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Background/aim: Non-small-cell lung cancer (NSCLC) is the most frequently diagnosed malignancy and the first cause of cancer-related death. Thus, finding alternative therapeutic options is crucial. Drug repurposing offers therapeutic options in a simplified and affordable manner, especially to cancer patients in developing countries. Several drugs including antihistamines and beta-adrenergic receptor blockers (beta-blockers) display antiproliferative properties on cancer cells. Interestingly, NSCLC patients who had used either antihistamines or beta-blockers showed improved response to chemotherapy or reduced mortality in comparison to non-users of any of these drugs. However, combination therapy is gaining substantial interest in many cancers including non-EGFR mutated NSCLC. Here, we investigated the antineoplastic effect of the combination of the antihistamine loratadine, the beta-blocker nebivolol, and the tyrosine-kinase inhibitor gefitinib on NSCLC cell lines., Materials and Methods: A-549 and NCI-H1975 cell lines were used. The effect of nebivolol, gefitinib, and loratadine on the metabolic activity was studied using the MTT assay. The inhibitory concentrations (IC 20 and IC 50 ) were calculated and used in the drug-combination experiments. Apoptosis was investigated using flow cytometry; and cell survival using the colony formation assay., Results: The combination nebivolol-loratadine-gefitinib produced a significant synergistic effect on inhibiting the metabolic activity and colony formation, as well as on promoting apoptosis in both cell lines. Noteworthy, the effect on the cell line carrying the EGFR mutation (NCI-H1975) was very similar to the cell line that does not exhibit such mutation (A-549 cells)., Conclusion: The nebivolol-gefitinib-loratadine combination may be a promising alternative for lung cancer treatment., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

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 (K b ) between desloratadine and ct-dsDNA was determined to be 2.2 × 10 5  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 K b value was found to be 8.85 × 10 4  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., Competing Interests: Declaration of competing interest The authors state that none of their known financial conflicts or interpersonal connections could have influenced the work that was published in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Paclitaxel (PTX) serves as a primary chemotherapy agent against diverse solid tumors including breast cancer, lung cancer, head and neck cancer and ovarian cancer, having severe adverse effects including PTX-induced peripheral neuropathy (PIPN) and hypersensitivity reactions (HSR). A recommended anti-allergic agent diphenhydramine (DIP) has been used to alleviate PTX-induced HSR. Desloratadine (DLT) is a third generation of histamine H 1 receptor antagonist, but also acted as a selective antagonist of 5HTR 2A . In this study we investigated whether DLT ameliorated PIPN-like symptoms in mice and the underlying mechanisms. PIPN was induced in male mice by injection of PTX (4 mg/kg, i.p.) every other day for 4 times. The mice exhibited 50% reduction in mechanical threshold, paw thermal response latency and paw cold response latency compared with control mice. PIPN mice were treated with DLT (10, 20 mg/kg, i.p.) 30 min before each PTX administration in the phase of establishing PIPN mice model and then administered daily for 4 weeks after the model was established. We showed that DLT administration dose-dependently elevated the mechanical, thermal and cold pain thresholds in PIPN mice, whereas administration of DIP (10 mg/kg, i.p.) had no ameliorative effects on PIPN-like symptoms. We found that the expression of 5HTR 2A was selectively elevated in the activated spinal astrocytes of PIPN mice. Spinal cord-specific 5HTR 2A knockdown by intrathecal injection of AAV9-5Htr2a-shRNA significantly alleviated the mechanical hyperalgesia, thermal and cold hypersensitivity in PIPN mice, while administration of DLT (20 mg/kg) did not further ameliorate PIPN-like symptoms. We demonstrated that DLT administration alleviated dorsal root ganglion neuronal damage and suppressed sciatic nerve destruction, spinal neuron apoptosis and neuroinflammation in the spinal cord of PIPN mice. Furthermore, we revealed that DLT administration suppressed astrocytic neuroinflammation via the 5HTR 2A /c-Fos/NLRP3 pathway and blocked astrocyte-neuron crosstalk by targeting 5HTR 2A . We conclude that spinal 5HTR 2A inhibition holds promise as a therapeutic approach for PIPN and we emphasize the potential of DLT as a dual-functional agent in ameliorating PTX-induced both PIPN and HSR in chemotherapy. In summary, we determined that spinal 5HTR 2A was selectively activated in PIPN mice and DLT could ameliorate the PTX-induced both PIPN- and HSR-like pathologies in mice. DLT alleviated the damages of DRG neurons and sciatic nerves, while restrained spinal neuronal apoptosis and CGRP release in PIPN mice. The underlying mechanisms were intensively investigated by assay against the PIPN mice with 5HTR 2A -specific knockdown in the spinal cord by injection of adeno-associated virus 9 (AAV9)-5Htr2a-shRNA. DLT inhibited astrocytic NLRP3 inflammasome activation-mediated spinal neuronal damage through 5HTR 2A /c-FOS pathway. Our findings have supported that spinal 5HTR 2A inhibition shows promise as a therapeutic strategy for PIPN and highlighted the potential advantage of DLT as a dual-functional agent in preventing against PTX-induced both PIPN and HSR effects in anticancer chemotherapy., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Background: Clostridium difficile infection (CDI) is a debilitating nosocomial infection. C. difficile produces toxins A and B, which cause inflammation. Existing therapies have issues with recurrence, cost, and safety. We aim to discover a safe, effective, and economical nonmicrobiological therapeutic approach against CDI., Methods: We included human primary peripheral blood mononuclear cells (PBMCs), fresh human colonic explants, and humanized HuCD34-NCG mice. Toxin A+B+ VPI 10463 and A-B+ ribotype 017 C. difficile strains were used. We used single-cell RNA profiling and high-throughput screening to find actionable toxin B-dependent pathways in PBMCs., Results: Histamine 1 receptor-related drugs were found among the hit compounds that reversed toxin-mediated macrophage inflammatory protein (MIP) 1α expression in PBMCs. We identified loratadine as the safest representative antihistamine for therapeutic development. Loratadine inhibited toxin B-induced MIP-1α secretion in fresh human colonic tissues. Oral loratadine (10 mg/kg/d) maintained survival, inhibited intestinal CCl3 messenger RNA expression, and prevented vancomycin-associated recurrence in the VPI 10463-infected mice and ribotype 017-infected hamsters. Splenocytes from loratadine-treated mice conferred anti-inflammatory effects to the VPI 10463-infected T/B-cell--deficient Rag-/- mice. Oral loratadine suppressed human MIP-1α expression in monocytes/macrophages in toxin B-expressing ribotype 017-infected humanized HuCD34-NCG mice., Conclusions: Loratadine may be repurposed to optimize existing therapies against CDI., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.

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-1β, 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.

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 5HTR 2A participates in the early stage of astrocyte activation, and 5HTR 2A antagonism may suppress astrocyte activation. In this study, we evaluated the therapeutic effects of desloratadine (DLT), a selective 5HTR 2A antagonist, in human SOD1 G93A (hSOD1 G93A ) ALS model mice, and elucidated the underlying mechanisms. HSOD1 G93A 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 (5HTR 2A ) 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 hSOD1 G93A mice. Spinal cord-specific knockdown of 5HTR 2A by intrathecal injection of adeno-associated virus9 (AAV9)-si-5Htr2a also ameliorated ALS pathology in hSOD1 G93A mice, and occluded the therapeutic effects of DLT administration. Furthermore, we demonstrated that DLT administration promoted autophagy to reduce mutant hSOD1 levels through 5HTR 2A /cAMP/AMPK pathway, suppressed oxidative stress through 5HTR 2A /cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway, and inhibited astrocyte neuroinflammation through 5HTR 2A /cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1 G93A mice. In summary, 5HTR 2A antagonism shows promise as a therapeutic strategy for ALS, highlighting the potential of DLT in the treatment of the disease. DLT as a 5HTR 2A antagonist effectively promoted autophagy to reduce mutant hSOD1 level through 5HTR 2A /cAMP/AMPK pathway, suppressed oxidative stress through 5HTR 2A /cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway, and inhibited astrocytic neuroinflammation through 5HTR 2A /cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1 G93A mice., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

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.

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 Ⅲ-4, a novel H1 receptor antagonist with significant H1 receptor antagonistic activity (IC 50  = 24.12 nM) and enhanced selectivity towards peripheral H1 receptor. In particular, Ⅲ-4 exhibits reduced M3 receptor inhibitory potency (IC 50  > 10,000 nM) and acceptable hERG inhibitory activity (17.6 ± 2.1 μM) compare with desloratadine. Additionally, Ⅲ-4 exhibits favorable pharmacokinetic properties, as well as in vivo efficacy and safety profiles. All of these reveal that Ⅲ-4 has potential to emerge as a novel H1 receptor antagonist for the treatment of allergic diseases. More importantly, the compound Ⅲ-4 (HY-078020) has recently been granted clinical approval., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and company that could be construed as influencing the position presented in, or the review of, the manuscript entitle., (Copyright © 2024. Published by Elsevier Masson SAS.)

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., Competing Interests: The authors declare no conflict of interest., (© 2024 by the authors.)

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.

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., (© 2023. The Author(s).)

Background/aim: Liver cancer is one of the malignancies with the highest mortality-to-incidence ratio worldwide. Therefore, novel therapeutic approaches are urgently needed. Combination therapy and drug repurposing can improve the response of the patients to therapy in several cancers. The aim of the present study was to merge these two strategies and evaluate whether the two-drug- or three-drug- combination of sorafenib, raloxifene, and loratadine improves the antineoplastic effect on human liver cancer cells in comparison to the single-drug effect., Materials and Methods: The human liver cancer cell lines HepG2 and HuH7 were studied. The effect of sorafenib, raloxifene, and loratadine on the metabolic activity was determined using the MTT assay. The inhibitory concentrations (IC 20 and IC 50 ) were calculated from these results and used in the drug-combination experiments. Apoptosis and cell survival were studied by flow cytometry and using the colony formation assay, respectively., Results: In both cell lines, sorafenib, raloxifene, and loratadine in two-drug and three-drug combinations significantly reduced metabolic activity and significantly increased the percentage of apoptotic cells compared to the single-drug effect. In addition, all the combinations significantly reduced the colony-forming capacity in the HepG2 cell line. Surprisingly, the effect of raloxifene on apoptosis was similar to that observed using the combinations., Conclusion: The triple combination sorafenib-raloxifene-loratadine may be a novel promising approach in the treatment of liver cancer patients., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

T cells play an essential role in the development of allergen-induced nasal hyperresponsiveness (NHR), a pathophysiological response in allergic rhinitis. The effects of histamine H1-receptor antagonists (antihistamines) on murine NHR models were investigated. Intragastric epinastine, fexofenadine, and loratadine administration suppressed allergen-induced immediate nasal response but not NHR in immunized mice. Regardless of the alleviation of stimulation-induced Th2 cytokine expression by loratadine and desloratadine in vitro, allergen-induced NHR and nasal eosinophil infiltration in Th2 cell-transferred mice were unaffected by loratadine in vivo. This influence on T cell-mediated NHR was excluded from the pharmacological effects of antihistamines., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

The transient receptor potential (TRP) channel TRPV2 is widely expressed in a variety of different cell types and tissues. However, elucidating the exact biological functions of TRPV2 is significantly hampered by the lack of selective pharmacological tools to modulate channel activity in vitro and in vivo. This study aimed to identify new compounds that modify TRPV2 activity via the use of a plate-based calcium imaging approach to screen a drug repurposing library. Three antihistaminic drugs, loratadine, astemizole and clemizole were identified to reduce calcium-influx evoked by the TRPV2 agonist tetrahydrocannabivarin in HEK293 cells expressing murine TRPV2. Using single-cell calcium-microfluorimetry and whole-cell patch clamp recordings, we further confirmed that all three compounds induced a concentration-dependent block of TRPV2-mediated Ca 2+ influx and whole-cell currents, with loratadine being the most potent antagonist of TRPV2. Moreover, this study demonstrated that loratadine was able to block both the human and mouse TRPV2 orthologs, without inhibiting the activity of other closely related members of the TRPV superfamily. Finally, loratadine inhibited TRPV2-dependent responses in a primary culture of mouse endometrial stromal cells and attenuated cell proliferation and migration in in vitro cell proliferation and wound healing assays. Taken together, our study revealed that the antihistaminic drugs loratadine, astemizole and clemizole target TRPV2 in a concentration-dependent manner. The identification of these antihistaminic drugs as blockers of TRPV2 may form a new starting point for the synthesis of more potent and selective TRPV2 antagonists, which could further lead to the unravelling of the physiological role of the channel., (Copyright © 2022. Published by Elsevier B.V.)

Loratadine is an anti-histamine routinely used for treating allergies. However, recent findings have shown that Loratadine may also have anti-inflammatory functions, while their exact mechanisms have not yet been fully uncovered. In this paper, we investigated whether Loratadine can be utilized as an anti-inflammatory drug through a series of in vitro and in vivo experiments using a murine macrophage cell line and an acute gastritis mouse model. Loratadine was found to dramatically reduce the expression of pro-inflammatory genes, including MMP1, MMP3, and MMP9, and inhibit AP-1 transcriptional activation, as demonstrated by the luciferase assay. Therefore, we decided to further explore its role in the AP-1 signaling pathway. The expression of c-Jun and c-Fos, AP-1 subunits, was repressed by Loratadine and, correspondingly, the expression of p-JNK, p-MKK7, and p-TAK1 was also inhibited. In addition, Loratadine was able to reduce gastric bleeding in acute gastritis-induced mice; Western blotting using the stomach samples showed reduced p-c-Fos protein levels. Loratadine was shown to effectively suppress inflammation by specifically targeting TAK1 and suppressing consequent AP-1 signaling pathway activation and inflammatory cytokine production.

Loratadine, 4-(8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylic acid ethyl ester, is an antihistamine drug with long-acting effects and has limited selectivity for peripheral H1 receptors. It is widely used for the prevention of allergic diseases such as rhinitis chronic urticaria, and asthma. This chapter discusses, by a critical extensive review of the literature, the description of loratadine in terms of its names, formulae, elemental composition, appearance, methods of preparation. The profile contains physicochemical properties of Loratadine, including pKa value, solubility and X-ray powder diffraction. In addition, it involves Fourier transform infrared spectrometry, nuclear magnetic resonance spectroscopy and mass spectroscopy for functional groups and structural confirmation of. The chapter also includes methods of analysis of the drug such as compendial, titrimetric, electrochemical, spectroscopic, chromatographic and capillary electrophoretic methods. The chapter also covers clinical applications of the drug such as its uses, doses, ADME profiles and mechanism of action., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: The work aimed to develop a co-loaded loratadine and sulpiride nasal nanoemulsion for allergic rhinitis management., Methods: Compatibility studies were conducted adopting differential scanning calorimetry and Fourier transform infrared spectroscopy. Nanoemulsion formulations were prepared using soybean lecithin, olive oil and tween 80. Sodium cholate and glycerol were employed as co-surfactants. Nanoemulsions were assessed for viscosity, pH, droplet size, polydispersity index, zeta potential, electrical conductivity, entrapment, In vitro drug release and corresponding kinetics. Stability of the selected formulation was investigated. The biological effectiveness was evaluated in rabbit models of ovalbumin-induced allergic rhinitis by measuring TNF-α, TGF-β and IL-1., Results: Compatibility studies revealed absence of drug/drug interactions. Nanoemulsions exhibited > 90% entrapment efficiency. The selected nanoemulsion demonstrated small droplet size (85.2   ±   0.2   nm), low PDI (0.35   ±   0.0) and appropriate Zeta Potential (-23.3   ±   0.2) and stability. It also displayed enhanced in vitro drug release following the Higuashi Diffusion and Baker-Lonsdale models. The mean relative mRNA expression of TNF-α, IL-1 and TGF-β significantly decreased from 9.59   ±   1.06, 4.15   ±   0.02 and 4.15   ±   0.02 to 1.28   ±   0.02, 1.93   ±   0.06 and 1.56   ±   0.02 respectively after treatment with the selected nanoemulsion formulation., Conclusion: The results reflected a promising potent effect of the combined loratadine and sulpiride nasal nanoemulsion in managing the symptoms of allergic rhinitis.

Context: Desloratadine, an H1 receptor antagonist, is suggested as an effective first-line drug for chronic urticarial (CU). However, the efficacy of desloratadine alone is limited, and the recurrence rate of CU is relatively high., Objective: We sought to evaluate the efficacy and clinical feasibility of desloratadine in combination with compound glycyrrhizin in the treatment of CU., Materials and Methods: A systematic literature search was conducted in the databases of the China National Knowledge Infrastructure Database, VIP, WanFang, PubMed, and Web of Science using subject terms: "Chronic urticaria", "Loratadine", and "Compound glycyrrhizin". Randomised controlled trials (RCTs) that compared the efficiency and safety of the combination treatment with desloratadine alone starting from January 1, 2014 until February 10, 2021 were selected by two co-first authors independently, and the extracted data were analysed using Rev Man 5.3 software., Results: Fourteen RCTs were included in our meta-analysis with a total of 1501 patients. The results showed that the combination treatment yielded a better treatment effect (total response rate: RR = 1.23, 95% CI: 1.17 to 1.29, p  < 0.00001; cure rate: RR = 1.50, 95% CI: 1.30 to 1.73, p  < 0.00001), lower recurrence rate as well as superior immune improvement than the treatment with desloratadine alone. In addition, there was no significant difference in the safety of the two treatments., Discussion and Conclusion: The combination of desloratadine and compound glycyrrhizin is a promising treatment for CU and is associated with decreased serum IgE level and improved proportions of CD4+ T and CD8+ T cells.

Impaired wound healing in people with diabetes has multifactorial causes, with insufficient neovascularization being one of the most important. Hypoxia-inducible factor-1 (HIF-1) plays a central role in the hypoxia-induced response by activating angiogenesis factors. As its activity is under precise regulatory control of prolyl-hydroxylase domain 2 (PHD-2), downregulation of PHD-2 by small interfering RNA (siRNA) could stabilize HIF-1α and, therefore, upregulate the expression of pro-angiogenic factors as well. Intracellular delivery of siRNA can be achieved with nanocarriers that must fulfill several requirements, including high stability, low toxicity, and high transfection efficiency. Here, we designed and compared the performance of layer-by-layer self-assembled siRNA-loaded gold nanoparticles with two different outer layers-Chitosan (AuNP@CS) and Poly L-arginine (AuNP@PLA). Although both formulations have exactly the same core, we find that a PLA outer layer improves the endosomal escape of siRNA, and therefore, transfection efficiency, after endocytic uptake in NIH-3T3 cells. Furthermore, we found that endosomal escape of AuNP@PLA could be improved further when cells were additionally treated with desloratadine, thus outperforming commercial reagents such as Lipofectamine ® and jetPRIME ® . AuNP@PLA in combination with desloratadine was proven to induce PHD-2 silencing in fibroblasts, allowing upregulation of pro-angiogenic pathways. This finding in an in vitro context constitutes a first step towards improving diabetic wound healing with siRNA therapy.

Heterotopic ossification (HO) is a pathological condition in which ectopic bone forms within soft tissues such as skeletal muscle. Human platelet-derived growth factor receptor α positive (PDGFRα+) cells, which were proved to be the original cells of HO were incubated in osteogenic differentiation medium with Food and Drug Administration-approved compounds. Alkaline phosphatase activity was measured as a screening to inhibit osteogenic differentiation. For the compounds which inhibited osteogenic differentiation of PDGFRα+ cells, we examined dose dependency of its effect using alizarin red S staining and its cell toxicity using WST-8. In addition, regulation of bone morphogenetic proteins (BMP)-Smad signaling which is the major signal of osteogenic differentiation was investigated by Western blotting to elucidate the mechanism of osteogenesis inhibitory effect by the compound. In vivo experiment, complete transverse incision of Achilles tendons in mice was made and mice were fed the compound by mixing with drinking water after operation. Ten weeks after operation, we assessed and quantified HO by micro-computed tomography scan. Intriguingly, we discovered desloratadine inhibited osteogenic differentiation of PDGFRα+ cells using the drug repositioning method. Desloratadine inhibited osteogenic differentiation of the cells dose dependently without cell toxicity. Desloratadine suppressed phosphorylation of Smad1/5/8 induced by BMP2 in PDGFRα+ cells. In Achilles tenotomy mice model, desloratadine treatment significantly inhibited ectopic bone formation compared with control. In conclusion, we discovered desloratadine inhibited osteogenic differentiation using human PDGFRα+ cells and proved its efficacy using Achilles tenotomy ectopic bone formation model in vivo. Our study paved the way to inhibit HO in early clinical use because of its guaranteed safety., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

We compared the effects of the first-, second- and third-generation antihistamines in different doses on enzyme activity and cytokine production by macrophages and their death using an in vitro model. It was found that decreasing the dose led to an increase in the number of viable cells; after contact with second-generation antihistamines (loratadine, desloratadine), apoptosis of macrophages predominated. A dose-dependent increase in activity of ATPase and 5'-AMP with less pronounced effect of second-generation drugs was revealed. It was shown that under the influence of drugs, macrophages do not produce IL-1β, but actively synthesize TNFα and IL-10, which indicates the immunomodulatory properties of these drugs.

Currently, there is an urgent need to find a treatment for the highly infectious coronavirus disease (COVID-19). However, the development of a new, effective, and safe vaccine or drug often requires years and poses great risks. At this critical stage, there is an advantage in using existing clinically approved drugs to treat COVID-19. In this study, in vitro severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike pseudotyped viral infection experiments indicated that histamine H 1 antagonists loratadine (LOR) and desloratadine (DES) could prevent entry of the pseudotyped virus into ACE2-overexpressing HEK293T cells and showed that DES was more effective. Further binding experiments using cell membrane chromatography and surface plasmon resonance demonstrated that both antagonists could bind to ACE2 and that the binding affinity of DES was much stronger than that of LOR. Molecular docking results elucidated that LOR and DES could bind to ACE2 on the interface of the SARS-CoV-2-binding area. Additionally, DES could form one hydrogen bond with LYS31 but LOR binding relied on non-hydrogen bonds. To our knowledge, this study is the first to demonstrate the inhibitory effect of LOR and DES on SARS-CoV-2 spike pseudotyped virus viropexis by blocking spike protein-ACE2 interaction. This study may provide a new strategy for finding an effective therapeutic option for COVID-19., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is a progressively neurodegenerative disease characterized by cognitive deficits and alteration of personality and behavior. As yet, there is no efficient treatment for AD. 5HT 2A receptor (5HT 2A R) is a subtype of 5HT 2 receptor belonging to the serotonin receptor family, and its antagonists have been clinically used as antipsychotics to relieve psychopathy. Here, we discovered that clinically first-line antiallergic drug desloratadine (DLT) functioned as a selective antagonist of 5HT 2A R and efficiently ameliorated pathology of APP/PS1 mice. The underlying mechanism has been intensively investigated by assay against APP/PS1 mice with selective 5HT 2A R knockdown in the brain treated by adeno-associated virus (AAV)-ePHP-si-5HT 2A R. DLT reduced amyloid plaque deposition by promoting microglial Aβ phagocytosis and degradation, and ameliorated innate immune response by polarizing microglia to an anti-inflammatory phenotype. It stimulated autophagy process and repressed neuroinflammation through 5HT 2A R/cAMP/PKA/CREB/Sirt1 pathway, and activated glucocorticoid receptor (GR) nuclear translocation to upregulate the transcriptions of phagocytic receptors TLR2 and TLR4 in response to microglial phagocytosis stimulation. Together, our work has highly supported that 5HT 2A R antagonism might be a promising therapeutic strategy for AD and highlighted the potential of DLT in the treatment of this disease., (© 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Antihistamines, which are commonly used to treat allergic reactions, are known for their side effects, which contribute to weight gain. It is hypothesized that simultaneous Brillouin elastography and Raman spectroscopy can be used to detect changes in adipose tissue associated with a prolonged intake of desloratadine, a commonly used second generation antihistamine. White and brown adipose tissue samples were excised from adult rats following 16 weeks of daily administration of desloratadine. It was found that the prolonged intake of desloratadine leads to an increase in Brillouin shift in both adipose tissue types. Raman spectra indicate that antihistamine use reduces protein-to-lipid ratio in brown adipose tissue but not white adipose tissue, indicating the effect on adipose tissue is location-dependent., (© 2020 Wiley-VCH GmbH.)

Purpose: To examine the effect of desloratadine on kidney ischemia-reperfusion (I/R) injury in albino Wistar male rats using biochemical and histopathological methods. Methods: The treated with ischemia-reperfusion + 5 mg/kg desloratadine (IRD) group ( n -6) was given 5 mg/kg desloratadine by gavage orally, and applied renal ischemia-reperfusion (BIR) group ( n -6) and control (SG) group undergoing Sham operation ( n -6) rats were given distilled water as solvent one hour before ketamine anesthesia. During the anesthesia period, ischemia was induced for 2 h unilaterally in the left kidney of all rats followed by reperfusion for 6 h. The kidneys of the SG group had sham operation without any intervention. Results: Our biochemical test results showed that malondialdehyde (MDA), nuclear factor kappa (NF-κB), tumor necrosis factor alpha (TNF-α), interleukin one beta (IL-1β), creatinine, and blood urea nitrogen (BUN) levels were significantly increased in the BIR group compared to the healthy control and IRD groups treated with desloratadine. Histopathological results were revealed tubular dilatation, tubular necrosis, loss of brushy margins, cast formation, and apoptotic bodies in tubular epithelial cells in the BIR group. There were no histopathological findings except for the swelling of tubule epithelial cells and the accumulation of proteinous material in some tubule lumens in renal tissue of desloratadine-treated rats. Conclusions: Experimental results suggested that desloratadine may be useful in the treatment of renal I/R injury.

Analogues of the conformationally dynamic Claritin (loratadine) and Clarinex (desloratadine) scaffolds have been enantio- and chemoselectively N -oxidized using an aspartic acid containing peptide catalyst to afford stable, helically chiral products in up to >99:1 er. The conformational dynamics and enantiomeric stability of the N -oxide products have been investigated experimentally and computationally with the aid of crystallographic data. Furthermore, biological assays show that rigidifying the core structure of loratadine and related analogues through N -oxidation affects antihistamine activity in an enantiomer-dependent fashion. Computational docking studies illustrate the observed activity differences.

Background: Chondrocytes in joint tissue are responsible for the synthesis and degradation of the cartilage matrix. Chondrocytes have been closely linked to the pathogenesis of osteoarthritis and cartilage damage. Targeted drug intervention directed at chondrocyte function is a promising strategy for the treatment of osteoarthritis. The effects of histamine receptor H1 (H1R) and its antagonist loratadine in osteoarthritic chondrocytes are less known., Materials and Methods: The inhibitory effects of loratadine on NLRP3 inflammasome and the NADPH oxidase subunit NOX4 were assessed in advanced glycation end products (AGEs)-treated SW1353 chondrocytes by real-time PCR, ELISA, and Western blot experiments. The mitochondrial ROS level was measured using the specific probe MitoSOX Red. The dependent effect of loratadine on the transcriptional factor nuclear factor erythroid 2-related factor 2 (NRF2) was evaluated through an oligo-based siRNA knockdown approach and Western blot analysis., Results: The expression of H1R was dose-responsively induced by AGEs in chondrocytes. Treatment with loratadine mitigated AGEs-induced oxidative stress, as revealed by suppressed production of mitochondrial ROS and the NADPH oxidase subunit NOX4. Loratadine treatment inhibited the expression of TxNIP and several components of the NLRP3 inflammasome complex, including NLRP3, ASC, and cleaved caspase 1 (P10). Moreover, loratadine suppressed the expression of NRF2, and the silencing of NRF2 abolished the suppressive effect of loratadine on NLRP3 inflammasome activation., Conclusion: Our study demonstrates that loratadine protects chondrocytes from AGEs-induced TxNIP/NLRP3 inflammasome activation by modulating the expression of the transcriptional factor NRF2. This finding implies that loratadine has therapeutic potential in the treatment of osteoarthritis and cartilage injury., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Gao and Zhang.)

Loratadine is an antihistamine drug that shows promise as an anti-inflammatory drug, but supportive studies are lacking. We elucidated the effects and mechanisms by which loratadine inhibits inflammatory responses. Molecular components were evaluated in macrophages by nitric oxide assay, polymerase chain reaction, luciferase assay, immunoblotting, overexpression strategies and cellular thermal shift assay. At the molecular level, loratadine reduced the levels of nitric oxide, iNOS, IL-1β, TNF-α, IL-6, and COX-2 in RAW264.7 cells treated with lipopolysaccharide. Loratadine also specifically inhibited the NF- k B pathway, targeting the Syk and Src proteins. Furthermore, loratadine bound Src in the bridge between SH2 and SH3, and bound Syk in the protein tyrosine kinase domain. The NF- k B signaling pathway was assessed along with putative binding sites through a docking approach. The anti-inflammatory effect of loratadine was tested using mouse models of gastritis, hepatitis, colitis, and peritonitis. Stomach tissue histopathology, liver morphology, and colon length in the loratadine group were improved over the group without loratadine treatment. Taken together, loratadine inhibited the inflammatory response through the NF- k B pathway by binding with the Syk and Src proteins., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The biopharmaceutical classification of drugs was designed as a basis for bio-waivers - a mechanism with the double ethical benefit of delivering new drug formulations to the market with less human testing and lower cost. However, many drugs defy simple classification because in vitro permeability and stability assessment can be challenging as shown in this study for desloratadine. Literature shows that desloratadine is highly soluble, while data on luminal stability and permeability are circumstantial. Combined with borderline bioavailability and not really known fraction of absorbed dose, desloratadine was found to be a good example for showing the innovative in vitro approaches necessary to unambiguously classify desloratadine according to Biopharmaceutical Classification System (BCS) guideline. Presented study undoubtedly confirmed that desloratadine solubility is high and dissolution is very rapid for immediate release reference tablets. We have demonstrated deslorata-dine stability under legally required conditions and also in more physiologically relevant media. High in vitro desloratadine permeability was confirmed using Caco-2 and Parallel Artificial Membrane Permeability Assay (PAMPA). Well-established in vitro model with rat intestinal tissue could not be used due to reasons elaborated in this paper.

Background: Crystal violet (CV) was used for several years in blood banks to eliminate the parasite Trypanosoma cruzi in endemic areas in order to prevent transfusion-transmitted Chagas disease. One mechanism of action described for CV involves inhibition of proline uptake. In T. cruzi, proline is essential for host cell infection and intracellular differentiation among other processes, and can be obtained through the proline permease TcAAAP069., Methodology/principal Findings: CV inhibited proline transporter TcAAAP069 and parasites overexpressing this permease were 47-fold more sensitive to this compound than control parasites. Using CV as reference molecule, loratadine, cyproheptadine, olanzapine and clofazimine were identified as structurally related compounds to CV (structural analogues) by in silico drug repurposing through a similarity-based virtual screening protocol. All these already-approved drugs for clinical use inhibited TcAAAP069 activity with different efficacies and also presented trypanocidal action in epimastigotes, trypomastigotes and amastigotes of the Y, CL Brener and Dm28c T. cruzi strains. Finally, a synergistic effect between benznidazole and the CV chemical analogues was evidenced by combination and dose-reduction indexes values in epimastigotes and trypomastigotes of the Y strain., Conclusions/significance: Loratadine, cyproheptadine and clofazimine inhibit TcAAAP069 proline transporter and also present trypanocidal effect against all T. cruzi life stages in strains from three different DTUs. These CV structural analogues could be a starting point to design therapeutic alternatives to treat Chagas disease by finding new indications for old drugs. This approach, called drug repurposing is a recommended strategy by the World Health Organization to treat neglected diseases, like Chagas disease, and combination therapy may improve the possibility of success of repositioned drugs., Competing Interests: The authors have declared that no competing interests exist. CAP and MRM are members of the career of scientific investigator (CONICET); MS is a research fellow from the Global Challenges Research Fund (GCRF), Neglected Tropical Diseases Network; EVV and CR are research fellows from CONICET, LG is a undergraduate student fellow.

Purpose: Pancreatic cancer (PC) is predicted to become the second leading cause of cancer associated deaths by 2020. Earlier, we confirmed the development and efficacy of our novel Loratadine Self-Microemulsifying-Drug-Delivery-System - Sulforaphane (LOR SMEDDS -SFN) nanoformulation in PC chemoprevention. In this report, we extend our studies to evaluate the PC chemoprevention efficacy of LOR SMEDDS - SFN., Methods: The nanoformulation was subjected to in vitro colony formation assays, in vivo oral pharmacokinetics and stability studies., Results: The colony formation assay using Panc-1 PC cells demonstrated a survival fraction of 0.74 with LOR-SFN (p < 0.001) which further reduced to 0.35 with LOR SMEDDS-SFN treatment (p  < 0.0001) confirming the synergistic chemoprevention efficacy of the nanoformulation. Further, the oral pharmacokinetic studies of LOR SMEDDS-SFN showed 4-fold and 9-fold increase in C max (503.2 ± 5.8 ng/mL) and oral bioavailability (20,274.8 ± 3711.0 ng·h/mL) for LOR compared to LOR-SFN combination respectively assuring the enhanced performance by the SMEDDS. Additionally, the formulation exhibited statistically non-significant alteration in globule size, zeta potential, drug content and in vitro drug release during stability studies confirming its stability and pharmaceutical acceptability., Conclusion: Our studies have demonstrated a potential of LOR SMEDDS-SFN nanoformulation as an effective PC chemoprevention strategy.

Background: There is a large inter-individual variation in cytochrome P450 2C19 (CYP2C19) activity. The variability can be caused by the genetic polymorphism of CYP2C19 gene. This study aimed to investigate the molecular and kinetics basis for activity changes in three alleles including CYP2C19*23, CYP2C19*24 and CYP2C19*25found in the Chinese population., Methods: The three variants expressed by bacteria were investigated using substrate (omeprazole and 3- cyano-7-ethoxycoumarin[CEC]) and inhibitor (ketoconazole, fluoxetine, sertraline and loratadine) probes in enzyme assays along with molecular docking., Results: All alleles exhibited very low enzyme activity and affinity towards omeprazole and CEC (6.1% or less in intrinsic clearance). The inhibition studies with the four inhibitors, however, suggested that mutations in different variants have a tendency to cause enhanced binding (reduced IC50 values). The enhanced binding could partially be explained by the lower polar solvent accessible surface area of the inhibitors relative to the substrates. Molecular docking indicated that G91R, R335Q and F448L, the unique mutations in the alleles, have caused slight alteration in the substrate access channel morphology and a more compact active site cavity hence affecting ligand access and binding. It is likely that these structural alterations in CYP2C19 proteins have caused ligand-specific alteration in catalytic and inhibitory specificities as observed in the in vitro assays., Conclusion: This study indicates that CYP2C19 variant selectivity for ligands was not solely governed by mutation-induced modifications in the active site architecture, but the intrinsic properties of the probe compounds also played a vital role., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Desloratadine, a potent antagonist for human histamine H1 receptor, has been revealed to exhibit antihistaminic activity and anti-inflammatory activity. However, it is not yet known whether desloratadine has any effect on the biological behaviors of tumor cells. In this study, we aimed to investigate the effects of desloratadine on cell growth and invasion in bladder cancer EJ and SW780 cells in vitro . We observed that desloratadine inhibited cell viability of EJ and SW780 cells in a dose- and time-dependent manner. Desloratadine treatment was also revealed to suppress colony-formation ability and induce cell cycle arrest at G1 phase in EJ cells. Desloratadine promoted cell apoptosis via modulating the expression of Bcl-2, Bax, cleaved caspase 3, and cleaved caspase 9 in EJ and SW780 cells. Western blot resulted showed that desloratadine also impaired the expression of autophagy-related proteins, such as Beclin 1, P62, and LC3I/II in EJ and SW780 cells; while autophagy inhibitor LY294002 reversed the effects of desloratadine on these proteins. Moreover, desloratadine remarkably attenuated cell migration and invasion. Furthermore, we illustrated that desloratadine downregulated the expression of N-cadherin, Vimentin, Snail1, and Snail2, while upregulated the expression of E-cadherin in EJ and SW780 cells in vitro . The level of interleukin 6 was reduced in desloratadine-treated cells, while upregulation of interleukin 6 significantly abolished the anticancer activity of desloratadine in cell invasion and Bcl-2, Bax, Beclin1, LC3-I/II, N-cadherin, and E-cadherin expression in EJ cells. Taken together, our data suggest a potential anticancer activity of desloratadine on cell growth and invasion for bladder cancer, which may be mediated by diminishing the epithelial-to-mesenchymal transition and interleukin 6.

Background: Histamine H 1 receptor antagonists are widely used in the treatment of allergic diseases. H 1 receptors are expressed on bone cells and histamine takes part in regulation of bone metabolism. Loratadine is often prescribed to children., Purpose: The aim of the present study was to investigate the effects of loratadine on the skeletal system of young rats., Material and Methods: Loratadine (0.5, 5, and 50 mg/kg p.o. daily) was administered for 4 weeks to male Wistar rats, 6-week-old at the start of the experiment. Bone mass, mass of bone mineral, calcium, and phosphorus content in the bone mineral of the tibia, femur, and L-4 vertebra, histomorphometric parameters of the femur, mechanical properties of the proximal tibial metaphysis, femoral diaphysis and femoral neck, and serum levels of bone turnover markers were examined., Results: Loratadine at 0.5 and 5 mg/kg did not significantly affect the skeletal system of young rats. At 50 mg/kg, loratadine decreased the femoral length, increased content of calcium and phosphorus in the bone mineral of the vertebra, and tended to improve mechanical properties of the tibial metaphysis., Conclusion: High-dose loratadine slightly but significantly affected development of the skeletal system in rapidly growing rats., Competing Interests: The authors report no conflicts of interest in this work., (© 2019 Folwarczna et al.)

Staphylococcus epidermidis and Staphylococcus aureus are important human pathogens responsible for two-thirds of all postsurgical infections of indwelling medical devices. Staphylococci form robust biofilms that provide a reservoir for chronic infection, and antibiotic-resistant isolates are increasingly common in both healthcare and community settings. Novel treatments that can simultaneously inhibit biofilm formation and antibiotic-resistance pathways are urgently needed to combat the increasing rates of antibiotic-resistant infections. Herein we report that loratadine, an FDA-approved antihistamine, significantly inhibits biofilm formation in both S. aureus and S. epidermidis . Furthermore, loratadine potentiates β-lactam antibiotics in methicillin-resistant strains of S. aureus and potentiates both β-lactam antibiotics and vancomycin in vancomycin-resistant strains of S. aureus . Additionally, we elucidate loratadine's mechanism of action as a novel inhibitor of the regulatory PASTA kinases Stk and Stk1 in S. epidermidis and S. aureus , respectively. Finally, we describe how Stk1 inhibition affects the expression of genes involved in both biofilm formation and antibiotic resistance in S. epidermidis and S. aureus .

Drug-target binding kinetics are an important predictor of in vivo drug efficacy, yet the relationship between ligand structures and their binding kinetics is often poorly understood. We show that both rupatadine ( 1 ) and desloratadine ( 2 ) have a long residence time at the histamine H 1 receptor (H 1 R). Through development of a [ 3 H]levocetirizine radiolabel, we find that the residence time of 1 exceeds that of 2 more than 10-fold. This was further explored with 22 synthesized rupatadine and desloratadine analogues. Methylene-linked cycloaliphatic or β-branched substitutions of desloratadine increase the residence time at the H 1 R, conveying a longer duration of receptor antagonism. However, cycloaliphatic substituents directly attached to the piperidine amine (i.e., lacking the spacer) have decreased binding affinity and residence time compared to their methylene-linked structural analogues. Guided by docking studies, steric constraints within the binding pocket are hypothesized to explain the observed differences in affinity and binding kinetics between analogues.

Background/aim: Previously, we showed that KBV20C cancer cells highly resistant to antimitotic drugs were sensitized by co-treatment with a repositioned drug fluphenazine., Materials and Methods: Considering that fluphenazine plays a role as a histamine receptor antagonist, we investigated low doses of 21 other histamine receptor antagonists (lidocaine, cimetidine, chlorpromazine, diphenhydramine, promethazine, ranitidine, famotidine, clemastine, chlorpheniramine, desloratadine, loratadine, cyproheptadine, azelastine, brompheniramine, carbinoxamine, fexofenadine, hydroxyzine, levocetirizine, meclizine, nizatidine, and pemirolast) to identify repositioned drugs for their sensitizing effects on antimitotic drug-resistant KBV20C cells at relatively low doses., Results: Co-treatment with loratadine, and with azelastine highly sensitized KBV20C cells to vincristine treatment. Loratadine and azelastine reduced cell viability, increased G 2 arrest, and up-regulated apoptosis when co-administered with vincristine. In detailed quantitative analysis, combination of vincristine with loratadine had a higher sensitization effect than that with azelastine. Azelastine had a higher P-glycoprotein (P-gp)-inhibitory activity, similar to that of verapamil, indicating that sensitization by vincristine-azelastine involved the P-gp-inhibitory effects of azelastine. However, loratadine had a very low P-gp-inhibitory activity, suggesting that loratadine sensitization to vincristine is independent of the P-gp-inhibition. Co-treatment with eribulin and loratadine increased the sensitization of KBV20C cells, suggesting that loratadine can be combined with other antimitotic drugs to sensitize resistant cancer cells., Conclusion: These findings provide important information regarding the sensitization of drug-resistant cells and indicate that loratadine may be used in patients with potentially resistant cancer without any toxic effects from P-gp inhibition., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

A recent in vitro study suggested that CYP2C8 is essential in the metabolism of desloratadine, an H1 receptor antagonist. If the proposed biotransformation mechanism takes place in vivo in humans, desloratadine could serve as a selective CYP2C8 probe substrate in drug-drug interaction studies. Glucuronide metabolites of clopidogrel and gemfibrozil act as time-dependent inhibitors of CYP2C8, but they have not been compared clinically. We conducted a randomized crossover study in 11 healthy subjects to characterize the involvement of CYP2C8 in desloratadine metabolism and to compare the CYP2C8 inhibitory strength of clopidogrel (300 and 75 mg on two following days) with that of gemfibrozil (600 mg BID for 5 days). Compared with placebo (control), clopidogrel increased the area under the plasma concentration-time curve (AUC 0-∞ ) and peak plasma concentration ( C max ) of desloratadine to 280% ( P = 3 × 10 -7 ) and 165% ( P = 0.0006), respectively. The corresponding increases by gemfibrozil were to 462% ( P = 4 × 10 -7 ) and 174% ( P = 0.0006). Compared with placebo, clopidogrel and gemfibrozil decreased 3-hydroxyloratadine AUC 0-71h to 52% ( P = 5 × 10 -5 ) and 6% ( P = 2 × 10 -8 ), respectively. Moreover, the 3-hydroxydesloratadine:desloratadine AUC 0-71 h ratios were 21% ( P = 7 × 10 -10 ) and 1.7% ( P = 8 × 10 -11 ) of control during the clopidogrel and gemfibrozil phases. Our results confirm that CYP2C8 plays a critical role in the formation of 3-hydroxydesloratadine in humans, making desloratadine a potential CYP2C8 probe substrate. Furthermore, the findings corroborate the previous estimates that clinically relevant doses of clopidogrel cause strong CYP2C8 inhibition, whereas those of gemfibrozil almost completely inactivate the enzyme in humans., (Copyright © 2019 by The Author(s).)

It has long been believed that histamine is associated with cutaneous melanogenesis. Specifically, H2-receptor antagonists reportedly inhibit melanogenesis, but H1-receptor antagonists, which are some of the most commonly prescribed medicines in dermatology, have not been studied to determine whether and how they regulate melanogenesis. Therefore, we screened H1-receptor antagonists to determine whether they inhibit melanogenesis and found that loratadine was particularly effective, in this regard without compromising cellular viability. Loratadine downregulated microphthalmia-associated transcription factor (MITF) and tyrosinase in melanocytes. To determine the intracellular signaling pathways, Akt was consistently activated by loratadine. PI3K/Akt pathway inhibitor, LY294002, restored the reduced melanin content that was induced by loratadine. In addition, phospho-GSK-3 β also was found to be increased following loratadine treatment. Loratadine reduced the amount of PKC- β II in the membrane fraction, thereby decreasing its activity. Taken together, our data indicate that loratadine regulates melanogenesis via Akt/MITF and PKC- β II signaling, thereby leading to the inhibition of melanogenic proteins. The antimelanogenic effects of loratadine have potentially significant and useful roles in dermatologic practice, although further clinical studies will be required to test this.

Chronic spontaneous urticaria (CSU) is a frequent disorder with recurrent itchy wheals and/or angioedema, and nearly 35% patients respond poorly to non-sedating H1 antihistamine treatment. CRP gene encodes the C-reactive protein, which is involved in the pathogenesis of CSU. To investigate the impacts of CRP polymorphisms on the susceptibility and therapeutic efficacy in the South Han CSU patients, we enrolled 145 CSU patients in our study. After 4-week non-sedating H1 antihistamine monotherapy treatment, more than 50% reduction of the severity score is considered as effective, or else non-effective. The CRP rs3093059T/C and rs2794521G/A genotypes of patients were determined by Sequenom MassARRAY. Functional studies including relative luciferase assay and β-hexosaminidase assay were conducted in HEK293T cells or RBL-2H3 cells to explore the function of variants. Forty (62.50%) CSU patients were effective when treated with mizolastine, and 55 (72.4%) patients were effective in the desloratadine group. We found that the patients carried with rs3093059TT genotype were significantly associated with good response (OR = 4.20, P = 0.015), had lower serum CRP, IL-6 and TNF-α levels than the CT/CC genotypes. In vitro, the rs3093059C allele exhibited significantly higher luciferase activity than wild allele (P < 0.001). From the β-hexosaminidase assay, we observed the inhibiting degranulation effects by mizolastine and this effect is weakened when with a higher dose CRP in RBL-2H3 cells. Our findings suggested that CSU patients carrying the rs3093059C allele may respond poorly to mizolastine with elevated serum CRP level., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This study aimed to establish mechanistic links between the prolonged intake of desloratadine, a common H1 receptor blocker (i.e., antihistamine), and development of obesity and metabolic syndrome. Male Sprague-Dawley rats were treated for 16 wk with desloratadine. We analyzed the dynamics of body weight gain, tissue fat accumulation/density, contractility of isolated mesenteric lymphatic vessels, and levels of blood lipids, glucose, and insulin, together with parameters of liver function. Prolonged intake of desloratadine induced development of an obesity-like phenotype and signs of metabolic syndrome. These alterations in the body included excessive weight gain, increased density of abdominal subcutaneous fat and intracapsular brown fat, high blood triglycerides with an indication of their rerouting toward portal blood, high HDL, high fasting blood glucose with normal fasting and nonfasting insulin levels (insulin resistance), high liver/body weight ratio, and liver steatosis (fatty liver). These changes were associated with dysfunction of mesenteric lymphatic vessels, specifically high lymphatic tone and resistance to flow together with diminished tonic and abolished phasic responses to increases in flow, (i.e., greatly diminished adaptive reserves to respond to postprandial increases in lymph flow). The role of nitric oxide in this flow-dependent adaptation was abolished, with remnants of these responses controlled by lymphatic vessel-derived histamine. Our current data, considered together with reports in the literature, support the notion that millions of the United States population are highly likely affected by underevaluated, lymphatic-related side effects of antihistamines and may develop obesity and metabolic syndrome due to the prolonged intake of this medication. NEW & NOTEWORTHY Prolonged intake of desloratadine induced development of obesity and metabolic syndrome associated with dysfunction of mesenteric lymphatic vessels, high lymphatic tone, and resistance to flow together with greatly diminished adaptive reserves to respond to postprandial increases in lymph flow. Data support the notion that millions of the USA population are highly likely affected by underevaluated, lymphatic-related side effects of antihistamines and may develop obesity and metabolic syndrome due to the prolonged intake of this medication.

The aim of this study was to determine whether loratadine, a selective inverse agonist of peripheral histamine H 1 receptors, would reduce emotional blushing. Loratadine (10 mg) or placebo was administered orally one hour before 31 healthy participants sang a children's nursery rhyme to evoke embarrassment and blushing. Skin blood flow was monitored via a laser Doppler probe attached to the cheek. Increases in facial blood flow while participants sang were greater in the loratadine than the placebo group (mean increase ± standard deviation 71 ± 52% in the loratadine group versus 35 ± 37%, p = .036). However, perceptions of blushing were similar in both groups. These findings suggest that loratadine augmented blushing rather than inhibiting it. Thus, histamine released during blushing may inhibit acute increases in facial blood flow by evoking H 1 receptor-mediated vasoconstriction., (Copyright © 2018 Elsevier B.V. and European College of Neuropsychopharmacology. All rights reserved.)

Purpose: Berberine and coenzyme Q10 (CoQ10) are agents with anti-inflammatory and antioxidant characteristics. The purpose of this study was to investigate the effectiveness of berberine and CoQ10 on allergic rhinitis., Methods: This study involved 30 Sprague-Dawley rats, and allergic rhinitis model was established with induction of ovalbumin. Rats were randomized into five groups. The first represented the control group, in which no allergy was established. The second represented the allergy group, in which allergy was induced but no treatment was given. In the remaining three groups, following induction of allergy, desloratadine at a dose of 10 mg/kg was given to Group 3, 100 mg/kg dose of berberine to Group 4, and 20 mg/kg dose of CoQ10 to Group 5. Nasal symptom scores, and plasma immunoglobulin-E, interleukin (IL)-4, IL-13, malondialdehyde (MDA) and nitric oxide (NO) levels were examined at the end of the study. Rats' nasal tissues were also subjected to histopathological immunohistochemical examination., Results: Nasal symptom scores, and plasma immunoglobulin-E, IL-4, IL-13, MDA and NO levels increased significantly in rats with induced allergic rhinitis. Berberine and CoQ10 significantly reduced these elevated levels. CoQ10 was also found as effective as desloratadin in terms of nasal symptom scores and biochemical parameters. At histopathological examination, severe allergic inflammation was observed in rats from allergic rhinitis group. At all treatment groups, the histopathological changes were significantly improved and only a mild inflammation was determined. Also, immunochemistry showed a significant improvement in all three treatment groups. Coenzyme Q10 and berberine were both effective in suppressing allergy symptoms., Conclusion: We think that berberine and coenzyme Q10 can usefully be employed as therapy due to their antioxidant and anti-inflammatory effects in an experimentally induced allergic rhinitis model.

Oxidized LDL (ox-LDL) is one of the major risk factors of atherosclerosis. Endothelial dysfunction caused by ox-LDL is an early event in the pathogenesis of cardiovascular diseases. Preclinical studies have been performed to explore efficient means of preventing endothelial abnormalities. In this study, we revealed that loratadine, a histamine H1 type receptor specific antagonist, possesses a protective effect by relieving ox-LDL-induced endothelial inflammation. Treatment of endothelial cells with ox-LDL induces expression of the H1 receptor. The presence of loratadine in endothelial culture efficiently suppressed ox-LDL-induced attachment of monocytes to endothelial cells, production of ROS and vascular adhesion molecules, and induction cytokines including VCAM-1, E-selectin, TNF-α, IL-6 and IL-8. Mechanistically, we show that loratadine potently blocks ox-LDL-induced JNK activation as well as the AP-1 and NF-κB signaling pathways. Collectively, our data disclose a new role for loratadine in endothelial protection., (Copyright © 2018. Published by Elsevier Masson SAS.)

Objective: Desloratadine, a third-generation antihistamine, is claimed to cause fewer central nervous system (CNS) adverse drug reactions (ADRs) than antihistamines of the first- and second-generation. While literature is inconclusive regarding the possible CNS effects, symptoms like somnolence and hallucinations are acknowledged ADRs of desloratadine, indeed suggesting some passage of this drug across the blood-brain barrier. Depression is currently not described as an ADR in the approved desloratadine product labelling., Materials and Methods: In a joint signal detection workshop with the Uppsala Monitoring Centre and the Netherlands Pharmacovigilance Centre Lareb, case reports of suspected drug-ADR associations were analysed., Results: Forty-nine unique case reports of desloratadine associated with depression or depressed mood were detected in the WHO global ADR database. In these reports, the median time to onset of depression was three days. Most patients recovered after withdrawal of desloratadine, and in five patients the symptoms of depression recurred after re-administration of desloratadine., Conclusion: We hypothesize that desloratadine may enter the CNS and that it hence in rare cases may cause a clinically relevant state of depression, a relation that patients and their treating physicians should be made aware of.

Fast dissolving oral film is a stamp-style, drug-loaded polymer film with rapid disintegration and dissolution. This new kind of drug delivery system requires effective taste masking technology. Suspension intermediate and liposome intermediate were prepared, respectively, for the formulation of two kinds of fast dissolving oral films with the aim of studying the effect of taste masking technology on the bioavailability of oral films. Loratadine was selected as the model drug. The surface pH of the films was close to neutral, avoiding oral mucosal irritation or side effects. The thickness of a 2 cm × 2 cm suspension oral film containing 10 mg of loratadine was 100 μm. Electron microscope analysis showed that liposomes were spherical before and after re-dissolution, and drugs with obvious bitterness could be masked by the encapsulation of liposomes. Dissolution of the two films was superior to that of the commercial tablets. Rat pharmacokinetic experiments showed that the oral bioavailability of the suspension film was significantly higher than that of the commercial tablets, and the relative bioavailability of the suspension film was 175%. Liposomal film produced a certain amount of improvement in bioavailability, but lower than that of the suspension film.

Background: Chronic spontaneous urticaria (CSU) is a common dermatological condition defined by the sudden occurrence of daily wheals and pruritus for at least six weeks. Multifactorial origin is suggested such as oxidative stress. This latter may play a double role as a trigger and remnant agent., Objectives: The first aim of this study is to investigate antioxidant status, inflammatory proteins, hematologic counts and clinical assessment in CSU patients. The second aim is to evaluate the effect of a first-line treatment: desloratadine 5 mg/d on these different parameters., Patients and Methods: This study enrolled 30 CSU patients and same number of controls. We assessed the urticaria activity score (UAS), total antioxidant status (TAS), glutathione S-transferase (GST), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), albumin, alpha1, alpha2, beta1 beta2, gamma globulins, c-reactive protein (CRP) and hematologic numeration., Results: At baseline alpha1, alpha2, beta1, beta2, gamma globulins, CRP, SOD activity, leukocytes and basophils were significantly higher in patients versus controls (p < 0.05). TAS, GST, CAT, GPx and albumin were significantly low in patients versus controls (p < 0.05). After treatment, TAS, GST and GPx were significantly increased in patients versus patients before treatment (p < 0.001). SOD, alpha1, alpha2, beta1, beta2, gamma globulins, CRP, albumin, leukocytes and basophils were significantly decreased after treatment versus before treatment (p < 0.05). A significant correlation between CRP and UAS (r = 0.3; p = 0.011) was noted. UAS assessment revealed the efficacy of 30 d-antihistaminic treatment., Conclusions: Desloratadine exerted anti-inflammatory and antioxidant effects on CSU patients revealed by CRP. Patients' remission was synergistic to CRP attenuation emphasizing CRP relevance for CSU clinical assessment.

Background: Zingiber cassumunar Roxb., commonly known as Phlai in Thai, has been used as a traditional medicine in Thailand for the treatment of various diseases, including inflammation and chronic airway disease., Objective: The purpose of this study was to assess the antihistaminic effect of Phlai on skin testing., Design, Setting, Participants and Intervention: This was a randomized, open-label, three-way crossover study. Twenty allergic rhinitis (AR) patients were enrolled. In randomized sequence, patients received a single dose of Phlai capsules (100 or 200 mg) or loratadine (10 mg) with a washout period of 1 week between each treatment., Main Outcome Measures: Skin prick testing for histamine and common aeroallergen (house dust mite) were performed before treatment and after 1, 2, 3, 4, 6, 8, 12 and 24 hours of treatment. The main treatment outcomes were the mean wheal and flare responses to the skin prick test after treatment., Results: Both 100 mg and 200 mg Phlai doses suppressed wheal and flare responses to house dust mite allergen, but only 200 mg of Phlai capsules significantly suppressed wheal and flare responses to histamine. Repeated measures analysis of variance showed that loratadine caused more wheal and flare suppression than Phlai capsules in responses to the histamine skin prick test. However, there were no significant differences among the effects of 100 mg Phlai capsules, 200 mg Phlai capsules and loratadine in suppression of wheal and flare induced by the mite skin prick test. Both doses of Phlai were well-tolerated with no adverse events., Conclusion: Both 100 mg (compound D 4 mg) and 200 mg (compound D 8 mg) Phlai capsules, when taken as a single therapeutic dose, inhibited skin reactivity to histamine and mite skin prick tests in AR patients., Trial Registration: Thai clinical trial registry (TCTR20160510001).

Levetiracetam (LEV) and its recently approved derivative brivaracetam are anti-epileptic drugs with a unique mechanism of action. The synaptic vesicle protein 2A (SV2A) was previously identified as their main target. In the current study, we tested a collection of 500 approved drugs for interaction with the human SV2A protein expressed in Chinese hamster ovary cells. Competition binding studies were performed using cell lysates with high SV2A expression and [ 3 H]brivaracetam as a radioligand. A hit rate of 3% was obtained, defined as compounds that inhibited radioligand binding by more than 90% at a screening concentration of 20 μM. Subsequent concentration-inhibition curves revealed the antihistaminic prodrug loratadine (K i  = 1.16 μM) and the antimalarial drug quinine (K i  = 2.03 μM) to be the most potent SV2A protein ligands of the investigated drug library. Both compounds were similarly potent as LEV (K i  = 1.74 μM), providing structurally novel scaffolds for SV2A ligands. A pharmacophore model was established, which indicated steric and electronic conformities of brivaracetam with the new SV2A ligands, and preliminary structure-activity relationships were determined. The anti-convulsive effects of the natural product quinine may - at least in part - be explained by interaction with SV2A. Loratadine and quinine represent new lead structures for anti-epileptic drug development., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)