DAPSONE AND RED BLOOD CELLS ------------------------------------------------ I have a patient (48 y/o WF) with cicatricial pemphigoid since Sept. of '93 who was brought under control with Dapsone so that she was lesion free by Dec. '94. Besides her good luck, her course was remarkable in that she never developed much of a hemolytic anemia, even at 100mg bid (Hgb 13.8-12.9, methemoglobin 3.2 with nl< 2.0). She discontinued therapy on her own and didn't flare for one year, at which time she returned with face and mouth lesions. I began her on Dapsone 100mg bid again (along with lectures on the nature of her disease and the medication), but she returned 2 weeks late and had on her own bumped her dose up to 3 and a half tablets a day, showing no signs of cyanosis. Her Hgb had fallen from 13.6 when on 100mg bid, to 12.5. Her disease was stable, but no better. My question is not about the clinical response (which is variable in this disease on this medication in any case), but about the oddly mild side effect profile in this patient. Is this a lack of absorbtion of the drug, or do some individuals just have unusually sturdy RBCs? (By the way, she really was on that high dose--she used up what I had prescribed and then started on an old bottle left over from the previous year). John Uhlemann MD ---------------- I've quite a number of CP patients on healthy doses of dapsone and a few have a similar mild decrease in Hb. I have no good explanation, but suspect that it may relate to the ave. age of the patients' RBCs. It seems that young RBCs have more G6PD than old ones and can withstand the drug better. You also may find that dapsone won't do the job in CP. We have had few dramatic successes from the drug and are turning to imuran or even cyclophosphamide in many patients. A randomized trial is really needed. Guy Webster MD -------------- I have only measured a methemaglobin in one patient who was symptomatic with methemaglobinemia. Are you, my cyber-colleagues, routinely measuring methemaglobin in your patients on dapsone? If so, how do you use this information in dosing your patients? I called a producer of DAPSONE 10 years ago to ask if Dapsone was a sulfonamide. He told me that it is a different moety and cross reactivity with sulfonamides is unlikely. Is this true? The patient described certainly could have had a reaction to dapsone. However, this patient may not be allergic to "sulfa's." Harry Goldin, M.D. ------------------ I never check methhemoglobin routinely - only if I suspect a problem [eg. the patient is blue, or has SOB, etc.] KC Smith MD FRCPC Niagara Falls ON ----------------- I agree almost totally. I check them more often only because we track labs over long periods of time in case we use the patients in studies. Other considerations are patients with cardio-pulmonary disease where real chronic low hgb/hct (revealed by low to nl hgb with high methgb) can cause initially asymptomatic chronic problems (pts have had pulmonary htn induced this way), and to check the pharmacologic effects of high doses (vs poor absorption, bad drug, non-compliance). Regarding "sulfas", sulfones, sulfonamides: they are different yet there are reports of cross reactivity between dapsone and bactrim ranging from 5%-50% in crossovers-mostly in HIV pts where sulfa/sulfone sensitivity is greater. There are also reports of non-cross reactivity which of course as a "negative" finding is not often reported when it happens. There are also reports stating as many as 30% of initially sulfa sensitive (mostly dermatitis) pts may not react on rechallenge, aside from the desensitization issue. In non-HIV pts the cross reactivity is probably lower. It all comes down to which V-D-J recombinations and somatic mutations occur, and which T and B cells get activated ie. _luck_. The experience with dapsone and sulfapyridine is low cross-reactivity of these sulfones, especially in seriously adverse reactions. My guess is this is because there is a central sulfone between 2 aminophenyl grps in dapsone and a central sulfonamide (sulfone+amide) between the aminophenyl and pyridyl grps in sulfapyridine. The central amide could be expected to contribute to any major epitope seen by the immune system and make a significant difference between these two. Having said all this there are patients get drug reactions credited to cross-reactivities between varying chemical sulfas. This is difficult to prove often without rechallenge. Some dapsone relevant reports: Pertel P; Hirschtick R. Adverse reactions to dapsone in persons infected with human immunodeficiency virus. Clin Infect Dis 1994 Apr;18(4):630-2 Jorde UP; Horowitz HW; Wormser GP. Utility of dapsone for prophylaxis of Pneumocystis carinii pneumonia in trimethoprim-sulfamethoxazole-intolerant, HIV-infected individuals AIDS 1993 Mar;7(3):355-9 Martin MA; Cox PH; Beck K; Styer CM; Beall GN. A comparison of the effectiveness of three regimens in the prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients. Arch Intern Med 1992 Mar;152(3):523-8 Medina I; Mills J; Leoung G; Hopewell PC; Lee B; Modin G; Benowitz N; Wofsy CB Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone. N Engl J Med 1990 Sep 20;323(12):776-82. Metroka CE; Lewis NJ; Jacobus DP. Desensitization to dapsone in HIV-positive patients. JAMA 1992 Jan 22-29;267(4):512 Piketty C; Gilquin J; Kazatchkine MD. Efficacy and safety of desensitization to trimethoprim-sulfamethoxazole in human immunodeficiency virus-infected patients. J Infect Dis 1995 Aug;172(2):611 Gluckstein D; Ruskin J. Rapid oral desensitization to trimethoprim-sulfamethoxazole: use in prophylaxis for Pneumocystis carinii pneumonia in patients with AIDS who were previously intolerant to TMP-SMZ. Clin Infect Dis 1995 Apr;20(4):849-53 Bissuel F; Cotte L; Crapanne JB; Rougier P; Schlienger I; Trepo C. Trimethoprim-sulphamethoxazole rechallenge in 20 previously allergic HIV-infected patients after homeopathic. AIDS 1995 Apr;9(4):407-8 Unique Identifier: 95314805 Bachmeyer C; Salmon D; Guerin C; Barre C; Hazebroucq G; Sicard D; Sereni D. Trimethoprim-sulphamethoxazole desensitization in HIV-infected patients: an open study. AIDS 1995 Mar;9(3):299-300 Moreno JN; Poblete RB; Maggio C; Gagnon S; Fischl MA Rapid oral desensitization for sulfonamides in patients with the acquired immunodeficiency syndrome. Ann Allergy Asthma Immunol 1995 Feb;74(2):140-6 David J. Altman, MD, PhD Dermatology Branch, NCI, NIH ---------------------------- To those of you out there interested in the methemoglobin discussion, one can add cimetidine TID 400mg to significantly decrease the methemoglobinemia and increase the trough Dapsone level. It is possible atleast the "blue" patients out there will be more comfortable. I discovered this several years ago at the poster exhibit at the Academy meeting. I will find the reference at my office the day after tomorrow for those interested, please email me directly. Diane Thaler MD --------------- I'm in the process of writing an article about the effects you describe above. Basically the anemia of dapsone is related to deficiencies of zinc and selenium and probably other dietary factors as well (vitamin A). You can order a serum carotene on the patient. It tells 1. about absorption (low means poor absorption) and 2. about vitamin A status (low leads to more anemia).Heavy periods in women also contribute to low iron stores. Your patient probably has a good diet/good absorption. Most patients in trouble with dapsone have multiple dietary deficiencies. Haines ELy MD, Grass Valley, Ca. ----------------- I have patients on 400 mg QD dapsone with Hgb WNL (but not really once you subtract MetHgb), however they have methemoglobinemia, haptoglobins showing hemolysis, high retics, and are a bit blue to say the least. Iron, B12, folate should be followed. There does seem to be quite a bit of individual variability in side effects and even these pharmacologic effects of dapsone. Absorption and the stability of old medication are good concerns and possible explanations as well. I have seen pts with absorption probs that resolve (exogenous or endogenous) and rapidly hemolyze a lot on the previously tolerated dose. David J. Altman, MD, PhD Dermatology Branch, NCI, NIH ---------------------------- Cimetidine Reduces Dapsone-Induced Hematological Toxicity in DH B.J.Dermatol l992; 127:426 L.E.Rhodes Br.J.Clin.Pharmac. (1992),34,244-249 The Use of Cimetidine to Reduce Dapsone-Dependent Methaemoglobinemia M.D.Coleman n.b. I have not looked for follow up articles. Diane Thaler ------------ In the first article you cite above the authors gave cimetidine 1.6 g daily to patients on dapsone 50-100mg/d to inhibit the toxic hydoxylamine metabolite of dapsone which causes methemoglobinemia. They gave the cimetidine for 3 months and noted the dapsone level rose from 2298+/- 849ng/ml at baseline to 3006 +/- 1131ng/ml at week 3. This rise was sustained during cimetidine administration. The take home lesson: Long-term concurrent cimetidine results in increased plasma dapsone levels without an increase in hemolysis and is accompanied by reduced methemoglobinemia. I'd like to call attention to another article: Increased translocation of escherichia coli and development of arthritis in vitamin A-deficient rats by Weidermann et al. Inf and Immun 1995:63(8):6062-3068. Many of our DH patients are severely deficient in micronutrients and vitamins because of their intestinal problems. This contributes more than anything to the toxicity of dapsone. Do serum carotene levels on your dh patients. Supplement with vitamin A in any case. Haines Ely MD -------------- ------- 4.29.96