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Clinical, Cosmetic and Investigational... 2021Lupus erythematosus (LE) is a chronic autoimmune condition with a wide spectrum of clinical presentations. Alopecias, both non-scarring and scarring, frequently occur in... (Review)
Review
Lupus erythematosus (LE) is a chronic autoimmune condition with a wide spectrum of clinical presentations. Alopecias, both non-scarring and scarring, frequently occur in the context of LE and can assume several different patterns. Furthermore, alopecia occurring with LE may be considered LE-specific if LE-specific features are present on histology; otherwise, alopecia is considered non-LE-specific. Non-scarring alopecia is highly specific to systemic LE (SLE), and therefore has been regarded as a criterion for the diagnosis of SLE. Variants of cutaneous LE (CLE), including acute, subacute, and chronic forms, are also capable of causing hair loss, and chronic CLE is an important cause of primary cicatricial alopecia. Other types of hair loss not specific to LE, including telogen effluvium, alopecia areata, and anagen effluvium, may also occur in a patient with lupus. Lupus alopecia may be difficult to treat, particularly in cases that have progressed to scarring. The article summarizes the types of lupus alopecia and recent insight regarding their management. Data regarding the management of lupus alopecia are sparse and limited to case reports, and therefore, many studies including in this review report the efficacy of treatments on CLE as a broader entity. In general, for patients with non-scarring alopecia in SLE, management is aimed at controlling SLE activity with subsequent hair regrowth. Topical medications can be used to expedite recovery. Prompt treatment is crucial in the case of chronic CLE due to potential for scarring and irreversible damage. First-line therapies for CLE include topical corticosteroids and oral antimalarials, with or without oral corticosteroids as bridging therapy. Second and third-line systemic treatments for CLE include methotrexate, retinoids, dapsone, mycophenolate mofetil, and mycophenolate acid. Additional topical and systemic medications as well as physical modalities used for the treatment of lupus alopecia and CLE are discussed herein.
PubMed: 33833540
DOI: 10.2147/CCID.S269288 -
Allergy Aug 2019Research into drug hypersensitivity associated with the expression of specific HLA alleles has focussed on the interaction between parent drug and the HLA with no...
BACKGROUND
Research into drug hypersensitivity associated with the expression of specific HLA alleles has focussed on the interaction between parent drug and the HLA with no attention given to reactive metabolites. For this reason, we have studied HLA-B*13:01-linked dapsone hypersensitivity to (a) explore whether the parent drug and/or nitroso metabolite activate T cells and (b) determine whether HLA-B*13:01 is involved in the response.
METHODS
Peripheral blood mononuclear cells (PBMC) from six patients were cultured with dapsone and nitroso dapsone, and proliferative responses and IFN-γ release were measured. Dapsone- and nitroso dapsone-specific T-cell clones were generated and phenotype, function, HLA allele restriction, and cross-reactivity assessed. Dapsone intermediates were characterized by mass spectrometry.
RESULTS
Peripheral blood mononuclear cells from six patients and cloned T cells proliferated and secreted Th1/2/22 cytokines when stimulated with dapsone (clones: n = 395; 80% CD4 CXCR3 CCR4 , 20% CD8+CXCR3 CCR4 CCR6 CCR9 CCR10 ) and nitroso dapsone (clones: n = 399; 78% CD4+, 22% CD8 with same chemokine receptor profile). CD4 and CD8 clones were HLA class II and class I restricted, respectively, and displayed three patterns of reactivity: compound specific, weakly cross-reactive, and strongly cross-reactive. Nitroso dapsone formed dimers in culture and was reduced to dapsone, providing a rationale for the cross-reactivity. T-cell responses to nitroso dapsone were dependent on the formation of a cysteine-modified protein adduct, while dapsone interacted in a labile manner with antigen-presenting cells. CD8 clones displayed an HLA-B*13:01-restricted pattern of activation.
CONCLUSION
These studies describe the phenotype and function of dapsone- and nitroso dapsone-responsive CD4 and CD8 T cells from hypersensitive patients. Discovery of HLA-B*13:01-restricted CD8 T-cell responses indicates that drugs and their reactive metabolites participate in HLA allele-linked forms of hypersensitivity.
Topics: Adult; Cross Reactions; Dapsone; Female; Gene Expression; HLA-B Antigens; Humans; Hypersensitivity; Immunophenotyping; Lymphocyte Activation; Male; Middle Aged; Nitroso Compounds; Sensitivity and Specificity; T-Lymphocyte Subsets; T-Lymphocytes
PubMed: 30844087
DOI: 10.1111/all.13769 -
Frontiers in Pharmacology 2022Adverse drug reactions (ADR) remain the major problems in healthcare. Most severe ADR are unpredictable, dose-independent and termed as type B idiosyncratic reactions.... (Review)
Review
Adverse drug reactions (ADR) remain the major problems in healthcare. Most severe ADR are unpredictable, dose-independent and termed as type B idiosyncratic reactions. Recent pharmacogenomic studies have demonstrated the strong associations between severe ADR and genetic markers, including specific HLA alleles (e.g., for carbamazepine-induced severe cutaneous adverse drug reactions [SCAR], for allopurinol-SCAR, for abacavir-hypersensitivity, for dapsone/co-trimoxazole-induced SCAR, and for terbinafine-induced liver injury), drug metabolism enzymes (such as for phenytoin-induced SCAR and missense variant of / for thiopurine-induced leukopenia), drug transporters (e.g., SLCO1B1 polymorphism for statin-induced myopathy), and T cell receptors (Sulfanilamide binding into the CDR3/Vα of the TCR 1.3). This mini review article aims to summarize the current knowledge of pharmacogenomics of severe ADR, and the potentially clinical use of these genetic markers for avoidance of ADR.
PubMed: 35548363
DOI: 10.3389/fphar.2022.886377 -
International Journal of Molecular... Dec 2022Some physicians use dapsone as part of the standard treatment of severe COVID-19 patients entering the ICU, though some do not. To obtain an indication of whether...
Some physicians use dapsone as part of the standard treatment of severe COVID-19 patients entering the ICU, though some do not. To obtain an indication of whether dapsone is helping or not, we undertook a retrospective chart review of 29 consecutive ICU COVID-19 patients receiving dapsone and 30 not receiving dapsone. As we previously reported, of those given dapsone, 9/29 (30%) died, while of those not given dapsone, 18/30 (60%) died. We looked back on that data set to determine if there might be basic laboratory findings in these patients that might give an indication of a mechanism by which dapsone was acting. We found that the neutrophil-to-lymphocyte ratio decreased in 48% of those given dapsone and in 30% of those not given dapsone. We concluded that dapsone might be lowering that ratio. We then reviewed collected data on neutrophil related inflammation pathways on which dapsone might act as presented here. As this was not a controlled study, many variables prevent drawing any conclusions from this work; a formal, randomized controlled study of dapsone in severe COVID-19 is warranted.
Topics: Humans; COVID-19; Neutrophils; Dapsone; Retrospective Studies; Intensive Care Units; Lymphocytes
PubMed: 36555204
DOI: 10.3390/ijms232415563 -
BMJ Case Reports Aug 2020Methaemoglobinaemia is a rare disease that is typically caused by a medication or other exogenous agent, with dapsone being the most common. It occurs when the...
Methaemoglobinaemia is a rare disease that is typically caused by a medication or other exogenous agent, with dapsone being the most common. It occurs when the concentration of methaemoglobin rises via ferrous haeme irons becoming oxidised to the ferric state, which shifts the oxygen dissociation curve to the left. The net result of an elevated methaemoglobin concentration is functional anaemia and impaired oxygen delivery to tissues. At lower blood levels, this can cause symptoms such as cyanosis, lethargy, headache and fatigue, whereas at higher levels it can be fatal. Here we discuss a subtle case of dapsone-induced methaemoglobinaemia presenting as subacute mental status changes and apparent hypoxia, thus highlighting the association between methaemoglobinaemia and dapsone. This case demonstrates the importance of thorough medication reconciliation and maintaining a broad differential diagnosis, while also recognising the significance of conflicting data and their implications for the workup.
Topics: Aged; Anti-Infective Agents; Confusion; Dapsone; Female; Humans; Memory Disorders; Methemoglobin; Methemoglobinemia; Oxygen
PubMed: 32843412
DOI: 10.1136/bcr-2020-235403 -
The Journal of Biological Chemistry Dec 2023Positive heterotropic cooperativity, or "activation," results in an instantaneous increase in enzyme activity in the absence of an increase in protein expression. Thus,...
Positive heterotropic cooperativity, or "activation," results in an instantaneous increase in enzyme activity in the absence of an increase in protein expression. Thus, cytochrome P450 (CYP) enzyme activation presents as a potential drug-drug interaction mechanism. It has been demonstrated previously that dapsone activates the CYP2C9-catalyzed oxidation of a number of nonsteroidal anti-inflammatory drugs in vitro. Here, we conducted molecular dynamics simulations (MDS) together with enzyme kinetic investigations and site-directed mutagenesis to elucidate the molecular basis of the activation of CYP2C9-catalyzed S-flurbiprofen 4'-hydroxylation and S-naproxen O-demethylation by dapsone. Supplementation of incubations of recombinant CYP2C9 with dapsone increased the catalytic efficiency of flurbiprofen and naproxen oxidation by 2.3- and 16.5-fold, respectively. MDS demonstrated that activation arises predominantly from aromatic interactions between the substrate, dapsone, and the phenyl rings of Phe114 and Phe476 within a common binding domain of the CYP2C9 active site, rather than involvement of a distinct effector site. Mutagenesis of Phe114 and Phe476 abrogated flurbiprofen and naproxen oxidation, and MDS and kinetic studies with the CYP2C9 mutants further identified a pivotal role of Phe476 in dapsone activation. MDS additionally showed that aromatic stacking interactions between two molecules of naproxen are necessary for binding in a catalytically favorable orientation. In contrast to flurbiprofen and naproxen, dapsone did not activate the 4'-hydroxylation of diclofenac, suggesting that the CYP2C9 active site favors cooperative binding of nonsteroidal anti-inflammatory drugs with a planar or near-planar geometry. More generally, the work confirms the utility of MDS for investigating ligand binding in CYP enzymes.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C9; Cytochrome P-450 Enzyme System; Dapsone; Flurbiprofen; Kinetics; Naproxen; Humans
PubMed: 37866634
DOI: 10.1016/j.jbc.2023.105368 -
Pharmaceutics Dec 2020Leprosy disease remains an important public health issue as it is still endemic in several countries. , the causative agent of leprosy, presents tropism for cells of the... (Review)
Review
Leprosy disease remains an important public health issue as it is still endemic in several countries. , the causative agent of leprosy, presents tropism for cells of the reticuloendothelial and peripheral nervous system. Current multidrug therapy consists of clofazimine, dapsone and rifampicin. Despite significant improvements in leprosy treatment, in most programs, successful completion of the therapy is still sub-optimal. Drug resistance has emerged in some countries. This review discusses the status of leprosy disease worldwide, providing information regarding infectious agents, clinical manifestations, diagnosis, actual treatment and future perspectives and strategies on targets for an efficient targeted delivery therapy.
PubMed: 33322356
DOI: 10.3390/pharmaceutics12121202 -
Clinical Case Reports May 2021Dapsone therapy is associated with methemoglobinemia. Pulse oximetry is used to indicate adequate oxygen saturations, and co-oximetry is needed to diagnose low arterial...
Dapsone therapy is associated with methemoglobinemia. Pulse oximetry is used to indicate adequate oxygen saturations, and co-oximetry is needed to diagnose low arterial oxygen saturations. Clinicians should aware while prescribing dapsone.
PubMed: 34084488
DOI: 10.1002/ccr3.4054 -
Clinical and Experimental Rheumatology May 2022Relapsing polychondritis (RP) evolves with variable and intermittent involvement of cartilage and proteoglycan-rich structures. Ocular manifestations are present in up... (Review)
Review
OBJECTIVES
Relapsing polychondritis (RP) evolves with variable and intermittent involvement of cartilage and proteoglycan-rich structures. Ocular manifestations are present in up to two-thirds of RP patients. Necrotising scleritis (NS) and peripheral ulcerative keratitis (PUK) may be inaugural and may lead to eye perforation and vision loss. We aimed to review NS and PUK in RP, in order to characterise them, to identify successful treatment options and unmet needs.
METHODS
A systematic review of the currently available evidence in PubMed, EMBASE and Scopus was performed according to PRISMA, including observational studies, single case reports and case series of NS/PUK in RP. Study design, number of patients, age, gender, treatment and outcome, were extracted. Two RP patients also provided their opinion.
RESULTS
Five case reports and two case series were eligible for inclusion. We identified 10 RP patients with eye-threatening complications (NS and/or PUK), 9 adults (2 males, 7 females, aged 35-72, median age 57.6 years) and one paediatric patient (F, 11 years). Apart from glucocorticoids, cyclophosphamide was effective in 4 patients; infliximab, high-dose immunoglobulins, dapsone, or cyclosporine were also successfully employed in a case each. Surgical repair was reported in 2 cases.
CONCLUSIONS
Ocular inflammation is often bilateral and recurring in RP; NS/PUK are rare complications. All patients who develop NS/PUK should be specifically questioned for RP signs and symptoms. Early institution of immunosuppressive therapies is mandatory. Increasing awareness, physicians' and patients' education and a multidisciplinary approach may help improve the prognosis of these serious complications of RP.
Topics: Adult; Child; Corneal Ulcer; Cyclophosphamide; Female; Humans; Infliximab; Male; Middle Aged; Polychondritis, Relapsing; Scleritis
PubMed: 35238768
DOI: 10.55563/clinexprheumatol/27n7im -
Clinical Medicine (London, England) Sep 2020Methaemoglobinaemia is an uncommon but potentially serious condition. It can be caused by congenital or acquired cause. Drug-induced methaemoglobinaemia is the commonest...
Methaemoglobinaemia is an uncommon but potentially serious condition. It can be caused by congenital or acquired cause. Drug-induced methaemoglobinaemia is the commonest cause of acquired methaemoglobinaemia. The clinical signs and symptoms of methaemoglobinaemia include dyspnoea, desaturation, presence of saturation gap, headache, nausea and seizures depending on level of serum methaemoglobinaemia. We illustrate a case of dapsone-induced methaemoglobinaemia and its successful treatment by intravenous methylene blue.
Topics: Dapsone; Humans; Methemoglobinemia; Methylene Blue
PubMed: 32934050
DOI: 10.7861/clinmed.2020-0364