Synergism of polysaccharide polymers in antihistamine eye drops: Influence on physicochemical properties and in vivo efficacy.

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.

Comparison of Pregabalin and Ketotifen in treatment of uremic pruritus in hemodialysis patients.

This study aims to compare the efficiency of Pregabalin and Ketotifen in treatment of uremic pruritus in hemodialysis (HD) patients. Thirty HD patients were randomly divided into two groups: A (Pregabalin 50 mg three times a day) and B (Ketotifen 1 mg twice a day). Efficacy of treatment and quality of life were weekly evaluated by visual analogue scale (VAS) and Itchy Quality of life, respectively. There was no significant difference between the two groups regarding demographic features, laboratory data, quality of life, and VAS before treatment. In the second week of treatment, the pruritus intensity was significantly lower in the Pregabalin group than the Ketotifen group (p = 0.026). The mean of life quality was significantly lower in Ketotifen than Pregabalin group in weeks 1, 2, and 4 (p = 0.001, p = 0.001, and p = 0.036, respectively). There was no significant difference between the two groups regarding the side effects of drugs. This study showed that a higher dose of Pregabalin could be a more effective treatment than Ketotifen without additive side effects in improving the quality of life in dialysis patients.

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.

Generic selection criteria for safety and patient benefit [V]: Comparing the pharmaceutical properties and patient usability of original and generic nasal spray containing ketotifen fumarate.

The pH, osmotic pressure (cryoscopy), viscosity, squeeze force, spray angle, and spraying frequency of nasal spray containing ketotifen fumarate (1 brand-name product and 8 generic products) were measured. Based on the results of pH measurement, all products were weakly acidic (4.0 to 5.1). For all products, the osmotic pressure ratio to physiological saline was approximately 1. The viscosity of various products ranged from approximately 1.0 to 1.5 mPa·s. The spray angle of drug solution differed among the products: minimum, 46 degrees (Sawai and Fusachol); and maximum, 68.7 degrees (Sekiton). In particular, TOA, Sawai, Fusachol, and TYK showed significantly smaller angles compared to Zaditen (brand-name product). Container properties varied among the products: minimum squeeze force, 19.0 N (Sekiton); and maximum squeeze force, 43.1 N (Sawai). Based on these results, although all the above products are identical in dosage form and active ingredient, the differences in pharmaceutical properties, such as container operations and drug-solution spraying/attachment, may markedly influence patients' subjective opinions.

Effect of ketotifen in obese patients with type 2 diabetes mellitus.

AIM: Mast cells are found to be an important contributor in obesity induced insulin resistance. We evaluate the effect of ketotifen in obese patient with type 2 diabetes (T2DM) treated with glimepiride. METHOD: In a randomized controlled study we recruited forty-eight obese patients with T2DM from Internal Medicine Department at Tanta University Hospital, Egypt. They were classified into three groups: group 1, those who received glimepiride (GL) 3mg/d alone; group 2, those who received GL 3mg/d+ketotifen 1mg once daily; and group 3, those who received GL 3mg/d+ketotifen 1mg twice daily. Fasting blood samples were obtained before and 12weeks after treatment for biochemical analysis of glycemic and inflammatory biomarkers. Data were statistically analyzed by paired Student's t-test and one way analysis of variance; p<0.05 was considered statistically significant. RESULTS: The obtained data suggested that the addition of ketotifen in twice daily dose has a beneficial effect on all measured parameters except adiponectin. However, glimepiride plus ketotifen once daily only affected the level of inflammatory biomarkers without any significant effect on other parameters. CONCLUSIONS: The co-administration of ketotifen twice daily plus glimepiride improves glycemic and inflammatory process in obese patients with T2DM.

Ketotifen-induced nocturnal bruxism.

UNLABELLED: Nocturnal bruxism is a common oromandibular movement disorder highly prevalent in children, but its pathophysiological mechanism has not been fully explained. Iatrogenic sleep bruxism has been described following treatment with several psychotropic medications. However, no case of antihistamine-induced bruxism has been reported to date. Herein, we describe a 4-year-old child who experienced nocturnal bruxism during treatment for bronchospasm and rhinitis with the antihistamine ketotifen. Drug rechallenge was also performed. CONCLUSION: The present case adds useful information to our knowledge of bruxism. Complex and poorly understood interactions between multiple central nervous system neurotransmitters, such as histamine, serotonin, and dopamine, are involved.

Word of caution before implementing ketotifen for gastrointestinal transit improvement.

The therapeutic potential of long-term ketotifen in irritable bowel syndrome and postoperative ileus is currently under investigation. Ambiguous results of prolonged postoperative ketotifen use on gastrointestinal passage have been found. The current data point at a hampered gastrointestinal transit after prolonged postoperative ketotifen use in a rodent ileus induction model. Therefore, caution should be taken when administering ketotifen in the perioperative phase.

Carryover effect on next-day sleepiness and psychomotor performance of nighttime administered antihistaminic drugs: a randomized controlled trial.

BACKGROUND: Antihistamines with strong sedative-hypnotic properties are frequently prescribed for insomnia secondary to allergy, but the potential risks of such administration have not been fully elucidated. SUBJECTS AND METHODS: This randomized, double-blind, placebo-controlled crossover study was conducted to evaluate next-day sleepiness and psychomotor performance following the administration of antihistamines. Twenty-two healthy male participants participated in four drug administration sessions with more than a 1-week interval between the sessions. Either zolpidem 10 mg, or diphenhydramine 50 mg, or ketotifen 1 mg, or a placebo was administered before sleep, and polysomnography was conducted to evaluate sleep. In the morning and afternoon of the day after administration, the participants were evaluated for subjective sleepiness, objective sleepiness, and psychomotor performance. RESULTS: The antihistamines with high blood-brain barrier-crossing efficiency were significantly associated with sleepiness and psychomotor performance decline the next day. Ketotifen showed the strongest carryover effect, followed by diphenhydramine. Compared with the placebo, no significant carryover effect was observed with zolpidem. CONCLUSION: The results suggest that the risk-benefit balance should be considered in the ready use of antihistamines that easily cross the blood-brain barrier for alleviating secondary insomnia associated with allergies.

Essential oil from Citrus aurantifolia prevents ketotifen-induced weight-gain in mice.

Obesity is a major health problem world-wide. Medical intervention is often needed to tackle this problem, and accordingly the need for developing more effective, safer and cheaper weight reducing drugs has become paramount in recent years. In the present study, the effects of lime (Citrus aurantifolia) essential oils in reducing body weight, individually and in co-administration with ketotifen, an antihistaminic drug that causes weight gain, has been investigated using a mouse model. During the 45 days experimental period, the mice that received ketotifen demonstrated an enhancement both in the amount of food intake and body weight compared with the control group. Groups treated with lime essential oil displayed a reduction in body weight and food consumption in mice, possibly through promoting anorexia which might have played a role in weight loss. Interestingly, co-administration of the lime essential oil and ketotifen caused significant suppression in gaining weight, as well as decreased body weights of mice. The data obtained in this study suggested that lime essential oil plays an important role in weight loss and could be useful in the treatment of drug-induced obesity and related diseases. The GC-MS analysis of the essential oils of C. aurantifolia was also performed and approximately 22 main components, with limonene (28.27%) being the principal one, were identified and quantified.

The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome.

BACKGROUND: Mast cell activation is thought to be involved in visceral hypersensitivity, one of the main characteristics of the irritable bowel syndrome (IBS). A study was therefore undertaken to investigate the effect of the mast cell stabiliser ketotifen on rectal sensitivity and symptoms in patients with IBS. METHODS: 60 patients with IBS underwent a barostat study to assess rectal sensitivity before and after 8 weeks of treatment. After the initial barostat, patients were randomised to receive ketotifen or placebo. IBS symptoms and health-related quality of life were scored. In addition, mast cells were quantified and spontaneous release of tryptase and histamine was determined in rectal biopsies and compared with biopsies from 22 age- and gender-matched healthy volunteers. RESULTS: Ketotifen but not placebo increased the threshold for discomfort in patients with IBS with visceral hypersensitivity. This effect was not observed in normosensitive patients with IBS. Ketotifen significantly decreased abdominal pain and other IBS symptoms and improved quality of life. The number of mast cells in rectal biopsies and spontaneous release of tryptase were lower in patients with IBS than in healthy volunteers. Spontaneous release of histamine was mostly undetectable but was slightly increased in patients with IBS compared with healthy volunteers. Histamine and tryptase release were not altered by ketotifen. CONCLUSIONS: This study shows that ketotifen increases the threshold for discomfort in patients with IBS with visceral hypersensitivity, reduces IBS symptoms and improves health-related quality of life. Whether this effect is secondary to the mast cell stabilising properties of ketotifen or H(1) receptor antagonism remains to be further investigated. Trial Registration Number NTR39, ISRCTN22504486.

Evidence for a role of mast cells in the mucosal injury induced by Newcastle disease virus.

We have previously demonstrated that mast cells were significantly increased during Newcastle disease virus (NDV) infection, but their precise role in the process is unknown. In this study, we investigated the role of mast cells in this process by using ketotifen, a mast cell membrane stabilizer. A total of 60 specific-pathogen-free chickens were randomly divided into 3 groups of 20 birds each (NDV-infected group, ketotifen-pretreated group, and the control group). The ketotifen-pretreated group was administered orally with ketotifen before NDV infection. On 12, 24, and 48 h postinfection, 5 chickens from each treatment were killed. Tissues of proventriculus were collected to quantify mast cells, the content of tryptase and histamine by cytochemistry, immunohistochemistry, and fluorescence analysis, respectively. The results showed that the population of mast cells and the content of tryptase and histamine were increased significantly in the proventriculus (P < 0.01) of infected birds compared with the control group. An acute mucosal injury was observed in the infected chickens. In contrast, among chickens pretreated with ketotifen, followed by NDV infection, the mast cells number and the content of tryptase and histamine were decreased significantly (P < 0.01). Likely as a result, the mucosal injury was remitted remarkably. The overall results of this experiment suggest that mast cells are implicated in NDV-induced mucosal injury. Inhibition of mast cell mediator release may represent a novel strategy to modulate this process.

Ocular comfort and drying effects of three topical antihistamine/mast cell stabilizers in adults with allergic conjunctivitis: a randomized, double-masked crossover study.

OBJECTIVE: The aim of this study was to compare short-term (5-minute) ocular comfort and drying effects of 3 topical antihistamine/mast cell stabilizers-epinastine, azelastine, and ketotifen-in patients with allergic conjunctivitis (AC). METHODS: Adults with a history of AC, as confirmed on skin testing conducted within the previous 2 years, were enrolled in this single-center, randomized, double-masked crossover study. At visit 1, patients were randomized to receive a single drop of epinastine in 1 eye and either azelastine or ketotifen in the other eye. Ocular comfort was assessed by patients on an 11-point scale (0 = very comfortable to 10 = very uncomfortable) immediately (0 minute) and at 0.5, 1, 2, and 5 minutes after instillation. Patients were also asked to describe how their eyes felt at 3 minutes using a standardized list of positive (soothing, smooth, refreshing, cool, and comfortable), neutral (thick, sticky, and filmy), and negative (stinging, irritating, and burning) descriptor words. At visits 2 to 4, patients were examined for ocular drying and tear-film stability using fluorescein staining and ocular protection index (OPI) evaluation, respectively. RESULTS: A total of 40 patients (27 women, 13 men; mean age, 40 years [range, 18-73 years]) were included in the study. The mean comfort score was significantly lower (indicating more comfort) with epinastine compared with azelastine at 0.5, 1, 2, and 5 minutes (between-treatment differences, 2.90, 1.85, 1.35, and 0.63, respectively; P < 0.001, P < 0.001, P = 0.001, and P = 0.019) and compared with ketotifen immediately after instillation (between-treatment difference, 1.2; P = 0.014). The mean ocular comfort score was significantly lower with ketotifen compared with azelastine at 0.5, 1, and 2 minutes (between-treatment differences, 2.35, 1.35, and 1.10, respectively; P = 0.001, P = 0.023, and P = 0.028). A majority (85%) of patients chose positive comfort descriptors to describe epinastine versus 34% with azelastine. No significant differences in fluorescein staining or OPI were observed. CONCLUSIONS: In this small study in patients with AC, following administration of a single drop, epinastine was rated as more comfortable than azelastine and ketotifen. None of the tested medications were associated with significant acute ocular drying effects.

Bioequivalence of two formulations of ketotifen fumarate ophthalmic solution: a single-center, randomized, double-masked conjunctival allergen challenge investigation in allergic conjunctivitis.

BACKGROUND: Ketotifen fumarate ophthalmic solution 0.025% (reference formulation), a topical mast cell stabilizer/antihistamine combination, has been found to be effective and well tolerated in the prevention of ocular itching associated with allergic conjunctivitis (AC). A recently developed formulation of ketotifen fumarate ophthalmic solution 0.025% (test formulation) contains the same active ingredient in the same concentration as the reference formulation, is intended for twice-daily dosing, and may provide a treatment option in patients with AC. OBJECTIVE: The aim of this study was to determine the clinical bioequivalence of the test and reference formulations using a conjunctival allergen challenge (CAC) model. METHODS: This prospective, randomized, double-masked, active- and placebo-controlled CAC study was conducted in a clinical setting (ORA Clinical Research and Development, North Andover, Massachusetts). Patients aged <18 years who had AC, a successful allergen challenge during screening and allergen confirmation visits, a history of ocular allergies, and positive skin-test reactivity were enrolled. Patients' eyes were randomized to receive the test or reference formulation or inactive vehicle (1 drop of 1 study medication per eye per visit). The primary efficacy end point was ocular itching, and the secondary end points were ocular redness, chemosis, lid swelling, tearing, and mucous discharge. Efficacy was assessed following challenge at 8 hours and 15 minutes after instillation. The test and reference formulations were considered bioequivalent if the 95% CIs for the differences in mean ocular itching scores between the 2 groups were within the range of 0.40 to 0.40. RESULTS: There were 108 patients enrolled (61 men, 47 women; mean age, 42 years; 91.7% white). The test and reference formulations both yielded clinically significant results compared with placebo in the prevention of ocular itching at CACs performed 8 hours and 15 minutes after instillation. At the 8-hour posttreatment CAC, the mean ocular itching scores for test formulation-treated eyes were 1.158, 1.265, and 1.305 units lower, respectively, than for eyes at 3, 5, and 7 minutes that were administered placebo. At 15-minute posttreatment CAC, the mean ocular itching scores for reference formulation-treated eyes at 3, 5, and 7 minutes were 1.481, 1.622, and 1.565 units lower, respectively, than for eyes that were administered placebo. With regard to the primary and secondary efficacy variables, no statistically significant differences were observed between test and reference formulations at any post-CAC time point. CONCLUSIONS: In this population of patients with AC, the test formulation of ketotifen fumarate ophthalmic solution 0.025% met criteria for bioequivalence to the reference formulation, as established by the protocol. The test and reference formulations were well tolerated in the population studied.