ABSTRACT
Naphthoquine is a promising candidate for antimalarial combination therapy. Its combination with artemisinin has demonstrated excellent efficacy in clinical trials conducted across various malaria-endemic areas. A co-formulated combination of naphthoquine and azithromycin has also shown high clinical efficacy for malaria prophylaxis in Southeast Asia. Developing new combination therapies using naphthoquine will provide additional arsenal responses to the growing threat of artemisinin resistance. Furthermore, due to its long half-life, the possible interaction of naphthoquine with other drugs also needs attention. However, studies on its pharmacodynamic interactions with other drugs are still limited. In this study, the in vitro interactions of naphthoquine with ivermectin, atovaquone, curcumin, and ketotifen were evaluated in the asexual stage of Plasmodium falciparum 3D7. By using the combination index analysis and the SYBR Green I-based fluorescence assay, different interaction patterns of selected drugs with naphthoquine were revealed. Curcumin showed a slight but significant synergistic interaction with naphthoquine at lower effect levels, and no antagonism was observed across the full range of effect levels for all tested ratios. Atovaquone showed a potency decline when combined with naphthoquine. For ivermectin, a significant antagonism with naphthoquine was observed at a broad range of effect levels below 75% inhibition, although no significant interaction was observed at higher effect levels. Ketotifen interacted with naphthoquine similar to ivermectin, but significant antagonism was observed for only one tested ratio. These findings should be helpful to the development of new naphthoquine-based combination therapy and the clinically reasonable application of naphthoquine-containing therapies. IMPORTANCE: Pharmacodynamic interaction between antimalarials is not only crucial for the development of new antimalarial combination therapies but also important for the appropriate clinical use of antimalarials. The significant synergism between curcumin and naphthoquine observed in this study suggests the potential value for further development of new antimalarial combination therapy. The finding of a decline in atovaquone potency in the presence of naphthoquine alerts to a possible risk of treatment or prophylaxis failure for atovaquone-proguanil following naphthoquine-containing therapies. The observation of antagonism between naphthoquine and ivermectin raised a need for concern about the applicability of naphthoquine-containing therapy in malaria-endemic areas with ivermectin mass drug administration deployed. Considering the role of atovaquone-proguanil as a major alternative when first-line artemisinin-based combination therapy is ineffective and the wide implementation of ivermectin mass drug administration in malaria-endemic countries, the above findings will be important for the appropriate clinical application of antimalarials involving naphthoquine-containing therapies.
Subject(s)
Antimalarials , Atovaquone , Curcumin , Drug Interactions , Ivermectin , Ketotifen , Naphthoquinones , Plasmodium falciparum , Plasmodium falciparum/drug effects , Atovaquone/pharmacology , Antimalarials/pharmacology , Naphthoquinones/pharmacology , Humans , Curcumin/pharmacology , Ivermectin/pharmacology , Ketotifen/pharmacology , Drug Synergism , Aminoquinolines/pharmacology , Malaria, Falciparum/drug therapy , Malaria, Falciparum/parasitology , 1-Naphthylamine/analogs & derivativesABSTRACT
BACKGROUND AND OBJECTIVE: Mast cells have been implicated in abdominal pain-associated disorders of gut-brain interaction, such as functional dyspepsia. As such, ketotifen, a second-generation antihistamine and mast cell stabilizer, could represent a viable treatment option in these conditions. The primary aim of the current pilot study was to assess clinical response to ketotifen and assess pharmacokinetics in youth with functional dyspepsia. METHODS: We conducted a pilot randomized, double-blind, placebo-controlled, cross-over trial of ketotifen in 11 youth with functional dyspepsia and duodenal mucosal eosinophilia with 4 weeks of active treatment at a dose of 1 mg twice daily. Global clinical response was graded on a 5-point Likert Scale. A single plasma sample was obtained at steady state for pharmacokinetic analysis. RESULTS: Ketotifen was not superior to placebo with regard to global clinical response. Only 18% of patients demonstrated a complete or near-complete clinical response. The estimated half-life was 3.3 h. CONCLUSIONS: While ketotifen was not superior to placebo, this study highlights several important challenges for developing drug trials for youth with chronic abdominal pain. Recommendations are made for designing a larger treatment trial for ketotifen in this patient group. CLINICAL TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov: NCT02484248.
Subject(s)
Cross-Over Studies , Dyspepsia , Eosinophilia , Ketotifen , Humans , Ketotifen/pharmacokinetics , Ketotifen/therapeutic use , Ketotifen/administration & dosage , Ketotifen/pharmacology , Pilot Projects , Child , Adolescent , Dyspepsia/drug therapy , Double-Blind Method , Female , Male , Eosinophilia/drug therapy , Histamine H1 Antagonists/pharmacokinetics , Histamine H1 Antagonists/therapeutic use , Histamine H1 Antagonists/administration & dosage , Intestinal Mucosa/metabolism , Abdominal Pain/drug therapy , Abdominal Pain/etiology , Treatment OutcomeABSTRACT
Cisplatin (CIS) stands as one of the most effective chemotherapy drugs currently available. Despite its anticancer properties, the clinical application of CIS is restricted due to nephrotoxicity. Our research aimed to specify the impact of ketotifen fumarate (KET) against nephrotoxicity induced by CIS in mice. Male NMRI mice were treated with KET (0.4, 0.8, and 1.6â¯mg/kg, ip) for seven days. On the fourth day of the study, a single dose of CIS (13â¯mg/kg, ip) was administered, and the mice were sacrificed on the eighth day. The results indicated that administration of KET attenuated CIS-induced elevation of BUN and Cr in the serum, as well as renal KIM-1 levels. This improvement was accompanied by a significant reduction in kidney tissue damage, which was supported by histopathological examinations. Likewise, the decrease in the ratio of GSH to GSSG and antioxidant enzyme activities (CAT, SOD, and GPx), and the increase in lipid peroxidation marker (TBARS) were reversed in KET-treated mice. The ELISA results revealed that KET-treated mice ameliorated CIS-induced elevation in the renal levels of TNF-α, IL-1ß, and IL-18. Western blot analysis exhibited that KET suppressed the activation of the transcription factor NF-κB and the NLRP3 inflammasome in the kidney of CIS-treated mice. Moreover, KET treatment reversed the changes in the protein expression of markers related to apoptosis (Bax, Bcl2, Caspase-3, and p53). Interestingly, KET significantly enhanced the cytotoxicity of CIS in HeLa cells. In conclusion, this study provides valuable insights into the promising effects of KET in mitigating CIS-induced nephrotoxicity.
Subject(s)
Acute Kidney Injury , Caspase 1 , Caspase 3 , Cisplatin , Ketotifen , NF-kappa B , NLR Family, Pyrin Domain-Containing 3 Protein , Signal Transduction , bcl-2-Associated X Protein , Animals , Cisplatin/toxicity , Male , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Signal Transduction/drug effects , Mice , NF-kappa B/metabolism , Caspase 1/metabolism , Acute Kidney Injury/chemically induced , Acute Kidney Injury/prevention & control , Acute Kidney Injury/drug therapy , Acute Kidney Injury/metabolism , Acute Kidney Injury/pathology , Caspase 3/metabolism , Humans , Ketotifen/pharmacology , bcl-2-Associated X Protein/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Apoptosis/drug effects , Kidney/drug effects , Kidney/pathology , Kidney/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/toxicity , HeLa Cells , Oxidative Stress/drug effectsABSTRACT
PURPOSE: To explore the cellular cross-talk of tumor-resident mast cells (MC) in controlling the activity of cancer-associated fibroblasts (CAF) to overcome tumor microenvironment (TME) abnormalities, enhancing the efficacy of immune-checkpoint inhibitors in sarcoma. EXPERIMENTAL DESIGN: We used a coculture system followed by further validation in mouse models of fibrosarcoma and osteosarcoma with or without administration of the MC stabilizer and antihistamine ketotifen. To evaluate the contribution of ketotifen in sensitizing tumors to therapy, we performed combination studies with doxorubicin chemotherapy and anti-PD-L1 (B7-H1, clone 10F.9G2) treatment. We investigated the ability of ketotifen to modulate the TME in human sarcomas in the context of a repurposed phase II clinical trial. RESULTS: Inhibition of MC activation with ketotifen successfully suppressed CAF proliferation and stiffness of the extracellular matrix accompanied by an increase in vessel perfusion in fibrosarcoma and osteosarcoma as indicated by ultrasound shear wave elastography imaging. The improved tissue oxygenation increased the efficacy of chemoimmunotherapy, supported by enhanced T-cell infiltration and acquisition of tumor antigen-specific memory. Importantly, the effect of ketotifen in reducing tumor stiffness was further validated in sarcoma patients, highlighting its translational potential. CONCLUSIONS: Our study suggests the targeting of MCs with clinically administered drugs, such as antihistamines, as a promising approach to overcome resistance to immunotherapy in sarcomas.
Subject(s)
B7-H1 Antigen , Immune Checkpoint Inhibitors , Mast Cells , Tumor Microenvironment , Humans , Mice , Animals , Mast Cells/drug effects , Mast Cells/immunology , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunology , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , Sarcoma/drug therapy , Sarcoma/pathology , Sarcoma/immunology , Ketotifen/pharmacology , Ketotifen/therapeutic use , Cell Line, Tumor , T-Lymphocytes/immunology , T-Lymphocytes/drug effects , Xenograft Model Antitumor Assays , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/drug effects , Female , Cancer-Associated Fibroblasts/drug effects , Cancer-Associated Fibroblasts/pathology , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Osteosarcoma/drug therapy , Osteosarcoma/pathology , Osteosarcoma/immunologyABSTRACT
Liver diseases caused by viral infections, alcoholism, drugs, or chemical poisons are a significant health problem: Liver diseases are a leading contributor to mortality, with approximately 2 million deaths per year worldwide. Liver fibrosis, as a common liver disease characterized by excessive collagen deposition, is associated with high morbidity and mortality, and there is no effective treatment. Numerous studies have shown that the accumulation of mast cells (MCs) in the liver is closely associated with liver injury caused by a variety of factors. This study investigated the relationship between MCs and carbon tetrachloride (CCl4)-induced liver fibrosis in rats and the effects of the MC stabilizers sodium cromoglycate (SGC) and ketotifen (KET) on CCl4-induced liver fibrosis. The results showed that MCs were recruited or activated during CCl4-induced liver fibrosis. Coadministration of SCG or KET alleviated the liver fibrosis by decreasing SCF/c-kit expression, inhibiting the TGF-ß1/Smad2/3 pathway, depressing the HIF-1a/VEGF pathway, activating Nrf2/HO-1 pathway, and increasing the hepatic levels of GSH, GSH-Px, and GR, thereby reducing hepatic oxidative stress. Collectively, recruitment or activation of MCs is linked to liver fibrosis and the stabilization of MCs may provide a new approach to the prevention of liver fibrosis.
Subject(s)
Carbon Tetrachloride , Cromolyn Sodium , Liver Cirrhosis , Liver , Mast Cells , Animals , Mast Cells/metabolism , Mast Cells/immunology , Mast Cells/drug effects , Carbon Tetrachloride/toxicity , Rats , Male , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , Liver Cirrhosis/immunology , Liver Cirrhosis/chemically induced , Cromolyn Sodium/pharmacology , Liver/pathology , Liver/metabolism , Liver/drug effects , Transforming Growth Factor beta1/metabolism , Rats, Sprague-Dawley , Ketotifen/pharmacology , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/pathology , Chemical and Drug Induced Liver Injury/immunology , Oxidative Stress/drug effects , NF-E2-Related Factor 2/metabolism , Signal Transduction/drug effects , Smad2 Protein/metabolism , Smad3 Protein/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Vascular Endothelial Growth Factor A/metabolismABSTRACT
The rapid and accurate detection of drug molecules in pharmaceutical formulations and biological samples is of paramount importance. In this research article, we present a novel colorimetric sensor based on carbon dots decorated silver nanoparticles (CDs/AgNPs) for the rapid detection of ketotifen (KTF), a widely used antihistamine drug. The CDs were synthesized via a facile one-step microwave-assisted method and subsequently conjugated onto AgNPs through a simple adsorption process, forming a stable CDs/AgNPs composite. The resulting composite exhibited unique optical properties, including a strong absorption peak at 410 nm with remarkable intensity reduction and color changes upon the addition of KTF. The developed colorimetric sensor exhibited a wide linear range of 3.0-40.0 µg mL-1 (R2 = 0.9996), with a %RSD of 2.41, and a low limit of detection (LOD) of 0.981 µg mL-1. Furthermore, the sensor's practical applicability was evaluated by successfully detecting KTF in eye drops and artificial aqueous humor, demonstrating a remarkable percentage recovery exceeding 96.0 %. Finally, a comprehensive evaluation of the greenness and blueness of the method was performed using analytical eco-scale, GAPI, AGREEprep, and BAGI tools. The results of these assessments indicate its exceptional sustainability. Overall, the proposed method holds significant potential for applications in pharmaceutical quality control and therapeutic monitoring, contributing to improved patient care and drug safety in the field of ophthalmology.
Subject(s)
Metal Nanoparticles , Humans , Silver , Ketotifen , Colorimetry/methods , Carbon , Ophthalmic Solutions , Aqueous HumorABSTRACT
Purpose: Topical antihistamines, such as olopatadine hydrochloride, an H1 receptor antagonist, are commonly prescribed for treating allergic conjunctivitis. Drug delivery via eye drops has many deficiencies including a short residence time due to tear drainage via the nasolacrimal duct, which results in a low bioavailability and potential for side effects. These deficiencies could be mitigated by a drug-eluting contact lens such as the recently approved ACUVUE® THERAVISION™ WITH KETOTIFEN which is a daily disposable etafilcon, a drug-eluting contact lens with ketotifen (19 µg per lens). Here, we investigate the feasibility of designing a drug-eluting lens with sustained release of olopatadine for treating allergies using an extended wear lens. Methods: Nanobarrier depots composed of vitamin-E (VE) are formed through direct entrapment by ethanol-driven swelling. The drug-loaded lenses are characterized for transparency and water content. In vitro release is measured under sink conditions and fitted to a diffusion control release model to determine diffusivity and partition coefficient. Results: In vitro studies indicate that ACUVUE OASYS® and ACUVUE TruEye™ lenses loaded with â¼0.3 g of VE/g of hydrogel effectively prolong olopatadine dynamics by 7-fold and 375-fold, respectively. Incorporation of VE into the lenses retains visible light transmission and other properties. Conclusion: The VE incorporation in commercial lenses significantly increases the release duration offering the possibility of antiallergy extended wear lenses.
Subject(s)
Contact Lenses , Vitamin E , Olopatadine Hydrochloride , Ketotifen/pharmacology , VitaminsABSTRACT
The incorporation of polymers into drug delivery vehicles has been shown to be a useful approach to prolong the residence time of drugs in the precorneal tear film and to improve penetration into biological membranes. The main objective of this research was to formulate novel viscous eye drops with ketotifen as the active ingredient, containing the polysaccharides: chitosan (MCH), hydroxypropyl guar gum (HPG) and hyaluronic acid (SH) alone and in combination as functional polymers. DSC and FT-IR techniques showed the compatibility between ketotifen and polymers. Physicochemical and rheological analysis at ambient and simulated physiological conditions, as well as the evaluation of mucoadhesive properties showed that vehicles containing combinations of polymers have suitable physicochemical and functional properties with demonstrated synergism between combined polymers (MCH and HPG i.e. SH and HPG). The drug permeability was successfully estimated in vitro using HCE-T cell-based models. MTT cytotoxicity assay demonstrates that the tested formulations were non-toxic and well tolerated. In vivo preclinical study on mice revealed that both vehicles containing mixed polymers enhanced and prolonged the antipruritic/analgesic-like effect of ophthalmic ketotifen. Based on these results, both combinations of polysaccharide polymers, especially SH-HPG, could be considered as potential new carriers for ketotifen for ophthalmic use.
Subject(s)
Ketotifen , Polymers , Animals , Mice , Ketotifen/adverse effects , Ophthalmic Solutions/chemistry , Spectroscopy, Fourier Transform Infrared , Polysaccharides/chemistry , Histamine AntagonistsABSTRACT
Fibrosis is a destructive, end-stage disease process. In the skin, it is associated with systemic sclerosis and scarring with considerable health burden. Ketotifen is a clinical antihistamine and mast cell stabilizer. Studies have demonstrated mast cell-dependent anti-fibrotic effects of ketotifen but direct effects on fibroblasts have not been determined. Human dermal fibroblasts were treated with pro-fibrotic transforming growth factor-ß1 (TGFß) followed by ketotifen or control treatments to determine direct effects on fibrotic fibroblasts. Ketotifen impaired TGFß-induced α-smooth muscle actin gene and protein responses and decreased cytoskeletal- and contractility-associated gene responses associated with fibrosis. Ketotifen reduced Yes-associated protein phosphorylation, transcriptional coactivator with PDZ binding motif transcript and protein levels, and phosphorylation of protein kinase B. In a fibroblast-populated collagen gel contraction assay, ketotifen reduced the contractile activity of TGFß-activated fibroblasts. In a murine model of bleomycin-induced skin fibrosis, collagen density and dermal thickness were significantly decreased in ketotifen-treated mice supporting in vitro findings. These results support a novel, direct anti-fibrotic activity of ketotifen, reducing pro-fibrotic phenotypic changes in fibroblasts and reducing collagen fibres in fibrotic mouse skin. Together, these findings suggest novel therapeutic potential and a novel mechanism of action for ketotifen in the context of fibrosis.
Subject(s)
Ketotifen , Scleroderma, Systemic , Humans , Mice , Animals , Ketotifen/pharmacology , Ketotifen/metabolism , Ketotifen/therapeutic use , Fibrosis , Skin/metabolism , Scleroderma, Systemic/metabolism , Collagen/metabolism , Fibroblasts/metabolism , Bleomycin/pharmacology , Transforming Growth Factor beta1/metabolism , Cells, Cultured , Transforming Growth Factor beta/metabolismABSTRACT
OBJECTIVES: To observe the effects of moxibustion on colonic mast cell degranulation and inflammatory factor expression in rats with diarrhea-predominant irritable bowel syndrome (IBS-D), and explore the potential mechanism of moxibustion in treating IBS-D. METHODS: Forty-five rat pups born from 5 healthy SPF-grade pregnant SD rats, with 8 rats were randomly selected as the normal group. The remaining 37 rats were intervened with maternal separation, acetic acid enema, and chronic restraint stress to establish the IBS-D model. The successfully modeled 32 rats were then randomly assigned to a model group, a ketotifen group, a moxibustion group, and a moxibustion-medication group, with 8 rats in each group. The rats in the ketotifen group were intervened with intragastric administration of ketotifen solution (10 mL/kg); the rats in the moxibustion group were intervened with suspended moxibustion on bilateral "Tianshu" (ST 25) and "Shangjuxu" (ST 37); the rats in the moxibustion-medication group were intervened with suspended moxibustion combined with intragastric administration of ketotifen solution. All interventions were administered once daily for 7 consecutive days. The diarrhea rate and minimum volume threshold of abdominal withdrawal reflex (AWR) were calculated before and after modeling, as well as after intervention. After intervention, colonic tissue morphology was observed using HE staining; colonic mucosal ultrastructure was examined by scanning electron microscopy; colonic mast cell ultrastructure was observed using transmission electron microscopy; mast cell degranulation was assessed by toluidine blue staining; serum and colonic levels of histamine, interleukin (IL)-1ß, IL-6, IL-1α, trypsin-like enzyme, and protease-activated receptor 2 (PAR-2) were measured by ELISA; the Western blot and real-time quantitative PCR were employed to evaluate the protein and mRNA expression of colonic IL-1ß, IL-6, IL-1α, trypsin-like enzyme, and PAR-2; the immunofluorescence was used to detect the positive expression of histamine, IL-1ß, IL-6, IL-1α, trypsin-like enzyme, and PAR-2 in the colonic tissue. RESULTS: Compared to the normal group, the rats in the model group exhibited extensive infiltration of inflammatory cells in colonic tissue, severe damage to the colonic mucosa, disordered arrangement of villi, reduced electron density, and a significant decrease in granule quantity within mast cells. The diarrhea rate and mast cell degranulation rate were increased (P<0.01), AWR minimum volume threshold was decreased (P<0.01); the serum and colonic levels of histamine, IL-1ß, IL-6, IL-1α, trypsin-like enzyme, and PAR-2 were elevated (P<0.01); the positive expression of histamine, as well as protein, mRNA and positive expression of IL-1ß, IL-6, IL-1α, trypsin-like enzyme, and PAR-2 in the colon were all elevated (P<0.01). Compared to the model group, the rats in the ketotifen group, the moxibustion group, and the moxibustion-medication group exhibited significantly reduced infiltration of inflammatory cells in colonic tissue, relatively intact colonic mucosa, orderly arranged villi, increased electron density, and an augmented number of mast cell granules; the diarrhea rate and mast cell degranulation rate were decreased (P<0.01), and AWR minimum volume threshold was increased (P<0.01); the serum and colonic levels of histamine, IL-1ß, IL-6, IL-1α, trypsin-like enzyme, and PAR-2 were reduced (P<0.01); the positive expression of histamine, as well as protein, mRNA and positive expression of IL-1ß, IL-6, IL-1α, trypsin-like enzyme, and PAR-2 in the colon were all decreased (P<0.01). Compared to the ketotifen group, the moxibustion group showed decreased serum levels of histamine, IL-6, and trypsin-like enzyme (P<0.01, P<0.05), as well as reduced colonic levels of IL-1ß and IL-6 (P<0.01, P<0.05); the protein expression of colonic IL-1ß, IL-1α, and PAR-2 was reduced (P<0.05), and the positive expression of colonic IL-1ß and trypsin-like enzyme was reduced (P<0.01, P<0.05). Compared to both the ketotifen group and the moxibustion group, the moxibustion-medication group exhibited decreased diarrhea rate and mast cell degranulation rate (P<0.01), an increased AWR minimum volume threshold (P<0.01), reduced serum and colonic levels of histamine, IL-1ß, IL-6, IL-1α, trypsin-like enzyme, and PAR-2 (P<0.01), decreased protein expression of colonic IL-1ß, trypsin-like enzyme, and PAR-2 (P<0.01, P<0.05), reduced mRNA and positive expression of colonic IL-1ß, IL-6, IL-1α, trypsin-like enzyme, and PAR-2 (P<0.01, P<0.05), and decreased positive expression of colonic histamine (P<0.01). CONCLUSIONS: Moxibustion on "Tianshu" (ST 25) and "Shangjuxu" (ST 37) might inhibit low-grade inflammatory reactions in the colon of IBS-D model rats. The mechanism may be related to the inhibition of histamine and trypsin-like enzyme secreted by mast cell, thereby reducing the expression of related inflammatory factors.
Subject(s)
Irritable Bowel Syndrome , Moxibustion , Rats , Animals , Irritable Bowel Syndrome/genetics , Irritable Bowel Syndrome/therapy , Rats, Sprague-Dawley , Mast Cells/metabolism , Trypsin , Cell Degranulation , Histamine , Interleukin-6 , Ketotifen , Maternal Deprivation , Diarrhea/etiology , Diarrhea/therapy , RNA, MessengerABSTRACT
Drug-eluting contact lenses (DECLs) incorporated with poly(lactic-co-glycolic acid) (PLGA) and various model drugs (ketotifen fumarate, bimatoprost and latanoprost) were fabricated using nanoelectrospray (nES) approach. The resulting DECLs demonstrated outstanding optical transmittance within the optical zone, indicating that the employed coating procedure did not compromise visual acuity under the prescribed spraying parameters. In vitro drug release assessments of the model drugs (ketotifen fumarate (KF), bimatoprost (BIM), and latanoprost (LN)) revealed a strong correlation between the model drug's hydrophobicity and the duration of drug release. Changing the drug loading of the more hydrophilic model drugs, BIM and KF, showed no impact on the drug release kinetics of DECLs loaded with BIM and KF. However, for the hydrophobic model drug, LN, the highest LN loading led to the most extended drug release. The conventional steam sterilisation method was found to damage the PLGA coating on the DECLs fabricated by nES. An alternative sterilisation strategy, such as radiation sterilisation may need to be investigated in the future study to minimise potential harm to the coating.
Subject(s)
Contact Lenses , Ketotifen , Latanoprost , Ketotifen/chemistry , Bimatoprost , Drug Delivery SystemsABSTRACT
Cyclosporine is an immunosuppressive drug that is used to prevent tissue rejection in organ transplants and to treat autoimmune diseases such as psoriasis and rheumatoid arthritis. It has important toxic effects in many organs such as the liver and kidney. The aim of this study was to determine and compare the effectiveness of the single and combined treatment of dipyridamole, which is a vasodilator and has an antioxidant effect, ketotifen which is toll-like receptor-4 inhibitory and has an antioxidant effect, quercetin which is an antioxidant and has an anti-inflammatory effect in cyclosporine-induced hepatorenal toxicity. Forty-eight Wistar Albino rats were divided into 7 groups. The research period was 21 days. The cyclosporine increased serum ALT and AST levels, in contrast to their increased levels prevented by all the treatments. The serum creatinine level decreased significantly with ketotifen and combined treatment, while cyclosporine partially increased serum creatinine and urea levels. The urine microalbumin and protein levels were increased significantly by cyclosporine, whereas they decreased with dipyridamole treatment. The protein levels decreased by quercetin and combined treatments. The kidney injury molecule- 1 and retinol-binding protein levels were increased by the cyclosporine, while ketotifen treatment partially decreased them. In conclusion, ketotifen and dipyridamole can prevent cyclosporine- induced hepatorenal toxicity and quercetin can increase the effectiveness of this treatment.
Subject(s)
Antioxidants , Quercetin , Rats , Animals , Quercetin/pharmacology , Quercetin/therapeutic use , Antioxidants/pharmacology , Antioxidants/therapeutic use , Cyclosporine/toxicity , Ketotifen/pharmacology , Ketotifen/therapeutic use , Dipyridamole/pharmacology , Dipyridamole/therapeutic use , Creatinine , Kidney , Rats, Wistar , Liver , Oxidative StressABSTRACT
Intranasal administration has been widely explored as a potential treatment for allergic rhinitis, and improving intranasal penetration and retention of drugs is a challenging requirement to further improve efficacy. Delivery strategies of nanocarriers that enhance mucosal adhesion or mucus penetration have been proposed to improve nasal drug delivery; however, delivery efficiency remains limited by excessive pulmonary deposition and nonspecific cell phagocytosis. In this work, a "nasal in situ assembly" strategy was presented to construct intranasal morphology transformation nanomedicines with enhanced effective drug concentration for long-term intervention of allergic rhinitis. The polymer-polypeptide nanomedicine (PHCK) with a CCR3 antagonistic peptide (C) and a pH-responsive polyethylene glycol (H) was developed, encapsulating ketotifen (KT). PHCK nanoparticles displayed nasal mucosa permeability and transformed to nanofibers in the acidic environment of the nasal cavity, realizing responsive burst release of KT simultaneously. The fibrotic reassembly reduced the cellular internalization of nanomedicine and increased the CCR3 blockade on the eosinophil (EOS) membranes. Both in vitro and in vivo data indicated that PHCK achieved improved drug accumulation and retention in the nasal cavity and decreased pulmonary deposition, then effectively inhibited mast cell degranulation and EOS chemotaxis. This study demonstrates that the "nasal in situ assembly" strategy can improve drug delivery efficiency upon nasal responsive morphologic transformation, providing exploratory perspectives for nasal delivery platforms establishment and boosting therapeutic effect of allergic rhinitis.
Subject(s)
Nanomedicine , Rhinitis, Allergic , Humans , Administration, Intranasal , Rhinitis, Allergic/drug therapy , Nasal Mucosa , Nasal Cavity , Ketotifen/therapeutic useABSTRACT
Introduction: Periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA) is the most frequent periodic fever syndrome in children. Its pathogenesis is still unknown, but some disease-modifying factors were observed. Several medications were tested for the long-term prophylaxis of inflammatory flares; however, none are standardly used. Methods: This prospective clinical trial enrolled 142 children (71 girls, 50%) meeting diagnostic criteria for PFAPA syndrome. We analysed selected clinical characteristics and compared laboratory parameters during the flare and attack-free period (at least two weeks after the attack). Moreover, we assessed the possible therapeutic effect of ketotifen on the duration of attack free-periods and clinical picture. Results: The mean age of patients was 6.81 ± 3.03 years and the mean age of onset of symptoms was 2.31 ± 2.02 years. No significant differences were observed between genders.We recorded a positive family history for PFAPA in 31.69% of patients. Attacks lasted for 2.8 ± 1.2 days, with intervals between attacks of 4 ± 1 weeks. We administered ketotifen in 111 (77.8%) patients, and a positive effect was observed in 86 (77.5%) of patients. We observed prolonged attack-free intervals in patients treated with ketotifen (14.7 ± 8.9 days in comparison with 4.4 ± 1.9 days before the treatment; p<0.001). The used dose of ketotifen was 0.08 ± 0.01 mg/kg/day. Mild side effects were observed in four patients (restlessness, irritability, agitation and constipation). Discussion: Our data supports the use of ketotifen for long-term prophylaxis in children with PFAPA syndrome with positive effects on the attenuation of disease activity and the prolongation of attack-free periods. Further well-designed studies should confirm the preliminary data.
Subject(s)
Lymphadenitis , Lymphadenopathy , Pharyngitis , Stomatitis, Aphthous , Child , Humans , Male , Female , Child, Preschool , Infant , Ketotifen/therapeutic use , Stomatitis, Aphthous/drug therapy , Stomatitis, Aphthous/diagnosis , Pharyngitis/drug therapy , Lymphadenitis/drug therapy , Syndrome , Anti-Inflammatory AgentsABSTRACT
Aim: This study characterized ex vivo release of ketotifen from etafilcon A contact lenses worn over 5 h. Materials & methods: 14 participants, 21 to 59 years, wore lenses with 19 µg ketotifen over 8 visits, for 1 min to 5 h. Residual ketotifen was measured using high-performance liquid chromatography (HPLC) compared with unworn lenses from the same lots to determine percent ketotifen remaining. Results: Residual ketotifen ranged from 16.19 µg ± 0.44 (84.1%) [1 minute] to 0.20 µg ± 0.07 (1.1%) [5 h]. No adverse events or clinically significant biomicroscopy changes were observed. Conclusion: The ketotifen-releasing etafilcon A lenses were well-tolerated with an acceptable safety profile in the population studied. The release of ketotifen from study lenses over 5 h was consistent with a diffusion-controlled system.
This article is about measuring how fast a medication to relieve itchy eyes from allergies is released from contact lenses that are worn for a single day and then discarded. The study showed that the medication is initially released rapidly over the first 15 min of wear and then more slowly over the next 4+ h until almost none remains. This means that people who have itchy eyes from allergies may be able receive their medication by just wearing these contact lenses each day during their allergy season, without having to put in extra eye drops.
Subject(s)
Contact Lenses , Ketotifen , Humans , Histamine Antagonists , MethacrylatesABSTRACT
In the ovaries, cyclic adenosine 3',5'-monophosphate (cAMP) is a second messenger supporting the generation of steroids. Phosphodiesterases (PDEs) are regulators of intracellular cAMP, and therefore, potential regulators of ovarian function. Interestingly, the family of PDE genes are differentially expressed in human oocytes and granulosa cells from primordial and primary follicles, suggesting diverse roles. In this study, we addressed the functions of PDE3B and PDE8B in primordial follicle regulation using inhibitors of PDE3B and PDE8B in murine ovary primary in vitro cultures. Inhibition of PDE8B in ovarian cultures prevented primordial follicle activation, while inhibition of PDE3B had no effect on follicle distribution in the ovary, under the tested conditions. As cAMP levels may increase steroid levels, we assessed the protein levels of the steroidogenic acute regulatory protein (StAR) and aromatase enzymes, and found that inhibition of PDE3B reduced StAR protein levels, whereas inhibition of PDE8 did not alter StAR expression in our murine ovary culture system conditions. Our results showed that ketotifen-induced inhibition of PDE8B can decrease primordial follicle activation, whereas we observed no effect of follicle distribution, when PDE3B was inhibited. Expression of the StaR enzyme was not altered when PDE8B was inhibited, which might reflect not sufficient inhibition by ketotifen to induce StAR alterations, or redundant mechanisms.
Subject(s)
Ovary , Phosphoric Diester Hydrolases , Animals , Female , Humans , Mice , 3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Ketotifen/metabolism , Ketotifen/pharmacology , Oocytes , Ovarian Follicle/metabolism , Ovary/metabolism , Phosphoric Diester Hydrolases/genetics , Phosphoric Diester Hydrolases/metabolism , Steroids/metabolismABSTRACT
PURPOSE: Neuroendocrine prostate cancer (NEPC), a highly aggressive subtype of prostate cancer displaying resistance to hormone therapy, presents a poor prognosis and limited therapeutic options. Here, we aimed to find novel medication therapies for NEPC and explore the underlying mechanism. METHODS: A high-throughput drug screening utilizing an FDA-approved drug library was performed and ketotifen, an antihistamine agent, was identified as a potential therapeutic candidate for NEPC. The whole-transcriptome sequencing analysis was conducted to explore mechanism of ketotifen inhibitory in NEPC. Multiple cell biology and biochemistry experiments were performed to confirm the inhibitory effect of ketotifen in vitro. A spontaneous NEPC mice model (PBCre4:Ptenf/f;Trp53f/f;Rb1f/f) was used to reveal the inhibitory effect of ketotifen in vivo. RESULTS: Our in vitro experiments demonstrated that ketotifen effectively suppressed neuroendocrine differentiation, reduced cell viability, and reversed the lineage switch via targeting the IL-6/STAT3 pathway. Our in vivo results showed that ketotifen significantly prolonged overall survival and reduced the risk of distant metastases in NEPC mice model. CONCLUSION: Our findings repurpose ketotifen for antitumor applications and endorse its clinical development for NEPC therapy, offering a novel and promising therapeutic strategy for this formidable cancer subtype.
Subject(s)
Ketotifen , Prostatic Neoplasms , Humans , Male , Mice , Animals , Ketotifen/therapeutic use , Interleukin-6/metabolism , Drug Repositioning , Prostatic Neoplasms/pathology , Cell Line, Tumor , STAT3 Transcription Factor/metabolismABSTRACT
AIMS: Microglia survey the brain environment by sensing alarm signals to provide the first line of defense against injury or infection after which they acquire an activated phenotype, but they also respond to chemical signals sent from brain mast cells, sentinels of the immune system, when these are degranulated in response to noxious agents. Nevertheless, excessive microglia activation damages the surrounding healthy neural tissue causing progressive loss of neurons and inducing chronic inflammation. Thus, it would be of intense interest the development and application of agents which prevent mast cell mediator release and inhibit the actions of such mediators once released on microglia. MAIN METHODS: Fluorescence measurements of fura-2 and quinacrine were used to measure intracellular Ca2+ signaling and exocytotic vesicle fusion in resting and activated microglia. KEY FINDINGS: We show that treatment of microglia with a cocktail of mast cell mediators induces microglia activation, phagocytosis, and exocytosis, and reveal by the first-time microglia undergo a phase of vesicular acidification just before the exocytotic fusion occurs. This acidification is an important process for vesicular maturation and contributes with â¼25 % to the content that the vesicle can store and later release by exocytosis. Pre-incubation with ketotifen, a mast cell stabilizer and H1R antagonist completely abolished histamine-mediated calcium signaling and acidification of microglial organelles, and concomitantly reduced the discharge of vesicle contents. SIGNIFICANCE: These results highlight a key role for vesicle acidification in microglial physiology and provide a potential therapeutic target for diseases related to mast cell and microglia-mediated neuroinflammation.
Subject(s)
Ketotifen , Microglia , Brain , Secretory Vesicles , Hydrogen-Ion ConcentrationABSTRACT
CLINICAL RELEVANCE: Practitioners can be reassured that this antihistamine-releasing contact lens has no additional effect on corneal epithelial integrity. BACKGROUND: To evaluate the effect of an antihistamine-releasing soft contact lens on corneal epithelium integrity when worn on a daily disposable modality for 12 weeks. METHODS: Two clinical trials using the same randomised, double-masked, placebo-controlled, parallel-group design enrolled healthy contact lens wearers. Participants wore either etafilcon A with 0.019 mg ketotifen (test; n = 374) or etafilcon A with no added drug (placebo; n = 186). Assessments were conducted at baseline, 1 week and 4, 8, and 12 weeks. Slit-lamp evaluations of corneal staining (using sodium fluorescein) in all regions of the corneas of both eyes were graded on a 0-4 scale. Data from all randomised participants were analysed. RESULTS: Corneal staining was infrequent and, where present, was mild (Grade 2) or trace (Grade 1). There were no Grade 3 or 4 findings of corneal staining. The overall proportion of findings of Grade 0 corneal staining was 95.86% with the test lens and 95.88% with the placebo lens. The odds of no staining were not statistically different between the test and placebo lenses (Odds Ratio: 0.96, 95% Confidence Intervals: 0.76 to 1.20). There were no serious ocular adverse events or signs of ocular surface medicamentosa. CONCLUSION: Both test and placebo lenses were well tolerated by subjects during the 3 months of wear. The antihistamine-releasing contact lens does not significantly impact corneal epithelial integrity.
Subject(s)
Contact Lenses , Cornea , Histamine H1 Antagonists , Ketotifen , Methacrylates , Cornea/drug effects , Epithelium, Corneal , Methacrylates/therapeutic use , Ketotifen/therapeutic use , Histamine H1 Antagonists/therapeutic use , Humans , Male , Female , Adult , Middle AgedABSTRACT
PURPOSE: To compare the ocular comfort at application of topical, over-the-counter, 0.7% olopatadine and 0.035% ketotifen fumarate anti-allergy eye drops. METHODS: This study recruited participants who were minimally symptomatic based upon Standard Patient Evaluation of Eye Dryness (SPEED) questionnaire scores (≤3 units) and who had minimal between-eye inter-ocular comfort differences as judged by visual analog scale scores (VAS; ≤7 units). Baseline comfort was evaluated by eye with a VAS. One drop of 0.7% olopatadine or 0.035% ketotifen fumarate was then applied to the right eye with the alternative drop being immediately applied to the left eye. Participants were next evaluated with the same comfort VAS by eye at drop application, and then at 30 s, 1 min, and 2 min post-application. LogMAR visual acuities and bulbar conjunctival redness were evaluated pre- and post-drop application to judge initial changes. RESULTS: This study enrolled 159 participants who had a mean ± SD age of 26.3 ± 7.7 years, and 78.6% of the participants were female. The VAS found that the 0.7% olopatadine drop was more comfortable than the 0.035% ketotifen fumarate drop at all time-points. There were no between-eye differences in LogMAR visual acuities, yet bulbar redness was significantly less in 0.7% olopatadine treated eyes compared 0.035% ketotifen fumarate treated eyes. CONCLUSION: This study found that topically applied 0.7% olopatadine drops were initially more comfortable than 0.035% ketotifen fumarate drops.