RESUMO
Through molecular recognition, drugs can interact and complex with macromolecules circulating in the body. The serum albumin transport protein, found in several mammals, has several interaction sites where these molecules can be located. The drug sulfasalazine (SSZ) is known in the literature to complex at drug site 1 (DS1) in human serum (HSA) and bovine serum (BSA) proteins. This complexation can be studied using various spectroscopic techniques. With the techniques used in this work, absorption in the ultraviolet and visible regions (UV-Vis) and electronic circular dichroism (ECD), a significant difference was observed in the results involving HSA and BSA. The application of theoretical methodologies, such as TD-DFT and molecular docking, suggests that the conformation that SSZ assumes in DS1 of the two proteins is different, which exposes it to different amino acid residues and different hydrophobicities. This difference in conformation may be related to the location of DS1 where the drug interacts or to the possibility of SSZ moving in the BSA site, due to its larger size, and moving less freely in HSA.
Assuntos
Simulação de Acoplamento Molecular , Soroalbumina Bovina , Sulfassalazina , Sulfassalazina/química , Soroalbumina Bovina/química , Humanos , Bovinos , Animais , Estereoisomerismo , Dicroísmo Circular , Albumina Sérica Humana/química , Teoria da Densidade FuncionalRESUMO
Sulfasalazine needs frequent daily dosing and the administration of numerous tablets per day pose challenges to patient compliance, contributing to increased adverse effects and difficulties in disease control. These inconveniences result in less effective treatment for arthritis associated with inflammatory bowel disease i.e. ulcerative colitis etc. To improve drug bioavailability, a delayed-release mechanism that releases the drug at the colon is necessary. To develop and optimize colon-targeted controlled release bilayer tablets coated with pH-dependent polymers. The bilayer tablets containing the immediate release part and sustained release part were developed. The tablets were coated with enteric-coated with Eudragit® S-100 and l-100 to achieve release in the colon. Granule properties and tablets were evaluated. The physicochemical parameters of the tablets were evaluated including, stability study, and drug release in 0.1 N HCl (pH 1.2), pH 6.8 phosphate buffer, pH 7.4 phosphate buffer for 2, 1, and up to 24 h respectively. Radiographic imaging and in vivo pharmacokinetic studies were also done in Rabbits. The bilayer tablets containing immediate and sustained release were successfully developed for the colon targeting. The granule properties were found within the acceptable range indicating good flow properties. The physicochemical properties of the tablets were also found acceptable. The tablets did not show release in 0.1 N HCl and 6.8 phosphate buffer but drug release was found under control in the 7.4 pH buffer. Sulfasalazine coated bilayer tablets were found stable and no significant changes were observed in the stability studies. Based on the X-ray studies, the formulated tablet remained discernible in the stomach, small intestine, and colon for a duration of up to 24 h. Finally, by the 32nd hour, the tablet was no longer visible in the X-ray examination, leading to the conclusion of complete drug release. The drug concentration in plasma remained within the therapeutic range for up to 24 h in vivo. These novel formulations present substantial advantages, providing prolonged targeted drug release and reducing systemic adverse effects. The results suggest promising potential for treating arthritis in Inflammatory bowel disease (IBD) patients, offering a solution to current delivery systems.
Assuntos
Preparações de Ação Retardada , Liberação Controlada de Fármacos , Sulfassalazina , Sulfassalazina/farmacocinética , Sulfassalazina/administração & dosagem , Sulfassalazina/química , Animais , Coelhos , Preparações de Ação Retardada/farmacocinética , Comprimidos , Artrite/tratamento farmacológico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Disponibilidade Biológica , Comprimidos com Revestimento Entérico , Ácidos Polimetacrílicos/química , Masculino , Colo/metabolismo , Colo/efeitos dos fármacos , Química Farmacêutica/métodos , Concentração de Íons de Hidrogênio , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Composição de Medicamentos/métodos , Estabilidade de MedicamentosRESUMO
A comprehensive understanding of ferroptosis signaling pathways significantly contributes to the advances in cancer ferrotherapy. Herein, we constructed a self-assembled prodrug nanosystem targeting system xc-, a key regulator for ferroptosis, to amplify the therapeutic efficacy of cancer ferrotherapy. The prodrug nanosystem is assembled between sulfasalazine (SSZ, a ferroptosis resistance inhibitor) and disulfide-bridged levodopa (DSSD) that can chelate Fe2+ ions to form SSZ-Fe2+@DSSD, and the resulting nanoassembly can not only inhibit ferroptosis resistance, but also generate ROS in the tumor microenvironment. Whereas the prodrug nanosystem is stable in the physiological environment, it becomes unstable in the tumoral and intracellular reductive microenvironment, where the disulfide linkers are disrupted by high levels of glutathione (GSH), triggering the release of active Fe2+ and SSZ. Under the Fenton reaction, the released Fe2+ thus can induce ferroptosis, which is amplified by SSZ-mediated inhibition of ferroptosis resistance to synergistically improve the therapeutic efficacy of ferroptosis. Our study thus provides an innovative prodrug strategy to advance anticancer ferroptosis.
Assuntos
Antineoplásicos/farmacologia , Materiais Biocompatíveis/farmacologia , Ferroptose/efeitos dos fármacos , Compostos Ferrosos/farmacologia , Levodopa/farmacologia , Pró-Fármacos/farmacologia , Sulfassalazina/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Compostos Ferrosos/química , Humanos , Levodopa/química , Teste de Materiais , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Oxirredução , Tamanho da Partícula , Pró-Fármacos/síntese química , Pró-Fármacos/química , Espécies Reativas de Oxigênio/metabolismo , Sulfassalazina/química , Microambiente Tumoral/efeitos dos fármacosRESUMO
This study demonstrated the tracking of ulcerative colitis, which is considered a stressful immune disease. Although there are many ways to test for this disease including dependence on gases, dyes, and painful anal endoscopy, these treatment modalities have many disadvantages. Hence, it is the utmost need of time to discover new methods to detect this chronic immune disease and to avoid the defects of traditional methodologies. Sulfasalazine (SSD) was labeled with iodine-131 (half-life: 8 days, Energy: 971 keV) under optimum reaction conditions including the amount of reducing agent, pH factor, chloramine-T (Ch-T) amount, and incubation period. Characterization was performed using 1 H/ 13 C-NMR, ESI-MS, and HPLC (UV/ Radio) techniques. The biodistribution study was performed in normal and ulcerative mice models, and in silico molecular docking study was performed to evaluate the possible mechanism of action to target peroxisome proliferator-activated receptor gamma (PPARγ). The high radiolabeling yield of [131 I]-sulfasalazine ([131 I]-SSD) was achieved ≥90% through the direct labeling method with radioactive iodine-131 in the presence of chloramine-T (100 µg). The radiotracer [131 I]-SSD was observed to be stable in normal saline and freshly eluted serum up to 12 hr at ambient temperature (37â ± 2â). The radiotracer [131 I]-SSD showed the highest uptake in the targeted organ (i.e., ulcerative colon) which was observed to be ≥75% injected dose per gram (% ID/g) organ for 24 hr postinjection (p.i). Furthermore, in silico data collected from molecular modeling analysis of SSD and [131 I]-SSD with antimicrobial protein (PDB code: 3KEG) and peroxisome proliferator-activated receptor gamma (PPARγ) (PDB code: 4XTA) showed azoreductase activity and high binding potential for PPAR-γ site, respectively. The results of biological studies obtained in this study enlighten the usefulness of radiotracer [131 I]-SSD as a potential imaging agent for ulcerative colitis.
Assuntos
Colite Ulcerativa/radioterapia , Isótopos de Iodo/química , Sulfassalazina/química , Animais , Cloraminas/química , Defensinas/química , Modelos Animais de Doenças , Humanos , Concentração de Íons de Hidrogênio , Isótopos de Iodo/farmacologia , Cinética , Masculino , Camundongos , Simulação de Acoplamento Molecular , Nitrorredutases/química , Oxirredução , PPAR gama/metabolismo , Proteínas de Plantas/química , Tomografia por Emissão de Pósitrons , Ligação Proteica , Conformação Proteica , Coloração e Rotulagem , Distribuição TecidualRESUMO
The xCT antiporter is a cell membrane protein involved in active counter-transportation of glutamate (outflux) with cystine (influx) over the human cell membrane. This feature makes the xCT antiporter a crucial element of the biosynthesis of the vital free radical scavenger glutathione. The prodrug sulfasalazine, a medication for the treatment of ulcerative colitis, was previously proven to inhibit the xCT antiporter. Starting from sulfasalazine, a molecular scaffold jumping followed by SAR-assisted design and synthesis provided a series of styryl hydroxy-benzoic acid analogues that were biologically tested inâ vitro for their ability to decrease intracellular glutathione levels using four different cancer cell lines: A172 (glioma), A375 (melanoma), U87 (glioma) and MCF7 (breast carcinoma). Depletion of glutathione levels varied among the compounds as well as among the cell lines. Flow cytometry using propidium iodide and the annexinâ V marker demonstrated minimal toxicity in normal human astrocytes for a promising candidate molecule (E)-5-(2-([1,1'-biphenyl]-4-yl)vinyl)-2-hydroxybenzoic acid.
Assuntos
Sistema y+ de Transporte de Aminoácidos/antagonistas & inibidores , Desenho de Fármacos , Pró-Fármacos/farmacologia , Sulfassalazina/farmacologia , Sistema y+ de Transporte de Aminoácidos/metabolismo , Humanos , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-Atividade , Sulfassalazina/síntese química , Sulfassalazina/químicaRESUMO
Solid lipid nanoparticles (SLNs) have the potential to enhance the systemic availability of an active pharmaceutical ingredient (API) or reduce its toxicity through uptake of the SLNs from the gastrointestinal tract or controlled release of the API, respectively. In both aspects, the responses of the lipid matrix to external challenges is crucial. Here, we evaluate the effects of lyophilization on key responses of 1:1 beeswax-theobroma oil matrix SLNs using three model drugs: amphotericin B (AMB), paracetamol (PAR), and sulfasalazine (SSZ). Fresh SLNs were stable with sizes ranging between 206.5-236.9 nm. Lyophilization and storage for 24 months (4-8 °C) caused a 1.6- and 1.5-fold increase in size, respectively, in all three SLNs. Zeta potential was >60 mV in fresh, stored, and lyophilized SLNs, indicating good colloidal stability. Drug release was not significantly affected by lyophilization up to 8 h. Drug release percentages at end time were 11.8 ± 0.4, 65.9 ± 0.04, and 31.4 ± 1.95% from fresh AMB-SLNs, PAR-SLNs, and SSZ-SLNs, respectively, and 11.4 ± 0.4, 76.04 ± 0.21, and 31.6 ± 0.33% from lyophilized SLNs, respectively. Thus, rate of release is dependent on API solubility (AMB < SSZ < PAR). Drug release from each matrix followed the Higuchi model and was not affected by lyophilization. The above SLNs show potential for use in delivering hydrophilic and lipophilic drugs.
Assuntos
Cacau/química , Portadores de Fármacos/química , Lipídeos/química , Nanopartículas/química , Preparações Farmacêuticas/química , Óleos de Plantas/química , Ceras/química , Acetaminofen/química , Anfotericina B/química , Composição de Medicamentos , Liofilização , Interações Hidrofóbicas e Hidrofílicas , Sulfassalazina/químicaRESUMO
Plasma-treated goethite nanoparticles with high surface area and improved density of surface hydroxyl groups were synthesized from natural goethite (NG) using Argon (PTG-Ar) and Nitrogen (PTG-N2) as plasma environment to enhance the performance of heterogeneous catalytic ozonation process. Synthesized samples were characterized by FESEM, EDX, TEM, XRD, XPS, BET-BJH, FTIR, AAS and pHPZC. Results indicated a significantly different morphology for the prepared samples with negligible change in crystal structure. Furthermore, the catalytic activity and synergy factor of the NG and PTG nanocatalysts were evaluated for degradation and mineralization of Sulfasalazine antibiotic (SSZ) as an environmental hazardous contaminant. The highest removal efficiency was achieved 96.05 % under the optimal operating conditions. The kinetic study confirmed the pseudo-first-order reaction for the degradation process. Moreover, the dissolved ozone concentration and effect of organic and inorganic salts were studied in order to assess the reactive oxidant species (ROSs) and catalyst active sites in the process. The mechanism investigation showed the catalytic ozonation of SSZ was mainly performed by successive attacks of hydroxyl radicals (â¢OH), superoxide radicals (O2-) and direct ozone molecules. Environmentally-friendly modification of the NG, negligible iron leaching, successive reusability and superior catalytic activity are the major benefits of the PTG nanoparticles.
Assuntos
Antibacterianos/química , Compostos de Ferro/química , Minerais/química , Nanoestruturas/química , Ozônio/química , Sulfassalazina/química , Poluentes Químicos da Água/química , Argônio , Catálise , Nitrogênio , Gases em Plasma , Espécies Reativas de Oxigênio/químicaRESUMO
Currently near-infrared (NIR) luminescence of lanthanide ions has received great attention because of their unique emissions in the near-infrared region (800-1700â¯nm). These NIR luminescent materials behave excellent applications in many fields such as sensors and probes in optical amplification, laser systems, biological systems and organic light-emitting diodes. In this work, two new near-infrared (NIR) emission three-dimensional (3D) YbIII and NdIII cluster-based coordination materials, namely {[Yb2(L)2(DMF)(H2O)4]·(DMF)2 (H2O)}n (NIR-MOF 1) and [Nd(L)(DMF)2]n (NIR-MOF 2) (H3Lâ¯=â¯terphenyl-3,4â³,5-tricarboxylic acid) have been synthesized through the facile sono-chemical preparation methods. Both the near-infrared materials 1 and 2 have been characterized by single crystal X-ray diffraction, powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM). Further the mixed-lanthanide near-infrared emission material Nd0.35Yb0.65L (NIR-MOF 3) can also be prepared under the sono-chemical conditions. NIR-MOF 3 can be successfully applied as the ratiometric NIR-MOF-based thermometer, which should origin from the emission intensity ratio between Yb3+ (976â¯nm) and Nd3+ (1056â¯nm) in the temperature range of 308-348â¯K. Besides these, the micro-morphologies of NIR-MOF 1 can be deliberately tuned through different sono-chemical reaction factors (reaction time, reaction temperature and sono-chemical powers). These tuned nano-sized materials NIR-MOF 1 (100â¯W, 80â¯min) can be utilized as the fluorescent sensing material to distinguish furazolidone and sulfasalazine from other antibiotics. At the same time, NIR-MOF 2 can be applied as the first example of MOFs-based sensors for discriminating l-arginine from other amino acids through the "turn-on" mode in the near-infrared emission region.
Assuntos
Antibacterianos/análise , Arginina/análise , Técnicas de Química Analítica/instrumentação , Raios Infravermelhos , Neodímio/química , Ondas Ultrassônicas , Itérbio/química , Antibacterianos/química , Arginina/química , Furazolidona/análise , Furazolidona/química , Cinética , Limite de Detecção , Modelos Moleculares , Conformação Molecular , Compostos Organometálicos/química , Solventes/química , Sulfassalazina/análise , Sulfassalazina/química , TemperaturaRESUMO
An effective steady-state redox balance is maintained in cancer cells, allowing for protection against oxidative stress and thereby enhancing cell proliferation and tumor growth. Disruption of this redox balance would increase the cellular content of reactive oxygen species (ROS) and potentiate oxidative stress-induced cell death in tumor cells, thus representing an effective strategy for cancer treatment. Glutathione (GSH) is a major reducing agent, and its cellular levels are determined at least partly by the availability of cysteine via xCT (SLC7A11)-mediated entry of cystine into cells. We developed a nanoplatform using ZnO nanoparticles (NPs) as a carrier, loaded with salicylazosulfapyridine (SASP), and stabilized with DSPE-PEG, to form ultra-small NPs (SASP/ZnO NPs). The goal of this NP strategy is to disrupt the redox balance in cells by two mechanisms: increased generation of ROS and decreased synthesis of GSH. Such an approach would be effective in killing tumor cells. As expected, the SASP/ZnO NPs enhanced ROS production because of ZnO and impaired GSH synthesis because of SASP-induced inhibition of xCT (SLC7A11) transport function. As a consequence, treatment of tumor cells with SASP/ZnO NPs in vitro and in vivo resulted in a synergistic disruptive effect on redox balance in tumor cells and induced cell death and decreased tumor growth. This ambidextrous approach has potential in cancer therapy by combining two complementary pathways to disrupt the redox balance in tumor cells.
Assuntos
Antineoplásicos/farmacologia , Nanopartículas/química , Neoplasias/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisteína/química , Cistina/metabolismo , Glutationa/metabolismo , Humanos , Nanopartículas/administração & dosagem , Neoplasias/patologia , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Sulfassalazina/química , Sulfassalazina/farmacologia , Óxido de Zinco/químicaRESUMO
System xc- (Sxc- ), a cystine-glutamate antiporter, is established as an interesting target for the treatment of several pathologies including epileptic seizures, glioma, neurodegenerative diseases, and multiple sclerosis. Erastin, sorafenib, and sulfasalazine (SSZ) are a few of the established inhibitors of Sxc- . However, its pharmacological inhibition with novel and potent agents is still very much required due to potential issues, for example, potency, bioavailability, and blood-brain barrier (BBB) permeability, with the current lead molecules such as SSZ. Therefore, in this study, we report the synthesis and structure-activity relationships (SAR) of SSZ derivatives along with molecular docking and dynamics simulations using the developed homology model of xCT chain of Sxc- antiporter. The generated homology model attempted to address the limitations of previously reported comparative protein models, thereby increasing the confidence in the computational modeling studies. The main objective of the present study was to derive a suitable lead structure from SSZ eliminating its potential issues for the treatment of glioblastoma multiforme (GBM), a deadly and malignant grade IV astrocytoma. The designed compounds with favorable Sxc- inhibitory activity following in vitro Sxc- inhibition studies, showed moderately potent cytotoxicity in patient-derived human glioblastoma cells, thereby generating potential interest in these compounds. The xCT-ligand model can be further optimized in search of potent lead molecules for novel drug discovery and development studies.
Assuntos
Sistema y+ de Transporte de Aminoácidos/antagonistas & inibidores , Antiporters/antagonistas & inibidores , Sulfassalazina/análogos & derivados , Sistema y+ de Transporte de Aminoácidos/metabolismo , Animais , Antiporters/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Ligantes , Simulação de Acoplamento Molecular , Ratos , Relação Estrutura-Atividade , Sulfassalazina/química , Sulfassalazina/farmacocinética , Sulfassalazina/farmacologiaRESUMO
The aim of this study was to develop and characterize a pH sensitive, biodegradable, interpenetrating polymeric network (IPNs) for colon specific delivery of sulfasalazine in ulcerative colitis. It also entailed in-vitro and in-vivo evaluations to optimize colon targeting efficiency, improve drug accumulation at the target site, and ameliorate the off-target effects of chemotherapy. Pectin was grafted with polyethylene glycol (PEG) and methacrylic acid (MAA) by free radical polymerization. Fourier transformed infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), energy dispersion X-ray (EDX) and powder X-ray diffraction (XRD) results confirmed the development of stable pectin-g-(PEG-co-MAA) hydrogels. The swelling and release studies exhibited that the hydrogels were capable of releasing drug specifically at colonic pH (pHâ¯7.4). The toxicological potential of polymers, monomers and hydrogel was investigated using the Balb/c animal model, that confirmed the safety of the hydrogels. In vitro degradation of the hydrogel was evaluated using pectinase enzyme in various simulated fluids and the results showed that the hydrogels were susceptible to biodegradation by the natural microflora of the colon. In-vivo study was performed using Dextran sulphate sodium (DSS) rat model proved the hydrogels to be effective in the management of UC.
Assuntos
Colite Ulcerativa/tratamento farmacológico , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Hidrogéis/química , Hidrogéis/metabolismo , Animais , Colite Ulcerativa/metabolismo , Colo/metabolismo , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Feminino , Concentração de Íons de Hidrogênio , Masculino , Metacrilatos/química , Camundongos , Camundongos Endogâmicos BALB C , Pectinas/química , Polietilenoglicóis/química , Sulfassalazina/química , Sulfassalazina/uso terapêuticoRESUMO
OBJECTIVE: A major challenge in targeting orally administered drugs to colon is their passage through the long gastrointestinal path comprising highly variant conditions in terms of pH, viscosity, gut motility and microbial flora. Approaches to pH controlled release and microbially triggered release have proved to be successful in achieving colon targeting only to a partial extent. METHODS: In an attempt to improve targeting, both these approaches have been combined together with the approach of liquisolid technology which, hitherto, remains unexplored for colon targeting. The combination of these three approaches is being reported for the first time to achieve colon targeting along with a burst release of a Biopharmaceutical Classification System (BCS) Class IV drug at the target site. pH controlled polymer, Eudragit® S-100 was used to prevent the release of sulfasalazine in the gastric region while microbially triggered polymers, pectin and guar gum were used to ferry the system through the intestinal region. RESULTS: Liquisolid formulation was designed to provide a burst release of sulfasalazine in colon on the digestion of polysaccharide coating. CONCLUSION: The results support the premise that the combination of pH sensitive, microbially triggered polymers and liquisolid formulation technique appears to be a pragmatic approach for colonic delivery of orally administered drugs.
Assuntos
Anti-Inflamatórios não Esteroides , Ceco/microbiologia , Colo/metabolismo , Sistemas de Liberação de Medicamentos , Polímeros , Sulfassalazina , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Liberação Controlada de Fármacos , Feminino , Concentração de Íons de Hidrogênio , Absorção Intestinal , Masculino , Polímeros/administração & dosagem , Polímeros/química , Ratos Sprague-Dawley , Solubilidade , Sulfassalazina/administração & dosagem , Sulfassalazina/químicaRESUMO
The aim of this study was to investigate the effects of a sulfasalazine-containing hyaluronic acid (SASP/HA) systems on in vitro anti-inflammation and the alleviation of cartilage degradation in both lipopolysaccharide (LPS)-stimulated synoviocytes and a rat model of monosodium iodoacetate (MIA)-induced osteoarthritis (OA). The SASP/HA resulted in long-term release of SASP from the SASP/HA for up to 60â¯days in a sustained manner. In vitro studies performed using real-time polymerase chain reaction (PCR) assay revealed that the SASP/HA was able to effectively and dose-dependently inhibit the mRNA expression levels of pro-inflammatory cytokines such as matrix metalloproteinases-3 (MMP-3), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in LPS-stimulated synoviocytes. In vivo studies showed that intra articular injection of SASP/HA greatly reduced the MIA-stimulated mRNA expression of MMP-3, COX-2, IL-6, and TNF-α in blood. Furthermore, these significant anti-inflammatory effects of SASP/HA contributed markedly to the alleviation of progression of MIA-induced OA and cartilage degradation, as demonstrated by X-ray, micro-computed tomography (micro-CT), gross findings, and histological evaluations. Therefore, our findings indicated that the long-term and sustained delivery of SASP using HA can play a therapeutic role in alleviating inflammation as well as protecting against cartilage damage in OA.
Assuntos
Cartilagem/metabolismo , Ácido Hialurônico , Osteoartrite/tratamento farmacológico , Sulfassalazina , Animais , Cartilagem/patologia , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Osteoartrite/induzido quimicamente , Osteoartrite/metabolismo , Osteoartrite/patologia , Ratos , Ratos Sprague-Dawley , Sulfassalazina/química , Sulfassalazina/farmacologiaRESUMO
The widespread occurrence of pharmaceuticals and their metabolites in natural waters has raised great concerns about their potential risks on human health and ecological systems. This study systematically investigates the degradation of sulfasalazine (SSZ) and its two human metabolites, sulfapyridine (SPD) and 5-aminosalicylic acid (5-ASA), by UV and UV/peroxydisulfate (UV/PDS) processes. Experimental results show that SPD and 5-ASA were readily degraded upon UV 254â¯nm direct photolysis, with quantum yields measured to be (8.6⯱â¯0.8)â¯×â¯10-3 and (2.4⯱â¯0.1)â¯×â¯10-2â¯molâ¯Einstein-1, respectively. Although SSZ was resistant to direct UV photolysis, it could be effectively removed by both UV/H2O2 and UV/PDS processes, with fluence-based pseudo-first-order rate constants determined to be 0.0030 and 0.0038â¯cm2â¯mJ-1, respectively. Second-order rate constant between SO4â¢- and SSZ was measured as (1.33⯱â¯0.01)â¯×â¯109â¯M-1s-1 by competition kinetic method. A kinetic model was established for predicting the degradation rate of SSZ in the UV/PDS process. Increasing the dosage of PDS significantly enhanced the degradation of SSZ in the UV/PDS process, which can be well predicted by the developed kinetic model. Natural water constituents, such as natural organic matter (NOM) and bicarbonate (HCO3-), influenced the degradation of SSZ differently. The azo functional group of SSZ molecule was predicted as the reactive site susceptible to electrophilic attack by SO4â¢- by frontier electron densities (FEDs) calculations. Four intermediate products arising from azo bond cleavage and SO2 extrusion were identified by solid phase extraction-liquid chromatography-triple quadrupole mass spectrometry (SPE-LC-MS/MS). Based on the products identified, detailed transformation pathways for SSZ degradation in the UV/PDS system were proposed. Results reveal that UV/PDS could be an efficient approach for remediation of water contaminated by SSZ and its metabolites.
Assuntos
Compostos de Sódio/efeitos da radiação , Sulfassalazina/química , Sulfassalazina/efeitos da radiação , Sulfatos/efeitos da radiação , Raios Ultravioleta , Poluentes Químicos da Água/química , Poluentes Químicos da Água/efeitos da radiação , Humanos , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/efeitos da radiação , Cinética , Mesalamina/química , Mesalamina/efeitos da radiação , Oxirredução , Fotólise , Compostos de Sódio/química , Sulfapiridina/química , Sulfapiridina/efeitos da radiação , Sulfatos/química , Purificação da ÁguaAssuntos
Fármacos Gastrointestinais/efeitos adversos , Síndrome de Stevens-Johnson/etiologia , Sulfapiridina/efeitos adversos , Sulfassalazina/efeitos adversos , Colite Ulcerativa/tratamento farmacológico , ELISPOT , Feminino , Humanos , Pessoa de Meia-Idade , Sulfapiridina/análise , Sulfassalazina/químicaRESUMO
BACKGROUND: Polysaccharide based delivery systems have been successfully used to target drugs to colon. In some recent reports, the superiority of concomitant administration of probiotics with such systems has been established. However, the pharmacokinetics of such symbiotic therapy remain unexplored hitherto. METHODS: This study deciphers the pharmacokinetic parameters of guar gum based colon targeted spheroids of sulfasalazine with co-administration of probiotics in experimental rats. Thirty rats were divided into five groups using Latin square design. These were subjected to treatment with delayed release formulation, uncoated spheroids, coated spheroid and coated spheroids along with probiotics. RESULTS: In case of delayed release formulation, negligible presence of sulfasalazine in plasma was observed in first 2h, followed by significant increase in sulfasalazine concentration after 3h. Higher plasma concentrations of sulfasalazine were detected for uncoated spheroids with and without probiotics. Negligible release of drug upto 5h and delayed Tmax in case of guar-gum coated sulfasalazine spheroids with or without probiotics clearly indicated successful formulation of colon targeted spheroids. Further, for coated spheroids (both with and without probiotics), the value of Tmax is found to be significantly higher than those with the other treatments. CONCLUSION: Colon targeted spheroids were therefore, found to reduce absorption of drug which, in turn, is expected to reduce the side effects as only local action in colon is required for treatment of colitis. This is the first report on pharmacokinetic study of a colon targeted delivery system co-administered with probiotics.
Assuntos
Colo/metabolismo , Sistemas de Liberação de Medicamentos , Galactanos/administração & dosagem , Fármacos Gastrointestinais/administração & dosagem , Mananas/administração & dosagem , Gomas Vegetais/administração & dosagem , Ácidos Polimetacrílicos/administração & dosagem , Probióticos/administração & dosagem , Sulfassalazina/administração & dosagem , Animais , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Feminino , Galactanos/química , Galactanos/farmacocinética , Fármacos Gastrointestinais/química , Fármacos Gastrointestinais/farmacocinética , Masculino , Mananas/química , Mananas/farmacocinética , Gomas Vegetais/química , Gomas Vegetais/farmacocinética , Ácidos Polimetacrílicos/química , Ácidos Polimetacrílicos/farmacocinética , Probióticos/química , Probióticos/farmacocinética , Ratos Sprague-Dawley , Sulfassalazina/química , Sulfassalazina/farmacocinéticaRESUMO
Because neutrophil extracellular trap (NET) formation is involved in the pathology of a wide variety of diseases, NET-regulating compounds are expected to be useful for the therapies of these diseases. In this study, we identified sulfasalazine (SSZ) as a potent enhancer of NET formation both in vitro and in vivo. Although SSZ did not increase the amount of ROS generated, it accelerated the generation of ether-linked oxidized phospholipids, such as PE (18;1e/15-HETE) and PC (16;0e/13-HODE). Trolox, but not 2-ME, effectively suppressed lipid oxidation and NET formation that were induced by SSZ. SSZ is known as a potent inducer of ferroptosis in cancer cells by inhibiting xCT, a component of the cystine transporter. However, we found that SSZ accelerated NET formation in an xCT-independent manner. Structure-activity relationship studies revealed that the sulfapyridine moiety of SSZ plays a central role in enhancing NET formation. Furthermore, we found that two additional sulfonamide and sulfone derivatives possess NET-inducing activity by accelerating lipid oxidation. These results indicate that the hyperoxidation of ether-linked phospholipids is a key mechanism for accelerating NET formation.
Assuntos
Armadilhas Extracelulares/química , Neutrófilos/metabolismo , Éteres Fosfolipídicos/química , Animais , Apoptose , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Sulfassalazina/químicaRESUMO
Chagas disease is one of the most important neglected parasitic diseases afflicting developed and undeveloped countries. There are currently limited options for inexpensive and secure pharmacological treatment. In this study, we employed a structure-based virtual screening protocol for 3180 FDA-approved drugs for repositioning of them as potential trans-sialidase inhibitors. In vitro and in vivo evaluations were performed for the selected drugs against trypomastigotes from the INC-5 and NINOA strains of T. cruzi. Also, inhibition of sialylation by the trans-sialidase enzyme reaction was evaluated using high-performance anion-exchange chromatography with pulse amperometric detection to confirm the mechanism of action. Results from the computational study showed 38 top drugs with the best binding-energies. Four compounds with antihistaminic, anti-hypertensive, and antibiotic properties showed better trypanocidal effects (LC50 range = 4.5-25.8 µg/mL) than the reference drugs, nifurtimox and benznidazole (LC50 range = 36.1-46.8 µg/mL) in both strains in the in vitro model. The anti-inflammatory, sulfasalazine showed moderate inhibition (37.6%) of sialylation in a trans-sialidase enzyme inhibition reaction. Sulfasalazine also showed the best trypanocidal effects in short-term in vivo experiments on infected mice. This study suggests for the first time that the anti-inflammatory sulfasalazine could be used as a lead compound to develop new trans-sialidase inhibitors.