RESUMEN
In a double-blind, randomized controlled trial, we investigated the effectiveness of adding antiplatelet drugs to up-dosing antihistamines for the treatment of chronic spontaneous urticaria (CSU) in patients with elevated D-dimer levels who had an inadequate response to conventional antihistamine doses. Twenty patients with Urticaria Activity Score over 7 days (UAS7) ≥16 and D-dimer >500 ng/mL were randomized to receive either antiplatelet therapy (cilostazol 150 mg/day + dipyridamole 50 mg/day) with antihistamine (desloratadine 20 mg/day) or antihistamine alone for 4 weeks. The antiplatelet group demonstrated a greater decrease in UAS7 compared to the control group (28.10 to 8.90 vs. 22.90 to 16.40, p < 0.001 vs. p = 0.054). Both groups experienced improved quality of life (DLQI), but the improvement was greater in the antiplatelet group (p = 0.046). D-dimer levels decreased only in the antiplatelet group (1133.67 ng/mL to 581.89 ng/mL, p = 0.013) with no significant change observed in the control group. This suggests that combining dipyridamole and cilostazol with up-dosing antihistamines may be more effective for CSU patients with high D-dimer levels compared to up-dosing antihistamines alone. This could be due to a reduction in platelet activation, as evidenced by the decrease in D-dimer levels observed in the antiplatelet group.
Asunto(s)
Urticaria Crónica , Cilostazol , Dipiridamol , Quimioterapia Combinada , Productos de Degradación de Fibrina-Fibrinógeno , Loratadina , Inhibidores de Agregación Plaquetaria , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Urticaria Crónica/tratamiento farmacológico , Cilostazol/administración & dosificación , Cilostazol/uso terapéutico , Dipiridamol/administración & dosificación , Dipiridamol/uso terapéutico , Método Doble Ciego , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Antagonistas de los Receptores Histamínicos/administración & dosificación , Antagonistas de los Receptores Histamínicos/uso terapéutico , Loratadina/administración & dosificación , Loratadina/uso terapéutico , Loratadina/análogos & derivados , Inhibidores de Agregación Plaquetaria/administración & dosificación , Calidad de Vida , Tetrazoles/administración & dosificación , Tetrazoles/uso terapéutico , Resultado del TratamientoRESUMEN
The primary obstacles in the management of Enterococcus and Streptococcal infections are drug resistance and biofilm formation. Our study revealed that loratadine at a concentration of ≥25 µM exhibited significant inhibitory effects on biofilm formation in 167 clinical strains of Enterococcus faecalis and 15 clinical isolates of Streptococcus agalactiae, Streptococcus pyogenes, and Streptococcus pneumoniae. Additionally, the antibiofilm activity against E. faecalis and Streptococcal was demonstrated by several loratadine derivatives with altered side-chain carbamate moieties. This study investigated the antibacterial activity of the loratadine derivative Lo-7 against clinical strains of S. agalactiae and S. pyogenes, with minimum inhibitory concentrations ranging from 12.5 to 25 µM. The findings revealed that a low concentration of loratadine derivative Lo-7 (3.125 µM) significantly augmented the bactericidal efficacy of vancomycin against multidrug-resistant (MDR) S. agalactiae, both in vitro and in vivo. The loratadine derivative Lo-7, even at low concentrations, demonstrated significant efficacy in eliminating intracellular MDR S. agalactiae within macrophages, potentially indicating a unique advantage over vancomycin, linezolid, and loratadine. Mechanistically, exposure to the loratadine derivative Lo-7 resulted in membrane depolarization without affecting membrane permeability in S. agalactiae. The potential targeting of the SecG subunit of the SecYEG membrane-embedded channel by the loratadine derivative Lo-7 in S. agalactiae was identified through quantitative proteomics, a drug affinity responsive target stability assay, and molecular docking.
Asunto(s)
Antibacterianos , Biopelículas , Loratadina , Pruebas de Sensibilidad Microbiana , Infecciones Estreptocócicas , Loratadina/farmacología , Loratadina/química , Antibacterianos/farmacología , Antibacterianos/química , Biopelículas/efectos de los fármacos , Infecciones Estreptocócicas/microbiología , Infecciones Estreptocócicas/tratamiento farmacológico , Humanos , Streptococcus agalactiae/efectos de los fármacos , Animales , Enterococcus/efectos de los fármacos , Streptococcus pyogenes/efectos de los fármacos , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/microbiología , Ratones , Vancomicina/farmacología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Enterococcus faecalis/efectos de los fármacosRESUMEN
Through the utilization of fluorescence spectroscopy, electrochemical, and molecular docking methods, this research investigates the interaction between the antihistamine drug desloratadine and calf thymus double-stranded DNA (ct-dsDNA). Deoxyguanosine (dGuo) and deoxyadenosine (dAdo) oxidation signals were diminished by incubation with varying concentrations of desloratadine, as determined by differential pulse voltammetry (DPV). This change was ascribed to desloratadine's binding mechanism to ct-dsDNA. The binding constant (Kb) between desloratadine and ct-dsDNA was determined to be 2.2 × 105 M-1 throughout electrochemical experiments. In order to further develop our comprehension of the interaction mechanism between desloratadine and ct-dsDNA, a series of spectroscopic experiments and molecular docking simulations were conducted. The Kb value was found to be 8.85 × 104 M-1 at a temperature of 25 °C by the use of fluorescence spectroscopic techniques. In summary, the utilization of electrochemical and spectroscopic techniques, alongside molecular docking investigations, has led to the prediction that desloratadine has the capability to interact with ct-dsDNA by groove binding.
Asunto(s)
ADN , Técnicas Electroquímicas , Loratadina , Simulación del Acoplamiento Molecular , Espectrometría de Fluorescencia , Loratadina/análogos & derivados , Loratadina/química , Loratadina/metabolismo , Loratadina/farmacología , ADN/metabolismo , ADN/química , Bovinos , Animales , Antagonistas de los Receptores Histamínicos H1 no Sedantes/metabolismo , Antagonistas de los Receptores Histamínicos H1 no Sedantes/químicaRESUMEN
Second-generation tricyclic H1 antihistamine loratadine (LTD) has a high permeability, low water solubility, and an oral absorption rate dependent on the rate at which it dissolves in the gastrointestinal tract. One approach suggested for improving the drug's solubility and rate of dissolution is natural solid dispersion (NSD). The present study evaluated the use of hydrophilic natural polymers, sodium alginate (SA), hyaluronic acid (HA), and xyloglucan (XG), in natural solid dispersion to enhance LTD solubility and dissolution rate. A total of 12 formulations comprising varied drug-to-polymer ratios were produced and analyzed for percentage yield, water solubility, and in vitro dissolution rate. The solubility of LTD was improved in all formulations. Excellent results were achieved with NSD1 (LTD: SA 1:0.25), with a high yield (99%), superior solubility (0.187) compared to pure loratadine (0.0021), and a speedy dissolution rate (98%) within 30 minutes. These studies suggest natural polymers like SA, HA, and XG can considerably increase LTD solubility. When introduced into NSD, these polymers effectively augment LTD dissolving rates, presenting attractive prospects for better bioavailability and therapeutic efficacy.
Asunto(s)
Loratadina , Polímeros , Solubilidad , Loratadina/química , Loratadina/farmacología , Polímeros/químicaRESUMEN
BACKGROUND: Intestinal mucosal immune cells, notably mast cells, are pivotal in ulcerative colitis (UC) pathophysiology. Its activation elevates tissue concentrations of histamine. Inhibiting colonic histamine release could be an effective therapeutic strategy for treating UC. Experimental model like 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats mimic human IBD, aiding treatment investigations. Drug repurposing is a promising strategy to explore new indications for established drugs. Desloratadine (DES) is second-generation antihistamine utilized for managing allergies by blocking histamine action in the body. It also has reported anti-inflammatory and antioxidant actions. OBJECTIVE: DES was investigated for its repurposing potential in UC by preclinical screening in TNBS-induced colitis in Wistar rats. METHODS: Therapeutic efficacy of DES was evaluated both individually and in combination with standard drug 5-aminosalicylicacid (5-ASA). Rats were orally administered DES (10 mg/kg), 5-ASA (25 mg/kg), and DES + 5-ASA (5 mg + 12.15 mg) following the induction of colitis. Parameters including disease activity score rate (DASR), colon/body weight ratio (CBWR), colon length, diameter, pH, histological injury, and scoring were evaluated. Inflammatory biomarkers such as IL-1ß, TNF-α, along with reduced glutathione (GSH), and malondialdehyde (MDA) were assessed. RESULTS: Significant protective effects of DES, especially in combination with 5-ASA, against TNBS-induced inflammation were observed as evidenced by reduced DASR, CBWR, and improved colon morphology. Drugs significantly lowered plasma and colon histamine and, cytokines levels. GSH restoration, and decreased MDA content were also observed. CONCLUSION: DES and DES + 5-ASA demonstrated potential in alleviating colonic inflammation associated with TNBS-induced colitis in rats. The effect can be attributed to its antihistamine, anticytokine, and antioxidative properties.
Asunto(s)
Antiinflamatorios , Antioxidantes , Colitis , Loratadina , Ratas Wistar , Ácido Trinitrobencenosulfónico , Animales , Loratadina/farmacología , Loratadina/análogos & derivados , Ácido Trinitrobencenosulfónico/toxicidad , Antioxidantes/farmacología , Ratas , Masculino , Antiinflamatorios/farmacología , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/patología , Colitis/metabolismo , Modelos Animales de Enfermedad , Mesalamina/farmacología , Colon/efectos de los fármacos , Colon/patología , Colon/metabolismoRESUMEN
Antihistamines relieve allergic symptoms by inhibiting the action of histamine. Further understanding of antihistamine transmembrane mechanisms and optimizing the selectivity and real-time monitoring capabilities of drug sensors is necessary. In this study, a micrometer liquid/liquid (L/L) interfacial sensor has served as a biomimetic membrane to investigate the mechanism of interfacial transfer of five antihistamines, i.e., clemastine (CLE), cyproheptadine (CYP), epinastine (EPI), desloratadine (DSL), and cetirizine (CET), and realize the real-time determinations. Cyclic voltammetry (CV) and differential pulse voltammetry (DPV) techniques have been used to uncover the electrochemical transfer behavior of the five antihistamines at the L/L interface. Additionally, finite element simulations (FEMs) have been employed to reveal the thermodynamics and kinetics of the process. Visualization of antihistamine partitioning in two phases at different pH values can be realized by ion partition diagrams (IPDs). The IPDs also reveal the transfer mechanism at the L/L interface and provide effective lipophilicity at different pH values. Real-time determinations of these antihistamines have been achieved through potentiostatic chronoamperometry (I-t), exhibiting good selectivity with the addition of nine common organic or inorganic compounds in living organisms and revealing the potential for in vivo pharmacokinetics. Besides providing a satisfactory surrogate for studying the transmembrane mechanism of antihistamines, this work also sheds light on micro- and nano L/L interfacial sensors for in vivo analysis of pharmacokinetics at a single-cell or single-organelle level.
Asunto(s)
Cetirizina , Clemastina , Ciproheptadina , Imidazoles , Loratadina , Loratadina/análogos & derivados , Loratadina/farmacología , Loratadina/análisis , Loratadina/química , Ciproheptadina/farmacología , Ciproheptadina/análogos & derivados , Ciproheptadina/análisis , Cetirizina/análisis , Cetirizina/farmacología , Cetirizina/química , Clemastina/análisis , Clemastina/farmacología , Clemastina/metabolismo , Antagonistas de los Receptores Histamínicos/farmacología , Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/análisis , Antagonistas de los Receptores Histamínicos/metabolismo , Técnicas Electroquímicas/métodos , Biomimética , Dibenzazepinas/farmacología , Dibenzazepinas/químicaRESUMEN
Most vegetable crops are severely affected by the uptake of heavy metals from the soil. Heavy metals in vegetable bodies generate reactive oxygen species (ROS) that unbalance the antioxidant defense system. This study was initiated to determine the physiological and biochemical characteristics of spinach plants grown on soil contaminated with heavy metals and responding to Bacillus cereus and Bacillus aerius were isolated from soil contaminated with heavy metals. Heavy metal contamination led to a significant reduction in seed germination, seedling biomass, protein, and total nitrogen content of spinach plants grown in contaminated soils compared to control soils. In contrast, a significant increase in the content of metallothioneins and antioxidant enzymes was observed. Plants inoculated with B. cereus and B. aerius significantly reduced the oxidative stress induced by heavy metals by improving seed germination (%), seedling growth, nitrogen, and protein content. The content of metallothioneins and the activities of antioxidant enzymes were reduced in spinach plants grown from seeds inoculated with bacterial strains. In addition, plants inoculated with, B. cereus and B. aerius showed greater stomata opening than plants grown on soil contaminated with heavy metals, whose stomata were almost closed. These results suggested that both bacterial strains enhanced plant growth by reducing oxidative stress caused by metals.
Asunto(s)
Loratadina/análogos & derivados , Metales Pesados , Contaminantes del Suelo , Spinacia oleracea , Antioxidantes/metabolismo , Metales Pesados/toxicidad , Estrés Oxidativo , Bacterias/metabolismo , Suelo/química , Plantas/metabolismo , Nitrógeno/metabolismo , Contaminantes del Suelo/toxicidad , Contaminantes del Suelo/metabolismoRESUMEN
Loratadine (LoR) is a highly lipophilic and practically insoluble in water, hence having a low oral bioavailability. As it is formulated as topical gel, it competitively binds with the receptors, thus reducing the side-effects. The objective of this study was to prepare LoR loaded nanosponge (LoR-NS) in gel for topical delivery. Nine different formulations of emulsion were prepared by solvent evaporation method with polyvinyl alcohol (PVA), ethyl cellulose (EC), and dichloromethane (DCM). Based on 32 Full Factorial Design (FFD), optimization was carried out by varying the concentration of LOR:EC ratio and stirring rate. The preparations were subjected for the evaluation of particle size (PS), in vitro release, zeta potential (ZP) and entrapment efficiency (EE). The results revealed that the NS dispersion was nanosized with sustained release profiles and significant PS. The optimised formulation was formulated and incorporated into carbopol 934P hydrogel. The formulation was then examined to surface morphological characterizations using scanning electron microscopy (SEM) which depicted spherical NS. Stability studies, undertaken for 2 months at 40 ± 2 °C/75 ± 5% RH, concluded to the stability of the formulation. The formulation did not cause skin irritation. Therefore, the prepared NS hydrogel proved to be a promising applicant for LoR as a novel drug delivery system (NDDS) for safe, sustained and controlled topical application.
Asunto(s)
Hidrogeles , Loratadina , Tamaño de la PartículaRESUMEN
BACKGROUND: Our aim was to measure the effectiveness of oral isotretinoin with desloratadine compared with oral isotretinoin alone in treating moderate to severe acne at a tertiary care teaching hospital in North India. In this study, 90 patients with moderate to severe acne were enrolled to participate based on their fulfilling the inclusion criteria. METHODS: A randomized, assessor-blinded, parallel-arm study was conducted. Randomization was done using computer-generated tables to allocate treatments in a 1:1 ratio. A low-dose oral isotretinoin at a dose of 0.3 mg/kg/day with tab desloratadine at 5 mg/day was applied to the study group and compared against the same patients going without the dosage when controls were conducted. Follow-up was at 4, 8, and 12 weeks. RESULTS: The primary outcome was an improved global acne grading system (GAGS) score and decreased acne lesion count. SECONDARY OUTCOME: patient satisfaction with treatment. The 90 participants were randomized and 15 participants dropped out of the study, leaving 75 participants for intention to treat analysis (n = 41, n = 30). At week 12, the GAGS score and acne lesion count between the study and control groups were comparable (P > 0.05). Pruritus reported was 9.76% in the study versus 33.33% in the control group (P = 0.018). Also, 53.66% of participants reported "excellent" treatment satisfaction in the study group versus 36.67% in the control group. CONCLUSIONS: The addition of desloratadine to an isotretinoin regimen has a role in reducing disease and therapy-related pruritus in acne and leads to improved patient satisfaction.
Asunto(s)
Acné Vulgar , Fármacos Dermatológicos , Isotretinoína , Loratadina , Satisfacción del Paciente , Índice de Severidad de la Enfermedad , Humanos , Isotretinoína/administración & dosificación , Isotretinoína/efectos adversos , Acné Vulgar/tratamiento farmacológico , Loratadina/administración & dosificación , Loratadina/análogos & derivados , Loratadina/efectos adversos , Femenino , Masculino , Administración Oral , Adulto Joven , Fármacos Dermatológicos/administración & dosificación , Fármacos Dermatológicos/efectos adversos , Adolescente , Adulto , Quimioterapia Combinada , Método Simple Ciego , Resultado del Tratamiento , Antagonistas de los Receptores Histamínicos H1 no Sedantes/administración & dosificación , Antagonistas de los Receptores Histamínicos H1 no Sedantes/efectos adversosRESUMEN
Desloratadine, a second-generation histamine H1 receptor antagonist, has established itself as a first-line drug for the treatment of allergic diseases. Despite its effectiveness, desloratadine exhibits an antagonistic effect on muscarinic M3 receptor, which can cause side effects such as dry mouth and urinary retention, ultimately limiting its clinical application. Herein, we describe the discovery of compound â ¢-4, a novel H1 receptor antagonist with significant H1 receptor antagonistic activity (IC50 = 24.12 nM) and enhanced selectivity towards peripheral H1 receptor. In particular, â ¢-4 exhibits reduced M3 receptor inhibitory potency (IC50 > 10,000 nM) and acceptable hERG inhibitory activity (17.6 ± 2.1 µM) compare with desloratadine. Additionally, â ¢-4 exhibits favorable pharmacokinetic properties, as well as in vivo efficacy and safety profiles. All of these reveal that â ¢-4 has potential to emerge as a novel H1 receptor antagonist for the treatment of allergic diseases. More importantly, the compound â ¢-4 (HY-078020) has recently been granted clinical approval.
Asunto(s)
Antagonistas de los Receptores Histamínicos H1 , Hipersensibilidad , Loratadina/análogos & derivados , Humanos , Antagonistas de los Receptores Histamínicos H1/farmacología , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Receptores Histamínicos H1/uso terapéutico , Loratadina/farmacología , Loratadina/uso terapéutico , Hipersensibilidad/tratamiento farmacológicoRESUMEN
AIMS: Breast cancer patients on chemotherapy who receive pegfilgrastim to prevent neutropenia may experience severe bone pain as a side effect. Traditional treatment recommendations include nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, opioids, and/or antihistamine use. However, little research was found comparing these interventions. The study aim was to address the gaps in literature and to explore the use of and perceived effectiveness of loratadine versus acetaminophen or NSAIDs in women with breast cancer treated with pegfilgrastim. This study also sought to understand how patients became aware of loratadine or other treatments for management of bone pain. DESIGN/METHODS: This cross-sectional study used survey methods to collect data from 66 adult female breast cancer patients receiving chemotherapy with pegfilgrastim. RESULTS: The incidence of bone pain was 45% (n = 30) in our sample, but more than half (n = 45; 69%) of the women took either acetaminophen, NSAIDs, or loratadine alone or in combination to prevent bone pain. All medication were rated as effective by patients, with acetaminophen slightly more effective than loratadine, and loratadine more effective than NSAIDs. CONCLUSIONS: Acetaminophen, NSAIDs, and loratadine are easily available and inexpensive. However, unlike acetaminophen and NSAIDs, loratadine is dosed once a day and well tolerated with minimal adverse effects. CLINICAL IMPLICATIONS: Randomized controlled trials are needed to adequately assess the effectiveness of all three medication options. Because little is known about optimal use of any of these medications for pegfilgrastim-induced bone pain, it is also important to identify the optimal time to initiate treatment and ideal treatment duration.
Asunto(s)
Enfermedades Óseas , Neoplasias de la Mama , Filgrastim , Dolor Musculoesquelético , Polietilenglicoles , Adulto , Femenino , Humanos , Loratadina/efectos adversos , Acetaminofén/efectos adversos , Estudios Transversales , Enfermedades Óseas/inducido químicamente , Enfermedades Óseas/tratamiento farmacológico , Enfermedades Óseas/epidemiología , Dolor Musculoesquelético/tratamiento farmacológico , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/tratamiento farmacológico , Antiinflamatorios no Esteroideos/uso terapéuticoRESUMEN
PURPOSE: This study aimed to examine the effectiveness of the combined maximal medical treatment for adenoid hypertrophy in preschool children. METHODS: Sixty-four children underwent one-year combined therapy with intranasal mometasone furoate, oral desloratadine, nasal saline irrigation, and bacteriotherapy. Additionally, decongestion drops were applied during scheduled breaks. RESULTS: Of the 64 treated children, 72% showed clinical improvement in adenoid symptoms while 28% did not improve and underwent surgery. These groups differed significantly in terms of the overall reduction in ailments after treatment (p < 0.001), infection rate (p < 0.001), catarrh severity (p < 0.001) and nasal patency (p < 0.001). Endoscopic examination confirmed that responders experienced, on average, a decrease of 8.4% in the adenoid/choana ratio and an improvement in mucosal coverage of the adenoid. These effects were not observed in the group of children whose parents opted for surgery after nine months of conservative treatment. CONCLUSIONS: The proposed new schema of long-term maximal medical treatment with the use of combined intermittent treatment of intranasal mometasone furoate and decongestion drops, oral desloratadine, nasal saline irrigation, and bacteriotherapy can be attempted in patients with adenoid hypertrophy symptoms, and responders may avoid the need for surgery. The applied treatment breaks resulted in a low number of therapeutic side effects.
Asunto(s)
Tonsila Faríngea , Loratadina/análogos & derivados , Humanos , Preescolar , Estudios Prospectivos , Furoato de Mometasona/uso terapéutico , Hipertrofia/tratamiento farmacológico , AdenoidectomíaRESUMEN
BACKGROUND: Tumor-associated inflammation suggests that anti-inflammatory medication could be beneficial in cancer therapy. Loratadine, an antihistamine, has demonstrated improved survival in certain cancers. However, the anticancer mechanisms of loratadine in lung cancer remain unclear. OBJECTIVE: This study investigates the anticancer mechanisms of loratadine in lung cancer. METHODS: A retrospective cohort of 4,522 lung cancer patients from 2006 to 2018 was analyzed to identify noncancer drug exposures associated with prognosis. Cellular experiments, animal models, and RNA-seq data analysis were employed to validate the findings and explore the antitumor effects of loratadine. RESULTS: This retrospective study revealed a positive association between loratadine administration and ameliorated survival outcomes in lung cancer patients, exhibiting dose dependency. Rigorous in vitro and in vivo assays demonstrated that apoptosis induction and epithelial-mesenchymal transition (EMT) reduction were stimulated by moderate loratadine concentrations, whereas pyroptosis was triggered by elevated dosages. Intriguingly, loratadine was found to augment PPARγ levels, which acted as a gasdermin D transcription promoter and caspase-8 activation enhancer. Consequently, loratadine might incite a sophisticated interplay between apoptosis and pyroptosis, facilitated by the pivotal role of caspase-8. CONCLUSION: Loratadine use is linked to enhanced survival in lung cancer patients, potentially due to its role in modulating the interplay between apoptosis and pyroptosis via caspase-8.
Asunto(s)
Antineoplásicos , Neoplasias Pulmonares , Animales , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Loratadina/farmacología , Loratadina/uso terapéutico , Estudios Retrospectivos , Caspasa 8 , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , PronósticoRESUMEN
Metastasis is the major obstacle to the survival of cancer patients. Herein, a series of new desloratadine platinum(IV) conjugates with promising antiproliferative and antimetastatic activities were developed and evaluated. The candidate complex caused significant DNA damage and stimulated mitochondrial apoptosis through the Bcl-2/Bax/caspase3 pathway. Then, it suppressed the epithelial-mesenchymal transition (EMT) process in tumors effectively through NMT-1/HPCAL1 and ß-catenin signaling. Subsequently, the angiogenesis was inhibited with the downregulation of key proteins HIF-1α, VEGFA, MMP-9, and CD34. Moreover, the antitumor immunity was effectively aroused by the synergism of EMT reversion and decrease of the histamine level; then, the macrophage polarization from M2- to M1-type and the increase of CD4+ and CD8+ T cells were triggered simultaneously in tumors.
Asunto(s)
Loratadina/análogos & derivados , Neoplasias , Platino (Metal) , Humanos , Platino (Metal)/farmacología , Linfocitos T CD8-positivos/metabolismo , Proliferación Celular , beta Catenina/metabolismo , Movimiento Celular , Transición Epitelial-Mesenquimal , Inmunidad , Línea Celular TumoralRESUMEN
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with progressive loss of motor neurons in the spinal cord, cerebral cortex and brain stem. ALS is characterized by gradual muscle atrophy and dyskinesia. The limited knowledge on the pathology of ALS has impeded the development of therapeutics for the disease. Previous studies have shown that autophagy and astrocyte-mediated neuroinflammation are involved in the pathogenesis of ALS, while 5HTR2A participates in the early stage of astrocyte activation, and 5HTR2A antagonism may suppress astrocyte activation. In this study, we evaluated the therapeutic effects of desloratadine (DLT), a selective 5HTR2A antagonist, in human SOD1G93A (hSOD1G93A) ALS model mice, and elucidated the underlying mechanisms. HSOD1G93A mice were administered DLT (20 mg·kg-1·d-1, i.g.) from the age of 8 weeks for 10 weeks or until death. ALS onset time and lifespan were determined using rotarod and righting reflex tests, respectively. We found that astrocyte activation accompanying with serotonin receptor 2 A (5HTR2A) upregulation in the spinal cord was tightly associated with ALS-like pathology, which was effectively attenuated by DLT administration. We showed that DLT administration significantly delayed ALS symptom onset time, prolonged lifespan and ameliorated movement disorders, gastrocnemius injury and spinal motor neuronal loss in hSOD1G93A mice. Spinal cord-specific knockdown of 5HTR2A by intrathecal injection of adeno-associated virus9 (AAV9)-si-5Htr2a also ameliorated ALS pathology in hSOD1G93A mice, and occluded the therapeutic effects of DLT administration. Furthermore, we demonstrated that DLT administration promoted autophagy to reduce mutant hSOD1 levels through 5HTR2A/cAMP/AMPK pathway, suppressed oxidative stress through 5HTR2A/cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway, and inhibited astrocyte neuroinflammation through 5HTR2A/cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1G93A mice. In summary, 5HTR2A antagonism shows promise as a therapeutic strategy for ALS, highlighting the potential of DLT in the treatment of the disease. DLT as a 5HTR2A antagonist effectively promoted autophagy to reduce mutant hSOD1 level through 5HTR2A/cAMP/AMPK pathway, suppressed oxidative stress through 5HTR2A/cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway, and inhibited astrocytic neuroinflammation through 5HTR2A/cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1G93A mice.
Asunto(s)
Esclerosis Amiotrófica Lateral , Astrocitos , Loratadina , Loratadina/análogos & derivados , Ratones Transgénicos , Médula Espinal , Superóxido Dismutasa-1 , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Astrocitos/patología , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Médula Espinal/efectos de los fármacos , Médula Espinal/patología , Médula Espinal/metabolismo , Ratones , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismo , Loratadina/farmacología , Loratadina/uso terapéutico , Humanos , Receptor de Serotonina 5-HT2A/metabolismo , Modelos Animales de Enfermedad , Masculino , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Antagonistas del Receptor de Serotonina 5-HT2/uso terapéutico , Ratones Endogámicos C57BLRESUMEN
Rapidly dissolving polymer thin films, or oral thin films (OTFs), have recently emerged as an improved oral drug delivery vehicle with its ability to bypass liver first pass metabolism, longer shelf-life, and simpler transport and distribution requirements, compared to traditional tablets and liquid formulations. Loratadine (LOR), an antihistamine commonly used to treat allergic rhinitis, undergoes liver first pass metabolism and is a prime candidate for incorporation within an OTF. However, loratadine is a BCS II drug with low aqueous solubility. Herein, the solubility of loratadine was improved by complexation with methyl ß-cyclodextrin (MBCD) by co-evaporation of 2:1, 1:1, and 1:2 LOR:MBCD ratios and incorporation into a pullulan-based OTF at 4 wt% by solvent casting at 50 °C for 30 - 35 min. A therapeutically relevant 10 mg LOR dose could be prepared in a 3 cm by 3 cm OTF. The feasibility of complexation was observed with a Bs-type phase solubility diagram, and complexation itself was confirmed via differential scanning calorimetry (DSC) by disappearance of the LOR melting peak, Fourier-transform infrared spectroscopy (FTIR) by shifting of the C=O peak, via 1H NMR spectroscopy by downfield shifting and change in peak multiplicity of the LOR aromatic protons, and via diffusion-ordered spectroscopy by a decrease in the diffusion coefficient of LOR:MBCD complex. LOR:MBCD could be incorporated homogeneously throughout an OTF, and LOR:MBCD OTFs exhibited reasonable mechanical strength and endured 12 ± 3 folds before breaking. LOR:MBCD OTFs disintegrated within 38 ± 10 s. The cumulative in vitro release of LOR:MBCD OTFs peaked at 80 % within 3-4 min of dissolution, and LOR in LOR:MBCD OTFs exhibited permeability across a 0.22 µm nitrocellulose membrane, demonstrating its applicability as a rapid drug delivery vehicle.
Asunto(s)
Ciclodextrinas , Loratadina , Loratadina/química , Sistemas de Liberación de Medicamentos , Solubilidad , Rastreo Diferencial de Calorimetría , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Methicillin-resistant Staphylococcus aureus (MRSA) has evolved to become resistant to multiple classes of antibiotics. New antibiotics are costly to develop and deploy, and they have a limited effective lifespan. Antibiotic adjuvants are molecules that potentiate existing antibiotics through nontoxic mechanisms. We previously reported that loratadine, the active ingredient in Claritin, potentiates multiple cell-wall active antibiotics in vitro and disrupts biofilm formation through a hypothesized inhibition of the master regulatory kinase Stk1. Loratadine and oxacillin combined repressed the expression of key antibiotic resistance genes in the bla and mec operons. We hypothesized that additional genes involved in antibiotic resistance, biofilm formation, and other cellular pathways would be modulated when looking transcriptome-wide. To test this, we used RNA-seq to quantify transcript levels and found significant effects in gene expression, including genes controlling virulence, antibiotic resistance, metabolism, transcription (core RNA polymerase subunits and sigma factors), and translation (a plethora of genes encoding ribosomal proteins and elongation factor Tu). We further demonstrated the impacts of these transcriptional effects by investigating loratadine treatment on intracellular ATP levels, persister formation, and biofilm formation and morphology. Loratadine minimized biofilm formation in vitro and enhanced the survival of infected Caenorhabditis elegans. These pleiotropic effects and their demonstrated outcomes on MRSA virulence and survival phenotypes position loratadine as an attractive anti-infective against MRSA.
Asunto(s)
Staphylococcus aureus Resistente a Meticilina , Loratadina/farmacología , Virulencia , Pruebas de Sensibilidad Microbiana , Antibacterianos/farmacología , Farmacorresistencia Microbiana , BiopelículasRESUMEN
Loratadine (LRD) belongs to second-generation tricyclic H1 antihistamine class, known for its non-sedating properties in allergic reactions. H1 antihistamines avoid and block the responses to allergens or histamine in nose and conjunctivae, thereby abolishing itching, congestion and sneezing. LRD is a Biopharmaceutical Class System (BCS) class II drug with dissolution or solubility limited absorption which limited the oral bioavailability and therapeutic efficacy of LRD. To improve the oral bioavailability of LRD for allergic disease (urticaria) treatment, LRD solid dispersions (LRD-SDs) were integrating into oro-dispersible films (ODFs). LRD-SDs were prepared through hot-melt extrusion method (HME) using d-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS-1000), and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SP). Subsequently, LRD-SDs were incorporated in ODFs by solvent casting method. The physicochemical and mechanical properties of LRD solid dispersions-loaded oro-dispersible films (LRD-SDs-ODFs), were evaluated. The in-vitro dissolution, ex-vivo permeation, oral bioavailability, and pharmacodynamics studies were conducted to evaluate LRD-SDs-ODFs efficiency. LRD-SDs-ODFs showed superior solubility and in-vitro dissolution results compared to that of pure LRD (p < 0.05). The solubility of the LRD-SD coded as LTS-4 was 190 times higher than the pure drug in aqueous media. The average hydrodynamic particle size (PS), polydispersity index (PDI), and zeta potential (ZP) of SD particles were 76 ± 2.1 nm, 0.20 ± 0.08 and - 19.16 ± 1.4 mV, respectively. Moreover, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) results confirmed the amorphousness of LRD in LRD-SDs-ODFs. The permeability flux of LRD was 44.6 ± 3.1 µg/cm2/h from DPF-5 formulation. Likewise, in vivo oral bioavailability of DPF-5 in Sprague-Dawley rats was significantly increased (p < 0.05) compared to free LRD. Further, wheal area was reduced 20 % higher than LRD in 8 h (p < 0.05). Overall, LRD-SDs-ODFs considerably enhanced LRD solubility, dissolution rate, bioavailability, and antihistaminic efficacy. Our findings show that SDs-ODFs is an effective carrier system for delivering poorly soluble LRD.
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Productos Biológicos , Loratadina , Ratas , Animales , Ratas Sprague-Dawley , Disponibilidad Biológica , Rastreo Diferencial de CalorimetríaRESUMEN
INTRODUCTION: Oral H1 antihistamines are the first-line treatment for patients with allergic rhinitis, while it is uncertain which kind and dosage of the antihistamines are more effective in improving symptoms of patients. OBJECTIVE: To evaluate the efficacy of different oral H1 antihistamine treatments on patients with allergic rhinitis by performing a network meta-analysis. METHODS: The search was executed in PubMed, Embase, OVID, the Cochrane Library and ClinicalTrials.gov for relevant studies. The network meta-analysis was performed by using Stata 16.0, and the outcome measures of the analysis were symptom score reductions of patients. Relative risks with 95% Confidence Intervals were used in the network meta-analysis to compare the clinical effect of treatments involved, and Surface Under the Cumulative Ranking Curves (SUCRAs) were also calculated to rank the treatments' efficacy. RESULTS: 18 eligible randomized controlled studies, involving a total of 9419 participants, were included in this meta-analysis. All the antihistamine treatments outperformed placebo in total symptom score reduction and each individual symptom score reduction. According to the results of SUCRA, rupatadine 20â¯mg and rupatadine 10â¯mg were ranked relatively high in reductions of total symptom score (SUCRA: 99.7%, 76.3%), nasal congestion score (SUCRA: 96.4%, 76.4%), rhinorrhea score (SUCRA: 96.6%, 74.6%) and ocular symptom score (SUCRA: 97.2%, 88.8%); rupatadine 20â¯mg and levocetirizine 5â¯mg were ranked relatively high in reductions of nasal itching score (SUCRA: 84.8%, 83.4%) and sneezing score (SUCRA: 87.3%, 95.4%); loratadine 10â¯mg was ranked the lowest in each symptom score reduction besides placebo. CONCLUSION: This study suggests that rupatadine is the most effective in alleviating symptoms of patients with allergic rhinitis among different oral H1 antihistamine treatments involved, and rupatadine 20â¯mg performs better than rupatadine 10â¯mg. While loratadine 10â¯mg has inferior efficacy for patients to the other antihistamine treatments.
Asunto(s)
Loratadina , Rinitis Alérgica , Humanos , Loratadina/uso terapéutico , Metaanálisis en Red , Ensayos Clínicos Controlados Aleatorios como Asunto , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Antagonistas de los Receptores Histamínicos/uso terapéutico , Rinitis Alérgica/tratamiento farmacológico , Resultado del TratamientoRESUMEN
BACKGROUND: The high prescription drug cost in the United States may negatively affect patient prognosis and treatment compliance. OBJECTIVE: To fill the knowledge gap and inform clinicians regarding rhinology medications price changes by evaluating trends in price changes of highly used nasal sprays and allergy medications. METHODS: The 2014-2020 Medicaid National Average Drug Acquisition Cost database was queried for drug pricing information for the following classes of medications: intranasal corticosteroids, oral antihistamines, antileukotrienes, intranasal antihistamines, and intranasal anticholinergics. Individual medications were identified by Food and Drug Administration-assigned National Drug Codes. Per unit, drug prices were analyzed for average annual prices, average annual percentage price changes, and inflation-adjusted annual and composite percentage price changes. RESULTS: Beclometasone (Beconase AQ, 56.7%, QNASL, 77.5%), flunisolide (Nasalide, -14.6%), budesonide (Rhinocort Aqua, -1.2%), fluticasone (Flonase, -6.8%, Xhance, 11.7%), mometasone (Nasonex, 38.2%), ciclesonide (Omnaris, 73.8%), combination azelastine and fluticasone (Dymista, 27.3%), loratadine (Claritin, -20.5%), montelukast (Singulair, 14.5%), azelastine (Astepro, 21.9%), olopatadine (Patanase, 27.3%), and ipratropium bromide (Atrovent, 56.6%) had an overall change in inflation-adjusted per unit cost between 2014 and 2020 (% change). Of 14 drugs evaluated, 10 had an increase in inflation-adjusted prices, for an average increase of 42.06% ± 22.27%; 4 of 14 drugs had a decrease in inflation-adjusted prices, for an average decrease of 10.78% ± 7.36%. CONCLUSION: The rising cost of highly used medications contributes to increased patient acquisition costs and may pose barriers of drug adherence to particularly vulnerable populations.