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

  • Author(s): Coleman, Michael D
  • et al.
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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].


Conclusion

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.

References

1. Wolf R, Tuzu NB, Tuzun Y. Dapsone: unapproved uses or indications. Clin Dermatol 2000; 8:37–53.

2. Bahadir S Cobanoglu U, Cimsit G, et al. Erythema dyschromicum perstans: response to dapsone therapy. Int J Dermatol 2004; 43: 220-222

3. Wilson JR, Hagood CO, Prather ID. Brown recluse spider bites: A complex problem wound. A brief review and case study. Ostomy Wound Man 2005; 51: 59-66.

4. Sangiolo D Storer B, Nash R, et al. Toxicity and efficacy of daily dapsone as Pneumocystis jiroveci prophylaxis after hematopoietic stem cell transplantation: a case-control study. Biol Blood Marrow Transplant 2003; 11:521-529.

5. Lee I, Barton TD, Goral S, et al. Complications related to dapsone use for Pneumocystis jiroveci pneumonia prophylaxis in solid organ transplant recipients. Am. J. Transplant. 2005; 5: 2791-2795.

6. Rybojad M, Ducloy G, Reymond JL, et al. Childhood pemphigus foliaceus: 2 cases. Ann. Derm. Venereol 1999; 126: 41-43

7. Coleman MD Dapsone mediated agranulocytosis: risks, possible mechanisms and prevention. Toxicology 2001; 162 53-60

8. Israili ZH, Cucinell SA, Vaught J, et al. Studies of the metabolism of DDS in man and experimental animals. Formation of N-hydroxy metabolites. J. Pharmac Exper Ther 1973; 187: 138-151.

9. Coleman MD, Rhodes LA, Scott AK, et al. The use of cimetidine to reduce dapsone-dependent methaemoglobinaemia in dermatitis herpetiformis patients. Brit. J. Clin Pharmac. 1992; 34 244-249.

10. Coleman MD Coleman NA Drug-Induced Methaemoglobinaemia Drug Safety 1996; 14 394-405.

11. Coleman MD, Scott AK, Breckenridge AM, et al. The use of cimetidine as a selective inhibitor of dapsone N-hydroxylation in man. Brit. J. Clin. Pharmac 1990; 30: 761-767.

12. Sharma VK Haber AD. Acquired methemoglobinemia: a case report of benzocaine-induced methemoglobinemia and a review of the literature. Clin Pulm Med 2002; 9; 53-58.

13. Ferguson AJ, Lavery GG. Deliberate self-poisoning with dapsone - A case report and summary of relevant pharmacology and treatment Anaesthesia 1997; 52: 359-363

14. Szeremeta W, Dohar JE Dapsone - induced methemoglobinemia:an anesthetic risk. Int J Ped Otorhinol 1995; 33: 75-80

15. Van der Ven AJM, Koopmans PP, Vree TB, et al. Drug intolerance in HIV disease J Antimicrob Chemother 1994; 34: 1-5.

16. Willsteed E, Lee M, Wong, LC et al. Sulfasalazine and dermatitis herpetiformis Austral. J Dermatol. 2005; 46: 101-103.

17. Williams S, MacDonald P, Hoyer JD, et al. Methemoglobinemia in Children With Acute Lymphoblastic Leukemia (ALL) Receiving Dapsone for Pneumocystis Carinii Pneumonia (PCP) Prophylaxis: A Correlation With Cytochrome b5 Reductase (Cb5R) Enzyme Levels. Pediatr Blood Cancer 2005; 44: 55–62.

18. Scheinfeld N. Cimetidine: A Review of the Recent Developments and Reports in Cutaneous Medicine. Dermatol Online J 2003; 9(2).

19. Coleman MD, Hadley S, Perris AD et al. Studies on the toxicity and efficacy of some ester analogues of dapsone in vitro using rat and human studies. Env. Tox. Pharm. 2002; 12: 7-13.

20. Bilska A, Wlodek P. Lipoic acid - the drug of the future? Pharm Rep 2005; 57: 570-577.

21. Biewenga GP, Haenen GRRM, Bast A. The pharmacology of the antioxidant lipoic acid. Gen Pharmacol 1997; 29: 315-331.

22. Coleman MD and Baker CD Effects of the antioxidants dihydrolipoic acid (DHLA) and probucol on xenobiotic-mediated methaemoglobin formation in human diabetic and non-diabetic erythrocytes in vitro Env. Tox. Pharmacol. 2001; 9: 161-167,

23. Coleman MD, Tolley HL, Desai AK. Monitoring antioxidant effects using methaemoglobin formation in diabetic erythrocytes. Brit J Diab Vas Dis 2001; 1: 88-92.

24. Coleman MD, Taylor CT. Effects of Dihydrolipoic acid (DHLA), α-Lipoic acid. N-Acetyl Cysteine and Ascorbate on Xenobiotic-Mediated Methaemoglobin Formation in Human Erythrocytes In-vitro. Env. Tox. Pharmacol 2003; 14: 121-127.

25. Coleman MD Fernandez S Khanderia L. A novel clinical monitoring method to evaluate a triple antioxidant combination (vitamins E, C and α-lipoic acid) in diabetic volunteers using in vitro methaemoglobin formation. Env. Tox. Pharmacol. 2003; 14: 33-42.

26. Packer L,Witt EH, Tritschler H J. Alpha-lipoic acid as a biological antioxidant. Free Radic Biol Med 1995; 19:227–250.

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