A docking model of dapsone bound to HLA-B*13:01 explains the risk of dapsone hypersensitivity syndrome.

BACKGROUND: Dapsone (4,4'-diaminodiphenylsulfone) has been widely used for the treatment of infections such as leprosy. Dapsone hypersensitivity syndrome (DHS) is a major side effect, developing in 0.5-3.6% of patients treated with dapsone, and its mortality rate is ∼10%. Recently, human leukocyte antigen (HLA)-B*13:01 was identified as a marker of susceptibility to DHS. OBJECTIVES: To investigate why HLA-B*13:01 is responsible for DHS from a structural point of view. METHODS: First, we used homology modeling to derive the three-dimensional structures of HLA-B*13:01 (associated with DHS) and HLA-B*13:02 (not so associated despite strong sequence identity [99%] with HLA-B*13:01). Next, we used molecular docking, molecular dynamic simulations, and the molecular mechanics Poisson-Boltzman surface area method, to investigate the interactions of dapsone with HLA-B*13:01 and 13:02. RESULTS: We found a crucial structural difference between HLA-B*13:01 and 13:02 in the F-pocket of the antigen-binding site. As Trp95 in the α-domain of HLA-B*13:02 is replaced with the less bulky Ile95 in HLA-B*13:01, we found an additional well-defined sub-pocket within the antigen-binding site of HLA-B*13:01. All three representative docking poses of dapsone against the antigen-binding site of HLA-B*13:01 used this unique sub-pocket, indicating its suitability for binding dapsone. However, HLA-B*13:02 does not seem to possess a binding pocket suitable for binding dapsone. Finally, a binding free energy calculation combined with a molecular dynamics simulation and the molecular mechanics Poisson-Boltzman surface area method indicated that the binding affinity of dapsone for HLA-B*13:01 would be much greater than that for HLA-B*13:02. CONCLUSIONS: Our computational results suggest that dapsone would fit within the structure of the antigen-recognition site of HLA-B*13:01. This may change the self-peptides that bind to HLA-B*13:01, explaining why HLA-B*13:01 is a marker of DHS susceptibility.

Dapsone in dermatology and beyond.

Dapsone (4,4'-diaminodiphenylsulfone) is an aniline derivative belonging to the group of synthetic sulfones. In 1937 against the background of sulfonamide era the microbial activity of dapsone has been discovered. Shortly thereafter, the use of dapsone to treat non-pathogen-caused diseases revealed alternate antiinflammatory mechanisms that initially were elucidated by inflammatory animal models. Thus, dapsone clearly has dual functions of both: antimicrobial/antiprotozoal effects and anti-inflammatory features similarly to non-steroidal anti-inflammatory drugs. The latter capabilities primarily were used in treating chronic inflammatory disorders. Dapsone has been investigated predominantly by in vitro methods aiming to get more insights into the effect of dapsone to inflammatory effector cells, cytokines, and/or mediators, such as cellular toxic oxygen metabolism, myoloperoxidase-/halogenid system, adhesion molecules, chemotaxis, membrane-associated phospholipids, prostaglandins, leukotrienes, interleukin-8, tumor necrosis factor α, lymphocyte functions, and tumor growth. Moreover, attention has been paid to mechanisms by which dapsone mediates effects in more complex settings like impact of lifespan, stroke, glioblastoma, or as anticonvulsive agent. Additionally, there are some dermatological investigations in human being using dapsone and its metabolites (e.g., leukotriene B4-induced chemotaxis, ultraviolet-induced erythema). It could be established that dapsone metabolites by their own have anti-inflammatory properties. Pharmacology and mechanisms of action are determining factors for clinical use of dapsone chiefly in neutrophilic and/or eosinophilic dermatoses and in chronic disorders outside the field of dermatology. The steroid-sparing effect of dapsone is useful for numerous clinical entities. Future avenues of investigations will provide more information on this fascinating and essential agent.

Rituximab for patients with refractory mucous membrane pemphigoid.

BACKGROUND: Mucous membrane pemphigoid (MMP) still represents a potentially life- and sight-threatening disease. In a subset of patients with severe MMP, conventional immunosuppressants are ineffective or contraindicated. OBSERVATIONS: Twenty-five patients with severe refractory MMP, including 5 with mucous membrane-dominant epidermolysis bullosa acquisita, received 1 or 2 cycles of rituximab (375 mg/m(2) weekly for 4 weeks). Twenty-one of the patients were receiving concomitant therapy with dapsone and/or sulfasalazine therapy, which was maintained during rituximab cycles. Complete responses in all affected sites (ocular and/or extraocular) were obtained in 17 patients (68%) by a median time of 12 weeks after the first cycle, and 5 additional patients responded completely after a second cycle, yielding an 88% complete response rate. In all but 1 of the 10 patients with ocular lesions, their eyes became noninflammatory within a mean of 10 weeks. Among the 3 patients (12%) who developed severe infectious complications, 2 (8%) died; they had been receiving concomitant conventional immunosuppressants and high-dose corticosteroids and were hypogammaglobulinemic. Treatment with immunosuppressants was discontinued for all other patients, and no other infection was observed. Ten patients experienced relapse after a mean of 4 (range, 1-16) months after achieving complete responses. CONCLUSIONS: Rituximab appears to have rapid and dramatic efficacy in patients with severe, refractory MMP. The occurrence of severe infections in patients receiving concomitant conventional immunosuppressants supports using rituximab without other immunosuppressants. Controlled prospective studies are warranted to define an optimal treatment protocol.

Raising antibodies in chickens against primaquine, pyrimethamine, dapsone, tetracycline, and doxycycline.

Antibodies against primaquine, pyrimethamine, dapsone, tetracycline, and doxycycline were raised in chickens inoculated with each drug conjugated to a rabbit albumin carrier. Antibody titres against drug and carrier were highest during week 6 postinoculation. Affinity purified anti-primaquine antibodies did not recognise other drugs, but affinity purified anti-doxycycline and anti-tetracycline antibodies recognised both tetracycline and doxycycline in addition to primaquine. Primaquine was detected in urine from 6 to 12 hours after ingestion of therapeutic doses of the drug by anti-primaquine antibodies in a competitive ELISA. Affinity purified anti-primaquine antibodies detected primaquine in the cytoplasm and localised in organelles in monocytes that had been incubated with therapeutic concentrations of the drug.

Prophylaxis for human immunodeficiency virus-related Pneumocystis carinii pneumonia: using simulation modeling to inform clinical guidelines.

BACKGROUND: Human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy (HAART) have experienced a dramatic decrease in Pneumocystis carinii pneumonia (PCP), necessitating reassessment of clinical guidelines for prophylaxis. METHODS: A simulation model of HIV infection was used to estimate the lifetime costs and quality-adjusted life expectancy (QALE) for alternative CD4 cell count criteria for stopping primary PCP prophylaxis in patients with CD4 cell count increases receiving HAART and alternative agents for second-line PCP prophylaxis in those intolerant of trimethoprim-sulfamethoxazole (TMP/SMX). The target population was a cohort of HIV-infected patients in the United States with initial CD4 cell counts of 350/microL who began PCP prophylaxis after their first measured CD4 lymphocyte count less than 200/microL. Data were from randomized controlled trials and other published literature. RESULTS: For patients with CD4 cell count increases during HAART, waiting to stop prophylaxis until the first observed CD4 cell count was greater than 300/microL prevented 9 additional cases per 1000 patients and cost $9400 per quality-adjusted life year (QALY) gained compared with stopping prophylaxis at 200/microL. For patients intolerant of TMP/SMX, using dapsone increased QALE by 2.7 months and cost $4500 per QALY compared with no prophylaxis. Using atovaquone rather than dapsone provided only 3 days of additional QALE and cost more than $1.5 million per QALY. CONCLUSIONS: Delaying discontinuation of PCP prophylaxis until the first observed CD4 cell count greater than 300/microL is cost-effective and provides an explicit "PCP prophylaxis stopping criterion." In TMP/SMX-intolerant patients, dapsone is more cost-effective than atovaquone.

Considerações acerca dos estados reacionais do portador de Hanseníase no Município de Itajaí / Considerations on reactional states of Itajaí's hansen's carriers

A pesquisa teve por objetivo, compreender e avaliar os estados reacionais de pacientes portadores de hanseníase e o tratamento das reações. O método de abordagem do estudo foi indutivo, tendo como base o referencial bibliográfico, tomou-se como fonte de dados os prontuários dos portadores de hanseníase, disponíveis no Programa de Controle de Hanseníase da Secretaria Municipal de Saúde de Itajaí. Através do trabalho com os 78 pacientes inscritos no programa, observou-se que: 60,3 por cento tem de 15-49 anos; 65,4 por cento são do sexo masculino; 70,5 por cento manifestam a forma Virchowiana da doença; 60,3 por cento apresentaram estados reacionais durante tratamento; metade destes aproximadamente apresentaram quadro clínico de neurite, tendo sido tratados com prednisona. Também foram observados outros sintomas clínicos como o eritema nodoso hansênico, e o tratamento de escolha, sempre que possível foi a talidomida. A avaliação dos estados reacionais indica que, mais da metade dos portadores em tratamento, apresentam esta manifestação imunológica. É julgada pela literatura como consequência da doença e possível reação ao esquema poliquimioterápico

A Mycobacterium leprae isolate resistant to dapsone rifampin, ofloxacin and sparfloxacin

Mycobacterium leprae were isolated from a Japanese patient, and susceptibility to antileprosy drugs was examined by the mouse foot pad method. The isolate was susceptible to clofazimine and clarithromycin, and resistant to dapsone, rifampin, ofloxacin and sparfloxacin. Mutations were identified in the genes associated with resistance to these drugs. The risk of the emergence of leprosy with multidrug resistance is emphasized.

Induction of lepromin positivity following immuno-chemotherapy with Mycobacterium w vaccine and multidrug therapy and its impact on bacteriological clearance in multibacillary leprosy: report on a hospital-based clinical trial with the candidate antileprosy vaccine.

A vaccine based on autoclaved Mycobacterium w was administered, in addition to standard multidrug therapy (MDT), to 157 bacteriologically positive, lepromin-negative, multibacillary (LL, BL and BB) leprosy patients. The vaccinees were supported by a well-matched control group of 147 patients with similar type of disease who received a placebo injection in addition to MDT. The MDT was given for a minimum period of 2 years and continued until skin-smear negativity, while the vaccine was given at 3-month intervals up to a maximum of 8 doses. The lepromin response evaluated in terms of percentage of subjects converting to positivity status, measurement in millimeters, and duration of lepromin positivity sustained, reflected a statistically significant better outcome in the vaccine group patients (especially LL and BL leprosy) in comparison to those in the placebo group. The data indicate that lepromin-positivity status seems to have an impact on accelerating the bacteriological clearance, as is evident by the statistically significant accelerated decline in the BI of those patients who converted to lepromin positivity as compared to those remaining lepromin negative throughout therapy and post-therapy follow up. To conclude, the addition of the Mycobacterium w vaccine to standard MDT induces a lepromin response of a statistically significant higher magnitude than that observed with MDT alone.

Síndrome de hipersensibilidad a la dapsona / Dapsone hypersensitivity syndrome

Las sulfonas han sido de gran ayuda en el tratamiento de la lepra. La dapsona (4,4' diaminofenilsulfona; DDS) es el derivado más utilizado. Su empleo se extiende a diversas dermatosis. Se describen variados efectos adversos con su administración, siendo los más severos: hemólisis, metahemoglobinemia, agranulocitosis, hepatitis, encefalopatía y raramente hipoalbuminemia. Una rara complicación la constituye el síndrome de hipersensibilidad a la dapsona (SHD) caracterizado por desarrollarse en las primeras semanas de iniciado el tratamiento con este fármaco. Dicha patología se presenta en su expresión más completa con hipertermia, dermatitis exfoliativa generalizada, poliadenopatías, anemia y hepatitis mixta. Dos datos son particularmente característicos de este cuadro: un síndrome mononucleosiforme y un recuento de eosinófilos elevado. Se presenta un paciente que recibiendo dapsona como parte del tratamiento de una lepra lepromatosa (LL) desarrolló un SHD

Síndrome de hipersensibilidad a la dapsona / Dapsone hypersensitivity syndrome

Las sulfonas han sido de gran ayuda en el tratamiento de la lepra. La dapsona (4,4 diaminofenilsulfona; DDS) es el derivado más utilizado. Su empleo se extiende a diversas dermatosis. Se describen variados efectos adversos con su administración, siendo los más severos: hemólisis, metahemoglobinemia, agranulocitosis, hepatitis, encefalopatía y raramente hipoalbuminemia. Una rara complicación la constituye el síndrome de hipersensibilidad a la dapsona (SHD) caracterizado por desarrollarse en las primeras semanas de iniciado el tratamiento con este fármaco. Dicha patología se presenta en su expresión más completa con hipertermia, dermatitis exfoliativa generalizada, poliadenopatías, anemia y hepatitis mixta. Dos datos son particularmente característicos de este cuadro: un síndrome mononucleosiforme y un recuento de eosinófilos elevado. Se presenta un paciente que recibiendo dapsona como parte del tratamiento de una lepra lepromatosa (LL) desarrolló un SHD (AU)

The influence of Maloprim chemoprophylaxis on cellular and humoral immune responses to Plasmodium falciparum asexual blood stage antigens in schoolchildren living in a malaria endemic area of Mozambique.

We examined the impact of chemoprophylaxis on the cellular and humoral immune responses to polypeptides of the asexual Plasmodium falciparum blood stage antigens, the glutamate rich protein GLURP and Pf155/RESA, both of which in previous field studies have been identified as potentially protective antigens. The study was carried out in the Escola Primária de Lingamo, a primary school in a suburban area of Maputo, Mozambique. A cohort of 392 schoolchildren (aged 7-12 years) was randomly allocated to two equal groups, one receiving chemoprophylaxis with dapsone/pyrimethamine (Maloprim), the other receiving placebo every week from December 1989 to November 1990. The groups were then followed until November 1991 without chemoprophylaxis. Cellular responses to immunodominant epitopes from Pf155/RESA and GLURP, and to non malaria antigens C. albicans and PPD, were assessed by lymphocyte proliferation assays in vitro. Anti-GLURP and anti-Pf155/RESA antibodies were detected by enzyme-linked immunosorbent assay (ELISA) and erythrocyte membrane immunofluorescence (EMIF), and total anti-P. falciparum antibodies were measured by indirect fluorescent antibody test (IFAT). Immunological reactivities were evaluated every six months, at the end of the rainy season and at the end of the dry season, both during the period of chemoprophylaxis and during the follow-up. The antibody response rate to the GLURP was lower in the Maloprim group than in the placebo group during the intervention phase. The lymphoproliferative response rate to the malaria antigens was significantly lower at the end of the rainy season than at the end of the dry season, but the difference between the experimental group and the control group of schoolchildren was not statistically significant. These results suggest that the antibody responses to the GLURP molecule and partly to the Pf155/RESA antigen in this study population were shortlived and dependent on frequent boostering, but whether these antigens play a role in the development of natural clinical immunity remains open. In the experimental group of schoolchildren weekly chemoprophylaxis successfully reduced the parasite rate during the rainy season from 43% to 4%, and during the dry season from 18% to 0%. Chemoprophylaxis may therefore have a useful role in combination with another partially effective malaria control measure such as insecticide-impregnated bed nets or a malaria vaccine.