Experimental and Theoretical Insights into the Intermolecular Interactions in Saturated Systems of Dapsone in Conventional and Deep Eutectic Solvents.

Solubility is not only a crucial physicochemical property for laboratory practice but also provides valuable insight into the mechanism of saturated system organization, as a measure of the interplay between various intermolecular interactions. The importance of these data cannot be overstated, particularly when dealing with active pharmaceutical ingredients (APIs), such as dapsone. It is a commonly used anti-inflammatory and antimicrobial agent. However, its low solubility hampers its efficient applications. In this project, deep eutectic solvents (DESs) were used as solubilizing agents for dapsone as an alternative to traditional solvents. DESs were composed of choline chloride and one of six polyols. Additionally, water-DES mixtures were studied as a type of ternary solvents. The solubility of dapsone in these systems was determined spectrophotometrically. This study also analyzed the intermolecular interactions, not only in the studied eutectic systems, but also in a wide range of systems found in the literature, determined using the COSMO-RS framework. The intermolecular interactions were quantified as affinity values, which correspond to the Gibbs free energy of pair formation of dapsone molecules with constituents of regular solvents and choline chloride-based deep eutectic solvents. The patterns of solute-solute, solute-solvent, and solvent-solvent interactions that affect solubility were recognized using Orange data mining software (version 3.36.2). Finally, the computed affinity values were used to provide useful descriptors for machine learning purposes. The impact of intermolecular interactions on dapsone solubility in neat solvents, binary organic solvent mixtures, and deep eutectic solvents was analyzed and highlighted, underscoring the crucial role of dapsone self-association and providing valuable insights into complex solubility phenomena. Also the importance of solvent-solvent diversity was highlighted as a factor determining dapsone solubility. The Non-Linear Support Vector Regression (NuSVR) model, in conjunction with unique molecular descriptors, revealed exceptional predictive accuracy. Overall, this study underscores the potency of computed molecular characteristics and machine learning models in unraveling complex molecular interactions, thereby advancing our understanding of solubility phenomena within the scientific community.

Synthesis, In Vitro, and In Silico Analysis of the Antioxidative Activity of Dapsone Imine Derivatives.

Dapsone (DDS) is an antibacterial drug with well-known antioxidant properties. However, the antioxidant behavior of its derivatives has not been well explored. In the present work, the antioxidant activity of 10 dapsone derivatives 4-substituted was determined by an evaluation in two in vitro models (DPPH radical scavenging assay and ferric reducing antioxidant power). These imine derivatives 1-10 were obtained through condensation between DDS and the corresponding aromatic aldehydes 4-substuited. Three derivatives presented better results than DDS in the determination of DPPH (2, 9, and 10). Likewise, we have three compounds with better reducing activity than dapsone (4, 9, and 10). In order to be more insight, the redox process, a conceptual DFT analysis was carried out. Molecular descriptors such as electronic distribution, the total charge accepting/donating capacity (I/A), and the partial charge accepting/donating capacity (ω+/ω-) were calculated to analyze the relative donor-acceptor capacity through employing a donor acceptor map (DAM). The DFT calculation allowed us to establish a relationship between GAPHOMO-LUMO and DAM with the observed antioxidant effects. According to the results, we concluded that compounds 2 and 3 have the lowest Ra values, representing a good antioxidant behavior observed experimentally in DPPH radical capturing. On the other hand, derivatives 4, 9, and 10 display the best reducing capacity activity with the highest ω- and Rd values. Consequently, we propose these compounds as the best antireductants in our DDS imine derivative series.

Antibacterial Activities and Molecular Docking of Novel Sulfone Biscompound Containing Bioactive 1,2,3-Triazole Moiety.

In this study, a new synthetic 1,2,3-triazole-containing disulfone compound was derived from dapsone. Its chemical structure was confirmed using microchemical and analytical data, and it was tested for its in vitro antibacterial potential. Six different pathogenic bacteria were selected. MICs values and ATP levels were determined. Further, toxicity performance was measured using MicroTox Analyzer. In addition, a molecular docking study was performed against two vital enzymes: DNA gyrase and Dihydropteroate synthase. The results of antibacterial abilities showed that the studied synthetic compound had a strong bactericidal effect against all tested bacterial strains, as Gram-negative species were more susceptible to the compound than Gram-positive species. Toxicity results showed that the compound is biocompatible and safe without toxic impact. The molecular docking of the compound showed interactions within the pocket of two enzymes, which are able to stabilize the compound and reveal its antimicrobial activity. Hence, from these results, this study recommends that the established compound could be an outstanding candidate for fighting a broad spectrum of pathogenic bacterial strains, and it might therefore be used for biomedical and pharmaceutical applications.

Synthesis, characterization and drug delivery application of Dapsone based double tailed biocompatible nonionic surfactant.

The increase in antimicrobial resistance has created a crisis that has become top priority for global policy and public health. Antibiotics are constantly being rendered in-effective due to the emergence of bacterial resistance; therefore, novel strategies for improving therapeutic efficacies of existing drugs must be focused. Advancements in nanotechnology have opened up new avenues for enhancing therapeutic efficacy of existing drugs via construction of intelligent and efficient delivery systems. This study reports the synthesis of Dapsone based nonionic surfactant and its utilization as delivery system for Ceftriaxone sodium. The synthesized nonionic surfactant was characterized via mass spectrometry and 1H NMR and IR spectroscopic techniques. The drug loaded vesicles of newly synthesized sulfur based nonionic were formed through thin film hydration method and characterized for drug entrapment efficiency, vesicles size, zeta potential, morphology using UV-vis spectrometry, dynamic light scattering (DLS) and atomic force microscopic (AFM) techniques. The biocompatibility of newly synthesized surfactant was assessed using blood hemolysis and in-vitro cells cytotoxicity. Antibacterial potential of drug loaded vesicles was assessed in gram positive and gram negative bacterial cultures. The spectroscopic results confirm successful synthesis of novel sulfur based nonionic surfactant that formed spherical shaped drug loaded vesicles with an average size of 97.95 ± 3.45 nm and 56.3 ± 3.15 % entrapment of the model drug (Ceftriaxone sodium). The vesicles displayed negative surface charge of -16.8 ± 3.72 mV and released the entrapped drug in a controlled way in-vitro drug release. The drug loaded vesicular formulation showed enhanced cellular uptake and greater antibacterial potentials when compared with control. Results of this study show that the Dapsone based surfactant is safe, biocompatible, non-toxic and can be used as promising vesicular carrier for enhancing therapeutic efficacy of antibacterial drug, Ceftriaxone sodium.

A theoretical study of chemical bonding and topological and electrostatic properties of the anti-leprosy drug dapsone.

The theoretical charge density study for the gas phase of anti-leprosy drug Dapsone has been carried out in the light of the theory of atoms in molecules using density functional theory employing B3LYP(6-311G++(d, p) hybrid functional completed with dispersion corrections. The Hirshfeld surface analysis as well as fingerprint plots has been utilized to visualize and quantify the intermolecular contacts present in the molecule. The topological properties such as electron density and its Laplacian, delocalization index have been elucidated to throw light into the chemical bonding and atomic and molecular details. The electron localization function has been used to visualize and deduce information on the lone pair and the subshells of the Cl atom. The electrostatic potential visualizes the positive and negative electrostatic potential regions which are susceptible to nucleophilic and electrophilic attack. On the whole, this study provides an exact mechanism, interaction, and topological and electrostatic properties of the drug through theoretical insights which all will be a platform for our further investigation of the interaction between dapsone and dihydropteroate synthase (DHPS).

Computer-aided synthesis of dapsone-phytochemical conjugates against dapsone-resistant Mycobacterium leprae.

Leprosy continues to be the belligerent public health hazard for the causation of high disability and eventual morbidity cases with stable prevalence rates, even with treatment by the on-going multidrug therapy (MDT). Today, dapsone (DDS) resistance has led to fear of leprosy in more unfortunate people of certain developing countries. Herein, DDS was chemically conjugated with five phytochemicals independently as dapsone-phytochemical conjugates (DPCs) based on azo-coupling reaction. Possible biological activities were verified with computational chemistry and quantum mechanics by molecular dynamics simulation program before chemical synthesis and spectral characterizations viz., proton-HNMR, FTIR, UV and LC-MS. The in vivo antileprosy activity was monitored using the 'mouse-foot-pad propagation method', with WHO recommended concentration 0.01% mg/kg each DPC for 12 weeks, and the host-toxicity testing of the active DPC4 was seen in cultured-human-lymphocytes in vitro. One-log bacilli cells in DDS-resistant infected mice footpads decreased by the DPC4, and no bacilli were found in the DDS-sensitive mice hind pads. Additionally, the in vitro host toxicity study also confirmed that the DCP4 up to 5,000 mg/L level was safety for oral administration, since a minor number of dead cells were found in red color under a fluorescent microscope. Several advanced bioinformatics tools could help locate the potential chemical entity, thereby reducing the time and resources required for in vitro and in vitro tests. DPC4 could be used in place of DDS in MDT, evidenced from in vivo antileprosy activity and in vitro host toxicity study.

Development and evaluation of dapsone tablets coated for specific colon release.

Objective: Drug release systems based on colonic microbiota have been explored with the use of polysaccharides, which are biodegradable. In order to modulate the release into the colon, dapsone tablets were developed, coated with Surelease® and chondroitin sulfate (SC).Methods: The formulation was developed using the wet granulation method, in the form of 9-millimetre circular tablets. The coating was applied in a perforated basin-type coating using different proportions of Surelease® and chondroitin sulfate. The tablets were assessed according to the criteria of mean weight, hardness, and friability. The dissolution test was performed in the dissolver IV apparatus, in media simulating the gastrointestinal system environments (pH 1.2-pH 6.0 and pH 7.2) for 420 min. The results were analyzed by statistical analysis and factorial design.Results: The results of mean weight, hardness, and friability met the pharmacopeial specifications. In the dissolution test, the results obtained demonstrated that Surelease® is able to offer effective protection to the drug, releasing minimum rates when used at 6% or 10% of the tablet's weight gain. The experiments showed that the drug was not able to spread through the coatings manufactured exclusively with Surelease® or even when SC was incorporated in different proportions. Only in the formulation where SC was included in the highest proportion (10%), and the weight gain of the tablet was lower (6%), the release of dapsone increased, reaching 9.5% of drug released. Through factorial planning, it was observed that the drug release rate increases when the weight gain of the tablet remains at the lower level (6%), while the amount of polysaccharide is increased (90:10).Conclusions: The data indicate that the proportion of polysaccharide for ethyl cellulose in the film and the thickness of the coating are the key parameters in controlling the release of the drug from the system.

Bilosomes as a novel carrier for the cutaneous delivery for dapsone as a potential treatment of acne: preparation, characterization and in vivo skin deposition assay.

In our study, the potential of bilosomes as novel vesicular carrier for the cutaneous delivery of the sulphone compound, Dapsone, for topical treatment of acne was investigated. The effect of different formulation variables (type and concentration of bile salt, and molar ratio of Span 60:cholesterol) on the properties of DPS-loaded bilosomes was investigated using a full factorial design. Design Expert software was used for data analysis and optimization of DPS-loaded bilosomes. The optimized bilosomes, chosen on the basis of their superior properties giving maximum entrapment, in vitro release after different time intervals and RE% with minimum vesicle size. Results showed that the bilosome system prepared using Span® 60: Cholesterol (5:1) and containing 0.25 M sodium deoxycholate as the bile salt was found to obey these criteria, with a desirability value of 0.637. Therefore, this system was chosen for further assessment for its morphological properties, zeta potential, thermal analysis using differential scanning calorimetry and X-ray diffractometry. Results revealed that the chosen bilosomes were spherical in shape with no aggregation, and contained DPS in a molecularly dispersed amorphous form. Finally, the capability of the optimized DPS-loaded bilosomes to deliver DPS through rat skin layers will be investigated and compared with that of DPS alcoholic solution. Results showed that the amounts of DPS retained in the skin treated with DPS-loaded bilosomes, and DPS alcoholic solution after 24 h were found to be 170.57 ± 55.12 and 120.24 ± 10.7 µg/mL, respectively, representing about 1.5-fold higher drug retained in the bilosomes-treated skin. Finally, the safety and the tolerability of the prepared bilosomes were assessed using histopathological examination, and revealed that the control untreated skin sections and skin sections treated with DPS-loaded bilosomes showed normal histological structures characterized by absence of defects or inflammation. Such results can be considered a good addition in the field of pharmaceutical drug delivery for effective topical therapy of acne.

Impact of nanostructured lipid carriers on dapsone delivery to the skin: in vitro and in vivo studies.

The main objective of this study was to develop, characterize and evaluate the potential use of dapsone-loaded nanostructured lipid carriers (NLCs) as a topical treatment for acne. Differently charged NLC formulations were successfully prepared using an emulsification/sonication method. The particle sizes ranged from 106.2 ±â€¯5.6 nm to 151.3 ±â€¯7.4 nm, and the NLCs possessed the predicted surface charges, depending on the emulsifier used (Tween 80, Transcutol P, or cetyltrimethylammonium bromide). The entrapment efficiencies ranged from 76.5 ±â€¯3.8% to 91.1 ±â€¯3.9%. Selected formulations were assessed for possible interactions, in vitro release, ex vivo skin permeation, pharmacological efficacy and safety compared with a hydroalcoholic solution. Dapsone was embedded in the lipid matrix of NLCs and behaved as controlled release system with a good occlusive effect. Dapsone-loaded cationic NLC formulation enhanced the skin permeation of dapsone, increase the amount of dapsone retained in the skin in controlled manner, and improved the anti-rosacea activity. Based on these encouraging results, cationic NLC represents a promising carrier for the safe topical delivery of dapsone.

Rhodium(III)-Catalyzed [4+2] Annulation via C-H Activation: Synthesis of Multi-Substituted Naphthalenone Sulfoxonium Ylides.

A convenient Rh(III)-catalyzed C-H activation and cascade [4+2] annulation for the synthesis of naphthalenone sulfoxonium ylides has been developed. This method features perfect regioselectivity, mild and redox-neutral reaction conditions, and broad substrate tolerance with good to excellent yields. Preliminary mechanistic experiments were conducted and a plausible reaction mechanism was proposed. The new type naphthalenone sulfoxonium ylides could be further transformed into multi-substituted naphthols, which demonstrates the practical utility of this methodology.

Dapsone Form V: A Late Appearing Thermodynamic Polymorph of a Pharmaceutical.

Five anhydrate polymorphs (forms I-V) and the isomorphic dehydrate (Hydehy) of dapsone (4,4'-diaminodiphenyl sulfone or DDS) were prepared and characterized in an interdisciplinary experimental and computational study, elucidating the kinetic and thermodynamic stabilities, solid form interrelationships, and structural features of the known forms I-IV, the novel polymorph form V, and Hydehy. Calorimetric measurements, solubility experiments, and lattice energy calculations revealed that form V is the thermodynamically stable polymorph from absolute zero to at least 90 °C. At higher temperatures, form II, and then form I, becomes the most stable DDS solid form. The computed 0 K stability order (lattice energy calculations) was confirmed with calorimetric measurements as follows, V (most stable) > III > Hydehy > II > I > IV (least stable). The discovery of form V was complicated by the fact that the metastable but kinetically stabilized form III shows a higher nucleation and growth rate. By combining laboratory powder X-ray diffraction data and ab initio calculations, the crystal structure of form V ( P21/ c, Z' = 4) was solved, with a high energy DDS conformation allowing a denser packing and more stable intermolecular interactions, rationalizing the formation of a high Z' structure. The structures of the forms I and IV, only observed from the melt and showing distinct packing features compared to the forms II, III, and V, were derived from the computed crystal energy landscapes. Dehydration modeling of the DDS hydrate led to the Hydehy structure. This study expands our understanding about the complex crystallization behavior of pharmaceuticals and highlights the big challenge in solid form screening, especially that there is no clear end point.

pH-responsive chitosan based hydrogels affect the release of dapsone: Design, set-up, and physicochemical characterization.

Dapsone (DAP) is a bactericidal agent used in the treatment of leprosy, caused by Mycobacterium leprae. Despite its therapeutic potential, DAP has low solubility, which results in allow therapeutic index and a high microbial resistance. Recently, new approaches were used to increase the DAP solubility. In particular, the use of interpenetrating polymer network (IPN)-hydrogels based chitosan (CS) for the controlled release of DAP provides some advantages because they can modify their swelling properties and network structures as a response to environmental stimuli. The aim of this study was to synthesize and physicochemically characterize pH-responsive chitosan/polymer hydrogels to control the release of DAP. For this reason, different combination of polymers, such as polyvinyl pyrrolidone, polyethylene glycol and hydroxypropyl methylcellulose, and concentrations of the cross-linking agents (glutaraldehyde) were used and then blended to the CS. The resulting hydrogels were evaluated in terms of physicochemical and swelling properties, rheological analysis and in vitro release of DAP at different pHs (1.2-6.8). Hydrogels were further characterized by Fourier transformed infrared (FT-IR) spectroscopy and scanning electron microscopy (SEM) analysis. pH-responsive DAP-loaded hydrogels may represent the set-up for developing potential oral formulations for the treatment of leprosy caused by Mycobacterium leprae.

Preparation of polyacrylamide/polylactic acid co-assembled core/shell nanofibers as designed beads for dapsone in vitro efficient delivery.

The main aim of this study is to synthesize and prepare polyacrylamide (PAM)/polylactic acid (PLA) co-assembled core/shell nanofibers in order to investigate an effective dapsone-loaded capability and dapsone-release in the aqueous medium. Dapsone (4,4-diamino-diphenyl sulfone) has high permeability and low solubility in water. In vitro release testing indicates that maximum incorporation of the dapsone nanoemulsions into core/shell nanofibrous structures were 77.71 after 400 min. Products were characterized with X-Ray Diffraction (XRD), Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), Fourier Transform Infrared Spectroscopy (FT-IR), Thermo-Gravimetric Analysis (TGA), Dynamic light scattering (DLS) analysis, Contact Angle Measurement (CAM) and nitrogen adsorption [i.e. Brunauer-Emmett-Teller (BET) Surface Area Analysis] techniques. The porosimetric measurements of the nanofibers structures showed that high porosity diameter, adsorption cross-section area, pore volumes and dead volume were obtained as 0.162 nm2, 0.1005 cm3g-1 and 15.693 cm3, respectively. TGA curve of the core/shell nanofibrous structures shows thermal stability between 240 °C and 260 °C.

DNA minor groove binding of a well known anti-mycobacterial drug dapsone: A spectroscopic, viscometric and molecular docking study.

Dapsone is a sulfone drug mainly used as anti-microbial and anti-inflammatory agent for the treatment of various diseases including leprosy. Recently, its interaction with protein (bovine serum albumin) is evidenced. But, the binding propensity of this anti-mycobacterial drug towards DNA is still unknown. Also, the mode of dapsone-DNA interaction (if any) is still an unknown quantity. In this study, we have taken a thorough attempt to understand these two unknown aspects using various biophysical and in silico molecular docking techniques. Both UV-visible and fluorescence titrimetric studies indicated that dapsone binds to CT-DNA with a binding constant in order of 104 M-1. Circular dichroism, thermal denaturation and viscosity experiments revealed that dapsone binds to the grooves of CT-DNA. Competitive DNA binding studies clearly indicated the minor groove binding property of this anti-mycobacterial drug. Molecular docking provided detailed information about the formation of hydrogen bonding in the dapsone-DNA complex. This in silico study further revealed that dapsone binds to the AT-rich region of the minor groove of DNA having a relative binding energy of -6.22 kcal mol-1. Overall, all these findings evolved from this study can be used for better understanding the medicinal importance of dapsone.

Clinical Experience With Once-Daily Dapsone Gel, 7.5% Monotherapy in Patients With Acne Vulgaris.

BACKGROUND: Dapsone gel, 7.5% is a topical medication approved for acne in patients aged 12 years and older. Clinical trials have demonstrated the safety and efficacy of once-daily dapsone gel, 7.5% in patients with moderate acne. OBJECTIVE: The objective of this report is to describe the clinical course of 8 patients who participated in a 12-week program using once-daily dapsone gel, 7.5% as monotherapy for acne in a real-world clinical setting. MONOTHERAPY PROGRAM: Male and female adults and adolescents with facial acne, representing a broad range of ages, skin phototypes, and ethnicities, and with no prior use of dapsone gel, 7.5% applied the product once daily for 12 weeks as monotherapy for acne. Photographs were taken at baseline and at 12 weeks. The treating dermatologists recorded observations of baseline disease, treatment tolerability, and outcomes. An independent rater assessed Global Acne Assessment Score (GAAS) at baseline and at 12 weeks based on photographs. Patients provided testimonials of their experience with treatment. PROGRAM OUTCOMES: Acne improvement was evident in the photographs of the 8 patients. Changes in GAAS at week 12 of treatment, as assessed by an independent rater, ranged from 1- to 3-grade improvement from baseline. CONCLUSION: Photographs, dermatologist reports, and patient commentary in an office-based practice demonstrated that 12 weeks of treatment with only topical dapsone gel, 7.5%, applied once daily, was effective and well tolerated as a stand-alone treatment in 8 patients with facial acne vulgaris, with results that are consistent with the phase 3 pivotal trials. J Drugs Dermatol. 2018;17(6):602-608.

Biomimetic Solid Lipid Nanoparticles of Sophorolipids Designed for Antileprosy Drugs.

The objective of the present work was to develop solid lipid nanoparticles (SLNs) as drug-encapsulating structures by the solvent injection method. In this report, for the first time the inherent potential of lactonic sophorolipid (glycolipid) was exploited to formulate SLNs. A range of different Pluronic copolymers were screened by dynamic and static light scattering with the aim of obtaining most stable SLNs. To comprehend the structure of the SLNs, techniques such as transmission electron microscopy, differential scanning calorimetry, Fourier transform infrared spectroscopy, and X-ray diffraction were employed. A clear correlation between the type of Pluronic and size and stability of the SLNs could be drawn. The vector properties of the formed SLNs were assessed for both the encapsulated hydrophobic drugs-rifampicin and dapsone. To elucidate the transport mechanism of drug release, kinetic modeling was carried out on the drug release profiles. The promising results of sophorolipid-based SLNs have actually established a new arena beneath the significantly developed field of SLNs.

Dapsone-Loaded Invasomes as a Potential Treatment of Acne: Preparation, Characterization, and In Vivo Skin Deposition Assay.

Dapsone (DPS) is a unique sulfone with antibiotic and anti-inflammatory activity. Owing to its dual action, DPS has a great potential to treat acne. Topical DPS application is expected to be effective in treatment of mild to moderate acne conditions. Invasomes are novel vesicles composed of phosphatidylcholine, ethanol, and one or mixture of terpenes of enhanced percutaneous permeation. In this study, DPS-loaded invasomes were prepared using the thin film hydration technique. The effect of different terpenes (Limonene, Cineole, Fenchone, and Citral) in different concentrations on the properties of the prepared DPS-loaded invasomes was investigated using a full factorial experimental design, namely, the particle size, drug entrapment, and release efficiency. The optimized formulation was selected for morphological evaluation which showed spherical shaped vesicles. Further solid-state characterization using differential scanning calorimetry and X-ray diffractometry revealed that the drug was dispersed in an amorphous state within the prepared invasomes. Finally, the ability of the prepared DPS-loaded invasomes to deliver DPS through the skin was investigated in vivo using wistar rats. The maximum in vivo skin deposition amount of DPS was found to be 4.11 mcg/cm2 for invasomes versus 1.71 mcg/cm2 for the drug alcoholic solution, representing about 2.5-fold higher for the invasomes compared to the drug solution. The AUC0-10 calculated for DPS-loaded invasomes was nearly 2-fold greater than that of DPS solution (14.54 and 8.01 mcg.h/cm2 for the optimized invasomes and DPS solution, respectively). These results reveal that the skin retention of DPS can be enhanced using invasomes.

Dapsone for topical use in extemporaneous preparations.

BACKGROUND: The sulfone dapsone has an established role in systemic therapy. Its pharmacological and toxicological properties are well known. Topically, dapsone is used in a gel formulation for the treatment of acne vulgaris. In addition, there have been individual case reports on the efficacy of topical dapsone preparations in the treatment of various neutrophilic dermatoses. To date, no finished medicinal product for topical use has been available in Germany. MATERIAL AND METHODS: Against this background, we set out to develop extemporaneous preparations containing dapsone (5 %) that meet the quality requirements of the European Pharmacopoeia as well as the manufacturing requirements of the German Ordinance on the Operation of Pharmacies (ApBetrO). These formulations included the incorporation of dapsone in a hydrophobic cream base ("hydrophobe Basiscreme DAC") as well as in methylprednisolone aceponate 0.1 % ointment (alternatively, in the latter's cream base without active ingredient). RESULTS: Tests aimed at investigating the physical, chemical, and microbiological stability of these formulations showed them to meet the aforementioned quality requirements. CONCLUSION: The extemporaneous formulations presented herein broaden the therapeutic options for topical treatment, in particular for patients with chronic inflammatory dermatoses associated with a neutrophilic pathogenesis.

Dapsone and Nitroso Dapsone Activation of Naïve T-Cells from Healthy Donors.

Dapsone (DDS) causes hypersensitivity reactions in 0.5-3.6% of patients. Although clinical diagnosis is indicative of a hypersensitivity reaction, studies have not been performed to define whether dapsone or a metabolite activates specific T-cells. Thus, the aims of this study were to explore the immunogenicity DDS and nitroso DDS (DDS-NO) using peripheral blood mononuclear cells from healthy donors and splenocytes from mice and generate human T-cell clones to characterize mechanisms of T-cell activation. DDS-NO was synthesized from DDS-hydroxylamine and shown to bind to the thiol group of glutathione and human and mouse albumin through sulfonamide and N-hydroxyl sulphonamide adducts. Naïve T-cell priming to DDS and DDS-NO was successful in three human donors. DDS-specific CD4+ T-cell clones were stimulated to proliferate in response to drug via a MHC class II restricted direct binding interaction. Cross reactivity with DDS-NO, DDS-analogues, and sulfonamides was not observed. DDS-NO clones were CD4+ and CD8+, MHC class II and I restricted, respectively, and activated via a pathway dependent on covalent binding and antigen processing. DDS and DDS-NO-specific clones secreted a mixture of Th1 and Th2 cytokines, but not granzyme-B. Splenocytes from mice immunized with DDS-NO were stimulated to proliferate in vitro with the nitroso metabolite, but not DDS. In contrast, immunization with DDS did not activate T-cells. These data show that DDS- and DDS-NO-specific T-cell responses are readily detectable.

Anti-glioma Activity of Dapsone and Its Enhancement by Synthetic Chemical Modification.

The sulfone dapsone is an old antibiotic used for the treatment of mycobacterial and protozoal infections. We postulated before that dapsone might possess biological activity exceeding its anti-infectious properties and that it could potentially be repurposed for the treatment of glioma. To test this hypothesis, we treated established and primary cultured glioma cells with dapsone or several dapsone analogues which we previously synthesized (D2-D5) and determined effects on proliferation, anchorage-independent growth and migration. While dapsone and its synthetic analogues D2-D5 displayed only modest anti-proliferative activity, important neoplastic features such as anchorage-independent growth, clonogenic survival and directed migration were significantly inhibited by dapsone treatment. Moreover, dapsone analogues D3, D4 and D5 yielded even enhanced anti-glioma activity against different pro-neoplastic features. Overall these data suggest that dapsone provides activity against glioma which can be further enhanced by molecular modifications. These compounds could potentially serve as a therapeutic adjunct to the treatment of gliomas in a repurposing approach.