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Toxicology Reports Dec 2023The case report describes a case of a severe dapsone (more than 200 tablets dapsone 100 mg) and mild methotrexate intoxication (10 tablets methotrexate 10 mg) as an...
The case report describes a case of a severe dapsone (more than 200 tablets dapsone 100 mg) and mild methotrexate intoxication (10 tablets methotrexate 10 mg) as an attempt to commit suicide, resulting in severe cyanosis with elevation in methemoglobin concentration, treated with methylene blue, ascorbic acid, folinic acid, multidose activated charcoal and hemodialysis. Measurements of blood gases, dapsone and methotrexate levels were performed. Furthermore a hepatitis, pulmonary artery thrombus and a strange taste sensation were diagnosed, probably related to dapsone. The patient recovered and was discharged from hospital after five days. Acute intoxication from excessive dapsone intake is uncommon and clear treatment guidelines are lacking. We here report the treatment modalities as a result of a dapsone intoxication, including the effects on the overall condition of the patient.
PubMed: 37868805
DOI: 10.1016/j.toxrep.2023.10.006 -
Asian Pacific Journal of Allergy and... Sep 2023Mast cells and eosinophils are considered pivotal contributors to the pathogenesis of chronic spontaneous urticaria (CSU). However, emerging evidence suggests that...
Mast cells and eosinophils are considered pivotal contributors to the pathogenesis of chronic spontaneous urticaria (CSU). However, emerging evidence suggests that neutrophils also play a central role. Cutaneous mast cells and macrophages orchestrate the recruitment of neutrophils through the regulation and activation of diverse processes, including heightened local vascular permeability and chemokine release. Studies have demonstrated increased activation and elevated levels of neutrophil-related cytokines in CSU patients. Moreover, neutrophils have been proposed as antigen-presenting cells during the late-phase reaction of immunoglobulin E-mediated allergy and have been associated with the expression of calcitonin gene-related protein and vascular endothelial growth factor in CSU. Histopathological analysis of lesional skin in CSU patients revealed significantly higher eosinophil and neutrophil counts than unaffected skin. However, the extent of neutrophil infiltration in the skin does not appear to correlate with the number of neutrophils in peripheral blood. The utility of the neutrophil-lymphocyte ratio as a marker for disease activity or remission in CSU remains inconclusive. Neutrophil-targeted therapy may confer benefits for CSU patients who exhibit resistance to antihistamines. Omalizumab has demonstrated its ability to reduce neutrophil counts, the neutrophil-lymphocyte ratio, and the neutrophil-monocyte ratio in peripheral blood. While dapsone and colchicine are recommended as alternative treatment options for CSU, their evidential support from published studies remains limited. Inhibitors targeting interleukin-1 and neutrophil-related cytokines have been proposed as potential therapeutic interventions for patients exhibiting neutrophil predominance. Further research is warranted to gain deeper insights into the involvement of neutrophils in CSU and to explore potential therapeutic interventions.
Topics: Humans; Urticaria; Neutrophils; Mast Cells; Vascular Endothelial Growth Factor A; Chronic Urticaria; Cytokines; Chronic Disease
PubMed: 37804482
DOI: 10.12932/AP-180623-1638 -
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 -
The Journal of Dermatological Treatment Dec 2023Schnitzler syndrome (SchS) is a rare autoimmune and inflammatory disease mediated by interleukin-1 beta (IL-1β). Recurrent monoclonal gammopathy and chronic urticarial...
Schnitzler syndrome (SchS) is a rare autoimmune and inflammatory disease mediated by interleukin-1 beta (IL-1β). Recurrent monoclonal gammopathy and chronic urticarial rash are the symptoms required for diagnosis according to the Strasbourg criteria. The low prevalence of this syndrome (around 300 cases have been reported) and confusion with other inflammatory disorders may delay the diagnosis for up to 5 years. Although the most effective treatment for SchS is anakinra, some patients do not respond to this treatment. We report a case of SchS in a 64-year-old woman with multiple episodes of fever, severe rash, erythema, arthralgia and dyspnea. The patient was successfully treated with canakinumab after anakinra intolerance and failure of colchicine, prednisone, methotrexate and dapsone. After the first dose of canakinumab the skin wounds rapidly improved and the patient did not require any concomitant treatments. The cause of SchS is still unknown and a differential diagnosis is recommended, especially with adult-onset Still´s disease due to their similar symptoms. Canakinumab, a specific anti-IL-1β antibody, blocks its binding to receptors, thereby preventing IL-1β-induced gene activation and production of inflammatory mediators. Canakinumab has proven to be an effective drug in SchS, providing an alternative to anakinra.
Topics: Adult; Female; Humans; Middle Aged; Schnitzler Syndrome; Interleukin 1 Receptor Antagonist Protein; Antibodies, Monoclonal, Humanized; Exanthema
PubMed: 37551725
DOI: 10.1080/09546634.2023.2242705 -
Annals of the Rheumatic Diseases Jan 2024Secukinumab is monoclonal antibody that targets interleukin 17 (IL-17) for treatment of psoriatic arthritis, psoriasis, and ankylosing spondylitis. We herein present a...
Secukinumab is monoclonal antibody that targets interleukin 17 (IL-17) for treatment of psoriatic arthritis, psoriasis, and ankylosing spondylitis. We herein present a psoriatic arthritis patient who developed leukocytoclastic vasculitis (LCV) following treatment with secukinumab. Genetic studies identified amino acid changes in two different IL-17 receptors, IL-17RA and IL-17-RC, and interacting DOCK8, Rab27A, and STX1 proteins. LCV completely resolved after withdrawal of the drug, transient treatment with dapsone and methylprednisolone, and switching to long-term therapy to IL-23 inhibitor tildrakizumab. This case reveals potential molecular bases of disease pathogenesis, intolerance of IL-17 blockade, and responsiveness to IL-23 inhibition in psoriatic arthritis.
Topics: Humans; Arthritis, Psoriatic; Interleukin-17; Antibodies, Monoclonal, Humanized; Vasculitis, Leukocytoclastic, Cutaneous; Interleukin-23; Psoriasis
PubMed: 37679036
DOI: 10.1136/ard-2023-224604 -
Parasites & Vectors Oct 2023In its 'Road map for neglected tropical diseases 2021-2030', the World Health Organization outlined its targets for control and elimination of neglected tropical... (Review)
Review
In its 'Road map for neglected tropical diseases 2021-2030', the World Health Organization outlined its targets for control and elimination of neglected tropical diseases (NTDs) and research needed to achieve them. For many NTDs, this includes research for new treatment options for case management and/or preventive chemotherapy. Our review of small-molecule anti-infective drugs recently approved by a stringent regulatory authority (SRA) or in at least Phase 2 clinical development for regulatory approval showed that this pipeline cannot deliver all new treatments needed. WHO guidelines and country policies show that drugs may be recommended for control and elimination for NTDs for which they are not SRA approved (i.e. for 'off-label' use) if efficacy and safety data for the relevant NTD are considered sufficient by WHO and country authorities. Here, we are providing an overview of clinical research in the past 10 years evaluating the anti-infective efficacy of oral small-molecule drugs for NTD(s) for which they are neither SRA approved, nor included in current WHO strategies nor, considering the research sponsors, likely to be registered with a SRA for that NTD, if found to be effective and safe. No such research has been done for yaws, guinea worm, Trypanosoma brucei gambiense human African trypanosomiasis (HAT), rabies, trachoma, visceral leishmaniasis, mycetoma, T. b. rhodesiense HAT, echinococcosis, taeniasis/cysticercosis or scabies. Oral drugs evaluated include sparfloxacin and acedapsone for leprosy; rifampicin, rifapentin and moxifloxacin for onchocerciasis; imatinib and levamisole for loiasis; itraconazole, fluconazole, ketoconazole, posaconazole, ravuconazole and disulfiram for Chagas disease, doxycycline and rifampicin for lymphatic filariasis; arterolane, piperaquine, artesunate, artemether, lumefantrine and mefloquine for schistosomiasis; ivermectin, tribendimidine, pyrantel, oxantel and nitazoxanide for soil-transmitted helminths including strongyloidiasis; chloroquine, ivermectin, balapiravir, ribavirin, celgosivir, UV-4B, ivermectin and doxycycline for dengue; streptomycin, amoxicillin, clavulanate for Buruli ulcer; fluconazole and isavuconazonium for mycoses; clarithromycin and dapsone for cutaneous leishmaniasis; and tribendimidine, albendazole, mebendazole and nitazoxanide for foodborne trematodiasis. Additional paths to identification of new treatment options are needed. One promising path is exploitation of the worldwide experience with 'off-label' treatment of diseases with insufficient treatment options as pursued by the 'CURE ID' initiative.
Topics: Humans; Ivermectin; Rifampin; Doxycycline; Fluconazole; Off-Label Use; Anti-Infective Agents; Drug Combinations; Neglected Diseases
PubMed: 37907954
DOI: 10.1186/s13071-023-05909-8 -
The Journal of Dermatological Treatment Dec 2024There is a lack of real-life safety data on treatment options for chronic urticaria in the presence of comedication and comorbidities.
BACKGROUND
There is a lack of real-life safety data on treatment options for chronic urticaria in the presence of comedication and comorbidities.
METHODS
We present a single-center UCARE pilot study of 212 outpatients with chronic urticaria. Patients were divided into three groups according to different CU therapies according to international guidelines.
RESULTS
Of 212 patients, 108 (mean age 48.9 years, 71.3% female) had 59 comorbidities, including cardiovascular, autoimmune and malignant diseases. Patients were followed for a mean of 24.6 months (SD ± 21.3). Urticaria therapies were divided into three groups: A: 105 (97.2%) with omalizumab and 2nd generation antihistamines), B: 16 patients (14.8%): dual therapy with antihistamines and cyclosporine in 10 (9.3%), montelukast in five (4. 6%), dapsone in four (3.7%), hydroxychloroquine in one patient (0.9%), C: 12 (11.1%) patients received a third drug for 4.9 months (SD ± 3.2) and one quadruple therapy (2.1 months). 10 out of 12 (83.3%) patients received montelukast, two (16.7%) cyclosporine, two (16.7%) dapsone and one (8.3%) hydroxychloroquine as a third drug for chronic urticaria.
CONCLUSIONS
Combining treatment modalities for chronic urticaria and comorbidities are available and feasible with a good safety profile.
Topics: Humans; Female; Middle Aged; Male; Hydroxychloroquine; Pilot Projects; Chronic Disease; Chronic Urticaria; Urticaria; Omalizumab; Histamine H1 Antagonists; Cyclosporine; Dapsone; Anti-Allergic Agents; Acetates; Cyclopropanes; Quinolines; Sulfides
PubMed: 38508226
DOI: 10.1080/09546634.2024.2329784 -
Crystal Growth & Design May 2024The dapsone/flavone cocrystal system served as a benchmark for both experimental and virtual screening methods. Expanding beyond this, two additional active...
The dapsone/flavone cocrystal system served as a benchmark for both experimental and virtual screening methods. Expanding beyond this, two additional active pharmaceutical ingredients (APIs), sulfanilamide and sulfaguanidine, structurally related to dapsone were chosen to investigate the impact of substituents on cocrystal formation. The experimental screening involved mechanochemical methods, slurry experiments, hot-melt extrusion, and the contact preparation method. The virtual screening focused on crystal structure prediction (CSP), molecular complementarity, hydrogen-bond propensity, and molecular electrostatic potentials. The CSP studies not only indicated that each of the three APIs should form cocrystals with flavone but also reproduced the known single- and multicomponent phases. Experimentally, dapsone/flavone cocrystals , , , and were reproduced, was identified as a nonstoichiometric hydrate, and a fifth cocrystal (), a -butanol solvate, was discovered. The cocrystal polymorphs and are enantiotripically related, and , exhibiting a different stoichiometric ratio, is enthalpically stabilized over the other cocrystals. For the sulfaguanidine/flavone system, two novel, enantiotripically related cocrystals were identified. The crystal structures of two cocrystals and a flavone polymorph were solved from powder X-ray diffraction data, and the stability of all cocrystals was assessed through differential scanning calorimetry and lattice energy calculations. Despite computational indications, a diverse array of cocrystallization techniques did not result in a sulfanilamide/flavone cocrystal. The driving force behind dapsone's tendency to cocrystallize with flavone can be attributed to the overall strength of flavone interactions in the cocrystals. For sulfaguanidine, the potential to form strong API···API and API···coformer interactions in the cocrystal is a contributing factor. Furthermore, flavone was found to be trimorphic.
PubMed: 38766642
DOI: 10.1021/acs.cgd.4c00293 -
Naunyn-Schmiedeberg's Archives of... Jul 2023Viral respiratory diseases (VRDs) cause lung inflammation and inflammatory cytokine production. We study whether dapsone is responsible for its observed preventive... (Randomized Controlled Trial)
Randomized Controlled Trial
Viral respiratory diseases (VRDs) cause lung inflammation and inflammatory cytokine production. We study whether dapsone is responsible for its observed preventive treatment effects of the sustained viral RNA interferon response. Around 2008 and 2012, Korea's Dementia Management Act stipulated drastic changes in the administration of dementia medication by medical staff. Participants were randomized and we compared leprosy patients with VRDs after prescribing dapsone as a standard treatment from 2005 to 2019. Significance was evaluated based on the dapsone-prescribed (+) subgroup and the dapsone-unprescribed (-) subgroup of the VRD diagnosed (+) and VRD undiagnosed (-) subgroup. We analyzed VRD ( +)/(- with dapsone (+)/(-) group and used a T-test, and designed the equation of acetylation with dapsone and acetylcholine (AA) equation. The 6394 VRD participants who received the dapsone intervention compared to the 3255 VRD participants in the control group demonstrated at T2 VRD (+) dapsone (-) (mean (M) = 224.80, SD = 97.50): T3 VRD (-) dapsone (+) (M = 110.87, SD = 103.80), proving that VRD is low when dapsone is taken and high when it is not taken. The t value is 3.10, and the p value is 0.004395 (significant at p < 0.05). After an increase in VRDs peaked in 2009, bronchitis, COPD, and pneumonia surged in 2013. The AA equation was strongly negatively correlated with the prevalence of bronchitis and chronic obstructive pulmonary disease (COPD): with bronchitis, r(15) = -0.823189, p = 0.005519, and with COPD, r(15) = -0.8161, p = 0.000207 (significant at p < 0.05). Dapsone treated both bronchitis and COPD. This study provides theoretical clinical data to limit acetylcholine excess during the VRD pandemic for bronchitis, COPD, and pneumonia.
Topics: Humans; Acetylcholine; Pulmonary Disease, Chronic Obstructive; Bronchitis; Pneumonia; Dapsone; Leprosy; Dementia
PubMed: 36773052
DOI: 10.1007/s00210-023-02407-7