Dapsone
Dapsone, also known as diaminodiphenyl sulfone, is an antibiotic commonly used in combination with rifampicin and clofazimine for the treatment of leprosy. 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. Additionally, it has been used for acne, dermatitis herpetiformis, and various other skin conditions. Dapsone is available both topically and by mouth.
Severe side effects may include a decrease in blood cells, red blood cell breakdown especially in those with glucose-6-phosphate dehydrogenase deficiency, or hypersensitivity. Common side effects include nausea and loss of appetite. Other side effects include liver inflammation and a number of types of skin rashes. While the safety of use during pregnancy is not entirely clear some physicians recommend that it be continued in those with leprosy. It is of the sulfone class.
Dapsone was first studied as an antibiotic in 1937. Its use for leprosy began in 1945. It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system. The form, which is taken by mouth, is available as a generic drug and not very expensive.
Medical uses
Infections
Dapsone is commonly used in combination with rifampicin and clofazimine for the treatment of leprosy. It is also used to both treat and prevent pneumocystis pneumonia. It is also used for toxoplasmosis in people unable to tolerate trimethoprim with sulfamethoxazole.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. A topical form of dapsone is also effective with potentially less side effects.
It is unclear if the combination with pyrimethamine is useful in the prevention of malaria.
Autoimmune disease
- Cutaneous lupus erythematosis. Dapsone is effective and safe in persons with moderate, severe, or refractory cutaneous lupus erythematosis.
- Idiopathic thrombocytopenic purpura. Dapsone is effective and safe for adjunctive glucocorticoid-sparing treatment of persons with idiopathic thrombocytopenic purpura and is preferred over danazol or interferon alpha in those people with antinuclear antibodies.
- Chronic spontaneous urticaria. Dapsone is effective and safe for treatment of second-line therapy for people with chronic spontaneous urticaria in those for whom antihistamines and other first-line agents have failed.
- Relapsing polychondritis. There are no clinical trials but there are many case reports that dapsone is effective at doses of 25 mg/day to 200 mg/day for treatment of relapsing polychondritis.
Other
Dapsone may be used to treat brown recluse spider bites that become necrotic.
Dapsone is the recommended treatment for erythema elevatum diutinum, as a review found that using oral dapsone alone was effective in 80% of early cases of the disease. However, dapsone can potentially cause severe side effects, meaning that sometimes steroids or other antibiotics should be used instead, although these alternative treatments are much less effective.
An August 2015 review notes that dapsone is reported to be effective against generalized granuloma annulare.
Dapsone has been use as a monomer in the design of dye adsorbent polymers.
Contraindications and precautions
People with porphyria, anemia, cardiac disease, lung disease, HIV infection, G6PD deficiency, and liver impairment are at higher risks of adverse effects when using dapsone.Recommend using pulse oximeter 2x/day to monitor for methemoglobinemia.
Adverse effects
Hypersensitivity reactions occur in 1.4% of persons treated with dapsone, and can be fatal in medical settings with low resources. It is a form of severe cutaneous adverse reactions in which a SCARs disorder, primarily the DRESS syndrome or a DRESS syndrome-like reaction occurs.Blood
The most prominent side-effects of this drug are dose-related hemolysis and methemoglobinemia. About 20% of patients treated with dapsone suffer hemolysis 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. A case of hemolysis in a neonate from dapsone in breast milk has been reported. Agranulocytosis occurs rarely when dapsone is used alone but more frequently in combination regimens for malaria prophylaxis. Abnormalities in white blood cell formation, including aplastic anemia, are rare, yet are the cause of the majority of deaths attributable to dapsone therapy.Liver
Toxic hepatitis and cholestatic jaundice have been reported by the manufacturer. These toxic reactions may also occur as part of the dapsone hypersensitivity syndrome or dapsone syndrome. Dapsone is metabolized by the Cytochrome P450 system, specifically isozymes CYP2D6, CYP2B6, CYP3A4, and CYP2C19. 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.Other adverse effects
Other adverse effects include nausea, headache, and rash, and insomnia, psychosis, and peripheral neuropathy. Effects on the lung occur rarely and may be serious, though are generally reversible.Dapsone syndrome
reactions occur in some patients. This reaction may be more frequent in patients receiving multiple-drug therapy.The reaction always involves a rash, may also include fever, jaundice, and eosinophilia, and is likely to be one manifestation of the SCARs reaction viz., the DRESS syndrome. In general, these symptoms will occur within the first six weeks of therapy or not at all, and may be ameliorated by corticosteroid therapy.
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, thereby inhibiting nucleic acid synthesis. Though structurally distinct from dapsone, the sulfonamide group of antibacterial drugs also work in this way.As an anti-inflammatory, dapsone inhibits the myeloperoxidase-H2O2-halide-mediated cytotoxic system in polymorphonucleocytes. As part of the respiratory burst that neutrophils use to kill bacteria, myeloperoxidase converts hydrogen peroxide into hypochlorous acid. 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. Myeloperoxidase inhibition has also been suggested as a neuron-sparing mechanism for reducing inflammation in neurodegenerative diseases such as Alzheimer's disease and stroke.
Dapsone's anti-inflammatory and immunomodulatory effects are thought to be its mechanism of action in treating dermatitis herpetiformis.
Dapsone is an odorless white to creamy-white crystalline powder with a slightly bitter taste.
History
Discovery
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 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, then with that of dapsone independently by Ernest Fourneau in France and Gladwin Buttle in the United Kingdom.Proposed use in antimalarial drugs
The spread of drug-resistant malaria in Africa has encouraged the development of new, low-cost antimalarial drugs. Plasmodium falciparum, one of the Plasmodium species that causes malaria, has developed resistance both to chloroquine and sulfadoxine/pyrimethamine, two of the most common treatments for malaria. Artemisinin, another antimalarial drug, had been developed in the 1980s but was too expensive for large-scale use. This led GlaxoSmithKline to develop Lapdap, a combination drug consisting of chlorproguanil and dapsone. Lapdap was licensed in the United Kingdom starting in October 2003.One advantage of Lapdap had was that chlorproguanil and dapsone are both low-cost drugs. Another was that by virtue of being of a combination drug, it was less likely to cause drug resistance. However, because dapsone causes hemolytic anemia in patients with G6PD deficiency, and because G6PD deficiency affects 10-25% of the population of sub-Saharan Africa, it was discovered that Lapdap is not safe for use in Africa. It was available in many African countries for four years before GlaxoSmithKline took it off the market in February 2008.