Dapsone toxicity

Bluhm RE, Adedoyin A, McCarver DG, et al. Development of dapsone toxicity in patients with inflammatory dermatoses activity of acetylation and hydroxyl-ation as risk factors. Clin Pharmacol Ther 1999 65 598-605. 

Coleman MD. Dapsone toxicity Some current perspectives. Gen Pharmacol 1995 26 1461-7. 

Twelve HIV-positive patients were given dapsone 100 mg daily for 2 weeks and then, in random order, either rifabutin 300 mg daily, fluconazole 200 mg daily, or fluconazole with rifabutin, each for 2 weeks. Rifabutin alone increased the clearance of dapsone by 67%. When combined with flueonazole, rifabutin increased the clearance of dapsone hy 38%, which shows that fluconazole partially attenuated the enzyme-inducing effects of rifabutin. Rifabutin increased the formation clearance of dapsone by 92%, which was again attenuated by fluconazole. Rifabutin did not affect the AUC of the hydroxylamine metabolite of dapsone, which is thought to be associated with dapsone toxicity. ... 

The serum levels of both drugs are possibly raised by concurrent use. Both increased efficacy and dapsone toxicity have been seen. 

Information is limited. The difference between the results of the two studies may be because the first was in AIDS patients with Pneumocystis pneumonia and the second was in asymptomatic HIV-positive patients whose drug metabolism may possibly be different. Concurrent use appears to be an effective form of treatment, but be alert for evidence of increased dapsone toxicity (methaemoglobinaemia). 

The first are competitors of PABA (p-aminobenzoic acid) and thus intermpt host de novo formation of the tetrahydrofoUc acid required for nucleic acid synthesis. Examples of dmgs that fall into this group are the sulfones and sulfonamides. The most weU-known of the sulfones is dapsone (70, 4,4 -diaminodiphenyl sulfone, DDS), whose toxicity has discouraged its use. Production of foHc acid, which consists of PABA, a pteridine unit, and glutamate, is disturbed by the substitution of a sulfonamide (stmcturally similar to PABA). The antimalarial sulfonamides include sulfadoxine (71, Fanasd [2447-57-6]) sulfadiazine (25), and sulfalene (72, sulfamethoxypyrazine [152-47-6] Kelfizina). Compounds of this group are rapidly absorbed but are cleared slowly. 

Frequency 45-65% of Caucasians and African Americans 10-15% of Asians Slow inactivation of drugs such as isoniazid (for tuberculosis), dapsone (for leprosy), and hydralazine (for high blood pressure), leading to toxicity from the drug at doses well tolerated in people with rapid acetylator phenotype Clinical consequences depend on the specific side effects of the drugs... 

The toxicity of dapsone is due to the cytochrome P-450-catalyzed oxygenation leading to iV-hydroxydapsone. This major metabolite enters red cells and is co-oxidized with oxyhemoglobin to generate a nitroso derivative and methemoglobin148. 

Fig. 8.22 Structures of sulfamethoxazole and dapsone, drugs which form toxic hydroxylamine metabolites.

Different antimalarials selectively kill the parasite s different developmental forms. The mechanism of action is known for some of them pyrimethamine and dapsone inhibit dihydrofolate reductase (p. 273), as does chlorguanide (proguanil) via its active metabolite. The sulfonamide sulfadoxine inhibits synthesis of dihydrofolic acid (p. 272). Chlo-roquine and quinine accumulate within the acidic vacuoles of blood schizonts and inhibit polymerization of heme, the latter substance being toxic for the schizonts. 

Although dapsone (Avlosulfon) was once used in the treatment and prophylaxis of chloroquine-resistant P. falciparum malaria, the toxicities associated with its administration (e.g., agranulocytosis, methemoglobinemia, hemolytic anemia) have severely reduced its use. 

Ocular toxicity is rare with dapsone. Reduced visual acuity has been described after overdosage (18). 

Serious cutaneous reactions, such as exfoliative dermatitis, toxic epidermal necrolysis, and erythema multiforme buUo-sum are extremely rare. Erythema nodosum leprosum has been described during dapsone therapy, mostly in the lepro-matous type of leprosy (10). If erythema nodosnm develops before the start of therapy, the drug should be withheld until the reaction has disappeared. Severe erythema nodosum can be controlled by short-term glucocorticoid therapy. Desensitization to dapsone in patients with hypersensitivity reactions has been proposed (29). 

McIntosh K, Cooper E, Xu J, Mirochnick M, Lindsey J, Jacobus D, Mofenson L, Yogev R, Spector SA, Sullivan JL, Sacks H, Kovacs A, Nachman S, Sleasman J, Bonagura V, McNamara J. Toxicity and efficacy of daily vs. weekly dapsone for prevention of Pneumocystis carinii pneumonia in children infected with human immunodeficiency virus. ACTG 179 Study Team. AIDS Clinical Trials Group. Pediatr Infect Dis J 1999 18(5) 432-9. 

Lau G. A fatal case of drug-induced multi-organ damage in a patient with Hansen s disease dapsone syndrome or rifampicin toxicity Forensic science international. 1995 May 22 73(2) 109-15. 

Methemoglobinemia toxicity is caused by several aromatic amines, including aniline and dapsone. and is a re.sult oftlie bioconversion of the aromatic amine to its A/-hydroxy... 

Ciccoli and coworkers have shown that incubation of rat erythrocytes with hydroxy lated metabolites of aniline, dapsone (39) and the corresponding hydroxylamines brings about enhanced release of iron and methemoglobin formation. This did not occur with parent compounds. That xenobiotics are effective only after biotransformation to metabolites in vivo is supported by acute intoxication of rats with aniline or 39 and marked increase in the erythrocyte content of free iron and of methemoglobin144. The potent toxicity of aniline-derived aminophenylnorharman in the liver of the gpt delta transgenic mouse has been demonstrated145,146. 

As a result of the inflammatory nature of asthma and the risk of toxicities from corticosteroids, a number of the drugs with antiinflammatory or immunomodulatory activity such as hydroxychloroquine, dapsone, gold, intravenous gamma-globulin, cyclosporine, and colchicine have been studied in severe steroid-dependent asthma with mixed results. ... 

As almost all foreign compounds are distributed via the bloodstream, the components of the blood are exposed at least initially to significant concentrations of toxic compounds. Damage to and destruction of the blood cells results in a variety of sequelae such as a reduced ability to carry oxygen to the tissues if red blood cells are destroyed. Aromatic amines such as aniline and the drug dapsone (4,4-diaminodiphenyl sulphone) are metabolized to hydroxylamines, and in the latter case the metabolite is concentrated in red blood cells. Also, nitro compounds such as nitrobenzene, which can be reduced to hydroxylamines, are similarly toxic to red blood cells. These hydroxylamines are often unstable and can be further oxidized to reactive products, in the presence of oxygen in the... 

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