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Improvement of patient tolerance to dapsone: current and future developments.

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Improvement of patient tolerance to dapsone: current and future developments.
Michael D Coleman
Dermatology Online Journal 13 (4): 18

School of Life and Health Sciences, Aston University, Birmingham, UK

Dapsone therapy has proven to be effective in the suppression of dermatitis herpetiformis since the 1950's. In addition, it has been successfully used for several other non-infectious, inflammatory conditions such as bullous pemphigoid, acne vulgaris, epidermolysis bullosa acquisita, and brown-recluse spider bite reaction [1, 2, 3]. The drug has become established as a second line therapy for Pneumocystis jiroveci pneumonia [4, 5] and remains part of various antimalarial and antileprosy treatments [1]. Dapsone is associated with dose-dependent hematological adverse effects, including methemoglobin formation and anemia, which can affect patient tolerance adversely [4, 6]. With the more serious adverse events such as agranulocytosis, the role of dose is less clear-cut and other factors such as immune reactivity may be more important [7]. It is established that the toxicity of dapsone is mostly due to its metabolism by N-hydroxylation to hydroxylamines; acetylation of the drug is not necessarily protective because these metabolites can also be N-hydroxylated [8].

The relevance of dapsone's toxicity is of particular importance in its dermatological roles because wide dosage ranges often must be explored to obtain adequate clinical response. Some patients may only achieve relief from the symptoms of dermatitis herpetiformis at doses four-fold higher than those used to treat leprosy [9]. This may result in methemoglobin levels that may not be life threatening, but do exert a far greater impact on patient quality of life than is often realized. This may be especially true when other underlying conditions exacerbate the clinical impact of the methemoglobin [5, 9, 10].

Strategies for improved patient tolerance of dapsone

In the early 1990's co-administration of cimetidine was attempted to improve patient tolerance to dapsone by diminishing the formation of the methemoglobin-forming N-hydroxylated metabolites [9, 11]. A protocol was developed in which cimetidine was given to dapsone patients in divided doses (1200mg total); this resulted in a 27 percent reduction in methemoglobin formation without loss of clinical efficacy. Although it means adding an additional drug, the safety of cimetidine and its over-the-counter availability yields an acceptable risk-benefit ratio. The use of cimetidine in this context has been cited subsequently [5,12, 13, 14, 15, 16, 17]; it has become an option in the control of the adverse reactions associated with dapsone, particularly when it is necessary to use doses in excess of 200 mg daily [18]. In cases of dapsone overdosage, cimetidine may also be useful as a supportive measure to reduce hepatic production of the hemoglobin-oxidizing hydroxylamines. Methylene blue administration facilitates the reduction of methemoglobin [12, 13].

Possible future combined strategies for improved dapsone tolerance

The market for the dermatological applications of dapsone is relatively small, so it is unlikely that potentially safer alternatives to the drug will be developed [19]. Therefore, unlicensed applications of dapsone for a variety of inflammatory conditions will continue for the foreseeable future. It is also clear that greater reductions in dapsone-mediated methemoglobin would be advantageous for patient welfare and compliance. A possible route where this could be achieved is through the concomitant administration of lipoic acid, a dietary constituent and supplement that has long been used in a variety of conditions related to oxidative stress [20].

Lipoic acid is reduced intracellularly to the thiol dihydrolipoic acid (DHLA) and it is likely that DHLA is the main cellular antioxidant [21]. In vitro studies with dapsone-related hydroxylamines in human erythrocytes have indicated that both DHLA and lipoic acid are capable of attenuating methemoglobin formation directly [22, 23, 24]. Interestingly, this effect is even more pronounced when the hydroxylamine is formed in vitro from hepatic microsomes in the presence of DHLA [22], rather than administered in a bolus dose. Hydroxylamine formation from microsomes in the presence of erythrocytes is a reasonable approximation of the situation in vivo where the hydroxylamine formed in the liver gradually enters the blood over the three hours or so before methemoglobin levels peak after an oral dose [9]. Although DHLA directly attenuates methemoglobin formation due to hydroxylamines, lipoic acid is more likely to exert its major effect through conversion to DHLA [25]. Supplementation of DHLA is impractical due to cost and its lack of stability. However, lipoic acid itself is safe, freely available commercially and is converted to DHLA in vivo [26]. In combination with other antioxidants, lipoic acid at a dosage of 90 mg daily increased total thiol levels in human erythrocytes [25].


It is possible that the effectiveness of cimetidine in the alleviation of dapsone toxicity may well be augmented safely by co-administration of lipoic acid and the exploration of this suggested combination might benefit those patients whose dapsone treatment is adversely affected by high toxicity.


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