.1493. PMID 19998329.
- ^ Aczone(Dapsone) Package insert. Irvine CA: Allergan Inc; September 2008
- ^ "Dapsone (Aczone)". Medications For Acne. PharmacistAnswers.
- ^ Jaffuel D, Lebel B, Hillaire-Buys D, Pene J, Godard P, Michel FB, Blayac JP, Bousquet J, Demolyi P (1998). "Eosinophilic pneumonia induced by dapsone". BMJ 317 (7152): 181. doi:10.1136/bmj.317.7152.181. PMC 28611. PMID 9665900.
- ^ Richardus JH, Smith TC (1989). "Increased incidence in leprosy of hypersensitivity reactions to dapsone after introduction of multidrug therapy". Lepr Rev 60 (4): 267–73. PMID 2491425.
- ^ Kumar RH, Kumar MV, Thappa DM (1998). "Dapsone syndrome—a five year retrospective analysis". Indian J Lepr 70 (3): 271–6. PMID 9801899.
- ^ Rao PN, Lakshmi TS (2001). "Increase in the incidence of dapsone hypersensitivity syndrome—an appraisal". Lepr Rev 72 (1): 57–62. PMID 11355519.
- ^ Joseph MS (1985). "Hypersensitivity reaction to dapsone. Four case reports". Lepr Rev 56 (4): 315–20. PMID 4079634.
- ^ Jamrozik K (1986). "Dapsone syndrome occurring in two brothers". Lepr Rev 57 (1): 57–62. PMID 3702581.
- ^ Hortaleza AR, Salta-Ramos NG, Barcelona-Tan J, Abad-Venida L (1995). "Dapsone syndrome in a Filipino man". Lepr Rev 66 (4): 307–13. PMID 8637384.
- ^ Tomecki KJ, Catalano CJ (1981). "Dapsone hypersensitivity. The sulfone syndrome revisited". Arch Dermatol 117 (1): 38–9. doi:10.1001/archderm.1981.01650010044023. PMID 6450569.
- ^ Kromann NP, Vilhelmsen R, Stahl D (1982). "The dapsone syndrome". Arch Dermatol 118 (7): 531–2. doi:10.1001/archderm.1982.01650190085028. PMID 7092282.
- ^ "Mechanisms of Action of Dapsone in Dermatological Diseases". Dapsone: Clinical Uses in Various Cutaneous Diseases. Medscape Today.
- ^ Begon E, Chosidow O, Wolkenstein P (December 2004). "[Disulone]". Ann Dermatol Venereol (in French) 131 (12): 1062–73. doi:10.1016/S0151-9638(04)93842-2. PMID 15692440.
- ^ Uetrecht JP (1995). "Myeloperoxidase as a generator of drug free radicals". Biochem. Soc. Symp. 61: 163–70. PMID 8660393.
- ^ Bozeman PM, Learn DB, Thomas EL (1990). "Assay of the human leukocyte enzymes myeloperoxidase and eosinophil peroxidase". J. Immunol. Methods 126 (1): 125–33. doi:10.1016/0022-1759(90)90020-v. PMID 2154520.
- ^ Bozeman PM, Learn DB, Thomas EL (1992). "Inhibition of the human leukocyte enzymes myeloperoxidase and eosinophil peroxidase by dapsone". Biochem. Pharmacol. 44 (3): 553–63. doi:10.1016/0006-2952(92)90449-s. PMID 1324677.
- ^ Stendahl O, Molin L, Lindroth M (1983). "Granulocyte-mediated release of histamine from mast cells. Effect of myeloperoxidase and its inhibition by antiinflammatory sulfone compounds". Int. Arch. Allergy Appl. Immunol. 70 (3): 277–84. doi:10.1159/000233335. PMID 6186607.
- ^ Kettle AJ, Gedye CA, Winterbourn CC (1993). "Superoxide is an antagonist of antiinflammatory drugs that inhibit hypochlorous acid production by myeloperoxidase". Biochem. Pharmacol. 45 (10): 2003–10. doi:10.1016/0006-2952(93)90010-t. PMID 8390258.
- ^ Kettle AJ, Winterbourn CC (1991). "Mechanism of inhibition of myeloperoxidase by anti-inflammatory drugs". Biochem. Pharmacol. 41 (10): 1485–92. doi:10.1016/0006-2952(91)90565-m. PMID 1850278.
- ^ 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.
- ^ Tréfouël, J. et T.; Nitti, F.; Bovet, D. (23 November 1935). "Activité du p.aminophénylsulfamide sur l’infection streptococcique expérimentale de la souris et du lapin". Comptes rendus des séances de la Société de biologie et de ses filiales (in French) 120: 756.
- ^ Fourneau, E.; Tréfouël, Th. et J.; Nitti, F.; Bovet, D. (1937). "Action antistreptococcique des dérivés sulfurés organiques". Comptes rendus de l'Académie des sciences (in French) 204: 1763.
- ^ Buttle, G.A.H.; Stephenson, D.; Smith, S.; Dewing, T.; Foster, G.E. (June 1937). "Treatment of streptococcal infections in mice with 4:4'diamino-dipheni-sulphone". Lancet 229 (5936): 1331–4. doi:10.1016/S0140-6736(00)75868-5.
- ^ "Leprosy | 14 History of dapsone and dyes". Retrieved 2009-02-24. (1937)
External links
- MedlinePlus Drug Information
- U.S. National Library of Medicine: Drug Information Portal - Dapsone
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Antimycobacterials, including tuberculosis treatment and leprostatic agents (J04)
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| Nucleic acid inhibitor |
Rifamycins/
RNA polymerase inhibitor |
- Rifampicin#
- Rifabutin
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- §Never to phase III
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