Are hypersensitivity reactions to dapsone becoming more frequent?

Smith, W. C.

doi:10.5935/0305-7518.19880009

Cited by 20 publications

(22 citation statements)

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“…In contrast, methaemoglobin formation was not inhibited by cimetidine or a number of drugs pharmacologically-related to dapsone. The presence of glutathione or ascorbate (500 FLM) did not alter the level of methaemoglobin observed.Keywords dapsone metabolism methaemoglobinaemia Introduction Dapsone (4,4'-diamino-diphenylsulphone) has McConkey, 1984) and in combination with pyribeen the major component of leprosy treatment methamine for malaria prophylaxis (Brucefor the last 40 years (Smith, 1988). The drug has Chwatt, 1982).…”

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confidence: 99%

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An investigation of the role of metabolism in dapsone‐induced methaemoglobinaemia using a two compartment in vitro test system.

Tingle

Coleman

Park

1990

Brit J Clinical Pharma

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1. We have utilized a two compartment system in which two teflon chambers are separated by a semi‐permeable membrane in order to investigate the role of metabolism in dapsone‐induced methaemoglobinaemia. Compartment A contained a drug metabolizing system (microsomes prepared from human liver +/‐ NADPH), whilst compartment B contained target cells (human red cells). 2. Incubation of dapsone (1‐ 100 microM) with human liver microsomes (2 mg protein) and NADPH (1 mM) in compartment A (final volume 500 microliters) led to a concentration‐ dependent increase in the methaemoglobinaemia (15.4‐18.9% at 100 microM) compared with control (2.3 +/‐ 0.4%) detected in the red cells within compartment B. In the absence of NADPH dapsone had no effect. 3. Of the putative dapsone metabolites investigated, only dapsone‐ hydroxylamine caused methaemoglobin formation in the absence of NADPH (40.6 +/‐ 6.3% with 100 microM). However, methaemoglobin was also detected when monoacetyl‐dapsone, 4‐amino‐4′‐nitro‐diphenylsulphone and 4‐aminoacetyl‐4′‐nitro‐diphenylsulphone were incubated with human liver microsomes in the presence of NADPH. 4 Dapsone‐dependent methaemoglobin formation was inhibited by addition of ketoconazole (1‐1000 microM) to compartment A, with IC50 values of 285 and 806 microM for the two liver microsomal samples studied. In contrast, methaemoglobin formation was not inhibited by cimetidine or a number of drugs pharmacologically‐ related to dapsone. The presence of glutathione or ascorbate (500 microM) did not alter the level of methaemoglobin observed.

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“…Keywords dapsone metabolism methaemoglobinaemia Introduction Dapsone (4,4'-diamino-diphenylsulphone) has McConkey, 1984) and in combination with pyribeen the major component of leprosy treatment methamine for malaria prophylaxis (Brucefor the last 40 years (Smith, 1988). The drug has Chwatt, 1982).…”

mentioning

confidence: 99%

An investigation of the role of metabolism in dapsone‐induced methaemoglobinaemia using a two compartment in vitro test system.

Tingle

Coleman

Park

1990

Brit J Clinical Pharma

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“…peak corresponding to the retention time of DDS NOH (Figure 3). No (Smith, 1988;Weetman et al, 1980). A number of studies have also noted the marked variation in DDS levels in individuals taking the same drug dose daily (DeGowin et al, 1966;Alexander et al, 1970).…”

Section: Metabolism and Covalent Binding Of Dds Nohmentioning

confidence: 99%

“…Dapsone (DDS) was introduced in the 1940s and remains the mainstay of the treatment of leprosy (Smith, 1988). It is also effective in a number of other conditions including malarial prophylaxis (with pyrimethamine, Bruce-Chwatt, 1982) and other inflammatory diseases such as rheumatoid arthritis (Swinson et al, 1981) and conditions characterized by polymorphonuclear leucocyte infiltration (Lang, 1979).…”

Section: Introductionmentioning

confidence: 99%

Bioactivation of dapsone to a cytotoxic metabolite by human hepatic microsomal enzymes.

Coleman¹,

Breckenridge²,

Park³

1989

Brit J Clinical Pharma

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1 Using human mononuclear leucocytes as target cells, we have investigated the bioactivation of dapsone (DDS) to a cytotoxic metabolite in the presence of microsomes from nine human livers. Values for NADPH dependent toxicity ranged from 8.8-27% (15.8 + 5.9%) and were similar to those for microsomes from control mice, 16-24% (19.0 ± 4.8%). 2 Microsomes prepared from mice induced with either phenobarbitone or beta-naphthoflavone did not produce significantly more NADPH dependent toxicity than microsomes prepared from control mice. 3 Cytotoxicity was abolished not only by ascorbic acid, but also by sub-physiological concentrations of N-acetylcysteine and glutathione. 4 DDS was metabolised in vitro to a hydroxylamine (metabolic conversion 3.1 ± 1.5%), which was oxidised further to a cytotoxic metabolite which also became irreversibly bound to protein.

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“…Dapsone (4,4'-diaminodiphcnyl sulfone; DDS) has been used as an antibacterial drug for over 50 years and remains a mainstay in the treatment of leprosy [1], It has also been used in the treatment of dermatitis herpetiformis [2], cutaneous leishmaniasis [3] and rheuma toid arthritis [4], and in combination with pyri methamine (Maloprim) as a malaria prophy lactic agent [5], Recently, DDS combined with trimethoprim has been shown to be an effec tive alternative to sulfamethoxazole plus tri methoprim for the treatment of Pneumocystis carinii pneumonia in patients with the ac quired immunodeficiency syndrome (AIDS)…”

Section: Introductionmentioning

confidence: 99%

Lack of Effect of Proguanil on the Pharmacokinetics of Dapsone in Healthy Volunteers

Nil¹,

Nil²

1993

Chemotherapy

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The multiple-dose kinetics of dapsone (DDS) and its principal metabolite monoacetyldapsone (MADDS) were determined in 6 healthy volunteers after daily administration of low-dose dapsone (10 mg). Comparison with a previous study involving the same volunteers on a daily regimen of proguanil (200 mg) plus dapsone (10 mg) revealed no statistically significant differences in the maximum plasma concentrations, area under the plasma drug concentration curves and elimination half-lives of both DDS and MADDS in the presence of proguanil. Although these findings suggest that proguanil does not alter the pharmacokinetics of DDS and MADDS, the possibility that proguanil affects the disposition of hydroxylated metabolites of dapsone, which appear to mediate dapsone toxicity, cannot be excluded.

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Are hypersensitivity reactions to dapsone becoming more frequent?

Cited by 20 publications

References 4 publications

An investigation of the role of metabolism in dapsone‐induced methaemoglobinaemia using a two compartment in vitro test system.

An investigation of the role of metabolism in dapsone‐induced methaemoglobinaemia using a two compartment in vitro test system.

Bioactivation of dapsone to a cytotoxic metabolite by human hepatic microsomal enzymes.

Lack of Effect of Proguanil on the Pharmacokinetics of Dapsone in Healthy Volunteers

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