RESUMEN

Fabricating injectable hydrogel with multiple functions and effective promotion of wound repair has a great prospect in treatment of bacterial infected wounds. Herein, a pH/reactive oxygen species (ROS) dual responsive injectable hydrogel (PVBDL-gel) was constructed, the PVBDL-gel was cross-linked by dynamic Schiff base bonds and borate ester bonds between poly(vanillin acrylate-co-3 acrylamide phenylboronic acid-co-N,N-dimethylacrylamide) (P(VA-co-AAPBA-co-DMA)), oligolysines and polyvinyl alcohol (PVA). The anti-inflammatory drug, dexamethasone sodium phosphate (DEX), was encapsulated in this hydrogel. The hydrogel exhibited excellent degradability, stable rheology and suitable tissue adhesion, more importantly, which showing pH/ROS responsive ability and controllable releasing of DEX. In vitro and in vivo experiment results showed that the PVBDL-gel with good biocompatibility and efficient anti-infection ability can effectively eradicate 99.9 % of pathogenic bacteria within 3 h and promote the repair and regeneration of bacterial infection wounds. This novel multifunctional injectable hydrogel has great application in the field of bacterial infection wound repair.

Asunto(s)

Antibacterianos , Antiinflamatorios , Vendajes , Dexametasona , Hidrogeles , Cicatrización de Heridas , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/administración & dosificación , Hidrogeles/química , Hidrogeles/farmacología , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/administración & dosificación , Animales , Cicatrización de Heridas/efectos de los fármacos , Ratones , Dexametasona/farmacología , Dexametasona/química , Dexametasona/administración & dosificación , Dexametasona/análogos & derivados , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus/efectos de los fármacos , Infección de Heridas/tratamiento farmacológico , Infección de Heridas/microbiología , Escherichia coli/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Concentración de Iones de Hidrógeno , Masculino , Tamaño de la Partícula

RESUMEN

BACKGROUND: Ataxia telangiectasia is a multisystem disorder with progressive neurodegeneration. Corticosteroids can improve neurological functioning in patients with the disorder but adrenal suppression and symptom recurrence on treatment discontinuation has limited their use, prompting the development of novel steroid delivery systems. The aim of the ATTeST study was to evaluate the efficacy and safety of intra-erythrocyte delivery of dexamethasone sodium phosphate compared with placebo in children with ataxia telangiectasia. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 trial was done at 22 centres in 12 countries (Australia, Belgium, Germany, India, Israel, Italy, Norway, Poland, Spain, Tunisia, the UK, and the USA). Eligible participants were children aged 6 years or older weighing more than 15 kg who met clinical criteria for ataxia telangiectasia but who had preserved autonomous gait. Participants were randomly assigned (1:1:1) to low-dose (approximately 5-10 mg), or high-dose (approximately 14-22 mg) intra-erythrocyte dexamethasone sodium phosphate, or placebo, using an independent interactive web response system, with minimisation for sex and age (6-9 years vs ≥10 years). Intravenous intra-erythrocyte dexamethasone sodium phosphate was administered once a month for 6 months. Participants, employees of the sponsor, investigators, all raters of efficacy endpoints, and central reviewers were masked to treatment assignment and dose allocations. The primary efficacy endpoint was change in the modified International Cooperative Ataxia Rating Scale (mICARS) from baseline to month 6, assessed in the modified intention-to-treat (mITT) population, which included all randomly assigned participants who received at least one dose of study drug and had at least one post-baseline efficacy assessment. This trial is registered with Clinicaltrials.gov (NCT02770807) and is complete. FINDINGS: Between March 2, 2017, and May 13, 2021, 239 children were assessed for eligibility, of whom 176 were randomly assigned. One patient assigned to high-dose intra-erythrocyte dexamethasone sodium phosphate did not initiate treatment. 175 patients received at least one dose of treatment (59 patients received the low dose and 57 received the high dose of intra-erythrocyte dexamethasone sodium phosphate, and 59 received placebo). The mITT population comprised 164 participants (56 children in the low-dose group, 54 children in the high-dose group, and 54 in the placebo group). Compared with the placebo group, no differences were identified with regard to change in mICARS score from baseline to 6 months in the low-dose group (least squares mean difference -1·37 [95% CI -2·932 to 0·190]) or the high-dose group (-1·40 [-2·957 to 0·152]; p=0·0765). Adverse events were reported in 43 (73%) of 59 participants in the low-dose group, 47 (82%) of 57 participants in the high-dose group, and 43 (73%) of 59 participants in the placebo group. Serious adverse events were observed in six (10%) of 59 participants in the low-dose group, seven (12%) of 57 participants in the high-dose group, and seven (12%) of 59 participants in the placebo group. There were no reports of hyperglycaemia, hypertension, hirsutism, or Cushingoid appearance in any of the treatment groups, nor any treatment-related deaths. INTERPRETATION: Although there were no safety concerns, the primary efficacy endpoint was not met, possibly related to delays in treatment reducing the number of participants who received treatment as outlined in the protocol, and potentially different treatment effects according to age. Studies of intra-erythrocyte delivery of dexamethasone sodium phosphate will continue in participants aged 6-9 years, on the basis of findings from subgroup analyses from this trial. FUNDING: EryDel and Quince Therapeutics.

Asunto(s)

Ataxia Telangiectasia , Dexametasona , Humanos , Dexametasona/administración & dosificación , Dexametasona/análogos & derivados , Método Doble Ciego , Niño , Femenino , Masculino , Adolescente , Ataxia Telangiectasia/tratamiento farmacológico , Resultado del Tratamiento , Eritrocitos/efectos de los fármacos

RESUMEN

With an ever-increasing burden of vision loss caused by diseases of the posterior ocular segment, there is an unmet clinical need for non-invasive treatment strategies. Topical drug application using eye drops suffers from low to negligible bioavailability to the posterior segment as a result of static and dynamic defensive ocular barriers to penetration, while invasive delivery systems are expensive to administer and suffer potentially severe complications. As the cornea is the main anatomical barrier to uptake of topically applied drugs from the ocular surface, we present an approach to increase corneal permeability of a corticosteroid, dexamethasone sodium-phosphate (DSP), using a novel penetration enhancing agent (PEA). We synthesised a novel polyacetylene (pAc) polymer and compared its activity to two previously described cell penetrating peptide (CPP) based PEAs, TAT and penetratin, with respect to increasing transcorneal permeability of DSP in a rapid ex-vivo porcine corneal assay over 60 min. The transcorneal apparent permeability coefficients (Papp) for diffusion of pAc, and fluorescein isothiocyanate (FITC) conjugated TAT and penetratin were up to 5 times higher (p < 0.001), when compared to controls. When pAc was used in formulation with DSP, an almost 5-fold significant increase was observed in Papp of DSP across the cornea (p = 0.0130), a significant 6-fold increase with TAT (p = 0.0377), and almost 7-fold mean increase with penetratin (p = 0.9540). Furthermore, we investigated whether the PEAs caused any irreversible damage to the barrier integrity of the corneal epithelium by measuring transepithelial electrical resistance (TEER) and immunostaining of tight junction proteins using zonula occludens-1 (ZO-1) and occludin antibodies. There was no damage or structural toxicity, and the barrier integrity was preserved after PEA application. Finally, an in-vitro cytotoxicity assessment of all PEAs in human retinal pigment epithelium cells (ARPE-19) demonstrated that all PEAs were very well-tolerated, with IC50 values of 64.79 mM for pAc and 1335.45 µM and 87.26 µM for TAT and penetratin, respectively. Our results suggest that this drug delivery technology could potentially be used to achieve a significantly higher intraocular therapeutic bioavailability after topical eye drop administration, than currently afforded.

Asunto(s)

Péptidos de Penetración Celular , Córnea , Dexametasona , Sistemas de Liberación de Medicamentos , Permeabilidad , Animales , Dexametasona/administración & dosificación , Dexametasona/farmacocinética , Dexametasona/análogos & derivados , Porcinos , Córnea/metabolismo , Córnea/efectos de los fármacos , Péptidos de Penetración Celular/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Humanos , Retina/metabolismo , Retina/efectos de los fármacos , Línea Celular , Productos del Gen tat/administración & dosificación , Productos del Gen tat/química , Administración Oftálmica , Administración Tópica , Soluciones Oftálmicas/administración & dosificación , Proteínas Portadoras/metabolismo , Polímeros/química

RESUMEN

Systemic drug administration provides convenience and non-invasive benefits for preventing and treating inner ear diseases. However, the blood-labyrinth barrier (BLB) restricts the transport of drugs to inner ear tissues. Ultrasound can stimulate specific areas and penetrate tissues, with the potential to overcome physiological barriers. We present a novel strategy based on low-pressure pulsed ultrasound assisted by microbubbles (USMB) to transiently open the BLB and deliver therapeutics into the inner ear. A pulsed ultrasound device with adjustable pressure was established; the generated ultrasound was transmitted through the external auditory canal into the guinea pig's inner ear. We observed that the application of microbubbles allowed the use of safe and efficient ultrasound conditions to penetrate the BLB. We found that USMB-mediated BLB opening seemed to be associated with a reduced expression of the tight junction proteins zonula occludens-1 and occludin. Following intravenous administration, hydrophilic dexamethasone sodium phosphate (DSP), hydrophobic curcumin (CUR), as well as drug-loaded nanoparticles (Fe3O4@CUR NPs) could be efficiently delivered into the inner ear. We observed better drug accumulation in the perilymph of the inner ear, resulting in less drug (cisplatin)-induced ototoxicity. Furthermore, physiological, hematological, and histological studies showed that the modulation of the BLB by low-pressure USMB was a safe process without significant adverse effects. We conclude that USMB could become a promising strategy for the systematic delivery of therapeutics in the treatment of inner ear diseases.

Asunto(s)

Curcumina , Dexametasona , Oído Interno , Enfermedades del Laberinto , Microburbujas , Animales , Cobayas , Oído Interno/metabolismo , Dexametasona/administración & dosificación , Dexametasona/análogos & derivados , Curcumina/administración & dosificación , Curcumina/farmacocinética , Curcumina/química , Enfermedades del Laberinto/terapia , Ondas Ultrasónicas , Sistemas de Liberación de Medicamentos , Masculino , Nanopartículas/administración & dosificación

RESUMEN

AIM: This study aimed to fabricate dexamethasone sodium phosphate loaded microneedle arrays (MNA) and investigate their efficiency in combination with iontophoresis for the treatment of hind paw oedema in rats. METHODS: Drug loaded polyvinyl alcohol, polyvinyl pyrrolidone and D-sorbitol-based MNA11 were fabricated by vacuum micromolding. Physicochemical, morphological, thermal, in-silico, in-vitro insertion ability (on parafilm) and drug release studies were performed. Ex-vivo permeation, in-vivo insertion and anti-inflammatory studies were performed in combination with iontophoresis. RESULTS: MNA11 displayed sharp-tipped projections and acceptable physicochemical features. Differential scanning calorimetry results indicated that drug loaded MNA11 were amorphous solids. Drug interacted with PVP and PVA predominately via hydrogen bonding. Parafilm displayed conspicuously engraved complementary structure of MNA11. Within 60 min, 91.50 ± 3.1% drug released from MNA11. A significantly higher i.e., 95.06 ± 2.5% permeation of drug was observed rapidly (within 60 min) from MNA11-iontophoresis combination than MNA11 i.e., 84.07 ± 3.5% within 240 min. Rat skin treated using MNA11 and MNA11-iontophoresis showed disruptions / microchannels in the epidermis without any damage to underlying anatomical structures. MNA11-iontophoresis combination led to significant reduction (83.02 ± 3.9%) in paw oedema as compared to MNA11 alone (72.55 ± 4.1%). CONCLUSION: MNA11-iontophoresis combination can act as a promising candidate to deliver drugs transcutaneously for treating inflammatory diseases.

Asunto(s)

Administración Cutánea , Antiinflamatorios , Dexametasona , Sistemas de Liberación de Medicamentos , Edema , Iontoforesis , Agujas , Absorción Cutánea , Piel , Animales , Iontoforesis/métodos , Dexametasona/administración & dosificación , Dexametasona/farmacocinética , Dexametasona/análogos & derivados , Ratas , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacocinética , Edema/tratamiento farmacológico , Sistemas de Liberación de Medicamentos/métodos , Piel/metabolismo , Piel/efectos de los fármacos , Masculino , Liberación de Fármacos , Inflamación/tratamiento farmacológico , Ratas Sprague-Dawley

RESUMEN

OBJECTIVE: To compare the effect of submucosal cryotherapy using cold saline to dexamethasone sodium phosphate and diclofenac sodium injections on substance P and interleukin 6 release in experimentally induced pulpal inflammation in rabbits' molar teeth. METHODOLOGY: Fifteen rabbits were randomly classified into 3 groups according to the submucosal injection given: cold saline, dexamethasone sodium phosphate, and diclofenac sodium. A split-mouth design was adopted, the right mandibular molars were experimental, and the left molars served as the control without injections. Intentional pulp exposures were created and left for 6 hours to induce pulpitis. Pulpal tissue was extracted and examined for SP and IL-6 levels using ELISA. Within each group, the level of cytokines released was measured for both control and experimental groups for intragroup comparison to determine the effect of injection. The percentage reduction of each mediator was calculated compared with the control side for intergroup comparison then the correlation between SP and IL-6 levels was analyzed using Spearman's rank order correlation coefficient. Statistical analysis was performed, and the significance level was set at p<0.05. RESULTS: Submucosal cryotherapy, dexamethasone sodium phosphate, and diclofenac sodium significantly reduced SP and IL-6 pulpal release. Submucosal cryotherapy significantly reduced SP more than and IL-6 more than dexamethasone sodium phosphate and diclofenac sodium. Pulpal reduction of SP and IL-6 showed a strong positive significant correlation. CONCLUSIONS: Submucosal cryotherapy reduces the pulpal release of SP and IL-6 and could be tested as an alternative to premedication to potentiate the effect of anesthesia and control postoperative endodontic pain.

Asunto(s)

Antiinflamatorios no Esteroideos , Crioterapia , Pulpa Dental , Dexametasona , Diclofenaco , Ensayo de Inmunoadsorción Enzimática , Interleucina-6 , Pulpitis , Distribución Aleatoria , Sustancia P , Animales , Conejos , Pulpitis/terapia , Diclofenaco/farmacología , Dexametasona/farmacología , Dexametasona/análogos & derivados , Interleucina-6/análisis , Crioterapia/métodos , Sustancia P/análisis , Antiinflamatorios no Esteroideos/farmacología , Pulpa Dental/efectos de los fármacos , Factores de Tiempo , Reproducibilidad de los Resultados , Resultado del Tratamiento , Masculino , Estadísticas no Paramétricas , Modelos Animales de Enfermedad , Antiinflamatorios/farmacología , Solución Salina , Valores de Referencia

RESUMEN

Nitrogen mustard (NM) is a potent vesicating chemical warfare agent that is primarily absorbed through skin, inhalation, or ocular surface. Ocular exposure of NM can cause acute to chronic keratopathy which can eventually lead to blindness. There is a current lack of effective countermeasures against ocular exposure of NM despite their imperative need. Herein, we aim to explore the sustained effect of Dexamethasone sodium phosphate (DSP)-loaded polymeric nanoparticles (PLGA-DSP-NP) following a single subconjunctival injection in the management and prevention of corneal injury progression upon exposure to NM. DSP is an FDA approved corticosteroid with proven anti-inflammatory properties. We formulated PLGA-DSP-NP with zinc chelation ion bridging method using PLGA polymer, with particles of approximately 250 nm and a drug loading of 6.5 wt%. Under in vitro sink conditions, PLGA-DSP-NP exhibited a sustained drug release for two weeks. Notably, in NM injured cornea, a single subconjunctival (SCT) injection of PLGA-DSP-NP outperformed DSP eyedrops (0.1%), DSP solution, placebo NP, and saline, significantly mitigating corneal neovascularization, ulceration, and opacity for the two weeks study period. Through PLGA-DSP-NP injection, sustained DSP release hindered inflammatory cytokine recruitment, angiogenic factors, and endothelial cell proliferation in the cornea. This strategy presents a promising localized corticosteroid delivery system to effectively combat NM-induced corneal injury, offering insights into managing vesicant exposure.

Asunto(s)

Dexametasona , Mecloretamina , Nanopartículas , Dexametasona/análogos & derivados , Animales , Mecloretamina/toxicidad , Modelos Animales de Enfermedad , Lesiones de la Cornea/prevención & control , Lesiones de la Cornea/inducido químicamente , Lesiones de la Cornea/patología , Lesiones de la Cornea/tratamiento farmacológico , Glucocorticoides , Sustancias para la Guerra Química/toxicidad , Ratones , Quemaduras Químicas/prevención & control , Quemaduras Químicas/tratamiento farmacológico , Quemaduras Oculares/inducido químicamente , Quemaduras Oculares/prevención & control , Conejos , Córnea/efectos de los fármacos , Córnea/patología , Córnea/metabolismo

RESUMEN

Acute respiratory distress syndrome (ARDS) is a critical illness characterized by severe lung inflammation. Improving the delivery efficiency and achieving the controlled release of anti-inflammatory drugs at the lung inflammatory site are major challenges in ARDS therapy. Taking advantage of the increased pulmonary vascular permeability and a slightly acidic-inflammatory microenvironment, pH-responsive mineralized nanoparticles based on dexamethasone sodium phosphate (DSP) and Ca2+ were constructed. By further biomimetic modification with M2 macrophage membranes, hybrid mineralized nanovesicles (MM@LCaP) were designed to possess immunomodulatory ability from the membranes and preserve the pH-sensitivity from core nanoparticles for responsive drug release under acidic inflammatory conditions. Compared with healthy mice, the lung/liver accumulation of MM@LCaP in inflammatory mice was increased by around 5.5 times at 48 h after intravenous injection. MM@LCaP promoted the polarization of anti-inflammatory macrophages, calmed inflammatory cytokines, and exhibited a comprehensive therapeutic outcome. Moreover, MM@LCaP improved the safety profile of glucocorticoids. Taken together, the hybrid mineralized nanovesicles-based drug delivery strategy may offer promising ideas for enhancing the efficacy and reducing the toxicity of clinical drugs.

Asunto(s)

Antiinflamatorios , Dexametasona , Glucocorticoides , Pulmón , Nanopartículas , Síndrome de Dificultad Respiratoria , Animales , Glucocorticoides/administración & dosificación , Glucocorticoides/farmacocinética , Glucocorticoides/uso terapéutico , Dexametasona/administración & dosificación , Dexametasona/farmacocinética , Dexametasona/uso terapéutico , Dexametasona/análogos & derivados , Distribución Tisular , Nanopartículas/química , Ratones , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Pulmón/metabolismo , Pulmón/efectos de los fármacos , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacocinética , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Liberación de Fármacos , Neumonía/tratamiento farmacológico , Neumonía/inducido químicamente , Células RAW 264.7 , Sistemas de Liberación de Medicamentos , Calcio/metabolismo , Citocinas/metabolismo

RESUMEN

OBJECTIVES: This study aimed to compare the side effects of different steroids used in the intratympanic injections (IT). METHODS: One hundred and sixty patients diagnosed with sudden sensorineural hearing loss and undergoing IT were assigned to four groups based on the type or concentration of steroids administered (Group DM5: 5 mg/ml Dexamethasone sodium phosphate; Group DM10: 10 mg/ml Dexamethasone sodium phosphate; Group MP: 40 mg/ml Methylprednisolone sodium succinate; Group BM: 4 mg/ml Betamethasone sodium phosphate). Each group comprised 40 patients, and all participants received IT six times. The study assessed and compared the degrees and duration of pain, dizziness, and tympanic membrane damage following IT. Patients were asked to report the pain they felt using the numeric rating scale (NRS). RESULTS: NRS scores for pain after IT showed significant differences among the four groups (p < 0.001). The average NRS scores for pain in each group were as follows: Group DM5: 1.53 ± 1.04; Group DM10: 1.45 ± 1.30; Group MP: 4.33 ± 2.22; Group BM: 6.03 ± 1.46. The durations of pain after IT also exhibited significant differences among the four groups (p < 0.001), with the longest duration observed in Group MP at 31.93 ± 15.20 min. CONCLUSION: Different types of steroids could lead to varying degrees of pain when used in IT. Betamethasone could cause the most severe pain, and methylprednisolone could result in the longest duration of pain.

Asunto(s)

Betametasona , Betametasona/análogos & derivados , Dexametasona , Dexametasona/análogos & derivados , Pérdida Auditiva Sensorineural , Pérdida Auditiva Súbita , Inyección Intratimpánica , Metilprednisolona , Humanos , Masculino , Femenino , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Betametasona/administración & dosificación , Betametasona/efectos adversos , Persona de Mediana Edad , Metilprednisolona/administración & dosificación , Metilprednisolona/efectos adversos , Adulto , Pérdida Auditiva Súbita/tratamiento farmacológico , Pérdida Auditiva Súbita/inducido químicamente , Pérdida Auditiva Sensorineural/inducido químicamente , Membrana Timpánica , Glucocorticoides/administración & dosificación , Glucocorticoides/efectos adversos , Hemisuccinato de Metilprednisolona/administración & dosificación , Hemisuccinato de Metilprednisolona/efectos adversos , Mareo/inducido químicamente , Anciano , Dolor/tratamiento farmacológico , Dolor/etiología , Dimensión del Dolor

RESUMEN

OBJECTIVES: To evaluate the pharmacokinetics, pharmacodynamics (PD), safety, and tolerability of epidural SP-102 (10 mg dexamethasone sodium phosphate injectable gel) compared to an intravenous injection of 10 mg dexamethasone sodium phosphate, USP (IV USP). MATERIALS AND METHODS: Subjects with lumbosacral radiculopathy received a single dose of epidural SP-102, followed by a single dose of IV USP 4 weeks later. Dexamethasone plasma levels, cortisol levels, white blood cells (WBC), and blood glucose levels were assessed. RESULTS: Twelve subjects entered and completed the study. The mean total dexamethasone exposure (AUClast and AUCinf) following SP-102 by epidural injection was equivalent to the total exposure following IV USP. A lower mean plasma Cmax (~ 50% lower) was observed following epidural administration compared to IV injection. PD parameters were similar between treatments. Adverse events (AEs) were mild, with no serious AEs or study discontinuations due to AEs. CONCLUSION: In this small study, epidural SP-102 injection was well tolerated, was not associated with greater systemic dexamethasone exposure than IV USP, and both treatments had similar PD effects on cortisol suppression, blood glucose, and WBC levels.

Asunto(s)

Glucemia , Hidrocortisona , Dexametasona/efectos adversos , Dexametasona/análogos & derivados , Humanos , Dolor

RESUMEN

Eight horses underwent IVRLP at two occasions through a 23-gauge 2 cm long butterfly catheter. Regional anaesthesia of the ulnar, median and medial cutaneous antebrachial nerves was performed prior, and an 8 cm rubber tourniquet was placed on the proximal radius for 30 minutes following the infusion. The first infusion consisted of 2 g of amikacin sulphate and 10 mg of dexamethasone phosphate diluted with 0.9% NaCl to a total volume of 100 ml. The second perfusion was performed after a 2-week washout period, the same protocol was used but without dexamethasone phosphate. Synovial fluid samples were collected from the metacarpophalangeal joint at T = 0, 0.5, 2, 12, 24 and 36 h post-infusion. Synovial fluid amikacin sulphate concentrations were determined by use of liquid chromatography/tandem mass-spectrometry. All horses (n = 8) remained healthy throughout the study, and no adverse effects associated with the study were encountered. No statistically significant differences were found in synovial fluid amikacin sulphate concentrations between the treatment and the control group at any of the time points. In conclusion, dexamethasone phosphate can be used in IVRLP concomitantly with amikacin sulphate in cases of distal limb inflammation and pain without decreasing the synovial fluid concentration of amikacin sulphate.

Asunto(s)

Amicacina , Líquido Sinovial , Amicacina/análisis , Amicacina/química , Animales , Antibacterianos/análisis , Dexametasona/análogos & derivados , Miembro Anterior , Caballos , Perfusión/veterinaria , Líquido Sinovial/química

Asunto(s)

Enfermedades de los Gatos , Dermatitis , Hipersensibilidad , Animales , Enfermedades de los Gatos/tratamiento farmacológico , Gatos , Dermatitis/veterinaria , Dexametasona/análogos & derivados , Dexametasona/uso terapéutico , Hipersensibilidad/veterinaria , Prurito/tratamiento farmacológico , Prurito/veterinaria

RESUMEN

Aspirin (also known as acetylsalicylic acid) is a drug intended to treat fever, pain, or inflammation. Treatment of moderate to severe cases of COVID-19 using aspirin along with dexamethasone has gained major attention globally in recent times. Thus, the purpose of this study was to use High-Performance Liquid Chromatography (HPLC) to evaluate the in vitro inhibition of CYP3A2 enzyme activity using aspirin in rat liver microsomes (RLMs). In this study, an efficient and sensitive HPLC method was developed using a reversed phase C18 column (X Bridge 4.6 mm × 150 mm, 3.5 µm) at 243 nm using acetonitrile and water (70:30 v/v). The linearity (r2 > 0.999), precision (<15%), accuracy and recovery (80-120%), limit of detection (5.60 µM and 0.06 µM), limit of quantification (16.98 µM and 0.19 µM), and stability of the newly developed method were validated for dexamethasone and 6ß-hydroxydexamethasone, respectively, following International Conference on Harmonization (ICH) guidelines. This method was applied in vitro to measure CYP3A2 activity. The results showed that aspirin competitively inhibits 6ß-hydroxylation (CYP3A2 activity) with an inhibition constant (Ki) = 95.46 µM and the concentration of the inhibitor causing 50% inhibition of original enzyme activity (IC50) = 190.92 µM. This indicated that there is a minimal risk of toxicity when dexamethasone and aspirin are co-administrated and a very low risk of toxicity and drug interaction with drugs that are a substrate for CYP3A2 in healthcare settings.

Asunto(s)

Aspirina/farmacología , Cromatografía Líquida de Alta Presión/métodos , Citocromo P-450 CYP3A/metabolismo , Animales , Aspirina/química , Citocromo P-450 CYP3A/efectos de los fármacos , Inhibidores Enzimáticos del Citocromo P-450/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Dexametasona/análogos & derivados , Dexametasona/farmacología , Masculino , Microsomas Hepáticos/metabolismo , Preparaciones Farmacéuticas/metabolismo , Isoformas de Proteínas/metabolismo , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/patogenicidad , Tratamiento Farmacológico de COVID-19

RESUMEN

Background: Asymmetric intracellular and extracellular ionic gradients are critical to the survivability of mammalian cells. Given the importance of manganese (Mn2+), calcium (Ca2+), and bicarbonate (HCO3-) ions, any alteration of the ion-content balance could induce a series of cellular responses. HCO3- plays an indispensable role for Mn-mediated Fenton-like reaction, but this is difficult to achieve because bicarbonates are tightly regulated by live cells, and are limited in anticancer efficacy. Methods: A responsive and biodegradable biomineral, Mn-doped calcium carbonate integrated with dexamethasone phosphate (DEX) (Mn:CaCO3-DEX), was reported to enable synergistic amplification of tumor oxidative stress, reduce inflammation, and induce Ca-overload cell apoptosis by elevating the intracellular and extracellular ionic gradients. Results: Under the acidic environment in tumor region, the ions (Mn2+, CO32-, Ca2+) were released by the degradation of Mn:CaCO3-DEX and then escalated oxidative stresses by triggering a HCO3--indispensable Mn-based Fenton-like reaction and breaking Ca2+ ion homeostasis to cause oxidative stress in cells and calcification. The released anti-inflammatory and antitumor drug, DEX, could alleviate the inflammatory environment. The investigations in vitro and in vivo demonstrated that the synergistic oncotherapy could effectively inhibit the growth of subcutaneous tumors and orthotopic liver tumors. Notably, normal cells showed greater tolerance of the synergistic influences. Conclusion: As an ion drug, Mn:CaCO3-DEX is an excellent potential diagnostic agent for precise orthotopic tumor management by the generation in situ of toxic ion and drug pools in the environment of tumor region, with synergistic effects of enhanced chemodynamic therapy, calcification, and anti-inflammation effects.

Asunto(s)

Antineoplásicos/farmacología , Carbonato de Calcio/farmacología , Dexametasona/análogos & derivados , Iones/farmacología , Antineoplásicos/química , Calcio/farmacología , Carbonato de Calcio/química , Línea Celular Tumoral , Dexametasona/química , Dexametasona/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Iones/toxicidad , Manganeso/farmacología , Estrés Oxidativo

RESUMEN

Purpose: To elucidate the mechanism behind epigenetic alteration associated with dexamethasone (DEX) sodium phosphate treatment. Methods: We performed enzyme-linked immunosorbent assay to quantify changes in global DNA methylation and hydroxymethylation, quantitative real-time PCR (qRT-PCR) of the DNA methylation- and hydroxymethylation-related gene, in vitro DNA methyltransferase (DNMT) enzymatic activity assays with purified DNMTs, and DNA hydroxymethylation pattern with super-resolution imaging. Results: We identified global DNA hypomethylation and hyper-hydroxymethylation upon DEX treatment, associated with aberrant mRNA expression levels of DNMT and ten-eleven translocation (TET) proteins. Additionally, DEX exposure could directly hinder DNMT activities. Conclusions: We showed that DEX-induced epigenetic alterations are linked to aberrant DNMT and TET expression, potentially through an essential role of DNMT.

Asunto(s)

Metilación de ADN , Epigénesis Genética , Dexametasona/análogos & derivados

RESUMEN

Dexamethasone is widely used in preclinical studies and clinical trials to treat inner ear disorders. The results of those studies vary widely, maybe due to the different dexamethasone formulations used. Laboratory (lab) and medical grade (med) dexamethasone (DEX, C22H29FO5) and dexamethasone dihydrogen phosphate-disodium (DPS, C22H28FNa2O8P) were investigated for biocompatibility and bio-efficacy in vitro. The biocompatibility of each dexamethasone formulation in concentrations from 0.03 to 10,000 µM was evaluated using an MTT assay. The concentrations resulting in the highest cell viability were selected to perform a bio-efficiency test using a TNFα-reduction assay. All dexamethasone formulations up to 900 µM are biocompatible in vitro. DPS-lab becomes toxic at 1000 µM and DPS-med at 2000 µM, while DEX-lab and DEX-med become toxic at 4000 µM. Bio-efficacy was evaluated for DEX-lab and DPS-med at 300 µM, for DEX-med at 60 µM, and DPS-lab at 150 µM, resulting in significantly reduced expression of TNFα, with DPS-lab having the highest effect. Different dexamethasone formulations need to be applied in different concentration ranges to be biocompatible. The concentration to be applied in future studies should carefully be chosen based on the respective dexamethasone form, application route and duration to ensure biocompatibility and bio-efficacy.

Asunto(s)

Dexametasona/análogos & derivados , Dexametasona/farmacología , Oído Interno/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Ensayos Clínicos como Asunto , Dexametasona/química , Dexametasona/uso terapéutico , Relación Dosis-Respuesta a Droga , Composición de Medicamentos , Humanos , Ratones , Células 3T3 NIH

RESUMEN

BACKGROUND: Macrophage activation syndrome is classified as a secondary form of hemophagocytic lymphohistiocytosis. It is a hyperinflammatory complication observed to be comorbid with a variety of autoimmune diseases, including adult-onset Still's disease and systemic juvenile idiopathic arthritis. Macrophage activation syndrome is less commonly detected in adult patients with systemic lupus erythematosus, which, if untreated, can be fatal, though determining the optimum treatment strategy is still a challenge. CASE PRESENTATION: Herein, we report a case of macrophage activation syndrome in a 33-year-old Egyptian female as an unusual complication of a systemic lupus erythematosus flare in adult patients. Our patient was initially treated with a combination of intravenous methylprednisolone pulse therapy and intravenous immunoglobulin therapy, which was followed by a course of oral prednisolone and oral cyclosporine with little response. Switching from oral prednisone to intravenous dexamethasone sodium phosphate showed a more favorable clinical and biochemical response. CONCLUSION: Macrophage activation syndrome is less commonly detected in adult patients with systemic lupus erythematosus. Our case demonstrates that dexamethasone sodium phosphate can be a successful alternative treatment for patients with systemic lupus erythematosus complicated by macrophage activation syndrome in whom the response to pulse methylprednisolone was inadequate to manage their illness, proving to be remarkably effective in a relatively short time frame.

Asunto(s)

Lupus Eritematoso Sistémico , Síndrome de Activación Macrofágica , Adulto , Ciclosporina/uso terapéutico , Dexametasona/análogos & derivados , Femenino , Humanos , Inmunoglobulinas Intravenosas , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/tratamiento farmacológico , Síndrome de Activación Macrofágica/tratamiento farmacológico , Síndrome de Activación Macrofágica/etiología , Metilprednisolona/uso terapéutico

RESUMEN

BACKGROUND: There are no liquid oral glucocorticoids labelled for management of pruritus and clinical lesions of feline hypersensitivity dermatitis (feline HD). HYPOTHESIS: First, to demonstrate that dexamethasone sodium phosphate (DexSP, DexajectSP, Henry Schein; Dublin, OH, USA; 4 mg/mL), an intravenous glucocorticoid, can be absorbed by healthy cats when administered orally. Second, to demonstrate the efficacy of orally administered DexSP for reducing pruritus and clinical lesions in patients with feline HD. ANIMALS: Seven healthy and 12 client-owned cats with HD. METHODS AND MATERIALS: Healthy cats were administered a single dose of 0.2 mg/kg DexSP p.o. and serum concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Feline HD patients were assessed with SCORing Feline Allergic Dermatitis (SCORFAD) and pruritus Visual Analog Scale (pVAS) at Visit 1 (V1) and after 20-31 days of receiving 0.2 mg/kg/day DexSP p.o. (V2). Complete blood cell counts, serum chemistry profile, and urinalysis were performed in 50% of feline HD patients at both visits. RESULTS: Healthy cats had detectable serum concentrations of DexSP following oral administration; concentrations ranged from 0.7 to 92.3 ng/mL. Feline HD patients showed significant decreases in SCORFAD and pVAS scores from V1 to V2. CONCLUSIONS: DexSP was absorbed when administered orally to healthy cats and 0.2 mg/kg/day DexSP is an efficacious dose to rapidly improve the pruritus and clinical lesions associated with feline HD.

Asunto(s)

Enfermedades de los Gatos , Dermatitis Atópica , Hipersensibilidad , Administración Oral , Animales , Enfermedades de los Gatos/tratamiento farmacológico , Gatos , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/veterinaria , Dexametasona/análogos & derivados , Hipersensibilidad/veterinaria , Prurito/inducido químicamente , Prurito/tratamiento farmacológico , Prurito/veterinaria

RESUMEN

A novel concentric experimental set-up was used to investigate short-duration topical co-iontophoresis of cationic buflomedil hydrochloride (BUF) and anionic dexamethasone phosphate (DEX-P) to the oral mucosa. A constant current of 3.0 mA (0.6 mA/cm2 for BUF and 1.95 mA/cm2 for DEX-P) was applied to porcine esophageal mucosa for 5, 10 and 20 min. Iontophoresis for only 5 min increased total delivery of BUF from 29.8 ± 5.1 nmol/cm2 to 194.3 ± 23.8 nmol/cm2 and DEX-P from 29.4 ± 1.2 nmol/cm2 to 193.3 ± 19.8 nmol/cm2 as compared to passive controls. Quantification of drug between the electrode compartments reported on lateral ion migration. In the absence of current, DEX-P did not migrate laterally; however, iontophoresis for 5 min increased DEX-P delivery >5-fold under the cathodal compartment (its application area) and >8-fold in the adjacent "inter-electrode" area. Similarly, delivery of BUF increased ~6.8-fold under the anodal compartment and ~12.8-fold under the cathode. The results showed that co-iontophoresis enabled the controlled simultaneous delivery of BUF and DEX-P achieving therapeutically relevant concentrations after current application for only 5 min. Short duration topical co-iontophoresis of single or multiple therapeutics to the mucosa increases local bioavailability and presents a patient-friendly treatment for diseases of the oral cavity.

Asunto(s)

Iontoforesis , Fibrosis de la Submucosa Bucal , Administración Cutánea , Animales , Dexametasona/análogos & derivados , Humanos , Mucosa Bucal , Pirrolidinas , Porcinos

RESUMEN

Mucoadhesive formulations capable of situ gelation are promising for improving ocular drug delivery. Here we investigated two types of nanogels based on anionic glycosaminoglycans with grafted thermo-responsive poly(N-isopropylacrylamide) chains. One type of nanogels were formed by thermo-induced gelling of heparin-graft-poly(N-isopropylacrylamide) and chondroitin sulfate-graft-poly(N-isopropylacrylamide) copolymers. Another type of nanogels was based on the same copolymers, but terminal groups of thermosensitive macromolecular chains were modified to form covalent disulfide cross-links. All types of nanogels were studied towards their ability to encapsulate and release model drug - dexamethasone. Mucoadhesivity of both thermo-gelled and covalently cross-linked polymeric systems, as well as their ability to interact with dexamethasone, was assessed by microscale thermophoresis (MST). Mucoadhesion properties were also evaluated by isothermal titration calorimetry (ITC), which were in good correlation with MST data. The presence of disulfide linkages and thiol groups were shown to favor improved binding of cross-linked nanogels to mucin. Moreover, in vivo intraocular pressure studies showed that presence of polymers in solution can alter the ocular absorption of carbonic anhydrase inhibitor from eyedrops. The pharmacological effect was in line with mucoadhesive properties of these copolymers.

Asunto(s)

Resinas Acrílicas/química , Inhibidores de Anhidrasa Carbónica/química , Dexametasona/análogos & derivados , Glicosaminoglicanos/química , Mucinas/química , Nanogeles , Piperazinas/química , Polímeros de Estímulo Receptivo/química , Temperatura , Adhesividad , Administración Oftálmica , Animales , Inhibidores de Anhidrasa Carbónica/administración & dosificación , Dexametasona/química , Composición de Medicamentos , Liberación de Fármacos , Femenino , Presión Intraocular/efectos de los fármacos , Masculino , Nanotecnología , Soluciones Oftálmicas , Piperazinas/administración & dosificación , Conejos , Ratas