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Biochimica Et Biophysica Acta.... Mar 2024L-Ser supply in the central nervous system of mammals mostly relies on its endogenous biosynthesis by the phosphorylated pathway (PP). Defects in any of the three...
L-Ser supply in the central nervous system of mammals mostly relies on its endogenous biosynthesis by the phosphorylated pathway (PP). Defects in any of the three enzymes operating in the pathway result in a group of neurometabolic diseases collectively known as serine deficiency disorders (SDDs). Phosphoserine phosphatase (PSP) catalyzes the last, irreversible step of the PP. Here we investigated in detail the role of physiological modulators of human PSP activity and the properties of three natural PSP variants (A35T, D32N and M52T) associated with SDDs. Our results, partially contradicting previous reports, indicate that: i. PSP is almost fully saturated with Mg under physiological conditions and fluctuations in Mg and Ca concentrations are unlikely to play a modulatory role on PSP activity; ii. Inhibition by L-Ser, albeit at play on the isolated PSP, does not exert any effect on the flux through the PP unless the enzyme activity is severely impaired by inactivating substitutions; iii. The so-far poorly investigated A35T substitution was the most detrimental, with a 50-fold reduction in catalytic efficiency, and a reduction in thermal stability (as well as an increase in the IC for L-Ser). The M52T substitution had similar, but milder effects, while the D32N variant behaved like the wild-type enzyme. iv. Predictions of the structural effects of the A35T and M52T substitutions with ColabFold suggest that they might affect the structure of the flexible helix-loop region.
Topics: Animals; Humans; Serine; Magnesium; Ions; Mammals; Dapsone; Phosphoric Monoester Hydrolases
PubMed: 38278334
DOI: 10.1016/j.bbadis.2024.167034 -
PLoS Neglected Tropical Diseases Jan 2024The occurrence of adverse drug events (ADEs) during dapsone (DDS) treatment in patients with leprosy can constitute a significant barrier to the successful completion of...
BACKGROUND
The occurrence of adverse drug events (ADEs) during dapsone (DDS) treatment in patients with leprosy can constitute a significant barrier to the successful completion of the standardized therapeutic regimen for this disease. Well-known DDS-ADEs are hemolytic anemia, methemoglobinemia, hepatotoxicity, agranulocytosis, and hypersensitivity reactions. Identifying risk factors for ADEs before starting World Health Organization recommended standard multidrug therapy (WHO/MDT) can guide therapeutic planning for the patient. The objective of this study was to develop a predictive model for DDS-ADEs in patients with leprosy receiving standard WHO/MDT.
METHODOLOGY
This is a case-control study that involved the review of medical records of adult (≥18 years) patients registered at a Leprosy Reference Center in Rio de Janeiro, Brazil. The cohort included individuals that received standard WHO/MDT between January 2000 to December 2021. A prediction nomogram was developed by means of multivariable logistic regression (LR) using variables. The Hosmer-Lemeshow test was used to determine the model fit. Odds ratios (ORs) and their respective 95% confidence intervals (CIs) were estimated. The predictive ability of the LRM was assessed by the area under the receiver operating characteristic curve (AUC).
RESULTS
A total of 329 medical records were assessed, comprising 120 cases and 209 controls. Based on the final LRM analysis, female sex (OR = 3.61; 95% CI: 2.03-6.59), multibacillary classification (OR = 2.5; 95% CI: 1.39-4.66), and higher education level (completed primary education) (OR = 1.97; 95% CI: 1.14-3.47) were considered factors to predict ADEs that caused standard WHO/MDT discontinuation. The prediction model developed had an AUC of 0.7208, that is 72% capable of predicting DDS-ADEs.
CONCLUSION
We propose a clinical model that could become a helpful tool for physicians in predicting ADEs in DDS-treated leprosy patients.
Topics: Adult; Humans; Female; Dapsone; Leprostatic Agents; Rifampin; Drug Therapy, Combination; Case-Control Studies; Clofazimine; Brazil; Leprosy; Drug-Related Side Effects and Adverse Reactions; World Health Organization
PubMed: 38271456
DOI: 10.1371/journal.pntd.0011901 -
Acta Dermato-venereologica Jan 2024Epidermolysis bullosa acquisita (EBA) rarely develops in childhood. This study retrospectively recruited paediatric patients with EBA (age ≤ 16 years), diagnosed by...
Epidermolysis bullosa acquisita (EBA) rarely develops in childhood. This study retrospectively recruited paediatric patients with EBA (age ≤ 16 years), diagnosed by clinical and histopathological features and results of immunofluorescence, immunoblotting and enzyme-linked immunosorbent assay (ELISA), and reviews their clinical manifestations, histopathology, immunological features, and responses to various treatments. All 7 included patients presented with inflammatory EBA. Among them, 3 had a bullous pemphigoid-like phenotype. Pathologically, in addition to dermal-epidermal blistering, in all patients, the distribution of neutrophils was superficial perivascular or interstitial, or in the dermal papilla. Mixed neutrophils and eosinophils were detected in 2 of the 3 patients with bullous pemphigoid-like phenotypes. In addition to treatment with glucocorticoids, dapsone was administered in 4 patients, while thalidomide and sulfasalazine were administered in 1 patient. All patients responded to the these therapies. Relapse was mainly due to reduction and cessation of glucocorticoids. In conclusion, EBA in childhood may be unique, and thus distinct from its adult counterpart. Specific treatment and follow-up protocols are required for therapy of this rare autoimmune skin disease in children.
Topics: Adult; Humans; Child; Adolescent; Epidermolysis Bullosa Acquisita; Pemphigoid, Bullous; Retrospective Studies; Autoimmune Diseases; Dapsone; Glucocorticoids
PubMed: 38270257
DOI: 10.2340/actadv.v104.11917 -
The American Journal of Tropical... Mar 2024Leprosy is a global health issue, causing long-term functional morbidity and stigma. Rapid diagnosis and appropriate treatment are important; however, early diagnosis is...
Leprosy is a global health issue, causing long-term functional morbidity and stigma. Rapid diagnosis and appropriate treatment are important; however, early diagnosis is often challenging, especially in nonendemic areas. Here, we report a case of borderline lepromatous leprosy accompanied by dapsone-induced (neutropenia, anemia, and methemoglobinemia) and clofazimine-induced (skin discoloration and ichthyosis) side effects and type 1 leprosy reactions during administration of the multidrug therapy. The patient completely recovered without developing any deformities or visual impairment. To ensure early diagnosis and a favorable outcome, clinicians should be aware of the diminished sensation of skin lesions as a key physical finding and manage the drug toxicities and leprosy reactions appropriately in patients on multidrug therapy.
Topics: Humans; Clofazimine; Dapsone; Drug Therapy, Combination; Leprostatic Agents; Leprosy; Leprosy, Borderline; Skin Diseases, Bacterial; Hypersensitivity; Peripheral Nervous System Diseases; Leprosy, Multibacillary; Leprosy, Lepromatous
PubMed: 38266303
DOI: 10.4269/ajtmh.22-0637 -
The World Allergy Organization Journal Jan 2024Trimethoprim-sulfamethoxazole (TMP-SMX) is a broad spectrum antibiotic in use for more than 50 years. It has an important indication as first line agent in the... (Review)
Review
Trimethoprim-sulfamethoxazole (TMP-SMX) is a broad spectrum antibiotic in use for more than 50 years. It has an important indication as first line agent in the prophylaxis of opportunistic infections, particularly pneumonia (PJP), in immunosuppressed patients. For those who have a history of allergy or severe intolerance to TMP-SMX, pentamidine, dapsone or atovaquone may be substituted; however there is evidence that TMP-SMX offers superior coverage for PJP, toxoplasmosis, and nocardiosis. Compared to pentamidine, it has the added benefit of cost-effectiveness and self-administration as opposed to required hospital attendance for administration. Many patients who report a history of allergy or adverse reaction to TMP-SMX (or "sulfur allergy") will be found not to be allergic; and even those who are allergic may be able to be desensitized. The evaluation and, where appropriate, removal of TMP-SMX allergy label enables the use of TMP-SMX for prophylaxis against opportunistic infections. This is a cost-effective intervention to optimize antimicrobial prescribing and reduce the risk of opportunistic infections in immunosuppressed patients.
PubMed: 38235260
DOI: 10.1016/j.waojou.2023.100856 -
Polimery W Medycynie 2024Dapsone (DAP) is an anti-inflammatory and antimicrobial active pharmaceutical ingredient used to treat, e.g., AIDS-related diseases. However, low solubility is a feature...
BACKGROUND
Dapsone (DAP) is an anti-inflammatory and antimicrobial active pharmaceutical ingredient used to treat, e.g., AIDS-related diseases. However, low solubility is a feature hampering its efficient use.
OBJECTIVES
First, deep eutectic solvents (DES) were used as solubilizing agents for DAP as an alternative to traditional solvents. Second, intermolecular interactions in the systems were described and quantified. Finally, the solubility prediction model, previously created using the machine learning protocol, was extended and improved using new data obtained for eutectic systems.
MATERIAL AND METHODS
New DES were created by blending choline chloride (ChCl) with 6 selected polyols. The solubility of DAP in these solvents was measured spectrophotometrically. The impact of water dilution on the solubility curve was investigated. Experimental research was enriched with theoretical interpretations of intermolecular interactions, identifying the most probable pairs in the systems. Dapsone self-association and its ability to interact with components of the analyzed systems were considered. Thermodynamic characteristics of pairs were utilized as molecular descriptors in the machine learning process, predicting solubility in both traditional organic solvents and the newly designed DES.
RESULTS
The newly formulated solvents demonstrated significantly higher efficiency compared to traditional organic solvents, and a small addition of water increased solubility, indicating its role as a co-solvent. The interpretation of the mechanism of DAP solubility highlighted the competitive nature of self-association and pair formation. Thermodynamic parameters characterizing affinity were instrumental in developing an efficient model for theoretical screening across diverse solvent classes. The study emphasized the necessity of retraining models when introducing new experimental data, as exemplified by enriching the model with data from DES.
CONCLUSIONS
The research showcased the efficacy of developing new DES for enhancing solubility and creating environmentally and pharmaceutically viable systems, using DAP as an example. Molecular interactions proved valuable in understanding solubility mechanisms and formulating predictive models through machine learning processes.
Topics: Solubility; Dapsone; Machine Learning; Deep Eutectic Solvents; Thermodynamics; Solvents
PubMed: 38197603
DOI: 10.17219/pim/177235 -
Cureus Dec 2023Leprosy, or Hansen's disease, mistakenly considered a disease from the past by some, is still common nowadays, especially in tropical and subtropical regions. In the...
Leprosy, or Hansen's disease, mistakenly considered a disease from the past by some, is still common nowadays, especially in tropical and subtropical regions. In the absence of appropriate medical treatment, it may progress and cause permanent damage to multiple organs. This case report illustrates the diagnostic challenge of a south-american adult man who had been living in Europe for over 14 years. He was referred to the Hematology department due to persistent lymphocytosis and a CD5+ B-cell lymphoproliferative disorder was identified. During clinical surveillance, the patient developed skin lesions in his limbs with associated hypoesthesia. A histological diagnosis of lepromatous leprosy was made, and he underwent a long-term three-drug therapeutic regimen (dapsone, rifampicin, and clofazimine). Adding to the complexity of the case, the patient progressed with splenomegaly and constitutional symptoms, more than 7 years after development of lymphocytosis. Through a comprehensive evaluation, a definitive diagnosis of mantle cell lymphoma was established and received 6-cycle R-CHOP induction, followed by maintenance rituximab. Importantly, prophylaxis for leprosy reactivation was not administered as there were no recommendations in available guidelines. Eventually, the patient experienced a leprosy relapse while on maintenance therapy, 58 months after completing the initial anti-leprous treatment. Clinical response was attained with a new treatment regimen consisting of rifampicin, clofazimine, and minocycline. Although leprosy is primarily observed in tropical and subtropical regions, the long incubation period of this disease combined with the global flow of migrants, made us consider it. Despite being rare, leprosy relapses can occur even after a few decades. The contribution of rituximab or previously administered chemotherapeutic agents is still unknown. The question remains whether antibiotic prophylaxis should be performed in patients undergoing immunochemotherapy for malignant diseases.
PubMed: 38186457
DOI: 10.7759/cureus.50007 -
Cureus Dec 2023Hansen disease, known as Leprosy, is an infectious disease caused by . The disease was once thought to be highly contiguous, and patients with leprosy were treated... (Review)
Review
Hansen disease, known as Leprosy, is an infectious disease caused by . The disease was once thought to be highly contiguous, and patients with leprosy were treated poorly and had to face discrimination due to the gruesome disease's complications. , the bacterium causative of leprosy, can generally be found in the nine-banded armadillo. The bacterium is transmitted via aerosol droplets and broken skin-to-skin contact. Once M enters the body, it will target peripheral nerves and the lining mucosa of the skin and eyes, thus causing inflammation and tenderness of the affected area. Over time, this will lead to peripheral neuropathy and weakness of the affected body parts. Treatment of leprosy involves multi-drug combinations such as dapsone, rifampin, and clofazimine. Even though leprosy is curable, early detection and treatment are crucial to preventing irreversible damage and disabilities. Prevention measures include early detection, treatment regimen adherence, close contact prophylaxis, contact tracing, and community awareness. This review aims to provide the latest diagnostic and therapeutic recommendations for leprosy. It outlines the epidemiology, microbiology, clinical treatment, and immunological methods used to detect leprosy.
PubMed: 38179342
DOI: 10.7759/cureus.49954