Ketotifen directly modifies the fibrotic response of human skin fibroblasts.

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.

Comparative evaluation of single and combined efficacy of dipyridamole, ketotifen and quercetin on cyclosporine induced hepatorenal toxicity.

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.

Intranasal Morphology Transformation Nanomedicines for Long-Term Intervention of Allergic Rhinitis.

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.

The use of ketotifen as long-term anti-inflammatory prophylaxis in children with PFAPA syndrome.

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.

Repurposing ketotifen as a therapeutic strategy for neuroendocrine prostate cancer by targeting the IL-6/STAT3 pathway.

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.

Evaluation of corneal staining with an antihistamine-releasing contact lens.

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.

Abdominal Massage Improves the Symptoms of Irritable Bowel Syndrome by Regulating Mast Cells via the Trypase-PAR2-PKCε Pathway in Rats.

Background: Irritable bowel syndrome (IBS) is a clinical disease mainly characterized as a syndrome of abdominal pain and discomfort, which frequently occurs in humans aged 20-50. Abdomen massage is of great medical significance for the health of the human body, including promoting intestinal peristalsis, relieving constipation, and facilitating weight loss. However, its potential benefits in alleviating IBS and the underlying mechanisms remain elusive. Methods: In this study, we established an IBS model in rats to evaluate the effects of abdomen massage. Forty male Sprague Dawley (SD) rats were randomly assigned into 4 groups: the normal (control) group, IBS group, abdominal massage group, and abdominal massage + ketotifen treatment group (n = 10 rats in each group). Abdominal massage was performed once a day for 5 minutes for 14 days. On day 14, the rats were euthanized and the tissues were analyzed by transmission electron microscopy (TEM), immunohistochemistry or immunofluorescence staining, and laser confocal focus to visualize the micromorphology of the intestinal mucosa. The expression of TRPV1 and the release of trypase were determined by RT-qPCR and western blot. Results: We found that compared with the control group, the mast cells in the IBS group were significantly increased and the increased MC was partially decreased by an abdominal massage with or without ketotifen treatment. We also found that TRPV1 was upregulated in the IBS group. Abdominal massage with or without ketotifen treatment could attenuate the upregulation of TRPV1 in IBS. Mechanically, results of IHC and western Blot suggested that abdominal massage reduces the sensitivity of IBS by regulating the trypase-PAR2-PKCε pathway. Conclusion: Overall, our results suggested that abdominal massage produces a beneficial effect in improving the symptoms of IBS through reducing mast cell recruitment and attenuating the trypase-PAR2-PKCε pathway. Ketotifen could promote the effect of abdominal massage on IBS treatment, which can serve as a potential therapeutic strategy for IBS.

Assessment of receptor affinities of ophthalmic and systemic agents in dry eye disease.

PURPOSE OF REVIEW: To explore our current understanding of receptor profiles acted upon by medications used to treat dry eye disease (DED). RECENT FINDINGS: Research into histaminic and muscarinic receptor affinities for drugs targeting the ocular surface has not kept up with bench research pertaining to the receptor profile of the ocular surface. These insights are necessary for better evaluation of medications used in DED and other allergic disorders. SUMMARY: At the H1 receptor, Ketotifen (pKa = 9.2), pyrilamine (pKa = 9.0), and epinastine (pKa = 8.0) had the highest affinities, whereas ranitidine (pKa = 4.2) and cimetidine (pKa = 4.9) had the lowest. Ketotifen, a second-generation antihistamine, was found to have a pKa of 6.7 at muscarinic receptors which was higher than that of diphenhydramine (pKa = 6.4), a first-generation antihistamine. Additionally, second-generation antihistamines have higher affinity for H3 receptors, which have been linked to urticaria, compared to first-generation. Azelastine, a second-generation, demonstrated significant affinity (pKa = 7.1) at the H3 receptor compared to all other drugs. Antazoline (pKa = 4.4) and diphenhydramine (pKa = 4.6), both first-generation antihistamines, had the lowest affinities for the H3 receptor. These findings raise questions about the use of antihistamines in the treatment of DED and allergic disorders.

Disease Course and Treatment Response of Eosinophilic Gastrointestinal Diseases in Children With Liver Transplantation: Long-Term Follow-Up.

INTRODUCTION: To describe the clinical and laboratory profile, natural course, treatment outcome, and risk factors of posttransplant esophageal and nonesophageal eosinophilic gastrointestinal disorders (EGIDs). METHODS: All children (aged <18 years) who underwent liver transplantation, between 2011 and 2019, in a single transplant center with a follow-up period of 1 year or more posttransplant and with a history of posttransplant endoscopic evaluation were included in this study. RESULTS: During the study period, 89 children met the inclusion criteria. Patients were followed for a median of 8.0 years. A total of 39 (44%) patients were diagnosed with EGID after transplantation. Of these, 29 (33%) had eosinophilic esophagitis (EoE), and 10 (11%) had eosinophilic gastritis, gastroenteritis or enterocolitis. In comparison with the non-EGID group, patients with EGID were younger at transplant (P ≤ 0.0001), transplanted more frequently due to biliary atresia (P ≤ 0.0001), and had higher rates of pretransplant allergy (P = 0.019). In the posttransplant period, they had higher rates of mammalian Target of Rapamycin inhibitor use (P = 0.006), Epstein-Barr virus viremia (P = 0.03), post-transplant lymphoproliferative disease (P = 0.005), and allergen sensitization (P ≤ 0.0001). In regression analysis, young age at transplant, age at diagnosis, pretransplant atopic dermatitis, and post-transplant lymphoproliferative disease were associated with an increased risk of EGID or EoE. Laboratory abnormalities such as anemia (P = 0.007), thrombocytosis (P = 0.012), and hypoalbuminemia (P = 0.031) were more commonly observed in the eosinophilic gastritis, gastroenteritis or enterocolitis group than in the EoE group. Following treatment, most patients had symptomatic resolution at 3 months and histologic resolution at 6 months postdiagnosis. Among the patients who had 5 years of follow-up, none recurred. DISCUSSION: EGID is a common posttransplant diagnosis, which seems to affect patients who are transplanted earlier and who have pretransplant atopy. Posttransplant EGID is responsive to treatment, but as histologic remission occurs after symptomatic resolution, the decision to perform control endoscopy should be delayed.

Clinical efficacy and safety of ketotifen in treating irritable bowel syndrome with diarrhea.

OBJECTIVE: The aim of the study was to investigate the clinical efficacy and safety of ketotifen for the treatment of irritable bowel syndrome with diarrhea (IBS-D). METHODS: A total of 108 enrolled IBS-D patients were randomly divided into a ketotifen group (n = 55) and a control (placebo) group (n = 53). The patients in the ketotifen group received ketotifen tablets (1 mg, oral) two times daily; patients in the control group received oral placebo for 8 weeks. Before and after 8 weeks of treatment, gastrointestinal symptoms, anorectal sensory function and the number and activity status of mast cells were assessed for both groups. RESULTS: (1) The overall effective rate of gastrointestinal symptom improvement in the ketotifen group was significantly higher than that in the control group (76.4 vs. 37.7%, P < 0.001). (2) First sensation, defecation urgency and discomfort/pain threshold in the ketotifen group improved significantly after treatment (P < 0.05); no significant changes were observed in the control group (P > 0.05). (3) In the ketotifen group, the number of mast cells in the terminal ileum decreased, and the percentages of degranulated mast cells in the sigmoid colon, ascending colon and terminal ileum decreased significantly after treatment compared with before treatment; these differences were statistically significant (P < 0.01). In the control group, the number of mast cells and the percentages of degranulated mast cells in various sites did not change significantly before and after treatment (P > 0.05). (4) Six patients (10.9%) in the ketotifen group experienced drowsiness and fatigue, but the symptoms disappeared after 1 week of treatment. CONCLUSION: Ketotifen significantly alleviated gastrointestinal symptoms and improved visceral hypersensitivity in patients with IBS-D. The therapeutic effect of ketotifen is related to a reduced number and decreased activity of mast cells in the intestinal mucosa, especially in the terminal ileum.

Combination treatment of allergic rhinitis using ketotifen fumarate and budesonide administered as nasal sprays
.

OBJECTIVE: This study aims to evaluate the clinical efficacy of ketotifen fumarate and budesonide administered as nasal sprays to treat allergic rhinitis. MATERIALS AND METHODS: A total of 96 allergic rhinitis patients, who were admitted to our hospital in recent years, were selected as research subjectes. All patients were treated with ketotifen fumarate and budesonide administered as nasal sprays. Clinical efficacy was evaluated after treatment. RESULTS: After treatment, the symptoms of nasal obstruction, nasal itching, sneezing, and runny nose significantly improved, and the score of these symptoms was significantly lower when compared to that before treatment (p < 0.05). After treatment, the eosinophils and IgE in peripheral blood of patients obviously reduced (p < 0.05). CONCLUSION: Combination treatment of allergic rhinitis using ketotifen fumarate and budesonide administered as nasal sprays has a good clinical effect in treating allergic rhinitis, which is of great significance to improve the clinical symptoms and immune function of patients. Ketotifen fumarate and budesonide have good therapeutic effects on allergic rhinitis. The combination of these two drugs can rapidly relieve allergic symptoms.

Ketotifen Modulates Mast Cell Chemotaxis to Kit-Ligand, but Does Not Impact Mast Cell Numbers, Degranulation, or Tumor Behavior in Neurofibromas of Nf1-Deficient Mice.

Neurofibromatosis Type 1 (NF1) is one of the most common genetic tumor predisposition syndromes in humans. Mutant NF1 results in dysregulated RAS allowing neoplasms throughout the neuroaxis. Plexiform neurofibromas (pNF) afflict up to 50% of patients with NF1. They are complex tumors of the peripheral nerve that cause major morbidity via nerve dysregulation and mortality via conversion to malignant sarcoma. Genetically engineered mouse models (GEMM) of NF1 provide valuable insights for the identification of therapies that have utility in people with pNF. Preclinical studies in GEMMs implicate mast cells and the c-Kit/Kit ligand pathway in pNF tumorigenesis. Kit ligand is a potent chemokine secreted by tumorigenic, Nf1-deficient Schwann cells. Ketotifen is an FDA-approved drug for the treatment of allergic conjunctivitis and asthma that promotes mast cell stabilization and has been used in prior case studies to treat or prevent pNFs. This study investigated the effect of ketotifen on mast cell infiltration and degranulation in the presence and absence of Kit ligand provocation and the effect of ketotifen on shrinking or preventing pNF formation in the Nf1flox/flox ;PostnCre + GEMM. Ketotifen decreased mast cell infiltration in response to exogenous Kit ligand administration, but did not affect mast cell degranulation. Importantly, ketotifen did not reduce mast cells numbers or activity in pNF and did not prevent pNF formation or decrease the volume of established pNF despite administration of pharmacologically active doses. These findings suggest that ketotifen has limited use as monotherapy to prevent or reduce pNF burden in the setting of Nf1 mutations.

Inhibition of Mast Cell Degranulation Relieves Visceral Hypersensitivity Induced by Pancreatic Carcinoma in Mice.

Cancer pain induced by pancreatic carcinoma is one of the most common symptoms and is difficult to endure, especially in the advanced stage. Evidence suggests that mast cells are recruited and degranulate in enteric disease-related visceral hypersensitivity. However, whether mast cells promote the visceral pain induced by pancreatic carcinoma remains unclear. Here, using toluidine blue staining and western blotting, we observed that mast cells were dramatically recruited to tissues surrounding pancreatic carcinoma, but not inside the carcinoma in patients with severe visceral pain. The levels of mast cell degranulation products, including tryptase, histamine, and nerve growth factor, were significantly increased in pericarcinoma tissues relative to their levels in normal controls, as evidenced by enzyme-linked immunosorbent assay. We determined that systemic administration of mast cell secretagogue compound 48/80 exacerbated pancreatic carcinoma-induced visceral hypersensitivity in a male BALB/c nude mouse model as assessed by measuring the hunching behavior scores and mechanical withdrawal response frequency evoked by von Frey stimulation. In contrast, the mast cell stabilizer ketotifen dose-dependently alleviated pancreatic cancer pain. In addition, we observed incomplete development of abdominal mechanical hyperalgesia and hunching behavior in mast cell-deficient mice with pancreatic carcinoma. However, ketotifen did not further attenuate visceral hypersensitivity in mast cell-deficient mice with carcinoma. Finally, we confirmed that intraplantar injection of pericarcinoma supernatants from BALB/c nude mice but not mast cell-deficient mice caused acute somatic nociception. In conclusion, our findings suggest that mast cells contribute to pancreatic carcinoma-induced visceral hypersensitivity through enrichment and degranulation in pericarcinoma tissues. The inhibition of mast cell degranulation may be a potential strategy for the therapeutic treatment of pancreatic carcinoma-induced chronic visceral pain.

Ketotifen fumarate attenuates feline gingivitis related with gingival microenvironment modulation.

Gingivitis is evidenced by inflammation of the free gingiva, and still reversible. If left untreated, it may then progress to periodontitis. In the present study, the therapeutical effect of ketotifen fumarate on gingivitis was explored. Domestic cats with varying degrees of gingivitis naturally were enrolled in this study. Subgroups of animals were treated twice daily for one week with or without ketotifen fumarate (5 mg/kg). Effects of ketotifen fumarate were measured on gingival index, cells accumulation, mediators release, receptor-ligand interaction, oxidative stress, MAPK and NF-κB pathways, epithelial barrier and apoptosis. Ketotifen fumarate attenuated the initiation and progression of gingivitis, inhibited the infiltrations of mast cells, B lymphocytes, T lymphocytes, macrophages, neutrophils and eosinophils as well as the release of IgE, ß-hexosaminidase, tryptase, chymase, TNF-α, IL-4, and IL-13, influenced endothelial cells, fibroblasts and epithelial cells proliferation and apoptosis, and induced Th2 cells polarization, where ketotifen fumarate also might affect their interactions. Ketotifen fumarate reduced the oxidative stress, and inhibited NF-κB and p38 MAPK related with mast cells and macrophages accumulation. Ketotifen fumarate improved the aberrant expression of ZO-1 and inhibits the following apoptosis. On the other hand, these cells and mediators augmented functional attributes of them involving SCF/c-Kit, α4ß7/VCAM-1 and IL-8/IL-8RB interactions, thus creating a positive feedback loop to perpetuate gingivitis, where an inflammation microenvironment was modeled. Our results showed a previously unexplored therapeutic potential of ketotifen fumarate for gingivitis and further suggest that, in addition to biofilms, targeting inflammation microenvironment could be new strategy for the treatment of gingivitis/periodontitis.

Topical antihistamines, mast cell stabilizers, and dual-action agents in ocular allergy: current trends.

PURPOSE OF REVIEW: To address the current trends of therapeutic mechanisms for treatment of allergic conjunctivitis (AC), based on topical antihistamines and mast cell stabilizers (MCS). RECENT FINDINGS: The antihistamine drug alcaftadine has H4 receptor inverse agonism, anti-inflammatory and MCS activities. The antihistamines levocabastine and azelastine are more effective than placebo in treatment of AC symptoms in randomized controlled trials (RCTs). The topical dual-action antihistamines/MCS olopatadine, azelastine, ketotifen, and epinastine are commonly used in Europe and in the United States for mild subtypes of AC. For the main symptoms of AC, ocular itch and conjunctival hyperemia, epinastine 0.05% was superior to placebo, but equal or more effective than olopatadine 0.1%, while the later was more effective than ketotifen. High concentration olopatadine 0.77% had longer duration of action, better efficacy on ocular itch, and a similar safety profile to low-concentration olopatadine 0.2%. The new formulas of topical dual-action agents present longer duration of action, leading to a decreased frequency of use. SUMMARY: The topical dual-action agents are the most effective agents treating signs and symptoms of mild forms of AC. There is superiority to the high-concentration olopatadine drug over other agents on ocular itch, with prolonged effect when used once-daily.

Inhibition of exosome release by ketotifen enhances sensitivity of cancer cells to doxorubicin.

Exosomes released from cancer cells support metastasis and growth of recipient cells and increase their resistance to chemotherapy. Therapeutic targeting of exosomes is a promising area in cancer research. Our aim is to test the effect of the mast cell stabilizer ketotifen on exosomes release from cancer cells and how this can modify their response to doxorubicin. Exosomes release from three cancer cell lines (MCF7, HeLa and BT549) was assessed by scan electron microscope and exosomes quantification kit. Doxorubicin export within exosomes was monitored flurometrically and cellular sensitivity to doxorubicin ± ketotifen was measured by sulphorhodamine-B and colony formation assays. The three cell lines release different amounts of exosomes with the highest quantity released from BT549 followed by MCF7 and then HeLa. Ketotifen (10 µmol L-1) reduced exosomes release in all three cell lines with different efficiency (HeLa>MCF7>BT549). Doxorubicin export via exosomes was highest in BT549, lower in HeLa and lowest in MCF7 cells. Pretreatment with ketotifen sensitized the cells to doxorubicin (HeLa>MCF7>BT549) with a sensitization factor of 27, 8 and 1.25 respectively. Increased sensitivity of cells to doxorubicin by ketotifen was proportional to its effect on exosomes release. Our data is the first report of ketotifen modulating exosomes release from cancer cells and opens the avenue for exosomes-targeting cancer therapy. The differential effects of ketotifen on doxorubicin exosomal export in the cell lines studied, suggests an opportunity of pharmacological enhancement of doxorubicin anti-tumor activity in some but not all cancer types.

Effect of varicocelectomy and/or mast cells stabilizer on sperm DNA fragmentation in infertile patients with varicocele.

This study aimed to assess the effect of varicocelectomy and/or mast cells (MCs) stabilizer on sperm DNA fragmentation in infertile men with varicocele (Vx). Overall, 120 infertile patients were randomized to three equal treatment arms; patients that underwent varicocelectomy, patients on 1 mg ketotifen twice daily for three months, and patients that underwent varicocelectomy followed with 1 mg ketotifen twice daily for three months. These patients were subjected to history taking, clinical examination, semen analysis, and estimation of sperm DNA fragmentation index (DFI). After 3 months, all investigated groups showed significant improvement regarding the mean total sperm count, sperm concentration, total sperm motility, and sperm normal forms percentage compared with the pre-treatment data. As well, the mean sperm DFI was significantly improved compared with the pre-treatment data; in men that underwent varicocelectomy (34.6% vs. 28.3%), in men on MC stabilizer only (33.4% vs. 27.8%), and in men that underwent varicocelectomy followed by MC stabilizer (34.3% vs. 25.1%). Sperm DFI improvement percentages showed the highest improvement in men that underwent varicocelectomy followed with MC stabilizer compared with the other two groups (26.8% vs. 18.2%, 16.8%). Sperm DFI improvement percentages showed significant increases in the infertile patients with Vx grade III compared to Vx grade II in all investigated groups. It is concluded that in infertile men associated with Vx and high sperm DFI, surgical repair followed with MCs stabilizer significantly improve sperm DFI compared with either surgical repair or MCs stabilizer alone.

Topical Olopatadine in the Treatment of Allergic Conjunctivitis: A Systematic Review and Meta-analysis.

PURPOSE: To assess the safety and efficacy of topical olopatadine versus placebo and other topical anti-allergic medications in treating allergic conjunctivitis. METHODS: We systematically searched the literature for randomized-controlled trials that included patients with allergic conjunctivitis, compared olopatadine versus placebo or alternative anti-allergic medications, and examined itch, conjunctival hyperemia, composite symptom or sign scores, and/or occurrence of adverse events. We assessed the safety and efficacy of topical olopatadine when compared with placebo or alternative anti-allergic medications using meta-analysis. RESULTS: When compared with placebo, topical olopatadine is associated with a pooled-mean difference (MD) in ocular itch of -1.33 (p < 0.00001) and ocular hyperemia of -0.92 (p < 0.00001). When compared with other agents, olopatadine was inferior to alcaftadine on ocular itch (pooled-MD = 0.39; p < 0.00001) but comparable with epinastine and ketotifen. CONCLUSIONS: Topical olopatadine is a safe and effective treatment modality for allergic conjunctivitis, whereas alcaftadine appears to be superior to olopatadine in reducing ocular itch.

Eosinophilic Gastroenteritis : Brief Review.

Eosinophilic gastroenteritis (EGE) is a rare disease which belongs to primary eosinophilic gastrointestinal disorders (primary EGIDs), characterized by an accumulation of eosinophils in the gastrointestinal (GI) tract and is strongly associated with atopy and allergy. The clinical presentations vary depending on the site and depth of eosinophilic intestinal infiltration. Radiology pictures may show irregular thickening of the folds, but these findings can also be present in other conditions like inflammatory bowel disease and lymphoma. The endoscopic appearance is also nonspecific. The definite diagnosis requires biopsy for histological evidence of GI eosinophilic infiltration and clinicians make the diagnosis in correlation with and by exclusion of other possible causes of eosinophilic infiltration. Because EGE is a rare disease, the treatment is based on limited case reports and clinicians' experience. Corticosteroids are the mainstay of therapy. The prognosis of EGE is relatively good when patients receive timely and proper treatment.