... daily, 8 to 12 hours apart. Instill ketotifen eye drops at around the same times every day. Follow ... than prescribed by your doctor.To instill the eye drops, follow these steps: Wash your hands thoroughly with ...
Italiano, Domenico; Bramanti, Placido; Militi, David; Mondello, Stefania; Calabro, Rocco Salvatore
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. 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.
Pauwels, R; Lamont, H; Van Der Straeten, M
A double-blind cross-over study showed that orally taken ketotifen and inhaled DSCG have a comparable protective effect on allergen-induced bronchoconstriction. Both drugs significantly inhibit the immediate bronchial reaction after a 3 day treatment with either 1 mg ketotifen or 20 mg DSCG four times daily. Late reactions, which occurred in three out of the ten patients, were inhibited in two of the three patients by ketotifen as by DSCG.
Maclay, W P; Crowder, D; Spiro, S; Turner, P
In a postmarketing surveillance of ketotifen (Zaditen), an oral preparation for the prophylaxis of bronchial asthma, 8291 patients completed records every three months for one year. The objectives were to record adverse events and efficacy and to communicate appropriate information to participating doctors and regulatory authorities. The patients recruited appeared to represent a typical cross section of patients with asthma in the United Kingdom. By subjective assessment 70% of patients found the medication efficacious. There were no unexpected or unacceptable side effects and those found were similar to those reported in clinical trials of ketotifen. Though this exercise showed that the pharmaceutical industry, regulatory authorities, and prescribing doctors were able to collaborate, the major outcome of the survey was already known. It remains to be seen whether this type of survey is of value in the continuing search for control and safety in prescribing. PMID:6423140
Habibi Asl, Bohlool; Vaez, Haleh; Imankhah, Turan; Hamidi, Samin
Purpose: Prescription of ketotifen as an effective antihistamine in asthma and allergic conditions is associated with side effect of weight gain. Caffeine is an agent which increases thermogenesis and improves energy expenditure and also effective in asthma. The aim of current study was to evaluate caffeine impact in reducing weight gain side effect of ketotifen. Methods: Male mice at the weight limit of 20-30 gr in 8 groups were randomly chosen and injected following drug dosages for 45 days intraperitoneally: control group (normal saline 10 ml/kg), three groups of ketotifen (4, 8, 16 mg/kg), three groups of caffeine (4, 8, 16 mg/kg) and one group of ketotifen (4 mg/kg) in combination with caffeine (4 mg/kg). Weight changes have been recorded and assessed every 3 days for 45 days. Results: The results showed that in all dosages of the two drugs, significant weight loss occurred in comparison with the control group. Conclusion: The effect of caffeine on weight loss according to our results, matches with human studies, while ketotifen contradictory to our assumption, resulted in weight loss which probably was related to the difference in metabolic pathways in mice and humans, or maybe the used doses of ketotifen in this study were insufficient to reduce TNF-α production or influence in serotonin release and be effective on appetite or weight gain. PMID:24409414
Milner, Erin; Sousa, Jason; Pybus, Brandon; Auschwitz, Jennifer; Caridha, Diana; Gardner, Sean; Grauer, Kristina; Harris, Erin; Hickman, Mark; Kozar, Michael P; Lee, Patricia; Leed, Susan; Li, Qigui; Melendez, Victor; Moon, Jay; Ngundam, Franklyn; O'Neil, Michael; Parriott, Sandi; Potter, Brittney; Sciotti, Rick; Tangteung, Anchalee; Dow, Geoffrey S
Ketotifen is known to exhibit antimalarial activity in mouse and monkey malaria models. However, the low plasma levels and short half life of the drug do not adequately explain its in vivo efficacy. We synthesized most of the known metabolites of ketotifen and evaluated their antimalarial activity and pharmacokinetics in mice. Norketotifen, the de-methylated metabolite of ketotifen, was a more potent antimalarial in vitro as compared to ketotifen, and exhibited equivalent activity in vivo against asexual blood and developing liver-stage parasites. After ketotifen dosing, norketotifen levels were much higher than ketotifen relative to the IC50s of the compounds against Plasmodium falciparum in vitro. The data support the notion that the antimalarial activity of ketotifen in mice is mediated through norketotifen.
Jagdis, Amanda; Berlin, Noam; Barron, Carly; Giruparajah, Mohana; Leader, Nathan; Maclachlan, Sean; Sussman, Gordon L
Oral immunotherapy (OIT) has shown promise in inducing desensitization for food allergy. However, there are safety concerns regarding the frequency and severity of adverse events during food OIT. To evaluate the effect of Ketotifen premedication on adverse reactions during peanut OIT. A randomized single blind placebo controlled pilot study was performed. Peanut OIT was performed using a previously published protocol. Ketotifen was up-titrated to 2 mg twice daily over two weeks (week -2 to 0), followed by a peanut OIT initial escalation day (day 1). Ketotifen was administered from week 0-4 of peanut OIT; reactions to peanut OIT doses were recorded by clinic staff and subject diary. Six subjects (median age 10 years, peanut IgE >100kUA/L) were enrolled, 4 randomized to Ketotifen, 2 to placebo. The most common side effect of Ketotifen was fatigue (9% during up-titration). The rate of reaction per peanut OIT dose was lower for subjects on ketotifen (K) compared to placebo (P) during initial escalation on day 1 (K: 22% (8/36) vs. P: 67% (12/18)); week 0-4 build-up doses (K: 75% (3/4) vs. P: 100% (2/2)); and week 0-4 home doses (K: 50% (54/108) vs. P: 82% (27/33)). The rate of gastrointestinal symptoms per peanut OIT dose was also lower for subjects on ketotifen during initial escalation on day 1 (K: 17% (6/36) vs. P: 61% (11/18)); week 0-4 build-up doses (K: 75% (3/4) vs P: 100% (2/2)); and week 0-4 home doses (K: 46% (50/108) vs. P: 82% (27/33)). Ketotifen premedication is well tolerated and reduces the rate of gastrointestinal symptoms during peanut OIT. These findings require confirmation in a larger study of Ketotifen premedication used throughout peanut OIT. NCT0162515.
Kidd, M; McKenzie, S H; Steven, I; Cooper, C; Lanz, R
Background: Ketotifen blocks histamine H1 receptors, stabilises mast cells, and prevents eosinophil accumulation. These multiple, pharmacological mechanisms provided the rationale for assessing the efficacy and safety of ketotifen 0.025% eye drops in subjects with seasonal allergic conjunctivitis (SAC) in an environmental setting. Methods: This was a double masked, randomised, multicentre trial conducted in Australia. Subjects were randomly assigned to ketotifen fumarate 0.025% ophthalmic solution, placebo (as vehicle), or levocabastine hydrochloride 0.05% ophthalmic suspension, twice daily in each eye for a 4 week period. Subjects were assessed at follow up (days 5–8) and termination (days 25–31) visits. The primary efficacy variable was the responder rate, based on the subjects’ assessment of global efficacy at the follow up visit. Results: 519 subjects were randomised to treatment. At the follow up visit, the responder rate, based on subjects’ assessment of global efficacy, was significantly greater in the ketotifen group (49.5%) than in the placebo group (33.0%) for subjects with a positive diagnostic test for pollen allergy (p = 0.02). The investigators’ assessment of responder rates also showed that ketotifen was superior to placebo (p = 0.001). Ketotifen produced a significantly better outcome than levocabastine (p<0.05) for relief of signs and symptoms of SAC, at both the follow up and the termination visit. The type and frequency of adverse events were similar across treatment groups. Conclusions: In an environmental setting, ketotifen fumarate 0.025% ophthalmic solution was well tolerated and effective in reducing the signs and symptoms of SAC, and in preventing their recurrence. Ketotifen consistently showed the best efficacy in comparison with both placebo and levocabastine. These results indicate that ketotifen eye drops are a valuable treatment option for this condition. PMID:14507747
Sobral, Manuela C C M; Sobral, Abilio J F N; Guthrie, J T; Gil, M H
Ketotifen was immobilised in cellulose acetate propionate (CAP) membranes and in cellulose acetate butyrate (CAB) membranes. The characteristics of each system were evaluated under a range of experimental conditions. The topography and uniformity of the membranes was assessed using scanning electron microscopy. The release characteristics associated with Ketotifen were monitored spectrophotometrically. The swelling capacity of the membranes was evaluated and attributed to the combined effects of diffusion and of complex dissociation, during swelling. The materials produced were able to provide controlled release of Ketotifen due to their controlled swelling behaviour and adequate release properties. The results showed that the release of Ketotifen from the CAB membranes is higher but the release from the CAP membranes is more uniform.
Greiner, Jack V; Michaelson, Clifford; McWhirter, Cecilia L; Shams, Naveed B K
This single-masked, contralateral-eye, active-controlled allergen-challenge study compared ketotifen fumarate .025% and cromolyn sodium 4% ophthalmic solutions in the prevention of ocular itching, tearing, and redness induced by allergen challenge. After a confirmatory conjunctival provocation test (CPT), 56 patients randomly received masked study medication (placebo in one eye, cromolyn in the other eye) four times daily for 2 weeks. At visit 3, patients received one drop of ketotifen in the eye previously treated with placebo and cromolyn in the other eye. Ocular comfort was assessed 30 seconds postinstillation, and a CPT was conducted 15 minutes and 4 hours postinstillation to evaluate ocular itching, tearing, and redness. Forty-seven patients were analyzed for efficacy. At the 15-minute and 4-hour challenges, ketotifen was superior to cromolyn in preventing itching (P < .001) at all assessments and redness (ciliary, conjunctival, and episcleral) (P < or = .001) at most assessments. Tearing scores were higher in cromolyn-treated eyes than in ketotifen-treated eyes. Patients reported greater comfort in the ketotifen-treated than in the cromolyn-treated eye (P = .066). The most common adverse event was burning/stinging with cromolyn. A single dose of ketotifen was superior to a 2-week four-times-daily regimen of cromolyn in alleviating symptoms of allergic conjunctivitis in the conjunctival allergen-challenge model.
Chen, Zimiao; Sun, Hongwei; Wang, Jian; Ni, Liansong; Gu, Xuejiang; Ge, Shengjie; Chen, Qiong; Mu, Liangshan; Cheng, Xingbo
We aim to explore effects of Ketotifen on metabolic profiles, inflammation and oxidative stress. Sprague Dawley (SD) male rats were randomly divided into normal control group (NC) and experimental groups, and experimental group rats were fed with high-sugar and fat diet for 6 weeks. Then, experimental group rats were divided into diabetes group (DM) and ketotifen treatment group (KT). KT group was given ketotifen via Intragastric for 8 weeks with the dosage of 0.09 mg/kg•d. Fasting plasma glucose (FPG) was measured using glucose oxidase-phenol amino phenazone method. Fasting insulin (FINS), total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were tested by enzyme-linked immunosorbent assay. Malondialdehyde (MDA) and superoxide dismutase (SOD) were quantified by spectrophotometer method. Before Ketotifen administration, compared with NC group, DM and KT groups showed significantly high levels of body weight, FPG, FINS, HOMA-IR, TC, TG, LDL, IL-6, TNF-α and MDA, and lower levels of HDL and SOD (All p <0.05). After 4 weeks of Ketotifen administration, levels of body weight, FPG, FINS, HOMA-IR, TC, TG, LDL, IL-6, TNF-α in KT group decreased significantly, and levels of HDL and SOD elevated significantly (All p <0.05). After 8 weeks of Ketotifen administration, levels of body weight, FPG, FINS, HOMA-IR, TC, TG, LDL, IL-6, TNF-α and MDA in KT group decreased more obviously, and levels of HDL and SOD elevated significantly further (All p <0.05). Ketotifen improved metabolic profiles, and ameliorated status of inflammation and oxidative stress.
Background Oral immunotherapy (OIT) has shown promise in inducing desensitization for food allergy. However, there are safety concerns regarding the frequency and severity of adverse events during food OIT. Objective To evaluate the effect of Ketotifen premedication on adverse reactions during peanut OIT. Methods A randomized single blind placebo controlled pilot study was performed. Peanut OIT was performed using a previously published protocol. Ketotifen was up-titrated to 2 mg twice daily over two weeks (week -2 to 0), followed by a peanut OIT initial escalation day (day 1). Ketotifen was administered from week 0–4 of peanut OIT; reactions to peanut OIT doses were recorded by clinic staff and subject diary. Results Six subjects (median age 10 years, peanut IgE >100kUA/L) were enrolled, 4 randomized to Ketotifen, 2 to placebo. The most common side effect of Ketotifen was fatigue (9% during up-titration). The rate of reaction per peanut OIT dose was lower for subjects on ketotifen (K) compared to placebo (P) during initial escalation on day 1 (K: 22% (8/36) vs. P: 67% (12/18)); week 0–4 build-up doses (K: 75% (3/4) vs. P: 100% (2/2)); and week 0–4 home doses (K: 50% (54/108) vs. P: 82% (27/33)). The rate of gastrointestinal symptoms per peanut OIT dose was also lower for subjects on ketotifen during initial escalation on day 1 (K: 17% (6/36) vs. P: 61% (11/18)); week 0–4 build-up doses (K: 75% (3/4) vs P: 100% (2/2)); and week 0–4 home doses (K: 46% (50/108) vs. P: 82% (27/33)). Conclusions Ketotifen premedication is well tolerated and reduces the rate of gastrointestinal symptoms during peanut OIT. These findings require confirmation in a larger study of Ketotifen premedication used throughout peanut OIT. Trial registration Clinical Trials number: NCT0162515 PMID:25031584
Osváth, P; Kelenhegyi, K; Micskey, E
The authors treated 17 food allergic, 2-14 year old children with chemoprophylactic drugs. The patients got either ketotifen or DSCG in random allocated for 4 weeks and thereafter a washout period of 2 weeks separated the trial period of the other drug. Oral challenge with the food was performed before the trial period and after a 4 week lasting elimination diet on the last day of each treatment. After the ketotifen therapy in 10 of the 17 patients no symptoms appeared after the challenge, whereas only 5 patients were completely protected by DSCG. However, with regards to isolated organ symptoms the two drugs were of equal value. In case of failure of one drug the other was effective with two exceptions. Symptoms of intolerance (vomiting, angioedema or abdominal cramps) occurred in 3 patients during DSCG treatment and in one of those getting ketotifen. In 3 cases of severe milk allergy (Heiner-Holland syndrome) symptom-free state could be attained only if diet was supplemented by ketotifen. Symptoms of food allergy can be well prevented in children through ketotifen therapy more than by DSCG.
Ang, Dennis C.; Hilligoss, Janna; Stump, Timothy
Objectives Compared to healthy controls, patients with fibromyalgia (FM) have more mast cells in the skin. Whether mast cells are involved in the pathogenesis of FM is unclear. We sought to determine the effects of a mast cell stabilizer (ketotifen) on FM symptoms. Methods Fifty-one FM subjects were randomized to daily oral ketotifen 2 mg BID (n=24) for 8 weeks or placebo (N=27). Mean age of subjects was 51.2 years (standard deviation/SD 8.4); 88% were female and 88% were white; 22% were taking concomitant opiates; and mean pressure pain sensitivity (range 0-20) was 10.0 (0.4). At study entry, the weekly average pain intensity was 6.4 (1.1) and the mean score on the Revised Fibromyalgia Impact Questionnaire (FIQR) was 66.8 (14.0). Results We found no statistically significant treatment group differences from baseline in either group for the two primary measures: weekly average pain intensity [ketotifen −1.3 (1.9) vs. placebo −1.5 (1.9), p=0.7]; and FIQR score [−12.1 (19.5) vs. −12.2 (18.1), p=0.9]. No secondary outcome measures (BPI pain intensity, and pressure pain sensitivity) reached statistical significance; results did not differ in the intent-to-treat and completer analyses. Other than transient sedation [6 (28.6%) vs. 1 (4.0%)], ketotifen was well tolerated. Discussion The study results question whether skin mast cells play a major role in the pathogenesis of FM. However, given the role of mast cells in peripheral and central nociception, and the minimal side effects of ketotifen, a randomized clinical trial using increasing doses of ketotifen may be warranted. PMID:25370135
Schuhl, J F; Holgado de Cuesta, D
A double-blind non crossover trial comparing disodium cromoglycate (DSCG), with ketotifen, was carried out in twenty-seven extrinsic asthmatic children over 12 weeks. Assessment was made using symptom score and drug score charts. Both drugs showed a similar protective effect in the group studied. None of the subjects had to withdraw from the trial and no side-effects were noted in weight-curve, arterial pressure and pulse rate. PEFR values remained unchanged for both drugs throughout the trial. A non-significant tendency for additional corticosteroid support in the Ketotifen group was noted.
Anoush, Mahdieh; Mohammad Khani, Mohammad Reza
Purpose: As H1 and H3 receptors’ roles has been defined in peripheral pains in some papers and because histamine is known for its role in inflammatory responses; this study investigated the possible analgesic and anti-inflammatory effects of ketotifen and fexofenadine as relatively safe long acting anti histamines in both chronic chemical pain and acute inflammation in rats. Methods: In this study, male Sprague-Dawley rats weighing 225-250 grams were used. In order to evaluate the chemical chronic pain, sub-plantar injection of formalin applied and the pain scores were recorded every 15 seconds during 60 minutes. Carrageenan injection to the right hind paw was used for induction of acute inflammation and the paw edema was measured every 60 minutes for 4 hours. Results: Based on the results, both ketotifen and fexofenadine were able to significantly diminish chemical acute and chronic pain as well as inflammation in comparison with the control group and the effects were acceptable according to the standard treatment. Both effects for fexofenadine started later than those of ketotifen. Conclusion: According to the outcomes of the study, ketotifen and fexofenadine demonstrated significant analgesic and anti-inflammatory characteristics in both models of chemical pain and acute inflammation in laboratory animals. PMID:26236660
Amirkhanlou, Saeid; Rashedi, Anna; Taherian, Jalal; Hafezi, Ali Akbar; Parsaei, Sahar
Objectives: Uremic pruritus is a common problem in hemodialysis patients. Several treatments have been used for decreasing itching in these patients. Gabapentin and ketotifen are two drugs used for treating uremic patients. The aim of this study was to compare gabapentin and ketotifen in treatment of uremic pruritus in hemodialysis patients. Methods: In this double-blind randomized clinical trial, 52 hemodialysis patients with uremic pruritus referred to 5azarTeaching Hospital in Gorgan in 2013 were studied. Patients were randomly assigned to two groups of 26 subjects (groups G and K). In group G, patients treated with gabapentin capsules 100 mg daily for 2 weeks, and in Group K, patients treated with ketotifen 1 mg twice daily for 2 weeks. Before and at the end of study, pruritus severity was determined based on Shiratori’s severity scores. Collected data were analyzed by SPSS-21 statistical software. Results: There was no significant different between two groups in the age and sex. After two weeks of treatment, severity of pruritus was significantly reduced in both groups (88.4% in group G vs. 76.9% in group K). Gabapentin compared with ketotifen had a better effect on improving itching in the age group of 30-60 years and in males. 5 patients (19.2%) in both groups suffered from drowsiness and dizziness, but no serious side effects were observed. Conclusions: The results showed that gabapentin and ketotifen significantly improved pruritus in hemodialysis patients, and no significant difference was observed between two groups. PMID:27022338
Martín, Andrea P; Urrets-Zavalia, Julio; Berra, Alejandro; Mariani, Ana Lía; Gallino, Norberto; Demel, Eduardo Gomez; Gagliardi, Julio; Baena-Cagnani, Carlos E; Urrets-Zavalia, Enrique; M Serra, Horacio
Background The efficacy and safety of ketotifen eye drop treatment in allergic conjunctivitis (AC) management is perfectly known by several studies, but the mechanism of action at the biochemical levels is poorly understood so we decided to perform an open, uncontrolled study in order to investigate the effect of the topical administration of ketotifen fumarate 0.05% on biochemical markers of inflammation on conjunctival cells in patients with AC. Methods Nineteen patients with symptoms and signs of AC (itching, discharge, burning, redness, increase in the watery discharge, swelling and follicles) and with a history of allergy were prescribed with two daily instillation of one drop of eyewash ketotifen fumarate 0,05% in both eyes during thirty days. They were studied by measuring clinical and immunologic parameters. Results Ketotifen fumarate treatment significantly reduced the total symptoms and signs score for each patient as well as each symptoms and signs at all time points compared with day 0 (p < 0.0001 and p < 0.016, respectively). Although the percentage of HLA-DR+ epithelial cells diminished only in 58% of patients, the numbers of CD29+ and eotaxin+ epithelial cells dropped significantly in 68% and 73 % of them (p < 0.0062 and <0.0082, respectively) as a consequence of the treatment. In 9 out of 19 patients a simultaneous decrease in the percentage of epithelial cells positive for CD29 and eotaxin was observed. Conclusion Ketotifen besides the well-known effect in reducing signs and symptoms of AC significantly diminished production of eotaxin and expression of CD29 by epithelial cells in patients with seasonal AC. PMID:12515585
Kim, Hyun Ji; Park, Mi Kyung; Kim, Soo Youl; Lee, Chang Hoon
The high mortality rates associated with cancer reflect the metastatic spread of tumor cells from the site of their origin. Metastasis, in fact, is the cause of 90% of cancer deaths. Therefore, considerable effort is being made to inhibit metastasis. In the present study, we screened ketotifen for anti-migratory and anti-invasive activities against MDA-MB-231 breast cancer and HT-1080 fibrosarcoma cancer cells. Cancer cell migration and invasion were measured using multi-well chambers. Additionally, western blots were used to examine the effects of ketotifen on the expressions of CDC42, Rho, Rac, and matrix metalloproteinase 9 (MMP-9). The results showed that ketotifen dose-dependently suppressed the migration and invasion of MDA-MB-231 and HT-1080 cells. Ketotifen also suppressed the expressions of CDC42, Rac, and Rho, which, significantly, are involved in MDA-MB-231 and HT-1080 cancer cell migration. Moreover, ketotifen suppressed the expression and activity of MMP-9, which is involved in degradation of the extracellular matrix leading to invasion. The overall data suggested that ketotifen suppresses the migration and invasion of MDA-MB-231 and HT-1080 cancer cells via inhibition of CDC42, Rac, Rho, and MMP-9 expression. PMID:25489422
Osváth, P; Endre, L
The authors treated 228 asthmatic children during a period of 3 years using a randomised scheme. After a short eliminatory trial the choice of preventive treatment was selected randomly using the patient's registration number. Four groups were formed: Hyposensitization, ACTH, DSCG and Ketotifen (Zaditen). Two thirds of the patients ameliorated in each group. According to the subjective opinion of the parents, 30-33% of the patients became symptomfree on each regimen. This figure was 50% in the hyposensitization and ACTH groups (13%). Serious asthma cases with more than 10 attacks in a year improved, mainly after DSCG or Ketotifen (Zaditen) therapy. The evaluation according to a symptom score and pulmonary function test shows definite amelioration in the groups chemoprophylactic drugs. After a change from the original therapy because of a failure, ACTH and Zaditen were the most successful second drug.
The effects of sodium cromoglycate and ketotifen were studied in a group of 20 patients in whom fish repeatedly provoked an attack of wheezing and dyspnoea within one hour of its being eaten. Fish ingestion resulted in a fall in forced expiratory volume in one second (FEV1) of at least 15%. All patients had a weal greater than 4 mm in response to fish antigen in the skinprick test and most had blood eosinophilia and raised serum IgE levels. Administration of drugs and placebos was carried out under double-blind conditions, in a randomised fashion, on different days. Cromoglycate blocked the fall in FEV1 either completely or significantly in 16 patients. Ketotifen did not appear to have any significant effect in the group as a whole. PMID:6412384
Khater, M M; Issa, Y M; Mohamed, S H
New modified carbon paste electrodes for determination of ketotifen fumarate in its pure and pharmaceutical preparations were constructed. The used modifiers are ketotifen phosphotungestate (Keto(3) PT), and ketotifen tetraphenylborate (Keto-TPB). Single and mixed ion-associate electrodes were prepared. Both Keto-TPB and mixed (Keto-TPB and Keto(3) PT) electrodes have a linearity range of 1.00 × 10(-5) -1.00 × 10(-2) mol L(-1) . The slopes were 58.30 and 54.20 mV/decade for Keto-TPB and mixed chemically modified carbon paste electrodes (CMCPE), respectively. The limits of detection were 1.42 × 10(-6) and 1.00 × 10(-5) mol L(-1) for Keto-TPB and mixed CMCPEs, respectively. The potential variation due to pH change is considered acceptable in the pH ranges 4.44-9.11 and 2.50-9.00 for Keto-TPB and mixed ion-exchanger CMCPE, respectively. The response time was ≤10 s for both electrodes. Selectivity coefficients values towards different inorganic cations, sugars, and amino acids reflect high selectivity of the prepared electrodes. Potentiometric titrations and standard addition methods were applied for the determination of ketotifen ion in its pure samples and pharmaceutical formulations (Zaditen tablet and syrup) using proposed electrodes. The electrodes were also tested in flow injection analysis (FIA). The results obtained from both methods were statistically treated by F- and t-tests. The carbon paste electrodes have the advantages of being more easily prepared and longer life span compared to the plastic membrane electrodes previously reported.
Visitsunthorn, N; Tuchinda, M; Vichyanond, P
The study was performed in 6 Thai children with primary acquired cold urticaria. They all suffered from generalized urticaria and two of them also had angioedema. All of them had normal erythrocyte sedimentation rate, complement 3 and negative VDRL, TPHA, hepatitis B screen and cold agglutinin titer. Cryoglobulin was checked in 3 cases and showed negative results A double-blind cross-over study to compare the effectiveness of cyproheptadine and ketotifen demonstrated that the efficacy of cyproheptadine and ketotifen on clinical symptoms and ice cube test was not significantly different (p > 0.05). Both of them showed good results in the treatment of cold urticaria with mild side effects. During the follow up, 5 cases showed complete recovery while the other one developed one or two exacerbations per year upon cold exposure. However, the symptoms were mild and subsided on administration of one or two doses of H1 antihistamine. Our data demonstrated that ketotifen was as effective as cyproheptadine in the treatment of cold urticaria in Thai children.
Asnaashari, Solmaz; Delazar, Abbas; Habibi, Bohlol; Vasfi, Roghayeh; Nahar, Lutfun; Hamedeyazdan, Sanaz; Sarker, Satyajit D
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.
Hida, Wilson Takashi; Nogueira, Daniel Cruz; Schaefer, Arthur; Dantas, Paulo Elias Correa; Dantas, Maria Cristina Nishiwaki
To compare the topical use of 0.025% ketotifen fumarate and 0.1% olopatadine hydrochloride in the treatment of patients with vernal keratoconjunctivitis. A study performed in one center, simple masked, parallel-group compared ketotifen and olopatadine. These patients were evaluated on four visits during the treatment (days 1, 7, 14 and 21), defined by ratings scores. Adverse events were the main variable of safety rating. On evaluating ocular itching, burning, tearing, conjunctival hyperemia, mucous discharge and photophobia, the ketotifen group showed a significant improvement of total signs and symptoms (p<0.05). Between the baseline and the 2nd visit, treatment with olopatadine resulted in decreased burning, but after the 4th visit, ketotifen was slightly better. Sand sensation, papillae and Horner-Trantas dots were not significantly different in both groups. Both drugs were efficient and safe relieving the main symptoms and signs of vernal keratoconjunctivitis. Between the same timepoints, there was a significant difference in favor of ketotifen-treated patients (p<0.05), showing improvement of itching, tearing, conjunctival hyperemia, mucous discharge and photophobia.
Oral challenge tests with acetylsalicylic acid, tartrazine or benzoic acid were performed in 7 intolerant asthmatic patients after a 3-day treatment with either orally taken ketotifen (1 mg twice daily) or inhaled disodium cromoglycate (20 mg four times daily) at random. Protection was noted with ketotifen in 5, with DSCG in 3 patients. On the evaluation of the mean percentage of the maximum decline in the forced expiratory volume in 1 sec (FEV1) only ketotifen afforded significant protection statistically (p less than 0.05). All the intolerant asthmatics studies showed, as an immunological abnormity, a slight, but significant decrease of the C1-inhibitor levels. Moreover, in three out of these the alpha 1-antitrypsin serum values were under the lower normal range.
Haicl, P; Cerná, H
A group of 25 patients with signs of seasonal allergic conjunctivitis treated during the period of 2 to 6 month with ketotifen fumarate 0.05% eye drops 2-3 times daily (Zaditen eye drops, Novartis Ophthalmic, AG, Switzerland) is described here. As subjective symptoms of itching, stinging, tearing, and mucous discharge were observed and evaluated, as well as objective signs of hyperemia of the conjunctiva and hypertrophy of the tarsal papillae. Similarly the onset of action, duration time, and toleration of the drug were assessed. Subjective symptoms disappeared after 10 days of treatment duration in 60% to 80% patients, after two months of treatment were present in the range 0% to 20%. Objective signs diminished after 10 days of treatment in 60%-72% patients, and after 2 months in 72% to 96% of patients. Hypertrophy of papillae of the tarsal conjunctiva did not totally disappear even after 6 month of treatment with ketotifen fumarate eye drops. Onset of action in all patients was 20 minutes or less, the duration of action was in the range of 8-13 hours. The drug was found as a good tolerable by all patients. Sixteen per cent of patients felt some burning following the instillation. The study states that ketotifen fumarate 0.05% eye drops are effective in a monotherapy of seasonal allergic conjunctivitis. Due to its multiple action, the drug prevents the allergic reaction as well. Subjective symptoms are influenced faster and more effective than the objective signs. The treatment of objective signs needs prolonged use of these drops.
Rezaei, Fatemeh; Ebrahimzadeh, Mohammad Ali; Daryani, Ahmad; Sharif, Mehdi; Ahmadpour, Ehsan; Sarvi, Shahabeddin
Toxoplasma gondii is a protozoan with worldwide distribution and in spite of increasing information about its biology, treatment of toxoplasmosis is restricted to a few drugs and unfortunately using of each of drugs is associated with significant side effects in patients. This study was designed to evaluate the efficacy of cromolyn sodium and ketotifen as alternative drugs for the treatment of toxoplasmosis. In vitro; in case group, concentrations of 1, 5, 10 and 15 µg/ml of ketotifen and cromolyn sodium were added to RPMI medium containing peritoneal macrophages. After 1 h incubation and adding tachyzoites to medium, efficacy rate of these drugs in entrance inhibition of Toxoplasma tachyzoites into macrophages were evaluated after 30 and 60 min. In vivo; case groups received ketotifen and cromolyn sodium with different concentrations at various times. Control groups received none of drugs. We found that in vitro; after 60 min the best efficacy of these drugs in inhibition of cell entrance of Toxoplasma was observed at 15 µg/ml (78.9 ± 1.70 and 91.97 ± 0.37 %, respectively) (P < 0.05). In vivo; after 60 min ketotifen at 2 mg/kg in 3 h before tachyzoite injection (69.83 ± 2.25 %), and cromolyn sodium, at 10 mg/kg in 6 h before tachyzoite injection (80.47 ± 2/49 %) had the best effect on inhibition of Toxoplasma entry into the cells (P < 0.05). Our findings show that ketotifen and cromolyn sodium are suitable drugs for entrance inhibition of tachyzoites into nucleated cells in vitro and in vivo.
Mortemousque, B; Bourcier, T; Khairallah, M; Messaoud, R; Brignole-Baudouin, F; Renault, D; Rebika, H; Brémond-Gignac, D
To compare preservative-free ketotifen 0.025% ophthalmic solution to olopatadine 0.1% ophthalmic solution in with the treatment of seasonal allergic conjunctivitis (SAC) in clinical practice. This was a comparative, randomised, investigator-masked, pilot clinical study in adult patients with documented history of SAC and presenting with moderate to severe itching and conjunctival hyperemia. Eligible patients initiated either ketotifen or olopatadine treatment at a dose of one drop twice daily for 28days. The resolution of ocular signs and symptoms was assessed on day 7 and day 28. Itching was also assessed within 15minutes following the first instillation (day 0). Conjunctival impression cytology was performed at each visit to assess the evolution of ICAM-1 expression (day 0, 7 and 28). Seventy-five patients were randomised (ketotifen: 38 patients; olopatadine: 37 patients). At day 28, the composite score for primary criteria (itching, tearing, and conjunctival hyperemia) improved from 6.8±1.2 to 0.9±1.0 in the Ketotifen group, without statistically significant difference between treatment groups (P=0.67). There was no relevant difference between treatment groups in other efficacy parameters, except a trend for a more rapid resolution of conjunctival hyperemia in the Ketotifen group. Both drugs were well tolerated, with a trend for a better tolerability reported by patients on ketotifen compared to those on olopatadine at day 7 (P=0.054). A rapid and comparable improvement in SAC was achieved after 28days of treatment with both preservative-free ketotifen and preserved olopatadine ophthalmic solutions, with a slightly better ocular tolerance with unpreserved ketotifen 0.025% eye drops. Copyright © 2013. Published by Elsevier Masson SAS.
Chen, Xiaoyan; Zhong, Dafang; Liu, Dan; Wang, Yingwu; Han, Ying; Gu, Jingkai
A sensitive and specific liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed for the investigation of the pharmacokinetics of ketotifen and its major metabolite, ketotifen N-glucuronide, in human plasma. The plasma samples were treated by liquid-liquid extraction and analyzed using LC/MS/MS with an electrospray ionization interface. Diphenhydramine was used as the internal standard. The method had a lower limit of quantitation of 10 pg/mL for ketotifen, which offered increased sensitivity, selectivity and speed of analysis, compared with existing methods. The intra- and inter-day precision were measured to be below 8.2% and accuracy between -2.4% and 3.4% for all QC samples. Incubation of the plasma samples with beta-glucuronidase allowed the quantitation of ketotifen N-glucuronide. This quantitation method was successfully applied to a pharmacokinetic study of ketotifen and its major metabolite after oral administration of 2 mg ketotifen fumarate to 16 healthy volunteers.
De Luca, L
The authors studied in 30 allergic children to foods the protection of fall of spirometric flow (FEV1) after food challenge, caused by ketotifen and DSCG. The first showed a greater number of total protection = 60% in comparison with DSCG = 53.3%. The supply of both drugs at the same time showed a great amplification of protective action: total protection 73.3%, partial 20%; amount of two protections = 93.3%.
Xu, Jinku; Li, Xinsong; Sun, Fuqian
The purpose of this work was to evaluate the usefulness of silicone hydrogel contact lenses loaded with ketotifen fumarate for ocular drug delivery. First, silicone contact lenses were prepared by photopolymerization of bitelechelic methacrylated polydimethylsiloxanes macromonomer, 3-methacryloxypropyltris(trimethylsiloxy)silane, and N,N-dimethylacrylamide using ethylene glycol dimethacrylate as a cross-linker and Darocur 1173 as an initiator followed by surface plasma treatment. Then, the silicone hydrogel matrices of the contact lenses were characterized by equilibrium swelling ratio (ESR), tensile tests, ion permeability, and surface contact angle. Finally, the contact lenses were loaded with ketotifen fumarate by pre-soaking in drug solution to evaluate drug loading capacity, in vitro and in vivo release behavior of the silicone contact lenses. The results showed that ESR and ion permeability increase, and the surface contact angle and tensile strength decreased with the increase of DMA component in the silicone hydrogel. The drug loading and in vitro releases were dependent on the hydrogel composition of hydrophilic/hydrophobic phase of the contact lenses. In rabbit eyes, the pre-soaked contact lenses sustained ketotifen fumarate release for more than 24 h, which leads to a more stable drug concentration and a longer mean retention time in tear fluid than that of eye drops of 0.05%.
Soltani, Saieede; Zakeri-Milani, Parvin; Barzegar-Jalali, Mohammad; Jelvehgari, Mitra
Purpose: The objective of this study was to develop, characterize, and comparatively investigate the ketotifen fumarate (KF) nanosuspensions (NSS) to enhance the permeability of KF. Methods: In the present work, the NSP and NSE were prepared by double-emulsion solvent evaporation/nanoprecipitation methods with poly (D,Llactide-co-glycolide) and Eudragit RL100 polymers, respectively. The loading efficiency, particle size, and polydispersity index of prepared different NSs were evaluated with scanning electron microscopy (SEM), X-ray diffraction, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and in vitro release and transcorneal permeation . NSs were also compared on the basis of particle size and polydispersity index. Results: Particle size, polydispersity index, and loading efficiency of NSP1 and NSE3 showed the best value (158 nm, 117 nm, 0.21, 0.43 and 43%, 95.23%, respectively). SEM showed spherical globules and DSC results showed the reduction in crystallinity. The NSE3 formulations demonstrated significantly (p<0.05) higher drug release rates than the NSP1 due to increases in the surface area. Comparative studies showed that NSE release and permeability are higher than NSP. Conclusion: It is concluded that both NSP and NSE provide a useful dosage form for the ocular drug delivery which can enhance the permeability of KF. PMID:27766218
Nasal challenge tests were used to compare the protective effect of pre-treatment with HC 20-511 (Ketotifen), a new antiallergic compound, clemastine, DSCG and beclomethasone dipropionate in 14 patients with hay fever. HC 20-511 and clemastine were tested in a double-blind fashion and DSCG and beclomethasone openly. Most of the patients experienced an intense nasal reaction when challenged with pollens without pre-treatment. The intensity of nasal reactions was determined by subjective symptoms, clinical findings and nasal peak expiratory flow values. All the drugs tested relieved the symptoms and signs induced by pollens in nasal challenge tests. This tendency was not, however, statistically significant for any of the drugs. When using the changes in nasal expiratory flow rate as a criterion of protectiveness, the differences among the compounds tested were also slight. HC 20-511 seems to be a promising antiallergic agent. However, long term clinical trials still are needed to establish its efficacy in various allergic disorders.
Raghu, Madihalli Srinivas; Basavaiah, Kanakapura; Prashanth, Kudige Nagaraj; Vinay, Kanakapura Basavaiah
One titrimetric and two spectrophotometric methods are described for the determination of ketotifen fumarate (KTF) in bulk drug and in tablets using cerium(IV) as the oxidimetric agent. In titrimetry (method A), the drug was treated with a measured excess of cerium(IV) in H2SO4 medium and after a standing time of 10 min, the surplus oxidant was determined by back titration with iron(II). The spectrophotometric procedures involve addition of a known excess of cerium(IV) to KTF in acid medium followed by the determination of unreacted oxidant by reacting with either p-dimethyl amino benzaldehyde and measuring the resulting colour at 460 nm (method B) or o-dianisidine and subsequent measurement of the absorbance of coloured product at 470 nm (method C). Titrimetric assay is based on a 1 : 2 reaction stoichiometry between KTF and cerium(IV) and the method is applicable over 2–18 mg range. In spectrophotometry, regression analysis of Beer's law plots showed a good correlation in 0.4–8.0 and 0.4–10.0 g mL−1 KTF ranges for method B and method C, respectively, and the corresponding molar absorptivity coefficients are calculated to be 4.0 × 104 and 3.7 × 104 L mol−1 cm−1. PMID:24324496
Elsayed, M M A; Abdallah, O Y; Naggar, V F; Khalafallah, N M
Deformable liposomes and ethosomes were investigated as carriers for skin delivery of ketotifen (KT) in terms of vesicle size, entrapment efficiency, stability, in vitro permeation and skin deposition properties. Phosphatidylcholine (PC) from soybean lecithin was used in the preparation of all vesicles. Sodium cholate, sodium deoxycholate and Tween 80 were investigated as edge activators in preparation of KT deformable liposomes. KT ethosomes were prepared in two PC concentrations, 2% and 4.25% w/v, in 30% v/v ethanol. KT deformable liposomes showed improved entrapment efficiency over KT ethosomes. KT deformable liposomes with Tween 80 as an edge activator were more stable upon storage at 5 +/- 1 degree C than those prepared using sodium cholate or sodium deoxycholate and were more stable than KT ethosomes. In vitro permeation and skin deposition studies employed only deformable liposomes with Tween 80 as an edge activator and ethosomes with 4.25% w/v PC concentration. Both of them improved skin delivery of KT over controls and over traditional liposomes, with greater improvement of KT skin deposition than KT skin permeation, hence are more useful for dermal than for transdermal delivery of KT.
Soltani, Saieede; Zakeri-Milani, Parvin; Barzegar-Jalali, Mohammad; Jelvehgari, Mitra
Purpose: The objective of this study was to develop, characterize, and comparatively investigate the ketotifen fumarate (KF) nanosuspensions (NSS) to enhance the permeability of KF. Methods: In the present work, the NSP and NSE were prepared by double-emulsion solvent evaporation/nanoprecipitation methods with poly (D,Llactide-co-glycolide) and Eudragit RL100 polymers, respectively. The loading efficiency, particle size, and polydispersity index of prepared different NSs were evaluated with scanning electron microscopy (SEM), X-ray diffraction, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and in vitro release and transcorneal permeation . NSs were also compared on the basis of particle size and polydispersity index. Results: Particle size, polydispersity index, and loading efficiency of NSP1 and NSE3 showed the best value (158 nm, 117 nm, 0.21, 0.43 and 43%, 95.23%, respectively). SEM showed spherical globules and DSC results showed the reduction in crystallinity. The NSE3 formulations demonstrated significantly (p<0.05) higher drug release rates than the NSP1 due to increases in the surface area. Comparative studies showed that NSE release and permeability are higher than NSP. Conclusion: It is concluded that both NSP and NSE provide a useful dosage form for the ocular drug delivery which can enhance the permeability of KF.
Leonardi, A; Busca, F; Tavolato, M; Secchi, A G
To compare the inhibitory effects of a topical combination product, cromolyn sodium (DSCG) 4% with the antihistamine, chlorpheniramine, with those of topical ketotifen 0.05% on the clinical allergic reaction induced by the conjunctival allergen challenge (CAC). Ten allergic but non-active patients were challenged in both eyes with increasing doses of specific allergen to obtain a positive bilateral reaction (visit 1). They were then rechallenged after 1 week to confirm the allergic threshold dose response (visit 2). After 2 weeks, a third CAC was performed bilaterally 30 minutes after topical application of DSCG-chlorpheniramine in one eye and ketotifen in the contralateral eye in a double-masked fashion (visit 3). Clinical signs and symptoms were registered 5, 10, 15, and 20 minutes after challenge using the standard scoring system. Tear cytology was performed 30 minutes after challenge. Comparing the two drug effects at visit 3, DSCG-chlorpheniramine was shown to be superior to ketotifen at all time points for itching (p < 0.01) and at 5 minutes for redness (p < 0.01). For the total signs score, DSCG-chlorpheniramine was shown to be superior to ketotifen at all time points (p < 0.01), and at 10 and 15 minutes for the total symptoms score (p < 0.05). Compared to visit 2, DSCG-chlorpheniramine significantly lowered itching (p < 0.001) and redness (p < 0.05) at 5, 10, 15, and 20 minutes after challenge. Ketotifen significantly lowered itching at 5 and 10 minutes (p < 0.001) and redness at 5, 10, and 15 minutes (p < 0.05). Both drugs reduced the total number of cells evaluated by tear cytology during the early-phase reaction (p < 0.05). DSCG-chlorpheniramine was found to be more effective than ketotifen at preventing itching and redness in the CAC model.
Hoshino, M; Nakamura, Y; Sim, J J; Tomioka, H
Asthma is a chronic inflammatory disorder of the airways that is characterized by infiltration of many inflammatory cells into the bronchial mucosa. We compared the effects of ketotifen, disodium cromoglycate (DSCG), and beclomethasone dipropionate (BDP) on inflammatory cells in the bronchial mucosa and on the asthma symptoms of patients with atopic asthma. In this 12-week parallel study, 32 patients were randomly allocated to either the ketotifen group (2 mg day-1, n = 13), DSCG group (8 mg day-1, n = 9) or BDP (400 micrograms day-1, n = 10). Each subject recorded daily asthma symptoms and peak expiratory flow (PEF). Before and after treatment, pulmonary function and bronchial responsiveness to methacholine were evaluated, and fibreoptic bronchoscopy and biopsy were performed before and after treatment. Biopsy specimens were obtained by bronchoscopy. We performed immunohistochemistry using specific monoclonal antibodies for activated eosinophils (EG2), mast cells (AA1), and T cells (CD3, CD4, and CD8). Our clinical findings showed significant improvement in symptom score and bronchial responsiveness (P < 0.01) each) in all groups. Both the DSCG and the BDP groups had significantly better symptom scores than the ketotifen group (P < 0.05, both groups). PEF significantly increased in the DSCG group in comparison to the ketotifen (P < 0.01) and BDP (P < 0.05) groups, FEV1% increased significantly in the DSCG (P < 0.01) and BDP (P < 0.05) groups in comparison to the ketotifen group. Compared with their baseline values, treatment significantly decreased EG2+ activated eosinophils, and CD3+ and CD4+ T cells, in each group (P < 0.01). Both the DSCG (P < 0.05) and the BDP groups (P < 0.01) exhibited significant decreases in AA1+ mast cell count, but this was not observed in the ketotifen group. Comparing before- and after-treatment values, only the DSCG group exhibited a significant decrease in the number of CD8+ T cells (P < 0.01). Ketotifen, DSCG, and BDP all showed
Phillips, M J; Meyrick Thomas, R H; Moodley, I; Davies, R J
The effect of ketotifen was compared with that of clemastine and chlorpheniramine, known antihistamines, and sodium cromoglycate, a drug considered to have mast cell "stabilizing' properties on histamine and allergen wealing reactions in human skin, in random order, double-blind, placebo controlled studies. Ketotifen was significantly more potent in the inhibition of both histamine (P less than 0.001) and allergen (P less than 0.001) skin wealing reactions than either clemastine or chlorpheniramine. Sodium cromoglycate had no significant effect on either histamine or allergen skin wealing reactions in any of the concentrations tested. However ketotifen, like clemastine, had a significantly greater inhibitory effect on histamine than on allergen induced weals (P less than 0.001) and both drugs were shown to act as competitive antagonists of histamine. Ketotifen has been shown to be a potent anti-histamine but there is no evidence from these in vivo studies to suggest that it has any additional inhibitory activity on release of mediators from mast cells in human skin. PMID:6405771
Gmür, H; Scherrer, M
16 cooperative asthmatic patients with exercise-induced asthma (with more than 15% decrease in FEV1 after strenuous work on a treadmill with 10% upward; pulse rates over 180 per minute during the work-phase) were selected to take part in a double-blind crossover trial. The 8 women and 8 men, with ages ranging from 15 to 57 years (mean 25) underwent 4 exercise tests. The effects on exercise-induced asthma of 20 mg disodium cromoglycate (DSCG) inhaled with a spinhaler 30 minutes before exercise were compared to 2 mg of ketotifen taken orally 3 hours before exercise, and likewise DSCG was compared to a placebo powder inhaled with a spinhaler, and ketotifen with placebo tablets. The whole study lasted from January to March. Ten minutes after exercise the following changes in FEV1 (in percent of control value measured before exercise) were seen: after inhalation of a placebo powder the FEV1 decreased to 66% with an almost equal decrease after taking placebo tablets (67%) (0.45 greater than p greater than 0.40) whereas, in comparison, the decrease in FEV1 after DSCG (84%) is smaller than that after inhalation of a placebo powder (66%) (p less than 0.0025). In contrast to these results was the equal decrease in FEV1 after ketotifen (70%) (0.35 greater than p greater than 0.30) and placebo tablets (67%). Although a relatively high chosen dosage of ketotifen was given, it does not seem capable of inhibiting mediator release from the bronchial mast-cells as DSCG does. It is concluded that ketotifen given orally 3 hours before the exercise test is not effective against exercise-induced asthma.
Clarke, C W; May, C S
1 Ketotifen (HC 20-511 Sandoz) 1 mg twice daily for 12 weeks was found to be equivalent to sodium cromoglycate (SCG) 20 mg four times daily for 12 weeks in 35 skin test positive asthmatic patients in a randomised double-blind cross-over study. 2 No statistically significant difference between the two drugs in mean values for daily peak flow rates, diary card scores and spirometry at monthly visits was demonstrated. 3 Treatment failures as judged by severe asthma requiring withdrawal from the trial or addition of short courses of prednisone occurred in three patients on each drug. 4 Sedation was noted by 10 patients onHC 20-511 and 5 on SCG. 5 Weight loss was noted in those patients on SCG, but not those on HC 20-511. PMID:6108129
Frag, Eman Y Z; Mohamed, Gehad G; Khalil, Mohamed M; Hwehy, Mohammad M A
This study compares between unmodified carbon paste (CPE; the paste has no ion pair) and polyvinyl chloride (PVC) membrane selective electrodes that were used in potentiometric determination of ketotifen fumarate (KTF), where sodium tetraphenylborate (NaTPB) was used as titrant. The performance characteristics of these sensors were evaluated according to IUPAC recommendations which reveal a fast, stable, and linear response for KTF over the concentration range of 10(-7) to 10(-2) mol L(-1). The electrodes show Nernstian slope value of 52.51 ± 0.20 and 51.51 ± 0.25 mV decade(-1) for CPE and PVC membrane electrodes at 30°C, respectively. The potential is nearly stable over the pH range 3.0-6.0 and 2.0-7.0 for CPE and PVC membrane electrodes, respectively. Selectivity coefficient values towards different inorganic cations, sugars, and amino acids reflect high selectivity of the prepared electrodes. The electrodes responses at different temperatures were also studied, and long operational lifetime of 12 and 5 weeks for CPE and PVC membrane electrodes, respectively, were found. These are used for determination of ketotifen fumarate using potentiometric titration, calibration, and standard addition methods in pure samples, its pharmaceutical preparations (Zaditen tablets), and biological fluid (urine). The direct potentiometric determination of KTF using the proposed sensors gave recoveries % of 98.97 ± 0.53 and 98.62 ± 0.74 with RSD 1.42 and 0.63% for CPE and PVC membrane selective electrodes, respectively. Validation of the method shows suitability of the proposed sensors for use in quality control assessment of KTF. The obtained results were in a good agreement with those obtained using the reported spectrophotometric method.
Frag, Eman Y. Z.; Mohamed, Gehad G.; Khalil, Mohamed M.; Hwehy, Mohammad M. A.
This study compares between unmodified carbon paste (CPE; the paste has no ion pair) and polyvinyl chloride (PVC) membrane selective electrodes that were used in potentiometric determination of ketotifen fumarate (KTF), where sodium tetraphenylborate (NaTPB) was used as titrant. The performance characteristics of these sensors were evaluated according to IUPAC recommendations which reveal a fast, stable, and linear response for KTF over the concentration range of 10−7 to 10−2 mol L−1. The electrodes show Nernstian slope value of 52.51 ± 0.20 and 51.51 ± 0.25 mV decade−1 for CPE and PVC membrane electrodes at 30°C, respectively. The potential is nearly stable over the pH range 3.0–6.0 and 2.0–7.0 for CPE and PVC membrane electrodes, respectively. Selectivity coefficient values towards different inorganic cations, sugars, and amino acids reflect high selectivity of the prepared electrodes. The electrodes responses at different temperatures were also studied, and long operational lifetime of 12 and 5 weeks for CPE and PVC membrane electrodes, respectively, were found. These are used for determination of ketotifen fumarate using potentiometric titration, calibration, and standard addition methods in pure samples, its pharmaceutical preparations (Zaditen tablets), and biological fluid (urine). The direct potentiometric determination of KTF using the proposed sensors gave recoveries % of 98.97 ± 0.53 and 98.62 ± 0.74 with RSD 1.42 and 0.63% for CPE and PVC membrane selective electrodes, respectively. Validation of the method shows suitability of the proposed sensors for use in quality control assessment of KTF. The obtained results were in a good agreement with those obtained using the reported spectrophotometric method. PMID:22013443
Zhu, Lina; Ao, Junping; Li, Peiling
In this study, an ion-activated ketotifen ophthalmic delivery system was developed by using a natural polysaccharide, deacetylase gellan gum. Its rheological characteristics, stability, in vitro gelation, release in vitro, and pharmacodynamic activity in vivo were investigated. The formulation had an optimum viscosity that will allow easy drop as a liquid, which then underwent a rapid sol-gel transition due to ionic interaction. There were negligible alterations in the initial values of viscosity of the formulations over a storage period of 180 days. The in vitro release profiles indicated that the release of ketotifen from in situ gels exhibited a sustained feature. Scintigraphic studies indicated that deacetylase gellan gum could increase the residence time of the formulation. At the same dose, in situ gels demonstrated a typical sustained and prolonged drug-effects behavior compared with the common drops.
Zhu, Lina; Ao, Junping; Li, Peiling
In this study, an ion-activated ketotifen ophthalmic delivery system was developed by using a natural polysaccharide, deacetylase gellan gum. Its rheological characteristics, stability, in vitro gelation, release in vitro, and pharmacodynamic activity in vivo were investigated. The formulation had an optimum viscosity that will allow easy drop as a liquid, which then underwent a rapid sol–gel transition due to ionic interaction. There were negligible alterations in the initial values of viscosity of the formulations over a storage period of 180 days. The in vitro release profiles indicated that the release of ketotifen from in situ gels exhibited a sustained feature. Scintigraphic studies indicated that deacetylase gellan gum could increase the residence time of the formulation. At the same dose, in situ gels demonstrated a typical sustained and prolonged drug-effects behavior compared with the common drops. PMID:26251573
Yamada, Koji; Takizawa, Fumitake; Tamura, Tadafumi; Kanda, Tomoyuki
Clinical reports have shown that some antihistamines, such as ketotifen, occasionally produced seizures, especially in pre-school age children or young patients with epilepsy. The purpose of this study was to investigate whether olopatadine, one of the most efficacious antihistamines, promotes seizures induced by electroshocks in young rats. We investigated the seizures induced by electroshock using increasing-current delivery in 3- or 4-week-old rats, and found that the threshold-current of tonic extensor seizures was elevated with age in weeks in the vehicle-treatment groups. While caffeine decreased the threshold-current in every age group of rats, pentylenetetrazole, a γ-aminobutyric acid (GABA)(A) receptor antagonist, significantly decreased them only in 4-week-old rats. On the other hand, ketotifen decreased them only in 3-weeks-old rats. In the 3-week-old rats, neither olopatadine nor fexofenadine had any effect on the threshold-currents of tonic extensor seizures. These results showed that histaminergic neuro-transmission in the brain plays a crucial role in inhibiting seizures in rats soon after weaning, but is no longer effective in rats as they approach sexual maturation. In addition, unlike ketotifen, olopatadine, as well as fexofenadine, do not promote the occurrence of seizures in infant rats.
Mokhtari, Ali; Ghazaeian, Mehrgan; Maghsoudi, Mahdieh; Keyvanfard, Mohsen; Emami, Iraj
A new method using chemiluminescence (CL) detection has been developed for the simple determination of ketotifen fumarate (KF). The method is based on the catalytic effect of KF in the CL reaction of tris(1,10 phenanthroline)ruthenium(II), Ru(phen)3 (2+), with Ce(IV) in sulfuric acid medium. The CL response was detected using a lab-made chemiluminometer. Effects of chemical variables were investigated and under optimum conditions, the CL intensity was proportional to the concentration of the drug over the range 0.34-34.00 µg mL(-1) KF. The limit of detection (S/N=3) was 0.09 µg mL(-1). Effects of common ingredients were investigated and the method was applied successfully for determining KF in pharmaceutical formulations and human plasma. The percent of relative standard deviation (n=11) at level of 3.4 µg mL(-1) of KF was 4.6% and the minimum sampling rate was 70 samples per hour. The possible CL mechanism is proposed based on the kinetic characteristic of the CL reaction, CL spectrum, UV-Vis and phosphorescence spectra.
Monument, Michael J.; Hart, David A.; Befus, A. Dean; Salo, Paul T.; Zhang, Mei; Hildebrand, Kevin A.
Background The propensity of the elbow to become stiff after trauma is widely appreciated and in this setting, the joint capsule is commonly recognized as the major motion-limiting anatomical structure. Affected joint capsules become fibrotic, characterized by myofibroblast hyperplasia and excessive collagen deposition. Mast cell hyperplasia is common within fibrotic tissue and mast cells are known to synthesize many profibrotic mediators. We have hypothesized that mast cell inhibition after skeletal injury will lessen the degree of contracture severity and will reduce myofibroblast hyperplasia within the joint capsule. Methods Posttraumatic contractures of the knee were created using a combination of intra-articular injury coupled to internal immobilization in skeletally mature, New Zealand white rabbits. Four groups of animals were studied: a non-operative control group (CON), an operative contracture group (ORC) and two-operative groups treated with a mast cell stabilizer, Ketotifen fumarate at doses of 0.5mg/kg (KF0.5) and 1.0mg/kg (KF1.0) twice daily, respectively. After 8 weeks of immobilization, flexion contractures were measured biomechanically and the posterior joint capsule was harvested for quantification of myofibroblast and mast cell numbers. Results Flexion contractures developed in the ORC group (58 ± 14°) and the severity of contracture was significantly reduced in both groups treated with Ketotifen (KF0.5: 42 ± 17° and KF1.0: 45 ± 10°, p<0.02). Joint capsule myofibroblast and mast cell numbers were significantly increased within the operative contracture group (p<0.001). In both surgical groups treated with Ketotifen, myofibroblast and mast cell numbers were significantly reduced (p<0.001). Conclusions The use of a mast cell stabilizer, Ketotifen was effective in reducing the biomechanical and cellular manifestations of joint capsule fibrosis in a rabbit model of posttraumatic joint contracture. This is suggestive that an inflammatory pathway
Soltani, Saieede; Zakeri-Milani, Parvin; Barzegar-Jalali, Mohammad; Jelvehgari, Mitra
Objective(s): Ketotifen fumarate (KF) is a selective and noncompetitive histamine antagonist (H1-receptor) that is used topically in the treatment of allergic conditions of rhinitis and conjunctivitis. The aim of this study was to formulate and improve an ophthalmic delivery system of KF. Ocular nanoparticles were prepared with the objective of reducing the frequency of administration and obtaining controlled release to improve the anti-inflammatory drug delivery. Materials and Methods: In the present study, ocular KF loaded Eudragit RL 100 nanoparticles were prepared using O/W solvent diffusion method. The nanoparticles were evaluated for particle size, entrapment efficiency, surface morphology, X-ray diffraction (XRD), Fourier transform spectroscopy (FTIR), and differential scanning calorimetry (DSC). In vitro release and permeation studies were also carried out on nanoparticles. Results: An average size range of 182 to 314.30 nm in diameter was obtained and encapsulation efficiency up to 95.0% was observed for all the formulations. Drug release for all formulations after 24 hr was between 65.51% and 88.82% indicating effective controlled release property of KF. The mechanism of drug release for best formulation was found to be fickian diffusion mechanism. KF nanoparticles containing high polymer concentration (1:15) presented a faster drug release and a higher drug penetration; on the contrary, nanoparticles containing low polymer concentration (1:7.5) were able to give a more sustained release of the drug and thus a slower KF permeation through the cornea. Conclusion: The study revealed that KF NPs were capable of releasing the drug for a prolonged period of time and increasing the ocular bioavailability. PMID:27403262
Acikgoz, Abdullah; Asci, Ramazan; Aydin, Oguz; Çavuş, Hikmet; Donmez, Gamze; Buyukalpelli, Recep
The aims of this study conducted on rats were to determine mast cell (MC) proliferation on undescended testes (UDTs); whether there is a correlation between MC proliferation and testicular damage; and whether testicular damage can be prevented with administration of an MC blocker. Sixty-five newborn male rats were divided into three groups. During the neonatal period, unilateral UDTs were experimentally induced in Group 2 and Group 3. The rats in Group 3 were given 1 mg/kg/day ketotifen orally until the end of the study. Groups 2 (n=30) and 3 (n=15) were divided into groups of ten and five rats, respectively, each of which underwent bilateral orchiectomy in either the prepubertal, pubertal, or adult period. Group 1 (n=15) underwent a sham operation followed by bilateral orchiectomy, with five rats in each of the prepubertal, pubertal, and adult periods. Testicular MCs in the interstitial and subtubular areas, biopsy scores, interstitial connective tissue, seminiferous tubule (ST) diameters, and the basement membrane thickness of STs were evaluated. In Group 2 the ST diameters in the UDTs decreased, the number of MCs in the interstitial and subtubular areas increased, ST basement membranes thickened, and spermatogenesis decreased. The number of MCs in the interstitial and subtubular areas of the descended testes increased and spermatogenesis decreased. In Group 3, the number of MCs in the interstitial and subtubular areas decreased. In unilateral UDTs, the number of MCs in the interstitial and subtubular areas increased in both testes. Fibrosis developed in the ST basement membranes and interstitial areas, and spermatogenesis deteriorated. Testicular fibrosis may be prevented with administration of an MC blocker. PMID:25364234
Brain histamine H1 receptor occupancy of orally administered antihistamines measured by positron emission tomography with 11C-doxepin in a placebo-controlled crossover study design in healthy subjects: a comparison of olopatadine and ketotifen
Tashiro, Manabu; Mochizuki, Hideki; Sakurada, Yumiko; Ishii, Kenji; Oda, Keiichi; Kimura, Yuichi; Sasaki, Toru; Ishiwata, Kiichi; Yanai, Kazuhiko
Aims The strength of sedation due to antihistamines can be evaluated by using positron emission tomography (PET). The purpose of the present study is to measure histamine H1 receptor (H1R) occupancy due to olopatadine, a new second-generation antihistamine and to compare it with that of ketotifen. Methods Eight healthy males (mean age 23.5 years-old) were studied following single oral administration of olopatadine 5 mg or ketotifen 1 mg using PET with 11C-doxepin in a placebo-controlled crossover study design. Binding potential ratio and H1R occupancy were calculated and were compared between olopatadine and ketotifen in the medial prefrontal (MPFC), dorsolateral prefrontal (DLPFC), anterior cingulate (ACC), insular (IC), temporal (TC), parietal (PC), occipital cortices (OC). Plasma drug concentration was measured, and correlation of AUC to H1R occupancy was examined. Results H1R occupancy after olopatadine treatment was significantly lower than that after ketotifen treatment in the all cortical regions (P < 0.001). Mean H1R occupancies for olopatadine and ketotifen were, respectively: MPFC, 16.7 vs. 77.7; DLPFC, 14.1 vs. 85.9; ACC, 14.7 vs. 76.1; IC, 12.8 vs. 69.7; TC, 12.5 vs. 66.5; PC, 13.9 vs. 65.8; and OC, 19.5 vs. 60.6. Overall cortical mean H1R occupancy of olopatadine and ketotifen were 15% and 72%, respectively. H1R occupancy of both drugs correlated well with their respective drug plasma concentrations (P < 0.001). Conclusion It is suggested that 5 mg oral olopatadine, with its low H1R occupancy and thus minimal sedation, could safely be used an antiallergic treatment for various allergic disorders. Abbreviations histamine H1 receptor (H1R), histamine H1 receptor occupancy (H1RO), dopamine D2 receptor (D2R), positron emission tomography (PET), blood–brain barrier (BBB), binding potential ratio (BPR), distribution volume (DV) PMID:16390347
Efficacy of olopatadine HCI 0.1%, ketotifen fumarate 0.025%, epinastine HCI 0.05%, emedastine 0.05% and fluorometholone acetate 0.1% ophthalmic solutions for seasonal allergic conjunctivitis: a placebo-controlled environmental trial.
Borazan, Mehmet; Karalezli, Aylin; Akova, Yonca Aydin; Akman, Ahmet; Kiyici, Halil; Erbek, Selim S
We aimed to compare the clinical efficacy and ocular surface variables of olopatadine, ketotifen fumarate, epinastine, emedastine and fluorometholone acetate ophthalmic solutions in preventing the signs and symptoms of seasonal allergic conjunctivitis (SAC). This was a prospective, randomized, double-blinded and placebo-controlled study. A total of 100 patients with SAC were randomly assigned to one of five groups, in which they were administered olopatadine, ketotifen fumarate, epinastine, emedastine or fluorometholone acetate, instilled twice daily for 2 weeks. One eye of each patient was treated with the study drug and the other was treated with a placebo. Signs and symptoms of allergic conjunctivitis (itching, redness, tearing, chemosis and eyelid swelling) were scored on a 4-point scale. Each symptom was assessed at baseline and then again after 1 and 2 weeks of treatment. Ocular surface variables were assessed by conjunctival impression cytology. At weeks 1 and 2, all antiallergic agents were significantly more effective than placebo in alleviating itching, redness, tearing, chemosis and eyelid swelling. Fluorometholone acetate was significantly less effective than the other agents in reducing itching and redness at all control visits. Ocular surface findings by impression cytology improved significantly after all treatments compared with placebo. In patients with SAC, olopatadine, ketotifen, epinastine and emedastine are more efficacious than fluorometholone acetate in preventing itching and redness. All the antiallergic agents gave similar results in terms of reducing tearing, chemosis and eyelid swelling. Our data showed that impression cytology parameters improved after treatment with antiallergic agents in patients with SAC.
Zi-qing, Hei; Xiao-liang, Gan; Pin-jie, Huang; Jing, Wei; Ning, Shen; Wan-ling, Gao
Background Mast cells were associated with intestinal ischemia-reperfusion injury, the study was to observe the influence of Ketotifen, Cromolyn Sdium(CS), and Compound 48/80(CP) on the survival rates on the third day after intestinal ischemia-reperfusion injury in rats. Methods 120 healthy Sprague-Dawley rats were randomly divided into 5 groups, Sham-operated group (group S), model group (group M), group K, group C and group CP. Intestinal damage was triggered by clamping the superior mesenteric artery for 75 minutes, group K, C, and CP were treated with kotifen 1 mg·kg-1, CS 50 mg·kg-1, and CP 0.75 mg·kg-1 i.v. at 5 min before reperfusion and once daily for three days following reperfusion respectively. Survival rate in each group was recorded during the three days after reperfusion. All the surviving rats were killed for determining the concentration of serum glutamic-oxaloacetic transaminase(AST), glutamic pyruvic transaminase(ALT), the ratio of AST compare ALT(S/L), total protein(TP), albumin(ALB), globulin(GLB), the ratio of ALB compare GLB(A/G), phosphocreatine kinase(CK), lactate dehydrogenase(LDH), urea nitrogen(BUN) and creatinine(CRE) at the 3rd day after reperfusion. And ultrastructure of IMMC, Chiu's score, lung histology, IMMC counts, the levels of TNF-α, IL-1β, IL-6 and IL-10 of the small intestine were detected at the same time. Results Intestinal ischemia-reperfusion injury reduced the survival rate. The concentrations of TP, ALB and level of IL-10 in intestine in group M decreased significantly while the concentrations of S/L, LDH and the levels of IL-6 and TNF-α in intestine increased significantly compared with group S (P < 0.05). Treatment with Ketotifen and CS increased the survival rate compared with group M (P < 0.05), attenuated the down-regulation or up-regulation of the above index (P < 0.05). Treatment with CP decreased the survival rate on the 3rd day after reperfusion compared with group M(P < 0.05). Group K and C had better
Wada, Yuko; Ami, Shyoko; Nozawa, Mitsuru; Goto, Miho; Shimokawa, Ken-Ichi; Ishii, Fumiyoshi
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.
7 5. Changes/ Problems ...….……………………………………………… 7 6. Products…………………………………….……….….……………. 7 7. Participants & Other Collaborating...on society beyond science and technology? Nothing to report. 5. CHANGES/ PROBLEMS Changes in approach and reasons for change Nothing to report...Actual or anticipated problems or delays and actions or plans to resolve them No problems in the current reporting period. The anticipated implementation
Elsayed, Mustafa M A; Abdallah, Ossama Y; Naggar, Viviane F; Khalafallah, Nawal M
Despite intensive research, the mechanisms by which vesicular systems deliver drugs into intact skin are not yet fully understood. In the current study, possible mechanisms by which deformable liposomes and ethosomes improve skin delivery of ketotifen under non-occlusive conditions were investigated. In vitro permeation and skin deposition behavior of deformable liposomes and ethosomes, having ketotifen both inside and outside the vesicles (no separation of free ketotifen), having ketotifen only inside the vesicles (free ketotifen separated) and having ketotifen only outside the vesicles (ketotifen solution added to empty vesicles), was studied using rabbit pinna skin. Results suggested that both the penetration enhancing effect and the intact vesicle permeation into the stratum corneum might play a role in improving skin delivery of drugs by deformable liposomes, under non-occlusive conditions, and that the penetration enhancing effect was of greater importance in case of ketotifen. Regarding ethosomes, results indicated that ketotifen should be incorporated in ethosomal vesicles for optimum skin delivery. Ethosomes were not able to improve skin delivery of non-entrapped ketotifen.
Previous editions are obsolete. SECURITY CLASSIFICATION OF THIS PAGE 19. Trials with other drugs, ketotifen, cyproheptadine , combretestatin, and an aryl...regimen. Recent studies of in vivo reversal of chloroquine- resistance have used the following drugs: WR 267634, ketotifen; WR 35917, cyproheptadine ; WR...WR 035917AB (BN:BL 08170), cyproheptadine M. WR 267634AC (BN:BM 01916), ketotifen 25 N. WR 035917AB (BN:BM 08170), cyproheptadine 26 0. WR 268766AA
of WR 26763AC (BN:BM 01916), ketotifen WR 035917AB (BN:BL 08170), cyproheptadine WR 1544BM (BN:AR 20613), chloroquine 42 H. Conclusions 43 hL _ _ -5...WR 6379, prochlorperazine plus WR 1544, chloroquine 52 19. Toxicity evaluation of WR 267634, ketotifen, and WR 035917, cyproheptadine , both in...days. Am - 42 - G. Limited toxicity evaluation of WR 267634AC(BN:BM 01916), ketotifen, and WR 035917AB(BN:BL 08170), cyproheptadine , both in combination
chloroquine- (12), ketotifen (1), tetrandrine (20, 21), and cyproheptadine susceptible clone D6 (50% inhibitory concentration [IC 5o], (16). !s3 ng/ml). IC... CYPROHEPTADINE KETOTIFEN N OCN3 HICO N ’IN ~~OCH3 NN H 0 OCH.3 TETRANDRINE FIG. 1. Structures of fluoxetine and other drugs that have been reported to
Unno, Katsuya; Ozaki, Tomoya; Mohammad, Shahid; Tsuno, Saki; Ikeda-Sagara, Masami; Honda, Kazuki; Ikeda, Masayuki
First generation H₁ histamine receptor antagonists, such as d-chlorpheniramine (d-CPA) and diphenhydramine, produce drowsiness in humans. They are currently used as over-the-counter sleep aids. However, the mechanisms underlying drowsiness induced by these H₁ histamine receptor antagonists remain obscure because they produce heterogeneous receptor-independent actions. Ketotifen is a second generation H₁ histamine receptor antagonist which is more permeable to the brain than newer H₁ histamine receptor antagonists. Therefore, to access sleep-inducing profiles by H₁ histamine receptor blocking actions, the present study compared the dose-dependent effects of diphenhydramine and ketotifen (1-40 mg/kg, intraperitoneal injection at dark onset time) on daily sleep-wake patterns in rats. Ketotifen dose-dependently decreased rapid-eye-movement (REM) sleep and increased non-REM sleep by amplifying slow-wave electroencephalogram powers. Diphenhydramine at 4 mg/kg transiently increased non-REM sleep and reduced REM sleep similar to the effects of ketotifen. The larger injections of diphenhydramine (10-40 mg/kg), however, reduced non-REM sleep, abolished slow-wave enhancements and facilitated wakefulness. The bi-directional action of diphenhydramine on sleep is similar to our former results using d-CPA. Taken together, the arousal effects caused by over-dose administrations of the first generation H₁ histamine receptor antagonists may be mediated by H₁ histamine receptor-independent actions. To further examine the tolerance of ketotifen-induced sleep, 3 mg/kg ketotifen was injected daily for 5 days 3 h before light onset time. These experiments consistently enhanced non-REM-sleep at the end of the active phase of rats, suggesting that ketotifen may function as a desirable sleep aid although the coincidental REM sleep reduction requires attention. Copyright © 2012 Elsevier B.V. All rights reserved.
The, Frans O; Buist, Marrije R; Lei, Aaltje; Bennink, Roelof J; Hofland, Jan; van den Wijngaard, René M; de Jonge, Wouter J; Boeckxstaens, Guy E
Although postoperative ileus (POI) is considered multifactorial, intestinal inflammation resulting from manipulation-induced mast cell activation is recognized as an important pathophysiological mechanism. Therefore, mast cell stabilization may represent a new therapeutic approach to shortening POI. The aim of this paper was to study the effect of ketotifen, a mast cell stabilizer, on postoperative gastrointestinal transit in patients who underwent abdominal surgery. In this pilot study, 60 patients undergoing major abdominal surgery for gynecological malignancy with standardized anesthesia were randomized to treatment with ketotifen (4 or 12 mg) or placebo. Patients were treated for 6 days, starting 3 days before surgery. Gastric emptying of liquids, selected as a primary outcome parameter, was measured 24 h after surgery using scintigraphy. Secondary end points were (scintigraphically assessed) colonic transit, represented as geometrical center of activity (segment 1(cecum) to 7(stool)) and clinical parameters. Gastric retention 1 h after liquid intake was significantly reduced by 12 mg (median 3% (1-7), P=0.01), but not by 4 mg ketotifen (18% (3-45), P=0.6) compared with placebo (16% (5-75)). Twenty-four hour colonic transit in placebo was 0.8 (0.0-1.1) vs. 1.2 (0.2-1.4) colon segments in the 12 mg ketotifen group (P=0.07). Abdominal cramps were significantly relieved in patients treated with 12 mg ketotifen, whereas other clinical parameters were not affected. Ketotifen significantly improves gastric emptying after abdominal surgery and warrants further exploration of mast cell stabilizers as putative therapy for POI.
Figus, Michele; Fogagnolo, Paolo; Lazzeri, Stefano; Capizzi, Federica; Romagnoli, Mariachiara; Canovetti, Annalisa; Iester, Michele; Ferreras, Antonio; Rossetti, Luca; Nardi, Marco
To compare the effects of topical antiallergic eyedrops in relieving the signs and symptoms of patients with allergic conjunctival pathology. In this multicenter, single-masked, randomized study, 240 patients with signs and symptoms of allergic conjunctivitis were randomized to receive 1 of the following 8 treatments twice daily: cromolyn sodium/chlorpheniramine maleate, diclofenac, epinastine, fluorometholone, ketotifen, levocabastine, naphazoline/antazoline, and olopatadine. Clinical signs and symptoms were evaluated by a masked operator using a 10-point scale at the moment of enrollment (day 0) and at weeks 1, 2, and 4. The percentage of patients achieving at least a small (at least 50% reduction of the total scale score) or a good (at least 75%) improvement of signs and symptoms was calculated at each visit. Tolerability was also evaluated as the duration of discomfort after instillation. All drugs gave some improvement in symptoms in more than 85% of cases. Epinastine and olopatadine obtained at least a good relief of symptoms in 37% and 33% of cases at week 1. At the end of the study, good improvement of symptoms was obtained in at least 70% of patients by epinastine, ketotifen, fluorometholone, and olopatadine, whereas a 75% improvement for signs was obtained only by fluorometholone and ketotifen. Naphazoline/antazoline induced higher discomfort compared to the other study treatments (p<0.0001). The efficacy of epinastine, ketotifen, and olopatadine in the treatment of allergic conjunctivitis was comparable to fluorometholone. Naphazoline/antazoline had lower tolerability than the other study treatments.
Eastman, Richard T; Pattaradilokrat, Sittiporn; Raj, Dipak K; Dixit, Saurabh; Deng, Bingbing; Miura, Kazutoyo; Yuan, Jing; Tanaka, Takeshi Q; Johnson, Ronald L; Jiang, Hongying; Huang, Ruili; Williamson, Kim C; Lambert, Lynn E; Long, Carole; Austin, Christopher P; Wu, Yimin; Su, Xin-Zhuan
Malaria is a deadly infectious disease in many tropical and subtropical countries. Previous efforts to eradicate malaria have failed, largely due to the emergence of drug-resistant parasites, insecticide-resistant mosquitoes and, in particular, the lack of drugs or vaccines to block parasite transmission. ATP-binding cassette (ABC) transporters are known to play a role in drug transport, metabolism, and resistance in many organisms, including malaria parasites. To investigate whether a Plasmodium falciparum ABC transporter (Pf14_0244 or PfABCG2) modulates parasite susceptibility to chemical compounds or plays a role in drug resistance, we disrupted the gene encoding PfABCG2, screened the recombinant and the wild-type 3D7 parasites against a library containing 2,816 drugs approved for human or animal use, and identified an antihistamine (ketotifen) that became less active against the PfABCG2-disrupted parasite in culture. In addition to some activity against asexual stages and gametocytes, ketotifen was highly potent in blocking oocyst development of P. falciparum and the rodent parasite Plasmodium yoelii in mosquitoes. Tests of structurally related tricyclic compounds identified additional compounds with similar activities in inhibiting transmission. Additionally, ketotifen appeared to have some activity against relapse of Plasmodium cynomolgi infection in rhesus monkeys. Further clinical evaluation of ketotifen and related compounds, including synthetic new derivatives, in blocking malaria transmission may provide new weapons for the current effort of malaria eradication.
A 76-year-old man with a longstanding history of cold sensitivity developed wheals after the application of an ice cube. Cold urticaria is a type of physical urticaria that is characterized urticaria and angioedema after exposure to cold. It may be idiopathic or secondary to hematologic or infectious diseases. Treatment of primary cold urticaria includes antihistamines; however, ketotifen, doxantrazole, zafirlukast, cyclosporine, and cold-tolerance induction may be tried in refractory cases.
Shii, Daisuke; Oda, Tomoko; Shinomiya, Katsuhiko; Katsuta, Osamu; Nakamura, Masatsugu
The effects of cyclosporine A eye drops on the early-phase reaction were investigated in a type-I allergic conjunctivitis model. Mice were actively sensitized with ragweed (RW) absorbed on aluminium hydroxide gel and challenged with RW for 10 days (single challenge model) or 10-14 days (repetitive challenge model) after the first sensitization. For the evaluation of itching, ovalbumin was used as an antigen instead of RW. The effects of cyclosporine A eye drops on increased vascular permeability, mast cell degranulation, and itching were evaluated and compared with those of other anti-allergic eye drops. In the single challenge model, cyclosporine A eye drops significantly inhibited the increase in vascular permeability and histological evaluations showed suppressed degranulation of mast cells. Disodium cromoglycate (DSCG) eye drops showed only a slight tendency to inhibit the increase in both pathophysiological parameters. Ketotifen or betamethasone eye drops significantly inhibited the increase in vascular permeability. The order of potency in the single challenge model was ketotifen > cyclosporine A > betamethasone. In the repetitive challenge model, cyclosporine A eye drops significantly inhibited the increase in vascular permeability and DSCG eye drops showed only slight inhibition. Ketotifen or betamethasone significantly inhibited the increase in vascular permeability. The order of potency in the repetitive challenge model was cyclosporine A > betamethasone > ketotifen. The effect of cyclosporine A eye drops on the itch-scratch response was studied. Cyclosporine A and DSCG significantly reduced the itch-scratch response in the single and repetitive challenge models; the effect of cyclosporine A in the repetitive challenge model was more potent than in the single challenge model. Those results suggest that administration of cyclosporine A eye drops inhibit the early-phase reaction in type-I allergic conjunctivitis, which may be mediated by the suppression of
vitro and included verapami., chlorprcmazine, pinch- lorperarine, cyprohaptadir.e. Icetatifen, a tiapamil analog (LRo :1-2933), an~d a chlorpromazine ...Actus: Chlorpromazine > prochior- peinazine > desipramine > Ro 11-2933 (tiapamil ar.alog)> kqtotý`fen. Cyprohoptading and vezaparnil were not... chlorpromazine , proch- lorperazine, cyproheptadine, ketotifen, a tiapamil analog (Ro 11-2933), and a chlorprom- azine analog (SKF 2133-A). Combinations of
Kubes, P; Kanwar, S; Niu, X F; Gaboury, J P
Recent work has demonstrated that inhibition of nitric oxide production with various nitric oxide synthesis inhibitors (L-NAME, L-NMMA) initiate leukocyte adhesion to postcapillary venules. The objective of this study was to elucidate the mechanism (or mechanisms) that promote the L-NAME-induced leukocyte response. Intravital microscopy was used to examine 25-40 microns venules in the rat mesentery. Nitric oxide synthesis was inhibited with L-NAME and leukocyte adhesion was observed over the first 60 min. The fourfold increase in leukocyte adhesion was independent of alterations in venular red blood cell velocity. The adhesion was superoxide-mediated inasmuch as superoxide dismutase (SOD) abolished the rise in leukocyte adhesion associated with nitric oxide synthesis inhibition. Ketotifen, a mast cell stabilizer, also abolished the rise in leukocyte adhesion induced by L-NAME. Histology revealed that mast cell degranulation occurred only in animals treated with L-NAME but not in animals pretreated with SOD or ketotifen. This observation suggests that mast cells become activated in the absence of nitric oxide production and superoxide contributes to the mast cell activation. The L-NAME-induced leukocyte adhesion could be reproduced by infusing hypoxanthine/xanthine oxidase (a superoxide generating system) or compound 48/80 (an activator of mast cells) and both responses were attenuated by ketotifen. These data suggest that inhibition of nitric oxide synthesis results in a superoxide and mast cell-dependent leukocyte adhesion.
Morgan, D J; Moodley, I; Cundell, D R; Sheinman, B D; Smart, W; Davies, R J
Plasma histamine and serum neutrophil chemotactic activity (S-NCA) were measured in ten atopic asthmatic patients on four separate occasions after allergen bronchial provocation testing (BPT). Single doses of inhaled sodium cromoglycate (SCG; 20 mg), clemastine (0.5 mg), ketotifen (0.5 mg) and isotonic saline (0.9% NaCl) placebo were administered 30 min before bronchial provocation testing in random order and double-blind. The airflow obstruction after BPT was monitored by measurement of forced expiratory volume in 1 s (FEV1). Plasma histamine was measured by the double-isotope radioenzymatic assay and S-NCA by a modified Boyden chamber technique. A highly significant decrease in FEV1 after BPT occurred on the placebo pre-treatment visit (P less than 0.001). Prior administration of inhaled SCG, clemastine and ketotifen significantly reduced the decrease in airflow obstruction seen after BPT when compared with placebo treatment (P less than 0.01, P less than 0.02, P less than 0.05 respectively). No significant alteration in plasma histamine was detected during allergen-induced airflow obstruction. Levels of S-NCA were significantly higher 5, 10 and 15 min after BPT when compared with the pre-challenge level (P less than 0.01, P less than 0.01, P less than 0.001 respectively). These levels were not significantly decreased when airflow obstruction was inhibited by the prior inhalation of SCG, clemastine or ketotifen.
Bahr, T; Schaper, U; Becker, K; Lueddeckens, G; Förster, W; Scheuch, D W; Grupe, R; Göres, E
Experiments were carried out to lower the mortality (LD70-90) of rats in ovalbumin-induced anaphylactic (DA) shock and in endotoxin-induced (ET) shock, and of mice after injection of Platelet-activating Factor (PAF shock) comparing the effects of the cyclooxygenase (COX)-inhibitors aspirin (ASA), indomethacin, of the COX-/lipoxygenase (LOX)-inhibitors nordihydroguajaretic acid (NDGA), phenidone and X 86 (analogue of BW 755c), of the inhibitor of thromboxane (TX) synthesis HOE 944, of the TX-antagonist BM 13177, of the PAF-antagonist BN 52021 and of ketotifen. Ketotifen was strongly effective in DA shock, COX- and LOX-inhibitors only slightly. Combined COX- and LOX-inhibitors and BN 52021 showed good effects in the ET shock. Ketotifen was inefficacious. All the used substances influenced the PAF shock. The shock syndromes were biochemically characterized by determination of isocitratedehydrogenase (ICDH) activity, lactate, glucose, haematocrit, numbers of thrombocytes and leucocytes, TXB2 and 6-keto-Prostaglandin(PG)F1 alpha.
Sinniah, Ajantha; Yazid, Samia; Perretti, M; Solito, Egle; Flower, R J
1.We investigated the role of Annexin (ANX)-A1 and its receptor, ALX/FPR2, in the regulation of mast cell degranulation produced by compound 48/80. 2.Both human cord-blood derived mast cells (CBDMCs) and murine bone marrow derived mast cells (BMDMCs) release phosphorylated ANX-A1 during treatment with glucocorticoids or the mast cell 'stabilising' drugs ketotifen and nedocromil. 3.Compound 48/80 also stimulated ANX-A1 phosphorylation and release and this was also potentiated by nedocromil. Anti-ANX-A1 neutralising monoclonal antibodies (Mabs) enhanced the release of pro-inflammatory mediators in response to compound 48/80. 4.Nedocromil and ketotifen potently inhibited the release of histamine, PGD2, tryptase and β-hexosaminidase from mast cells challenged with compound 48/80. Anti-ANX-A1 neutralising Mabs prevented the inhibitory effect of these drugs. 5.BMDMCs derived from Anx-A1−/− mice were insensitive to the inhibitory effects of nedocromil or ketotifen but cells retained their sensitivity to the inhibitory action of hu-r-ANX-A1. 6.The fpr2/3 antagonist WRW4 blocked the action of nedocromil on PGD2, but not histamine, release. BMDMCs derived from fpr2/3−/− mice were insensitive to the inhibitory effects of nedocromil on PGD2, but not histamine release. 7.Compound 48/80 stimulated both p38 and JNK phosphorylation in CBDMCs and this was inhibited by nedocromil. Inhibition of p38 phosphorylation was ANX-A1 dependent. 8.We conclude that ANX-A1 is an important regulator of mast cell reactivity to compound 48/80 exerting a negative feedback effect through a mechanism that depends at least partly on the FPR receptor.
Calvo, Patricia; Ropero, Inés; Pintor, Jesús
Abstract Purpose: Treatment with topical eye drops for long-standing ocular diseases like allergy can induce detrimental side effects. The purpose of this study was to investigate in vitro cytotoxicity of commercially preserved and unpreserved anti-allergic eye drops on the viability and barrier function of monolayer and stratified human corneal-limbal epithelial cells. Methods: Cells were treated with unpreserved ketotifen solution, benzalkonium chloride (BAC)-containing anti-allergic drugs (ketotifen, olopatadine, levocabastine) as well as BAC alone. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to determine cell viability. Effects of compounds on barrier function were analyzed measuring transepithelial electrical resistance (TEER) to determine paracellular permeability and rose bengal assays to evaluate transcellular barrier formation. Results: The BAC-preserved anti-allergic formulations and BAC alone significantly reduced cell viability, monolayer cultures being more sensitive to damage by these solutions. Unpreserved ketotifen induced the least diminution in cell viability. The extent of decrease of cell viability was clearly dependent of BAC presence, but it was also affected by the different types of drugs when the concentration of BAC was low and the short time of exposure. Treatment with BAC-containing anti-allergic drugs and BAC alone resulted in increased paracellular permeability and loss of transcellular barrier function as indicated by TEER measurement and rose bengal assays. Conclusions: The presence of the preservative BAC in anti-allergic eye drop formulations contributes importantly to the cytotoxic effects induced by these compounds. Stratified cell cultures seem to be a more relevant model for toxicity evaluation induced on the ocular surface epithelia than monolayer cultures. PMID:25100331
George, Mathew; Joseph, Lincy; Ramaswamy
This study investigated antipruritic and anti-inflammatory effect of Centella asiatica extract in rats and anti-allergic in vitro using sheep (Capra hircus) serum method and compound 48/80 induced mast cell degranulation method, compared with standard drug ketotifen fumarate. In rats, extract of Centella asiatica administered orally was examined for anti-pruritic study and chlorpheniramine maleate was used as standard drug while carageenan paw induced inflammatory method was used for the antiinfammatory study. The results show that the extracts of Centella asiatica exhibited antiallergic, anti-pruritic and anti-inflammatory activities.
Jauhonen, Hanna-Mari; Laihia, Jarmo; Oksala, Olli; Viiri, Johanna; Sironen, Reijo; Alajuuma, Päivi; Kaarniranta, Kai; Leino, Lasse
Our purpose was to investigate the effect of locally administered cis-urocanic (cis-UCA) in two experimental models of allergic conjunctivitis. The compound 48/80 (C48/80)-induced ocular irritation model (IgE-independent) and the ovalbumin (OA)-induced ocular allergy model (IgE-mediated) were used to test and compare the effect of cis-UCA on dexamethasone, ketotifen and olopatadine. In the C48/80 model, clinical severity scoring from photographs, immunohistochemical analysis of nuclear Ki-67 antigen to quantify actively proliferating epithelial cells and of caspase-3 enzyme to identify apoptotic activity in the conjunctival tissue were used. In the OA model, an Evans Blue stain concentration of conjunctival tissue was used to evaluate vascular leakage due to allergic reaction. The cis-UCA was well tolerated and effective in both the IgE-independent and -mediated rat models. Treatment with C48/80 caused conjunctival hyperaemia, which was significantly inhibited by ketotifen at the 6 h time point (p = 0.014) and by dexamethasone and cis-UCA 0.5% at 12 (p = 0.004) and 24 (p = 0.004) hour time points. In a comparison between the active drug treatments, only ketotifen showed a significant difference (p = 0.023) to cis-UCA treatment at the 1 h time point, otherwise there were no statistically significant differences between the active drugs. Ketotifen, dexamethasone and cis-UCA 0.5% significantly inhibited the C48/80-induced nuclear accumulation of Ki-67, without differences between the active treatment groups. In the OA model, cis-UCA 0.5% did not inhibit the vascular leakage of conjunctiva, whereas cis-UCA 2.5% of was at least equally effective compared to olopatadine, abolishing the allergic vascular leakage response almost completely. The present findings in the two AC models suggest that cis-UCA might have anti-allergic potency both in immediate and delayed-type allergic reactions in the eye.
Iwama, T.; Nagai, H.; Suda, H.; Tsuruoka, N.; Koda, A.
1. An intratracheal injection of murine recombinant interleukin 5 (mrIL-5, 2-15 microgram/0.25 ml/animal) induced a dose-dependent increase in the number of macrophages, eosinophils, neutrophils and epithelial cells in the bronchoalveolar lavage fluid (BALF) of guinea-pigs 24 h after administration. Bovine serum albumin (15 micrograms/0.25 ml/animal), used as a reference material, did not cause any change of this type. 2. The intratracheal administration of mrIL-5 at a dose of 15 microgram showed a tendency to increase the number of these pulmonary inflammatory cells and epithelial cells in the BALF at 12 h with a significant increase observed at 24 h. 3. Prednisolone (20 mg kg-1, i.p.) inhibited the mrIL-5-induced increase in macrophages, eosinophils, neutrophils and epithelial cells. Ketotifen (2 mg kg-1, i.p.) reduced the mrIL-5-induced increase in the eosinophil, neutrophil and epithelial cell populations. The simultaneous injection of 2% disodium cromoglycate (DSCG) into the trachea prevented the mrIL-5-induced increase in the number of airway epithelial cells, without affecting changes in the other inflammatory leukocytes. 4. These results suggest that mrIL-5 is a potent inducer of lung inflammation, in terms of increased inflammatory leukocytes and epithelial cells in guinea-pig BALF. Prednisolone, DSCG and ketotifen are effective against mrIL-5-induced pulmonary inflammation, especially the desquamation of bronchial epithelial cells. PMID:1596681
Rosas Vargas, Miguel A; Moncayo Coello, Vivian; García Cárdenas, Eustorgio; Valencia Mayoral, Pedro; Sienra Monge, Juan José Luis; del Río Navarro, Blanca E
Eosinophilic colitis is a rare entity of unknown etiology characterized by diarrhea, abdominal pain, and gastrointestinal bleeding. Diagnosis includes histopathological infiltration of more than 20 eosinophils in colon. It is frequently associated with milk hypersensitivity and, less usual, with other foods and increased IgE. Histopthological appearance of eosinophil mediators has been observed in the gut. It is sometimes related to the degree of infiltration of eosinophils in the gut as well as to the disease severity. There is not an established treatment for this entity, although systemic steroids have been used with certain efficacy. However, there is a recurrence of the symptoms when the therapy stops, besides the well known side effects of the long-term use of steroids. Cromolyn inhibits mast cell degranulation and prevents liberation of mediators. It is successful in certain cases, specially the severe ones. However, it is not available for its use in our country. Ketotifen, as last resource in our patients with bad response to habitual treatment and restriction diet, was used. Although its use is controversial, we consider that stabilizing mast cell membrane with subsequent inhibition of degranulation and recruitment of eosinophils to sites of inflammation, would also restrain histamine liberation and blockage of H1 receptors, which would diminish local damage induced by eosinophils. Nonetheless ketotifen mechanism of action is unknown, our patients improved after treatment with this drug.
Zur, E; Kaczmarski, M
Dietary elimination is a treatment of first choice in food hypersensitivity. Such therapy is not always enough to stop the disease and introduction of pharmacological treatment is necessary. In prevention and long term treatment antiallergic drugs are recommended. The aim of the study was to assess efficacy and safety of oral sodium cromoglycate in treatment of food hypersensitivity in the youngest children. In our study we examined: the group of 25 children aged 6 months-3 years treated with oral cromolyn sodium during the period 4-20 weeks and 29 children aged 6 months-3 years treated with ketotifen. Symptoms from skin, digestive and respiratory tract, behaviour status were evaluated for drugs efficacy. Cromolyn and ketotifen effected a significant decrease in total symptoms score. The treatment was well tolerated. No serious side effects were noted. The incidents of skin rash, disquiet during the night, diarrhoea and urticaria were only 8 percent. Sodium cromoglycate is safe and effective drug in treatment of food allergy in children; specially in symptoms from gastrointestinal tract and multi-organs allergy.
Naya, M J; Pereboom, D; Ortego, J; Alda, J O; Lanas, A
BACKGROUND: Reactive oxygen metabolites have been associated with gastrointestinal injury. OBJECTIVE: To investigate whether mucosal reactive oxygen metabolites are involved in acid and pepsin induced oesophagitis, and if so, which specific metabolites. METHODS: The effects of free radical scavengers and the anti-inflammatory drug ketotifen on rabbit oesophagitis induced by acidified pepsin were studied. Isolated oesophageal cells were obtained before and after oesophageal injury and the generation of superoxide anion and hydrogen peroxide was analysed by flow cytometry. The presence of inflammatory cells was determined by indirect immunofluorescence with a mouse antirabbit CD11b antibody. RESULTS: Of the free radical scavengers tested, superoxide dismutase, which reacts with the superoxide anion, significantly reduced oesophagitis, whereas catalase, which reacts with hydrogen peroxide, had only a mild effect and dimethylsulphoxide had no effect. Ketotifen significantly reduced the inflammation and also prevented the induction of oesophagitis. Isolated cells obtained from the oesophageal mucosa after acidified pepsin exposure generated increased amounts of superoxide anions, which were mainly produced by CD11b positive cells. CONCLUSIONS: Reactive oxygen metabolites, especially superoxide anion, produced by inflammatory cells play a significant part in the genesis of oesophagitis induced by acid and pepsin in rabbits and might be a target for future medical therapy. Images PMID:9071927
Nakazawa, Yosuke; Oka, Mikako; Takehana, Makoto
Abstract Allergic conjunctivitis (AC), which is characterized by ocular itching, hyperemia, and edema, deteriorates quality of life. In this study, effects of anti-allergic drugs were evaluated by assessing eye-scratching behavior, the number of eosinophils in conjunctiva epithelial tissues, and concentrations of chemical mediators in the tears of the guinea pig model of ovalbumin (OA)-induced AC. Methodology On day 0, 3-week-old guinea pigs were sensitized by OA subconjunctival injections. On days 15, 17, and 19, OA solution was administered. Anti-allergic eye drops were administered 5 and 15 min before the final OA challenge on day 19. Scratching behavior within 1 h after OA exposure was studied. Eosinophils in the conjunctiva were stained with Giemsa reagent. Histamine and substance P (SP) concentrations in tears were measured using ELISA. Results Subconjunctivally injected guinea pigs were observed for clinical symptoms. Scratching responses significantly reduced with ketotifen or olopatadine treatment. Eosinophil numbers reduced in animals treated with ketotifen, levocabastine, or tranilast. Histamine and/or SP concentrations in tears were inhibited by some of these anti-allergic drugs. Conclusions It is important to assess the anti-allergic AC drugs objectively because there are several of these drugs currently available. This model allows for an objective evaluation of anti-allergic drugs for AC. PMID:28848937
Tieppo, A; White, C J; Paine, A C; Voyles, M L; McBride, M K; Byrne, M E
In this paper, we demonstrate the successful in vivo extended release of a small molecular weight therapeutic, ketotifen fumarate (MW=425), from molecularly imprinted, therapeutic contact lenses. This is the first time that a steady, effective concentration of drug is maintained in the tear film from a contact lens for an extended period of time for the entire duration of lens wear. Poly(HEMA-co-AA-co-AM-co-NVP-co-PEG200DMA) soft contact lenses were prepared (100±5 μm thickness, diameter 11.8 mm, power zero), and a constant tear film concentration of 170±30 μg/mL was measured for up to 26 hrs in a New Zealand white rabbit model. The results showed a dramatic increase in ketotifen mean residence time (MRT) and bioavailability compared to topical drop therapy and drug soaked lenses. The MRT for imprinted lenses was 12.47±3.99 hrs, ~4 and 50 fold greater than non-imprinted lenses and 0.035% eye drops (Zaditor®), respectively. Furthermore, AUC(0-26 hrs) was 9 and 94 fold greater for imprinted lenses than non-imprinted lenses and eye drops, respectively. The results indicate that molecular imprinting provides an exciting rational engineering strategy for sustained release. It is clear that imprinted lenses are very promising combination devices and are much more effective and efficient delivery devices than eye drops.
Katayose, Yasuko; Aritake, Sayaka; Kitamura, Shingo; Enomoto, Minori; Hida, Akiko; Takahashi, Kiyohisa; Mishima, Kazuo
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. 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. 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. 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. Copyright © 2012 John Wiley & Sons, Ltd.
Morais-Almeida, M; Marinho, S; Gaspar, A; Arêde, C; Loureiro, V; Rosado-Pinto, J
Physical urticaria includes a heterogeneous group of disorders characterized by the development of urticarial lesions and/or angioedema after exposure to certain physical stimuli. The authors present the case of a child with severe acquired cold urticaria secondary to infectious mononucleosis. Avoidance of exposure to cold was recommended; prophylactic treatment with ketotifen and cetirizine was begun and a self-administered epinephrine kit was prescribed. The results of ice cube test and symptoms significantly improved. Physical urticaria, which involves complex pathogenesis, clinical course and therapy, may be potentially life threatening. Evaluation and diagnosis are especially important in children. To our knowledge this is the first description of persistent severe cold-induced urticaria associated with infectious mononucleosis in a child.
Knoche, A; Yokoyama, H; Ponomarenko, A; Frisch, C; Huston, J; Haas, H L
The histaminergic neurons located in the posterior hypothalamus modulate whole brain activity in a manner dependent on behavioral state. We have investigated their influence on high-frequency oscillation (200-Hz ripples) in the hippocampal CA1 region of freely moving rats. The occurrence of these ripples, assumed to be involved in memory trace formation, was markedly enhanced after injection of the H1-antagonists pyrilamine and ketotifen in a lateral ventricle, indicating a tonic activity of the histaminergic system. The H2- and H3-antagonists cimetidine and thioperamide were ineffective. We suggest a mediation of these effects through blocking the known histaminergic excitation of septal neurons. Histamine administered by the intracerebroventricular route had an inhibitory action on ripples. H1-receptor activation, which has been shown to inhibit learning and memory, thus shifts hippocampal activity away from high-frequency oscillation toward theta activity.
Mikuni, I; Fujiwara, T; Togawa, K; Mochida, H; Arai, Y; Kubota, A; Mizushima, N
A 0.1% Ketotifen ophthalmic preparation was evaluated in 11 cases of conjunctivitis due to Japanese cedar pollinoisis (three cases also associated with vernal catarrh). The following results were obtained concerning the safety and the therapeutic efficacy of the preparation. (1) In the computation of the overall effects of the preparation, a marked therapeutic effect was noted in three out of 11 cases studied while one case remained unaffected. The overall effective rate was computed to be 91%. (2) The time required for the preparation to take effect was found to be 3 days or less in seven cases (70.0%) out of 10 in which therapeutic effects were noted. (3) In observations of the adverse effects of the preparation, transient irritation at the site of application was noted in seven cases. No other serious side effects were recorded. From the above results, it was concluded that the present preparation is an effective therapeutic agent for conjunctivitis caused by pollinosis.
Kang, Ju Wan
Second-generation antihistamines are widely prescribed for the control of symptoms of allergic inflammation such as itchy hives, coryza, and itchy eyes. In rare circumstances, these drugs might provoke allergic inflammation. Hypersensitivity to bepotastine besilate, a second-generation antihistamine has never been reported. A 17-year-old schoolgirl, whose paroxysmal itchy hives had been controlled with bepotastine, experienced aggravation of the hives. An oral provocation test confirmed her hypersensitivity to bepotastine and cross-reactivity to levocetirizine. She showed no reaction to chlorpheniramine, ketotifen, or olopatadine among the 13 antihistamines tested. While searching for an antihistamine to control her itchy hives, we found that she also exhibited cross-reactivity to various antihistamines with different chemical structures from that of bepotastine, which is not predicted according to the chemical classification of antihistamines. We report a case of hypersensitivity to bepotastine besilate in a patient with chronic spontaneous urticaria. PMID:27803886
Yokoyama, H; Onodera, K; Iinuma, K; Watanabe, T
The effects of intracerebroventricular (ICV) administration of histamine and its selective agonists on electrically and pentylenetetrazole-induced convulsions in mice were studied. The ICV administration of histamine decreased seizure susceptibility on electrically and pentylenetetrazole-induced convulsions significantly and dose-dependently. The inhibitory effects of histamine were well antagonized by centrally acting histamine H1 antagonists such as pyrilamine (or mepyramine) and ketotifen, but not by a peripherally acting histamine H1 antagonist, astemizole, or a centrally acting H2 antagonist, zolantidine. The ICV administration of 2-thiazolylethylamine, a selective histamine H1 agonist, also decreased seizure susceptibility, which could be antagonized by centrally acting histamine H1 antagonists, whereas dimaprit, a selective histamine H2 agonist, did not affect seizure susceptibility. These findings strengthened the idea that the central histaminergic neuron system plays an inhibitory role in convulsions.
Durand, Christelle; Pezet, Sophie; Eutamène, Hélène; Demarquay, Christelle; Mathieu, Noëlle; Moussa, Lara; Daudin, Rachel; Holler, Valérie; Sabourin, Jean-Christophe; Milliat, Fabien; François, Agnès; Theodorou, Vassilia; Tamarat, Radia; Benderitter, Marc; Sémont, Alexandra
Each year, millions of people worldwide are treated for primary or recurrent pelvic malignancies, involving radiotherapy in almost 50% of cases. Delayed development of visceral complications after radiotherapy is recognized in cancer survivors. Therapeutic doses of radiation may lead to the damage of healthy tissue around the tumor and abdominal pain. Because of the lack of experimental models, the underlying mechanisms of radiation-induced long-lasting visceral pain are still unknown. This makes managing radiation-induced pain difficult, and the therapeutic strategies proposed are mostly inefficient. The aim of our study was to develop an animal model of radiation-induced visceral hypersensitivity to (1) analyze some cellular and molecular mechanisms involved and (2) to test a therapeutic strategy using mesenchymal stromal cells (MSCs). Using a single 27-Grays colorectal irradiation in rats, we showed that such exposure induces a persistent visceral allodynia that is associated with an increased spinal sensitization (enhanced p-ERK neurons), colonic neuroplasticity (as increased density of substance P nerve fibers), and colonic mast cell hyperplasia and hypertrophy. Mast cell stabilization by ketotifen provided evidence of their functional involvement in radiation-induced allodynia. Finally, intravenous injection of 1.5 million MSCs, 4 weeks after irradiation, induced a time-dependent reversion of the visceral allodynia and a reduction of the number of anatomical interactions between mast cells and PGP9.5+ nerve fibers. Moreover, unlike ketotifen, MSC treatment has the key advantage to limit radiation-induced colonic ulceration. This work provides new insights into the potential use of MSCs as cellular therapy in the treatment of pelvic radiation disease.
Infection with Salmonella typhimurium can produce multiple organ dysfunctions. However, document concerning with gastric hemorrhagic ulcers occur in this infectious disease is lacking. The aim was to study modulation of gastric hemorrhagic ulcer by oxidative stress and mast cell histamine in S. typhimurium-infected rats. Additionally, the protective effects of drugs, such as ofloxacin, lysozyme chloride, ketotifen, ranitidine, and several antioxidants, including exogenous glutathione (GSH), allopurinol and dimethylsulfoxide (DMSO) were evaluated. Male Wistar rats were injected intrajejunally with a live culture of S. typhimurium (1 x 10(10) colony-forming units/rat) and followed by deprivation of food for 36 h. Age-matched control rats received sterilized vehicle only. Rat stomachs were irrigated for 3 h with either normal saline or a simulated gastric juice containing 100 mM HCl, 17.4 mM pepsin and 54 mM NaCl. S. typhimurium caused aggravation of offensive factors, including enhancing gastric acid back-diffusion, mucosal lipid peroxide generation, histamine release, microvascular permeability and hemorrhagic ulcer, as well as an attenuation of defensive substances, such as mucosal GSH and mucus level. Intragastric irrigation of gastric juice caused further aggravation of these gastric biochemical parameters. This exacerbation of ulcerogenic factors was abolished by pretreatment of ofloxacin and lysozyme chloride. Antioxidants, such as reduced GSH, allopurinol and DMSO also produced significant (P < 0.05) amelioration of gastric damage in S. typhimurium infected rats. In conclusion, gastric oxidative stress and histamine play pivotal roles in the formation of hemorrhagic ulcers that were effectively ameliorated by ofloxacin, lysozyme chloride, ketotifen, ranitidine, diamine oxidase and various antioxidants in S. typhimurium-infected rats.
Futamura, Masaki; Goto, Shiho; Kimura, Ryoko; Kimoto, Izumi; Miyake, Mio; Ito, Komei; Sakamoto, Tatsuo
Various volatile organic compounds (VOCs) act as a causative agent of skin inflammation. We investigated the effect of topical application of several VOCs and formalin on microvascular leakage in rat skin. We tested capsaicin, which is a reagent that specifically causes the skin response via endogenously released tachykinins. Evans blue dye extravasation served as an index of the increase in skin vascular permeability. After shaving the abdomen, we applied formalin, m-xylene, toluene, styrene, benzene, ethylbenzene, acetone, diethyl ether, hexane, heptane, cyclohexane and capsaicin to the skin. At 40min after application, skin samples were collected. Among all of the VOCs tested, all of the aromatic compounds significantly produced skin microvascular leakage that was similar to formalin and capsaicin. We also investigated the skin responses seen after the intravenous administration of CP-99,994 (1.5 or 5mg/kg), which is a tachykinin NK1 receptor antagonist, ketotifen (1 or 3mg/kg), which is a histamine H1 receptor antagonist that stabilizes the mast cells, and the topical application of capsazepine (22.5 or 50mM), which is the transient receptor potential vanilloid 1 (TRPV1) antagonist. The response induced by formalin and capsaicin was completely inhibited by CP-99,994. On the other hand, the antagonist partially reduced the response induced by m-xylene, toluene and styrene by 39%, 50% and 46%, respectively. Capsazepine and ketotifen did not alter the response induced by formalin or any of the aromatic compounds. Like capsaicin, formalin and the aromatic compounds at least partially caused skin microvascular leakage, which was due to tachykinin NK1 receptor activation related to the release of tachykinins from the sensory nerve endings. However, it is unlikely that mast cells and TRPV1 play an important role in the skin response.
Pinacho-García, Manuel; Marichal-Cancino, Bruno A; Villalón, Carlos M
Since histamine H3 and H4 receptors are coupled to heterotrimeric Gi/o proteins, a signal transduction pathway associated with inhibition of neurotransmitter release, the present study has investigated the inhibition of the rat cardioaccelerator sympathetic outflow induced by the H3/H4 receptor agonist immepip by using antagonists for histamine H1 (ketotifen), H2 (ranitidine), H3 (thioperamide) and H4 (JNJ7777120) receptors. For this purpose, 102 male Wistar rats were pithed, artificially ventilated and prepared for either preganglionic spinal (C7-T1) stimulation of the cardioaccelerator sympathetic outflow (n=90) or i.v. bolus injections of noradrenaline (n=12). This approach resulted in frequency-dependent and dose-dependent tachycardic responses, respectively. I.v. continuous infusions of immepip (3 and 10 μg/kg min), but not of saline (0.02 ml/min), dose-dependently inhibited the sympathetically-induced tachycardic responses. Moreover, the cardiac sympatho-inhibition induced by 10 μg/kg min immepip (which failed to affect the tachycardic responses to i.v. noradrenaline) was: (i) unaltered after i.v. treatment with 1 ml/kg vehicle, 100 μg/kg ketotifen, 3000 μg/kg ranitidine, 30 μg/kg thioperamide or 300 μg/kg JNJ7777120; and (ii) abolished after 100 μg/kg thioperamide (i.v.). These doses of antagonists, which did not affect per se the sympathetically-induced tachycardic responses, were high enough to block their respective receptors. In conclusion, the cardiac sympatho-inhibition induced by 10 μg/kg.min immepip involves histamine H3 receptors, with further pharmacological evidence excluding the involvement of H1, H2 and H4 receptors.
Nabe, Takeshi; Kijitani, Yurie; Kitagawa, Yuriko; Sakano, Emi; Ueno, Tomoko; Fujii, Masanori; Nakao, Shintaro; Sakai, Masaru; Takai, Shinji
It has been reported that chymase activity was increased in allergic conjunctivitis patients and this activity was correlated with the severity of the disease. However, the precise roles of chymase in allergic conjunctivitis are unclear, and whether chymase inhibitors are effective for allergic conjunctivitis has not been reported even in experimental animal models. In this study, the roles of chymase in the pathogenesis were evaluated using a selective chymase inhibitor, ONO-WH-236, in a guinea pig model of allergic conjunctivitis induced by cedar pollen. Sensitized guinea pigs were challenged by the pollen, followed by assessing redness and edema in the conjuntiva, and counting the frequency of eye scratching as an itch-associated response. Treatment with the ONO-WH-236 (40 and 80 mg/kg, p.o.) dose-dependently inhibited the induction of redness, edema and scratching behavior. An anti-histaminic drug, ketotifen (3 mg/kg, p.o.), also significantly inhibited conjunctivitis symptoms. Chymase activity was increased in ophthalmic lavage fluid immediately after the pollen challenge. The increase in chymase activity was inhibited by in vivo treatment with ONO-WH-236. Interestingly, increased histamine in the ophthalmic lavage fluid immediately after the challenge was also inhibited by the chymase inhibitor. Administration of human recombinant chymase by eye dropping (0.09 and 0.9 μg/eye) dose-dependently induced scratching behavior, which was inhibited by not only ONO-WH-236 but also ketotifen; however, chymase administration induced only weak redness in the conjunctiva, which was resistant to treatment with anti-histaminic drugs. In conclusion, it was suggested that chymase was released from mast cells after antigen challenge, followed by the induction of conjunctivitis symptoms through histamine release from mast cells. Thus, chymase could be a potential target for pharmacotherapy for allergic conjunctivitis.
Heinemann, A.; Jocic, M.; Herzeg, G.; Holzer, P.
1. Primary afferent neurones releasing the vasodilator, calcitonin gene-related peptide, mediate the gastric hyperaemic response to acid back-diffusion. The tachykinins neurokinin A (NKA) and substance P (SP) are located in the same neurones and are co-released with calcitonin gene-related peptide. In this study we investigated the effect and possible role of tachykinins in the acid-evoked gastric vasodilatation in urethane-anaesthetized rats. 2. Gastric acid back-diffusion, induced by perfusing the stomach with 15% ethanol in the presence of 0.05 M HCl, increased gastric mucosal blood flow by 60-90%, as determined by the hydrogen clearance technique. NKA and SP (0.14-3.78 nmol min-1 kg-1, infused intra-aortically) inhibited the gastric mucosal hyperaemic response to acid back-diffusion in a dose-dependent manner, an effect that was accompanied by aggravation of ethanol/acid-induced macroscopic haemorrhagic lesions. 3. The inhibitory effect of NKA (1.26 nmol min-1 kg-1) on the acid-induced gastric mucosal vasodilatation was prevented by the tachykinin NK2 receptor antagonists, MEN 10,627 (200 nmol kg-1) but left unaltered by the NK1 receptor antagonist, SR 140,333 (300 nmol kg-1) and the mast-cell stabilizer, ketotifen (4.6 mumol kg-1). 4. Under basal conditions, with 0.05 M HCl being perfused through the stomach, NKA (1.26 nmol min-1 kg-1) reduced gastric mucosal blood flow by about 25%, an effect that was abolished by SR 140,333 but not MEN 10,627 or ketotifen. 5. SR 140,333, MEN 10,627 or ketotifen had no significant effect on basal gastric mucosal blood flow nor did they modify the gastric mucosal hyperaemic reaction to acid back-diffusion. 6. The effect of NKA (1.26 nmol min-1 kg-1) in causing vasoconstriction and inhibiting the vasodilator response to acid back-diffusion was also seen when blood flow in the left gastric artery was measured with the ultrasonic transit time shift technique. 7. Arginine vasopressin (AVP, 0.1 nmol min-1 kg-1) induced gastric
Pauly, A.; Brasnu, E.; Riancho, L.; Brignole-Baudouin, F.
Purpose To compare the effects of benzalkonium chloride (BAC)-preserved and unpreserved antiallergic eye drops on the human 3D-reconstituted corneal epithelial model (3D-HCE). Methods 3D-HCE were treated for 24 h followed or not by a 24 h post-incubation recovery period (24 h+24 h) with phosphate-buffered saline (PBS), 0.01% BAC, unpreserved formulations of ketotifen, N Acetyl-Aspartyl Glutamic Acid (NAAGA), cromoglycate, or BAC-preserved commercial formulations of ketotifen, olopatadine, epinastine, and levocabastine. The 3D-HCE viability was evaluated using the 3-(4,5-Dimethylthiazol-2-yl) -2,5-Diphenyltetrazolium Bromide (MTT) test at 24 h and 24 h+24 h. At 24 h, the numbers of Cluster of Differentiation 54 (CD54)- and Ki67-immunopositive cells as well as the number of apoptotic deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells were evaluated on 3D-HCE frozen sections. The expression of the tight junction-associated protein occludin was also assessed using fluorescence confocal microscopy on flat-mounted 3D-HCE epithelia. Results The MTT and the TUNEL tests revealed a significant decrease of cell viability and an increased apoptosis in the superficial layers of the 3D-HCE only when treated with BAC-containing formulations and in a BAC concentration-dependent manner. The expression of CD54 and Ki67 in the basal layers was also increased in this group. A concentration-dependent disorganization of occludin distribution in the epithelium treated with BAC-containing solutions was also observed. The unpreserved formulations induced effects comparable to the control. Conclusions BAC-preserved solutions decreased cell viability and induced apoptosis in a concentration-dependent manner. Moreover, they induced CD54 expression, proliferation in the basal layers, and changes in the distribution of occludin, which is consistent with a disorganization of the tight-junctions and suggests the loss of the epithelial barrier function. On the
Morrison, Juliet; Rathore, Abhay P S; Mantri, Chinmay K; Aman, Siti A B; Nishida, Andrew; St John, Ashley L
There are no approved therapeutics for the treatment of dengue disease despite the global prevalence of dengue virus (DENV) and its mosquito vectors. DENV infections can lead to vascular complications, hemorrhage, and shock due to the ability of DENV to infect a variety of immune and nonimmune cell populations. Increasingly, studies have implicated the host response as a major contributor to severe disease. Inflammatory products of various cell types, including responding T cells, mast cells (MCs), and infected monocytes, can contribute to immune pathology. In this study, we show that the host response to DENV infection in immunocompetent mice recapitulates transcriptional changes that have been described in human studies. We found that DENV infection strongly induced metabolic dysregulation, complement signaling, and inflammation. DENV also affected the immune cell content of the spleen and liver, enhancing NK, NKT, and CD8(+) T cell activation. The MC-stabilizing drug ketotifen reversed many of these responses without suppressing memory T cell formation and induced additional changes in the transcriptome and immune cell composition of the spleen, consistent with reduced inflammation. This study provides a global transcriptional map of immune activation in DENV target organs of an immunocompetent host and supports the further development of targeted immunomodulatory strategies to treat DENV disease.IMPORTANCE Dengue virus (DENV), which causes febrile illness, is transmitted by mosquito vectors throughout tropical and subtropical regions of the world. Symptoms of DENV infection involve damage to blood vessels and, in rare cases, hemorrhage and shock. Currently, there are no targeted therapies to treat DENV infection, but it is thought that drugs that target the host immune response may be effective in limiting symptoms that result from excessive inflammation. In this study, we measured the host transcriptional response to infection in multiple DENV target organs
Rachmilewitz, D; Stamler, J S; Bachwich, D; Karmeli, F; Ackerman, Z; Podolsky, D K
Recent studies have suggested that nitric oxide (NO.), the product of nitric oxide synthase in inflammatory cells, may play a part in tissue injury and inflammation through its oxidative metabolism. In this study the colonic generation of oxides of nitrogen (NOx) and nitric oxide synthase activity was determined in ulcerative colitis and Crohn's disease. Colonic biopsy specimens were obtained from inflammatory bowel disease patients and from normal controls. Mucosal explants were cultured in vitro for 24 hours and NOx generation was determined. Nitric oxide synthase activity was monitored by the conversion of [3H]-L-arginine to citrulline. Median NOx generation by inflamed colonic mucosa of patients with active ulcerative colitis and Crohn's colitis was 4.2- and 8.1-fold respectively higher than that by normal human colonic mucosa. In ulcerative colitis and Crohn's colitis nitric oxide synthase activity was 10.0- and 3.8-fold respectively higher than in normal subjects. Colonic NOx generation is significantly decreased by methylprednisolone and ketotifen. The decrease in NOx generation by cultured colonic mucosa induced by methylprednisolone suggests that NO synthase activity is induced during the culture and the steroid effect may contribute to its therapeutic effect. Enhanced colonic NOx generation by stimulated nitric oxide synthase activity in ulcerative colitis and Crohn's disease may contribute to tissue injury. PMID:7541008
Zhao, Wenting; Pang, Qin; Xu, Ruixue; Liu, Jianwen; Liu, Shengfa; Li, Jian; Su, Xin-Zhuan
Leucocytozoon parasites infect many species of avian hosts, including domestic chicken, and can inflict heavy economic loss on the poultry industry. Two major species of Leucocytozoon parasites have been reported in China, L. sabrazesi and L. caulleryi, although L. sabrazesi appears to be more widespread than L. caulleryi in southern China. The traditional method for detecting Leucocytozoon infection is microscopic examination of blood smears for the presence of mature gametocytes in circulation, which may miss infections with low parasitemia (gametocytemia) or immature gametocytes. Here we developed a PCR-based method to monitor L. sabrazesi infections at seven sites in four provinces of China after testing two PCR primer pairs based on parasite mitochondrial cytochrome b (cytb) and cytochrome c oxidase III (coxIII) genes. We compared the results of PCR detection with those of microscopic observation. As expected, the PCR assays were more sensitive than microscope examination in detecting L. sabrazesi infection and were able to detect parasite DNA after gametocytes disappeared in the blood stream. Using these methods, we investigated monthly dynamics of L. sabrazesi in chickens from a free-range farm in Xiamen, Fujian province of China, over one year. Our results showed that chickens were infected with L. sabrazesi year-round in southern China. Finally, we tested several compounds for potential treatment of Leucocytozoon infections, including primaquine, ketotifen, clomipramine hydrochloride, desipramine hydrochloride, sulfaquinoxaline, and pyrimethamine. Only primaquine had activity against L. sabrazesi gametocytes. Our results provide important information for controlling parasite transmission in southern China and disease management.
Devos, Fien C; Boonen, Brett; Alpizar, Yeranddy A; Maes, Tania; Hox, Valérie; Seys, Sven; Pollaris, Lore; Liston, Adrian; Nemery, Benoit; Talavera, Karel; Hoet, Peter H M; Vanoirbeek, Jeroen A J
Asthma may be induced by chemical sensitisers, via mechanisms that are still poorly understood. This type of asthma is characterised by airway hyperreactivity (AHR) and little airway inflammation. Since potent chemical sensitisers, such as toluene-2,4-diisocyanate (TDI), are also sensory irritants, it is suggested that chemical-induced asthma relies on neuro-immune mechanisms.We investigated the involvement of transient receptor potential channels (TRP) A1 and V1, major chemosensors in the airways, and mast cells, known for their ability to communicate with sensory nerves, in chemical-induced AHR.In vitro intracellular calcium imaging and patch-clamp recordings in TRPA1- and TRPV1-expressing Chinese hamster ovarian cells showed that TDI activates murine TRPA1, but not TRPV1. Using an in vivo model, in which an airway challenge with TDI induces AHR in TDI-sensitised C57Bl/6 mice, we demonstrated that AHR does not develop, despite successful sensitisation, in Trpa1 and Trpv1 knockout mice, and wild-type mice pretreated with a TRPA1 blocker or a substance P receptor antagonist. TDI-induced AHR was also abolished in mast cell deficient Kit(Wsh) (/Wsh) mice, and in wild-type mice pretreated with the mast cell stabiliser ketotifen, without changes in immunological parameters.These data demonstrate that TRPA1, TRPV1 and mast cells play an indispensable role in the development of TDI-elicited AHR. Copyright ©ERS 2016.
Da'as, Sahar; Teh, Evelyn M; Dobson, J Tristan; Nasrallah, Gheyath K; McBride, Eileen R; Wang, Hao; Neuberg, Donna S; Marshall, Jean S; Lin, Tong-Jun; Berman, Jason N
We previously identified a zebrafish mast cell (MC) lineage and now aim to determine if these cells function analogously in innate and adaptive immunity like their mammalian counterparts. Intraperitoneal (IP) injection of compound 48/80 or live Aeromonas salmonicida resulted in significant MC degranulation evident histologically and by increased plasma tryptase compared with saline-injected controls (p=0.0006, 0.005, respectively). Pre-treatment with ketotifen abrogated these responses (p=0.0004, 0.005, respectively). Cross-reactivity was observed in zebrafish to anti-human high-affinity IgE receptor gamma (FcɛRIγ) and IgE heavy chain-directed antibodies. Whole mount in situ hybridization on 7-day embryos demonstrated co-localization of cpa5, a MC-specific marker, with myd88, a toll-like receptor adaptor, and zebrafish FcɛRI subunit homologs. Zebrafish injected IP with matched dinitrophenyl-sensitized mouse (anti-DNP) IgE and DNP-BSA or trinitrophenyl-sensitized mouse (anti-TNP) IgE and TNP-BSA demonstrated increased plasma tryptase compared with mismatched controls (p=0.03, 0.010, respectively). These results confirm functional conservation and validate the zebrafish model as an in vivo screening tool for novel MC modulating agents. Copyright © 2010 Elsevier Ltd. All rights reserved.
Staats, K A; Schönefeldt, S; Van Helleputte, L; Van Rillaer, M; Lampi, Y; Dooley, J; Van Den Bosch, L; Liston, A
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease leading to progressive and lethal paralysis. The disease process is multi-factorial and is characterized by selective motor neuron degeneration. Previous work demonstrated that the local concentration of various growth factors can influence motor neuron survival and disease progression. A potential role for c-kit, a growth factor receptor present in the spinal cord, in ALS is unknown. To dissect the role of c-kit in ALS we interbred SOD1(G93A) mice with kit(w-sh/w-sh) mice, which have a 70% decrease in c-kit expression in the spinal cord. kit(w-sh/w-sh) SOD1(G93A) mice have a reduced survival compared to SOD1(G93A) mice, while the amount of motor neurons at end stage is similar. By means of grip strength and nerve conductance analysis we show that kit(w-sh/w-sh) mice have diminished strength and slightly impaired compound muscle action potential latency, although the number of neurons is similar across genotypes. Decreasing kit gene expression in SOD1(G93A) mice is detrimental and our results imply that this effect is independent of mast cells, as tested by ketotifen administration. To conclude, our data expand on the protective role of growth factors in ALS, as decreasing c-kit by approximately 70% is detrimental in SOD1(G93A) mice.
Zhang, Lei; Song, Jun; Hou, Xiaohua
Irritable bowel syndrome (IBS) is traditionally defined as a functional disorder since it lacks demonstrable pathological abnormalities. However, in recent years, low grade inflammatory infiltration, often rich in mast cells, in both the small and large bowel, has been observed in some patients with IBS. The close association of mast cells with major intestinal functions, such as epithelial secretion and permeability, neuroimmune interactions, visceral sensation, and peristalsis, makes researchers and gastroenterologists to focus attention on the key roles of mast cells in the pathogenesis of IBS. Numerous studies have been carried out to identify the mechanisms in the development, infiltration, activation, and degranulation of intestinal mast cells, as well as the actions of mast cells in the processes of mucosal barrier disruption, mucosal immune dysregulation, visceral hypersensitivity, dysmotility, and local and central stress in IBS. Moreover, therapies targeting mast cells, such as mast cell stabilizers (cromoglycate and ketotifen) and antagonists of histamine and serotonin receptors, have been tried in IBS patients, and have partially exhibited considerable efficacy. This review focuses on recent advances in the role of mast cells in IBS, with particular emphasis on bridging experimental data with clinical therapeutics for IBS patients.
Prete, Antonio Del; Ortosecco, Giovanni; Borrelli, Antonella; Prete, Salvatore Del; Mancini, Aldo
Background. We report a case of bilateral posterior subcapsular cataracts (PSCs) in a 24-year-old man with an allergic conjunctivitis history caused by a long-term therapy with glucocorticoids. Case Presentation. The patient showed a visual acuity of 9/10 for both eyes. He followed a therapy with ketotifen and bilastine for four years. During the last six months before our evaluation, he was treated with chloramphenicol and betamethasone, interrupted for onset of cataracts and increased intraocular pressure. We treated him with ophthalmic gel preparation containing a new recombinant form of manganese superoxide dismutase (rMnSOD) at a concentration of 12.5 μg/mL, only for the right eye, while left eye was treated with standard protocol of Bendazac-lysine g 0.5. Conclusion. This case report shows the protective effects of rMnSOD versus PSC disease, probably due to the capacity of rMnSOD of countering free radical species. PMID:27610257
Radielovic, P; Morley, J; Hansel, T T; Medici, T C
This international, multicenter clinical trial was designed to compare the efficacy and safety of two different formulations of ketotifen: Zaditen SRO and Zaditen Standard Form. In a randomized double-blind study over a 12-week treatment period, 3 parallel groups of asthmatic subjects received Zaditen SRO (2 mg once daily), Zaditen SRO (4 mg once daily), or Zaditen Standard Form (1 mg twice daily). Asthmatic subjects (362 evaluable cases, aged 6-29 years) kept daily records of clinical symptoms, use of concomitant medication, and peak flow recordings and were examined at 2-week intervals up to the end of the study. Zaditen SRO 4 mg administered once a day at night showed a statistically significant faster onset of action and was more clinically effective than Zaditen Standard Form. The Zaditen SRO 4-mg and 2-mg formulations were at least as well tolerated as the standard form, with somnolence occurring equally after both formulations. In conclusion, Zaditen SRO (4 mg once daily) was found to be equally safe and more effective in the prophylactic treatment of mild and moderate bronchial asthma than Zaditen Standard Form (1 mg twice daily).
Grumetto, Lucia; Prete, Antonio Del; Ortosecco, Giovanni; Borrelli, Antonella; Prete, Salvatore Del; Mancini, Aldo
Background. We report a case of bilateral posterior subcapsular cataracts (PSCs) in a 24-year-old man with an allergic conjunctivitis history caused by a long-term therapy with glucocorticoids. Case Presentation. The patient showed a visual acuity of 9/10 for both eyes. He followed a therapy with ketotifen and bilastine for four years. During the last six months before our evaluation, he was treated with chloramphenicol and betamethasone, interrupted for onset of cataracts and increased intraocular pressure. We treated him with ophthalmic gel preparation containing a new recombinant form of manganese superoxide dismutase (rMnSOD) at a concentration of 12.5 μg/mL, only for the right eye, while left eye was treated with standard protocol of Bendazac-lysine g 0.5. Conclusion. This case report shows the protective effects of rMnSOD versus PSC disease, probably due to the capacity of rMnSOD of countering free radical species.
Choi, Bong Seok; Hong, Suk Jin; Park, Suk Hyun; Kim, Heng Mi; Choe, Byung-Ho
Eosinophilic gastroenteritis (EGE) is a disorder characterized by eosinophilic infiltration of the bowel wall and various gastrointestinal (GI) manifestations. This study aimed to evaluate the characteristics of EGE in infants and children. A total of 22 patients were diagnosed with histologic EGE (hEGE) or possible EGE (pEGE). Serum specific IgE levels, peripheral eosinophil counts, and endoscopic biopsies were carried out. In the hEGE group (n = 13), initial symptoms included hematemesis, abdominal pain, and vomiting. Three of the subjects had normal endoscopic findings. Eight patients were categorized into the infant group and 5 into the child group. All patients in the infant group showed clinical improvement after switching from cow's milk feeding to special formula or breast feeding. The infant group showed a higher eosinophil count in the gastric mucosal biopsy than the child group. In the pEGE group (n = 9) initial symptoms included hematemesis, abdominal pain, and vomiting. Seven patients in this group showed a good response to treatment with restriction of the suspected foods and/or the administration of ketotifen. Both hEGE and pEGE groups showed clinical improvement after restriction of suspected foods in the majority of cases and also showed a similar clinical course. EGE should be considered in the differential diagnosis of patients with chronic abdominal pain, vomiting, and hematemesis of unknown cause. The infant group may have a better prognosis than the child group if treated properly.
Matsumoto, Itsuro; Inoue, Yasuhisa; Tsuchiya, Katsuhiko; Shimada, Toshio; Aikawa, Tadaomi
The effect of intracerebroventricular infusion of compound 48/80 (C48/80), a mast cell secretagogue, on adrenal cortisol secretion was investigated in dogs under pentobarbital sodium anesthesia. A marked increase in adrenal cortisol secretion was elicited by C48/80 along with a concomitant increase in the plasma levels of cortisol and immunoreactive ACTH, but neither arterial blood pressure and heart rate nor the plasma histamine level altered significantly. Pretreatment with either anti-CRF antiserum or pyrilamine maleate (H(1) histamine-receptor antagonist) significantly attenuated the C48/80-evoked increase in cortisol secretion, but pretreatment with metiamide (H(2)-receptor antagonist) significantly potentiated it. Significant attenuation of the C48/80-evoked increase in cortisol also occurred in dogs given ketotifen, a mast cell stabilizing drug, before pharmacologic challenge. In the pars tuberalis and median eminence (ME), mast cells were highly concentrated in close association with the primary plexus of the hypophysial portal system. Degranulated mast cells were extensively found in the ME of C48/80-treated animals. These results suggest that mast cells located in these regions liberated histamine within the brain as a result of degranulation induced by C48/80 and that this led to activation of the hypothalamic-pituitary-adrenocortical axis.
Chauhan, Sanjay P; Sheth, N R; Suhagia, B N
The presence of potentially active nutrients and their multifunctional properties make prickly pear a perfect candidate for the production of phytopharmaceutical products. Among the numerous Opuntia species, bioactive compounds have been isolated and characterized primarily from Opuntia ficus-indica, Opuntia polycantha, Opuntia stricta, Opuntia dilleni for various medicinal properties. Based on the traditional use of prickly pear for enhancement of immune function, the objective of the present study to evaluate the effect of prickly pear on mast cell degranulation function. The Opuntia fruit juice (OFJ) (10-200 μl/ml) were studied for the effect on sensitized rat peritoneal mast cell degranulation induced by immunological (egg albumin), and nonimmunological (compound 48/80) stimuli and compared with that of the reference standard, sodium cromoglycate and ketotifen (10 μg/ml). The OFJ exhibited significantly (P < 0.001) concentration dependent inhibition of mast cell degranulation. The IC50 value of OFJ was found 12.24 and 18 μl/ml for immunological and nonimmunological induced mast cell degranulation, respectively. The betacyanin is an active principle compound in prickly pear that may responsible for mast cell stabilizing action.
Kitanaka, Junichi; Kitanaka, Nobue; Tatsuta, Tomohiro; Miyoshi, Akio; Koumoto, Atena; Tanaka, Koh-Ichi; Nishiyama, Nobuyoshi; Morita, Yoshio; Takemura, Motohiko
The administration of methamphetamine (METH; 10mg/kg, i.p.) to male ICR mice induced bizarre behaviors including persistent locomotion and stereotypical behaviors, which were classified into four categories: stereotypical head-bobbing, circling, sniffing, and biting. Pretreatment with l-histidine (750 mg/kg, i.p.) significantly decreased the stereotypical biting induced by METH and significantly increased persistent locomotion. This effect of l-histidine on behavior was completely abolished by simultaneous administration of pyrilamine or ketotifen (brain-penetrating histamine H(1) receptor antagonists; 10mg/kg each, i.p.), but not by the administration of fexofenadine (a non-sedating histamine H(1) receptor antagonist that does not cross the blood-brain barrier; 20mg/kg), zolantidine (a brain-penetrating histamine H(2) receptor antagonist; 10mg/kg), thioperamide, or clobenpropit (brain-penetrating histamine H(3) receptor antagonists; 10mg/kg each). The histamine content of the hypothalamus was significantly increased by l-histidine treatment. These data suggest that l-histidine modifies the effects of METH through central histamine H(1) receptors.
Barrenberg, Eva; Garbe, Edeltraut
Little is known about the extent of switches from prescription-only (Rx) to over-the-counter (OTC) status in Europe and about the pharmacological properties of the switched substances. The objectives of this study were to provide an overview of the substances that were switched from Rx to OTC status in Germany between 2006 and 2015 and to assess their pharmacological properties. Session minutes of the German Expert Advisory Committee for Prescription-Only Issues, changes to the German Ordinance on Prescription-Only Medicines and the Summary of Product Characteristics of the switched substances were analysed. Pharmacological properties were studied in relation to the EU Guideline on Changing the Classification for the Supply of a Medicinal Product for Human Use (the 'EU switch guide'). Between 2006 and 2015, seven substances (almotriptan, omeprazole, benzydamine, ibuprofen/pseudoephedrine, racecadotril, ketotifen and levonorgestrel) were switched from Rx to OTC status in Germany. In all cases, the OTC status was restricted to certain indications, doses, pack sizes, or other limitations. Notwithstanding recommendations of the EU switch guide, some of the switched substances might interact with commonly used drugs potentially resulting in serious adverse drug reactions or have contraindications or warnings regarding substantial parts of the population. The stipulations of the EU switch guide were fully met for only some switches, while this was not completely the case for others. Further development of guidance on balancing risks and benefits of OTC availability is recommended.
Olopatadine hydrochloride exerts a wide range of pharmacological actions such as histamine H(1) receptor antagonist action, chemical mediator suppressive action, and eosinophil infiltration suppressive action. Olopatadine hydrochloride 0.1% ophthalmic solution (Patanol((R))) was introduced to the market in Japan in October 2006. In a conjunctival allergen challenge (CAC) test, olopatadine hydrochloride 0.1% ophthalmic solution significantly suppressed ocular itching and hyperemia compared with levocabastine hydrochloride 0.05% ophthalmic solution, and the number of patients who complained of ocular discomfort was lower in the olopatadine group than in the levocabastine group. Conjunctival cell membrane disruption was observed in vitro in the ketotifen fumarate group, epinastine hydrochloride group, and azelastine hydrochloride group, but not in the olopatadine hydrochloride 0.1% ophthalmic solution group, which may potentially explain the lower discomfort felt by patients on instillation. Many other studies in humans have revealed the superiority of olopatadine 0.1% hydrochloride eye drops to several other anti-allergic eye drops. Overseas, olopatadine hydrochloride 0.2% ophthalmic solution for a once-daily regimen has been marketed under the brand name of Pataday((R)). It is expected that olopatadine hydrochloride ophthalmic solutions may be used in patients with a more severe spectrum of allergic conjunctival diseases, such as vernal keratoconjunctivitis or atopic keratoconjunctivitis, in the near future.
Olopatadine hydrochloride exerts a wide range of pharmacological actions such as histamine H1 receptor antagonist action, chemical mediator suppressive action, and eosinophil infiltration suppressive action. Olopatadine hydrochloride 0.1% ophthalmic solution (Patanol®) was introduced to the market in Japan in October 2006. In a conjunctival allergen challenge (CAC) test, olopatadine hydrochloride 0.1% ophthalmic solution significantly suppressed ocular itching and hyperemia compared with levocabastine hydrochloride 0.05% ophthalmic solution, and the number of patients who complained of ocular discomfort was lower in the olopatadine group than in the levocabastine group. Conjunctival cell membrane disruption was observed in vitro in the ketotifen fumarate group, epinastine hydrochloride group, and azelastine hydrochloride group, but not in the olopatadine hydrochloride 0.1% ophthalmic solution group, which may potentially explain the lower discomfort felt by patients on instillation. Many other studies in humans have revealed the superiority of olopatadine 0.1% hydrochloride eye drops to several other anti-allergic eye drops. Overseas, olopatadine hydrochloride 0.2% ophthalmic solution for a once-daily regimen has been marketed under the brand name of Pataday®. It is expected that olopatadine hydrochloride ophthalmic solutions may be used in patients with a more severe spectrum of allergic conjunctival diseases, such as vernal keratoconjunctivitis or atopic keratoconjunctivitis, in the near future. PMID:19668750
Kishimoto, Kazuya; Kaneko, Satoshi; Ohmori, Kenji; Tamura, Tadafumi; Hasegawa, Kazuhide
Olopatadine hydrochloride (olopatadine) is an antiallergic drug with histamine H1 receptor antagonistic activity. Recently, olopatadine has been shown to bind to S100A12 which is a member of the S100 family of calcium-binding proteins, and exerts multiple proinflammatory activities including chemotaxis for monocytes and neutrophils. In this study, we examined the possibility that the interaction of olopatadine with S100A12 inhibits the proinflammatory effects of S100A12. Pretreatment of olopatadine with S100A12 reduced migration of THP-1, a monocyte cell line, induced by S100A12 alone, but did not affect recombinant human regulated upon activation, normal T cell expressed and secreted (RANTES)-induced migration. Amlexanox, which also binds to S100A12, inhibited the THP-1 migration induced by S100A12. However, ketotifen, another histamine H1 receptor antagonist, had little effect on the activity of S100A12. These results suggest that olopatadine has a new mechanism of action, that is, suppression of the function of S100A12, in addition to histamine H1 receptor antagonistic activity. PMID:16864903
Robertson, K E; Mueller, B A
Uremic pruritus and its treatment are reviewed. Pruritus affects 50-90% of patients undergoing peritoneal dialysis or hemodialysis; symptoms usually begin about six months after the start of dialysis and range from localized and mild to generalized and severe. The mechanism underlying uremic pruritus is poorly understood; possibilities include secondary hyperparathyroidism and divalent-ion abnormalities; histamine, allergic sensitization, and proliferation of skin mast cells; hypervitaminosis A; iron-deficiency anemia; neuropathy and neurologic changes; or some combination of these. The cornerstone of therapy for uremic pruritus is regular, intensive, efficient dialysis. Other nonpharmacologic measures consist of the use of non-complement-activating dialysis membranes, compliance with dietary restrictions, electric-needle (acupuncture) therapy, and ultraviolet light therapy. Pharmacologic treatments that have been used include activated charcoal, antihistamines, capsaicin, cholestyramine, emollients and topical corticosteroids, epoetin, pizotyline, ketotifen, and nicergoline. Treatment results have been highly variable, and many of the clinical trials have been flawed. Phosphate-binding agents appear to be the most effective. Although enough is known to determine a reasonable set of steps in approaching a patient's uremic pruritus, more research is needed to understand the pathophysiology of this condition and to establish more reliable treatments. Pruritus is a common and sometimes severe complication of chronic renal failure. Efficient dialysis, dietary restrictions, phosphate-binding therapy, and phototherapy are the most effective treatments currently available.
Kozyrskyj, Anita L; Mustard, Cameron A; Becker, Allan B
Investigation into the origins of asthma is contingent on definitions of asthma, which can differentiate asthma from transient wheezing syndromes in children. This research was undertaken to develop a definition for asthma derived from health care administrative records, which would identify children with persistent asthma. Using population-based, health care administrative data, children with possible asthma were identified as having one or more physician visits or hospitalizations for asthma or bronchitis diagnoses from January 1995 to December 1995, or, in the absence of asthma-like diagnoses, one or more prescriptions for asthma prophylaxis drugs or ketotifen concomitant with a beta-agonist, or two or more prescriptions for beta-agonists. The likelihood of persistent asthma, defined as repeated health care and prescription use for asthma from 1996 to 1998, was assessed for various asthma markers and risk factors in 29,198 children with possible asthma. Children with asthma prescription drugs or asthma health care use not limited to the winter season were three to six times more likely than children without these characteristics to have persistent asthma. The likelihood of persistent asthma was elevated to a substantial degree in the presence of both of these markers. The inclusion of these measures in a diagnosis-based definition improves the ability to identify persistent asthma in children.
Li, Jun; Yan, Xiao-ming
To investigate the cytotoxic effect of three kinds of topical ocular anti-allergic agent, including olopatadine 0.1% (A group), ketotifen fumarate 0.025% (B group) and pemirolast potassium 0.1% (C group), on cultured human corneal epithelial cells in vitro. Primary human corneal epithelial cells were cultured with keratinocyte serum-free medium. The cells were exposed to three kinds of topical ocular anti-allergic agent for a period of 10 min, 30 min, 2 h, 6 h, 12 h and 24 h. Toxicity was examined in three ways. MTT assay was used to quantify cytotoxicity. Cell membrane permeability and intracellular esterase activity were analyzed with live-dead viability staining of fluorescent calcein-AM/ethidium homodimer. The morphologic analysis was performed by light and scanning electron microscopy. Statistical methods adopted one-way ANOVA (analysis of variance) and Student-Newman-Keuls q test between each group. The P-value of 0.05 was considered statistically significant. (1) Morphologic changes: The Findings under the light microscopy were demonstrated that cells became round or edematic and detached from dishes after exposure to topical ocular anti-allergic agent. The cellular damage was more severe with longer exposure time and increasing concentration. Likewise, the electron microscopy examination showed reduced microvilli with longer exposure time and increasing concentration. The cellular changes of 20.0% olopatadine 0.1% were reduced when compared to the other agents. (2) Live/dead viability/cytotoxicity assay: Ethidium homodimeric permeates damaged cell membranes and results in red fluorescence. These results indicated that cell membrane damage caused by 20.0% olopatadine 0.1% at 6, 12, 24 h was less than those of ketotifen fumarate 0.025% and pemirolast potassium 0.1%. The data of A group were (29.7 +/- 2.6)%, (36.9 +/- 3.2)%, (51.2 +/- 4.3)%, B group were (36.5 +/- 3.1)%, (48.5 +/- 4.3)%, (75.5 +/- 3.8)% and C group were (37.1 +/- 2.2)%, (52.7 +/- 3.4)%, (71
Uccello-Barretta, Gloria; Nazzi, Samuele; Zambito, Ylenia; Di Colo, Giacomo; Balzano, Federica; Sansò, Marco
An interaction between tamarind seed polysaccharide (TSP) and hyaluronic acid (HA) in aqueous solution has been ascertained. Various TSP/HA mixtures have been studied as the basis for the development of a potential excipient for eye drops synergistically improved over those of the separate polymers. Information about the nature of interpolymer interactions, and their dependence on TSP/HA ratios were obtained by NMR spectroscopy in solution. Superior mucin affinity of TSP/HA mixtures with respect to the single polysaccharides was assessed by NMR proton selective relaxation rate measurements. The mucoadhesivity of the TSP/HA (3/2) mixture, evaluated in vitro by NMR or viscometry, and in vivo by its mean and maximum residence time in rabbit precorneal area, is stronger than that of the component polysaccharides or the TSP/HA mixtures of different composition. TSP/HA (3/2) is little viscous and well tolerated by rabbit eyes. It stabilizes the tear film, thereby prolonging the residence of ketotifen fumarate and diclofenac sodium in tear fluid, but is unable to permeabilize the cornea. In conclusion, mucoadhesivity is responsible for the TSP/HA (3/2) synergistic enhancement of either extra- or intra-ocular drug bioavailability.
Han, Wei; Xu, Jing Dong; Wei, Feng Xian; Zheng, Yong Dong; Ma, Jian Zhong; Xu, Xiao Dong; Wei, Zhen Gang; Wang, Wen; Zhang, You Cheng
The peach tree, Prunus persica (L.) Batsch, is widely cultivated in China, and its flowers have been used for centuries in traditional Chinese medicine to treat gut motility disorders. But few studies have explored the pharmacological effect of Prunus persica (L.) Batsch flowers on gastrointestinal motility. In this study, the activities of different extracts from Prunus persica (L.) Batsch flowers on the smooth muscle contractions were evaluated using isolated colon model, and the ethyl acetate extract (EAE) showed the strongest effects in vitro. EAE (10(-8)-10(-5) g/mL) caused a concentration-dependent stimulatory effect in rat colonic tissue. Additionally, ketotifen (100 µM), cimetidine (10 µM), and pyrilamine (1 µM) produced a significant inhibition of contractions caused by EAE. Furthermore, immunofluorescence and toluidine blue staining revealed increased numbers of mast cells in the EAE group, and EAE increased histamine release from the colonic tissues. These data indicate that EAE has significant prokinetic activity and acts by a mechanism that mainly involves mast cell degranulation. Our study provides a pharmacological basis for the use of an extract of Prunus persica (L.) Batsch flowers in the treatment of gut motility disorders.
Rivera, Dagmar García; Balmaseda, Ivones Hernández; León, Alina Alvarez; Hernández, Belkis Cancio; Montiel, Lucía Márquez; Garrido, Gabino Garrido; Cuzzocrea, Salvatore; Hernández, René Delgado
Vimang is the brand name of formulations containing an extract of Mangifera indica L., ethnopharmacologically used in Cuba for the treatment of some immunopathological disorders, including bronchial asthma, atopic dermatitis and other allergic diseases. However, the effects of Vimang on allergic response have not been reported until now. In this study, the effects of Vimang and mangiferin, a C-glucosylxanthone isolated from the extract, on different parameters of allergic response are reported. Vimang and mangiferin showed a significant dose-dependent inhibition of IgE production in mice and anaphylaxis reaction in rats, histamine-induced vascular permeability and the histamine release induced by compound 48/80 from rat mast cells, and of lymphocyte proliferative response as evidence of the reduction of the amount of B and T lymphocytes able to contribute to allergic response. In these experiments, ketotifen, promethazine and disodium cromoglicate were used as reference drugs. Furthermore, we demonstrated that Vimang had an effect on an in-vivo model of inflammatory allergy mediated by mast cells. These results constitute the first report of the anti-allergic properties of Vimang on allergic models, as well as suggesting that this natural extract could be successfully used in the treatment of allergic disorders. Mangiferin, the major compound of Vimang, contributes to the anti-allergic effects of the extract.
Zhang, Hua; Verkman, A.S.
Eosinophils are abundant in inflammatory demyelinating lesions in neuromyelitis optica (NMO). We used cell culture, ex vivo spinal cord slices, and in vivo mouse models of NMO to investigate the role of eosinophils in NMO pathogenesis and the therapeutic potential of eosinophil inhibitors. Eosinophils cultured from mouse bone marrow produced antibody-dependent cell-mediated cytotoxicity (ADCC) in cell cultures expressing aquaporin-4 in the presence of NMO autoantibody (NMO-IgG). In the presence of complement, eosinophils greatly increased cell killing by a complement-dependent cell-mediated cytotoxicity (CDCC) mechanism. NMO pathology was produced in NMO-IgG–treated spinal cord slice cultures by inclusion of eosinophils or their granule toxins. The second-generation antihistamines cetirizine and ketotifen, which have eosinophil-stabilizing actions, greatly reduced NMO-IgG/eosinophil–dependent cytotoxicity and NMO pathology. In live mice, demyelinating NMO lesions produced by continuous intracerebral injection of NMO-IgG and complement showed marked eosinophil infiltration. Lesion severity was increased in transgenic hypereosinophilic mice. Lesion severity was reduced in mice made hypoeosinophilic by anti–IL-5 antibody or by gene deletion, and in normal mice receiving cetirizine orally. Our results implicate the involvement of eosinophils in NMO pathogenesis by ADCC and CDCC mechanisms and suggest the therapeutic utility of approved eosinophil-stabilizing drugs. PMID:23563310
Zuliani, Juliana P; Freitas, Thalma A; Conceição, Isaltino M; Kwasniewski, Fábio H
Tityus serrulatus venom (Tsv)-induced pulmonary edema can occur in severe envenomation and the mechanisms involved are not completely understood. Therefore, we studied the effect of pharmacological modulation of the mast cell activation and the histamine antagonism on airways edema (investigated by Evans blue dye extravasation) and measured 5-hydroxytryptamine (5-HT) concentration in bronchoalveolar lavage fluid (BALF) in rats envenomed by Tsv. Additionally, the in vitro effect of Tsv on mast cells was studied using histological method and 5-HT release from mesenteric and peritoneal mast cells. We found that i.v. injection of Tsv increase vascular permeability in trachea, upper and lower bronchi and in lung parenchyma. This was not affected by ketotifen, a mast cell "stabilizer," or by pretreatment with pyrilamine (histamine H1 receptor antagonist). Moreover, 5-HT was not found in BALF of envenomed rats. In vitro experiments showed that Tsv did not induce mast cell degranulation nor release of 5-HT by mesenteric or peritoneal mast cells, in sharp contrast to preparations challenged by a mast cell activator, compound 48/80. In conclusion, our results show that Tsv causes strong edema in rat airways which is independent of mast cell activation and show that mast cells are not directly activated by Tsv. Copyright © 2011 Elsevier GmbH. All rights reserved.
Kwasniewski, Fábio H; Landgraf, Richardt G; Jancar, Sonia
Allergy to components of the diet is followed by gut inflammation which in children, sometimes progress to mucosal lesions and anaphylaxis. In newborns suffering of cow's milk allergy, bloody stools, rectal bleeding and ulcerations are found. The rat systemic anaphylaxis is a suitable model to study the intestinal lesions associated to allergy. In the present study we used this model to investigate some mechanisms involved. We found that 15 min after antigen challenge of sensitized rats, hemorrhagic lesions develop in the small intestine. The lesions were more severe in jejunum and ileum compared to duodenum. Pretreatment of the rats with a platelet-activating factor-receptor antagonist (WEB-2170) reduced the lesions whereas inhibition of endogenous nitric oxide by l-NAME, greatly increased the hemorrhagic lesions and mortality. Both, lesions and mortality were reversed by l-arginine. The hemorrhagic lesions were also significantly reduced by the mast cell stabilizers, disodium cromoglycate and ketotifen as well as by neutrophils depletion (with anti-PMN antibodies) or inhibition of selectin binding (by treatment with fucoidan). Thus, the intestinal hemorrhagic lesions in this model are dependent on platelet-activating factor, mast cell granule-derived mediators and neutrophils. Endogenous nitric oxide and supplementation with l-arginine has a protective role, reducing the lesions and preventing mortality. These results contributed to elucidate mechanisms involved in intestinal lesions which could be of relevance to human small bowel injury associated to allergy.
Sakaguchi, M; Mase, A; Iizuka, A; Yuzurihara, M; Ishige, A; Amagaya, S; Komatsu, Y; Takeda, H; Matsumiya, T
Examination was made of the pharmacological characteristics of Sho-seiryu-to, an antiallergic kampo medicine. Sho-seiryu-to suppressed histamine release from rat peritoneal mast cells, but failed to inhibit the binding of [3H]-mepyramine to histamine H1 receptors in guinea pig cerebral cortex and lung. Sho-seiryu-to had no effect on cutaneous reactions induced by serotonin, platelet-activating factor (PAF), leukotriene (LT) C4 or LTD4. Ketotifen prolonged electrically induced convulsions, while Sho-seiryu-to did not. Sho-seiryu-to did not affect salivation induced by pilocarpine. Sho-seiryu-to thus does not appear to inhibit histamine H1 receptors or inflammation induced by serotonin, PAF, LTC4 and LTD4, but suppresses mast cell activity. Sho-seiryu-to would thus have only a few side effects such as dry mouth and convulsions due mainly to the blockage of the action of muscarinic in salivary glands and histamine in the brain.
Sakaguchi, M; Iizuka, A; Yuzurihara, M; Ishige, A; Komatsu, Y; Matsumiya, T; Takeda, H
The pharmacological characteristics of Sho-seiryu-to, an antiallergic Kampo medicine, were investigated. Forty-eight-hour passive cutaneous anaphylactic (PCA) reaction was significantly inhibited in rats orally administered Sho-seiryu-to (1000 mg/kg). Sho-seiryu-to significantly inhibited increase in vascular permeability induced by histamine. These data confirm previous findings that Sho-seiryu-to has antiallergic activity in animals and suggest that the antagonism of histamine may be an antiallergic mechanism of Sho-seiryu-to. Sho-seiryu-to did not affect locomotor activity or motor coordination in mice. Although ketotifen prolonged sleeping time induced by pentobarbital, Sho-seiryu-to had no such effect. Nor was there any effect on oxotremorine-induced tremor and [3H]-mepyramine binding to histamine H1 receptors in rat brain. Thus, Sho-seiryu-to appears to be useful for treating type I allergy, with relatively few side effects such as sedation and drowsiness due mainly to blockade of histamine H1 and muscarinic receptors in the brain.
Akkemik, Ebru; Budak, Harun; Ciftci, Mehmet
Inhibitory effects of some drugs on glucose 6-phosphate dehydrogenase from the erythrocytes of human have been investigated. For this purpose, at the beginning, erythrocyte glucose 6-phosphate dehydrogenase was purified 2256 times in a yield of 44.22% by using ammonium sulphate precipitation and 2', 5'-ADP Sepharose 4B affinity gel. Temperature of +4°C was maintained during the purification process. Enzyme activity was determined with the Beutler method by using a spectrophotometer at 340 nm. This method was utilized for all kinetic studies. Ketotifen, dacarbazine, thiocolchicoside, meloxicam, methotrexate, furosemide, olanzapine, methylprednizolone acetate, paricalcitol, ritodrine hydrochloride, and gadobenate-dimeglumine were used as drugs. All the drugs indicated the inhibitory effects on the enzyme. Ki constants for glucose 6-phosphate dehydrogenase were found by means of Lineweaver-Burk graphs. While methylprednizolone acetate showed competitive inhibition, the others displayed non-competitive inhibition. In addition, IC(50) values of the drugs were determined by plotting Activity% vs [I].
Nguyen, Chi Huu; Brenner, Stefan; Huttary, Nicole; Li, Yuanfang; Atanasov, Atanas Georgiev; Dirsch, Verena M; Holzner, Silvio; Stadler, Serena; Riha, Juliane; Krieger, Sigurd; Milovanovic, Danijela; Fristiohardy, Adryan; Simonitsch-Klupp, Ingrid; Dolznig, Helmut; Saiko, Philipp; Szekeres, Thomas; Giessrigl, Benedikt; Jäger, Walter; Krupitza, Georg
Secretion of 12(S)-HETE by breast cancer emboli provokes "circular chemorepellent induced defects" (CCIDs) in the adjacent lymphatic vasculature facilitating their intravasation and lymph node metastasis which determines prognosis. Therefore, elucidating the mechanism of lymph endothelial cell (LEC) wall disintegration may provide cues for anti-metastatic intervention. The role of intracellular free Ca(2+) for CCID formation was investigated in LECs using MCF-7 or MDA-MB231 breast cancer cell spheroids in a three-dimensional cell co-culture model. 12(S)-HETE elevated the Ca(2+) level in LEC by activating PLC/IP3. Downstream, the Ca(2+)-calmodulin kinase MYLK contributed to the phosphorylation of Ser19-MLC2, LEC contraction and CCID formation. Approved clinical drugs, lidoflazine, ketotifen, epiandrosterone and cyclosporine, which reportedly disturb cellular calcium supply, inhibited 12(S)-HETE-induced Ca(2+) increase, Ser19-MLC2 phosphorylation and CCID formation. This treatment strategy may reduce spreading of breast cancer through lymphatics.
Misticoni, G; Marchetti, F; D'Andrea, N
41 pediatricians agreed to register on a very simple form, all the cases of children affected by bronchial asthma visited in their clinic during october 1993. The data included basic information related to the therapy prescribed, its duration, a judgement on the efficacy of symptoms control and the main problems encountered with the children and their families. 237 cases were reported (mean age 4.6 year, range 2 months-13 years). 80% of children were monitored by the pediatrician; 47% had allergic reactions. The main drug used for profilaxis is ketotifen, a compound without documented efficacy; the main route for drug administration (especially during acute attacks) is by mouth, instead of by aerosol, evidencing problems in the health education on practical skills. In fact the main problems encountered by doctors are related to the communication with patients and families. This survey represents also a research model for involving health care providers and easily and quickly obtaining a useful, methodologically sound and interesting picture of everyday practice.
Han, Wei; Xu, Jing Dong; Wei, Feng Xian; Zheng, Yong Dong; Ma, Jian Zhong; Xu, Xiao Dong; Wei, Zhen Gang; Wang, Wen; Zhang, You Cheng
The peach tree, Prunus persica (L.) Batsch, is widely cultivated in China, and its flowers have been used for centuries in traditional Chinese medicine to treat gut motility disorders. But few studies have explored the pharmacological effect of Prunus persica (L.) Batsch flowers on gastrointestinal motility. In this study, the activities of different extracts from Prunus persica (L.) Batsch flowers on the smooth muscle contractions were evaluated using isolated colon model, and the ethyl acetate extract (EAE) showed the strongest effects in vitro. EAE (10−8–10−5 g/mL) caused a concentration-dependent stimulatory effect in rat colonic tissue. Additionally, ketotifen (100 µM), cimetidine (10 µM), and pyrilamine (1 µM) produced a significant inhibition of contractions caused by EAE. Furthermore, immunofluorescence and toluidine blue staining revealed increased numbers of mast cells in the EAE group, and EAE increased histamine release from the colonic tissues. These data indicate that EAE has significant prokinetic activity and acts by a mechanism that mainly involves mast cell degranulation. Our study provides a pharmacological basis for the use of an extract of Prunus persica (L.) Batsch flowers in the treatment of gut motility disorders. PMID:25821812
Chauhan, Sanjay P.; Sheth, N. R.; Suhagia, B. N.
Background: The presence of potentially active nutrients and their multifunctional properties make prickly pear a perfect candidate for the production of phytopharmaceutical products. Among the numerous Opuntia species, bioactive compounds have been isolated and characterized primarily from Opuntia ficus-indica, Opuntia polycantha, Opuntia stricta, Opuntia dilleni for various medicinal properties. Objective: Based on the traditional use of prickly pear for enhancement of immune function, the objective of the present study to evaluate the effect of prickly pear on mast cell degranulation function. Materials and Methods: The Opuntia fruit juice (OFJ) (10-200 μl/ml) were studied for the effect on sensitized rat peritoneal mast cell degranulation induced by immunological (egg albumin), and nonimmunological (compound 48/80) stimuli and compared with that of the reference standard, sodium cromoglycate and ketotifen (10 μg/ml). Results and Conclusion: The OFJ exhibited significantly (P < 0.001) concentration dependent inhibition of mast cell degranulation. The IC50 value of OFJ was found 12.24 and 18 μl/ml for immunological and nonimmunological induced mast cell degranulation, respectively. The betacyanin is an active principle compound in prickly pear that may responsible for mast cell stabilizing action. PMID:25883521
Zhang, Lei; Song, Jun; Hou, Xiaohua
Irritable bowel syndrome (IBS) is traditionally defined as a functional disorder since it lacks demonstrable pathological abnormalities. However, in recent years, low grade inflammatory infiltration, often rich in mast cells, in both the small and large bowel, has been observed in some patients with IBS. The close association of mast cells with major intestinal functions, such as epithelial secretion and permeability, neuroimmune interactions, visceral sensation, and peristalsis, makes researchers and gastroenterologists to focus attention on the key roles of mast cells in the pathogenesis of IBS. Numerous studies have been carried out to identify the mechanisms in the development, infiltration, activation, and degranulation of intestinal mast cells, as well as the actions of mast cells in the processes of mucosal barrier disruption, mucosal immune dysregulation, visceral hypersensitivity, dysmotility, and local and central stress in IBS. Moreover, therapies targeting mast cells, such as mast cell stabilizers (cromoglycate and ketotifen) and antagonists of histamine and serotonin receptors, have been tried in IBS patients, and have partially exhibited considerable efficacy. This review focuses on recent advances in the role of mast cells in IBS, with particular emphasis on bridging experimental data with clinical therapeutics for IBS patients. PMID:26755686
Thin layer chromatography-densitometric determination of some non-sedating antihistamines in combination with pseudoephedrine or acetaminophen in synthetic mixtures and in pharmaceutical formulations.
El-Kommos, Michael E; El-Gizawy, Samia M; Atia, Noha N; Hosny, Noha M
The combination of certain non-sedating antihistamines (NSA) such as fexofenadine (FXD), ketotifen (KET) and loratadine (LOR) with pseudoephedrine (PSE) or acetaminophen (ACE) is widely used in the treatment of allergic rhinitis, conjunctivitis and chronic urticaria. A rapid, simple, selective and precise densitometric method was developed and validated for simultaneous estimation of six synthetic binary mixtures and their pharmaceutical dosage forms. The method employed thin layer chromatography aluminum plates precoated with silica gel G 60 F254 as the stationary phase. The mobile phases chosen for development gave compact bands for the mixtures FXD-PSE (I), KET-PSE (II), LOR-PSE (III), FXD-ACE (IV), KET-ACE (V) and LOR-ACE (VI) [Retardation factor (Rf ) values were (0.20, 0.32), (0.69, 0.34), (0.79, 0.13), (0.36, 0.70), (0.51, 0.30) and (0.76, 0.26), respectively]. Spectrodensitometric scanning integration was performed at 217, 218, 218, 233, 272 and 251 nm for the mixtures I-VI, respectively. The linear regression data for the calibration plots showed an excellent linear relationship. The method was validated for precision, accuracy, robustness and recovery. Limits of detection and quantitation were calculated. Statistical analysis proved that the method is reproducible and selective for the simultaneous estimation of these binary mixtures. Copyright © 2013 John Wiley & Sons, Ltd.
Ali, Maryam; Horikawa, Shin; Venkatesh, Siddarth; Saha, Jishnu; Hong, Jong Wook; Byrne, Mark E
Zero-order or concentration independent release kinetics are highly desirable from drug delivery devices. In this paper we demonstrate experimentally, for the first time, zero-order release of a small molecular weight therapeutic, ketotifen fumarate (MW=425), from molecularly imprinted hydrogels used as therapeutic contact lenses. We performed dynamic, in vitro drug release studies from imprinted hydrogel contact lenses within a novel microfluidic device that simulates the volumetric flow rates, tear volume and tear composition of the eye. Imprinted gels with multiple functional monomers and complexation points to the drug demonstrated a significantly delayed release of drug compared to less functionalized systems. There were no statistical differences in experimentally determined equilibrium swollen polymer volume fractions, which correlate with molecular weight between crosslinks and mesh size of the gel. Under infinite sink conditions, imprinted contact lenses demonstrated Fickian (concentration dependent) release kinetics with diffusion coefficients ranging from 4.04 x 10(-9) to 5.57 x 10(-10) cm(2)/s. The highest functionalized gel exhibited a diffusion coefficient averaging ten times smaller than less functionalized gels and released drug for over 5 days with 3 distinct rates of release. Under physiological volumetric flow rates, the release rate was constant for a duration of 3.5 days delivering a therapeutically relevant dosage and was fit to a power law model indicating zero-order release characteristics with n=0.981+/-0.006 (r(2)=0.997). This work demonstrates the potential of micro/nanofluidic devices to determine physiological release rates and stresses the importance of matching local conditions to adequately characterize drug delivery devices. It also demonstrates the enormous potential for molecular imprinting to further tailor therapeutic release kinetics via the imprinting process.
Podlesnik, Christopher A.; Jimenez-Gomez, Corina
Although drugs may serve as reinforcers or punishers of operant behavior, the punishing function has received much less experimental attention than the reinforcing function. A sensitive method for studying drug-induced punishment is to assess choice for a punished response over an unpunished response. In these experiments, rats chose between pressing one lever and receiving a sucrose pellet or pressing another lever and receiving a sucrose pellet plus an intravenous injection of histamine. When sucrose was delivered equally frequently for either the punished or the unpunished response, rats selected the unpunished lever consistently, but decreases in the punished response did not differ as a function of intravenous histamine dose (0.1–1 mg/kg/inj). Changing the procedure so that sucrose was delivered on the unpunished lever with p = .5 increased the rats’ responding on the punished lever with saline injections. In addition, the same range of histamine doses produced a much larger range of responses on the punished lever that was dose dependent. Using these procedures to assess the receptors mediating histamine’s effects, the histamine H1-receptor antagonists, pyrilamine and ketotifen, antagonized the punishing effect of histamine, but the histamine H2-receptor antagonist ranitidine did not. However, ranitidine pretreatments reduced histamine-induced heart-rate increases to a greater extent than did the histamine H1-receptor antagonists when administered at the same doses examined under conditions of histamine punishment. Overall, the present findings extend the general hypothesis that activation of histamine H1-receptors mediates the punishing effects of histamine. They also introduce methods for rapidly assessing pharmacological mechanisms underlying drug-induced punishment. PMID:23982898
Andreev-Andrievskiy, Alexander; Popova, Anfisa; Lagereva, Evgeniia; Osipov, Daniil; Berkut, Antonina; Grishin, Eugene; Vassilevski, Alexander
Bites of tiger spiders belonging to Poecilotheria genus cause moderate to severe pain and long-lasting local or generalized muscle cramps in humans. Bites occur in regions of the spiders' natural habitat, India and Sri Lanka, but the popularity of these colorful tarantulas as pets leads to reports of envenomation cases worldwide. Treatment is predominantly symptomatic and often inadequate since there is almost no clinical or toxicology research data available, and physicians outside India or Sri Lanka typically have no experience in treating such cases. We report toxicity studies of venom from nine Poecilotheria species in laboratory mice (Mus musculus Balb/C males). LD50 values are 5-14 mg of lyophilized crude venom per 1 kg (i.v.). The major symptoms of envenomation include tonic-clonic seizures, jerks, characteristic motor stereotypy, and hyperalgesia and point to voltage-gated sodium channels as a potential target of the venom components. Poecilotheria fasciata venom effects were studied in detail at a sub-lethal dose of 5 mg/kg (LD50 = 12 mg/kg). 13 widely used pharmacological agents (atropine, chloropyramine, chlorpromazine, diazepam, ethanol, flupirtine, haloperidol, ketotifen, lamotrigine, oxcarbazepine, tolperisone, xylazine, and CaCl2) were checked for ability to suppress the envenomation symptoms. Chlorpromazine (10 mg/kg, i.p.), oxcarbazepine (60 mg/kg, p.o.), tolperisone (50 mg/kg, s.c.) and xylazine (2.5 mg/kg, i.p.) were found effective as a pretreatment to mitigate muscle cramps and motor stereotypy. When administered after envenomation chlorpromazine (5 mg/kg, i.v.) effectively reduced the cramps, while oxcarbazepine (30 mg/kg, i.v.) and xylazine (1 mg/kg, i.v.) suppressed the stereotypy. Copyright © 2017 Elsevier Ltd. All rights reserved.
Heidari, Alireza; Seraj, Bahman; Shahrabi, Mahdi; Maghsoodi, Hamideh; Kharazifard, Mohammad Javad; Zarabian, Tara
Objectives: Asthma is a common chronic disease. Asthma and anti-asthmatic medications have been suggested as risk factors for increased susceptibility to caries. This study was conducted to evaluate the effects of different types and forms of antihistaminic medications and the duration of drug consumption on the severity of dental caries in asthmatic children. Materials and Methods: This cross-sectional study was conducted in Asthma and Allergy Department of Children’s Medical Center in Tehran, Iran. Eighty-five children between three to 12 years who had been diagnosed with asthma, by means of taking medical history, clinical examination and spirometry were chosen by non-simple random sampling. The participants and their parents were interviewed. Oral examination was performed by a qualified dentist. The data were collected by use of questionnaires and analyzed by the stepwise multivariate linear regression analysis, using SPSS version 16. P<0.05 was considered statistically significant. Results: There was a significant correlation between the number of cetirizine and ketotifen tablets taken and decayed/missing/filled (dmf/DMF) teeth score (P=0.006). There were no correlations between the number of consumed sprays and dmf/DMF score (P=0.923), the duration of drug therapy (P=0.907) or the type of medication taken including ß2 agonists, antihistamines, steroids or a combination of them (P=0.907). Conclusions: The present study showed that the tablet form of medications significantly increased the severity of dental caries even in presence of confounders (sex, age, duration of disease, tooth brushing, sugar consumption, fluoride therapy, mouth dryness). PMID:28127315
Ding, Qiang; Fang, Sui; Chen, Xueqin; Wang, Youxin; Li, Jian; Tian, Fuyun; Xu, Xiang; Attali, Bernard; Xie, Xin; Gao, Zhaobing
The organophosphate-induced delayed neuropathy (OPIDN), often leads to paresthesias, ataxia and paralysis, occurs in the late-stage of acute poisoning or after repeated exposures to organophosphate (OP) insecticides or nerve agents, and may contribute to the Gulf War Syndrome. The acute phase of OP poisoning is often attributed to acetylcholinesterase inhibition. However, the underlying mechanism for the delayed neuropathy remains unknown and no treatment is available. Here we demonstrate that TRPA1 channel (Transient receptor potential cation channel, member A1) mediates OPIDN. A variety of OPs, exemplified by malathion, activates TRPA1 but not other neuronal TRP channels. Malathion increases the intracellular calcium levels and upregulates the excitability of mouse dorsal root ganglion neurons in vitro. Mice with repeated exposures to malathion also develop local tissue nerve injuries and pain-related behaviors, which resembles OPIDN. Both the neuropathological changes and the nocifensive behaviors can be attenuated by treatment of TRPA1 antagonist HC030031 or abolished by knockout of Trpa1 gene. In the classic hens OPIDN model, malathion causes nerve injuries and ataxia to a similar level as the positive inducer tri-ortho-cresyl phosphate (TOCP), which also activates TRPA1 channel. Treatment with HC030031 reduces the damages caused by malathion or tri-ortho-cresyl phosphate. Duloxetine and Ketotifen, two commercially available drugs exhibiting TRPA1 inhibitory activity, show neuroprotective effects against OPIDN and might be used in emergency situations. The current study suggests TRPA1 is the major mediator of OPIDN and targeting TRPA1 is an effective way for the treatment of OPIDN.
O'Donnell, S. R.; Barnett, C. J.
1. The relative potencies, and equilibrium dissociation constants, for nine antagonists of platelet activating factor (Paf) have been determined on rabbit platelets (in diluted platelet-rich plasma (PRP)) in experiments in which the aggregatory response to Paf was measured. 2. Log concentration-response (% maximum) curves to Paf were obtained in the absence (controls) and presence of different concentrations of each Paf antagonist drug. The antagonists shifted the Paf curves to a higher concentration range and the slopes of the Schild plots, constructed from these data, suggested that the drugs were competitive antagonists of Paf. The slopes of the Schild plots for CV-3988 and SRI 63-119 were greater than 1. 3. The pA2 values (pKB values in parentheses) were: WEB 2086 7.31 (7.63); SRI 63-119 6.95; L-652,731 6.71 (6.73); BN 52021 6.38 (6.47); SRI 63-072 6.36 (6.43); CV-3988 5.87; 48740 RP 4.97 (5.07); ketotifen 4.94 (4.95); thiazinamium 4.73 (4.76). 4. This study provides, for the first time, some functional response data for Paf antagonists (pKB values) which are in an appropriate form for use in classifying putative Paf receptors. The study also provides the comparative potencies of these Paf antagonists in inhibiting Paf-induced platelet aggregation. WEB 2086 was the most potent of the drugs examined. PMID:3293683
Manrique-Maldonado, Guadalupe; Altamirano-Espinoza, Alain H; Marichal-Cancino, Bruno A; Rivera-Mancilla, Eduardo; Avilés-Rosas, Victor; Villalón, Carlos M
This study has investigated whether pharmacological activation of Gi/o coupled histamine H3/H4 receptors inhibits the rat vasodepressor sensory outflow. For this purpose, 100 male Wistar rats were pithed, artificially ventilated and pretreated (i.v.) with: 25mg/kg gallamine, 2mg/kg/min hexamethonium and 20μg/kg/min methoxamine, followed by i.v. continuous infusions of physiological saline (0.02ml/min) or immepip (3.1, 10 or 31μg/kg/min; a histamine H3/H4 receptor agonist). Under these conditions, electrical stimulation (0.56-5.6Hz; 50V and 2ms) of the spinal cord (T9-T12) resulted in frequency-dependent vasodepressor responses, which were: (i) unchanged during the infusions of saline or immepip (3.1μg/kg/min); and (ii) significantly but, surprisingly, not dose-dependently inhibited by 10 and 31μg/kg/min immepip. Moreover, the sensory-inhibition by 10μg/kg/min immepip (which failed to inhibit the vasodepressor responses by i.v. bolus injections of α-CGRP; 0.1-1µg/kg) was: (i) essentially unaltered after i.v. administration of saline (1ml/kg) or blocking doses of the antagonists ketotifen (100μg/kg; H1), ranitidine (1000μg/kg; H2) or JNJ7777120 (310μg/kg; H4); and (ii) abolished after i.v. thioperamide (310µg/kg; H3). In conclusion, our results suggest that immepip-induced inhibition of the vasodepressor sensory outflow is mainly mediated by prejunctional activation of histamine H3 receptors.
Sarna, Sushil K.
The development of IBS symptoms – altered bowel function and abdominal cramping in a subset of adult subjects exposed to severe enteric infections opened up an unprecedented opportunity to understand the etiology of this poorly understood disorder. Perhaps, for the reasons that these symptoms follow a severe enteric infection, and mucosal biopsy tissues are readily available, the focus of most studies thus far has been to show that mild/low-grade mucosal inflammation persisting after the initial infection has subsided causes the IBS symptoms. Parallel studies in non-infectious IBS patients, who did not have prior enteritis, showed similar mild mucosal inflammation. Together, these studies examined the mucosal infiltration of specific immune cells, increase of select inflammatory mediators, mast cell and enterochromaffin cell hyperplasia, and epithelial permeability. In spite of the fact that the data on these topics were not consistent among different studies and clinical trials with prednisone, fluoxetine, and ketotifen failed to provide relief of IBS symptoms, the predominant conclusions were that mild mucosal inflammation is the cause of IBS symptoms. However, the circular smooth muscle cells, and myenteric neurons are the primary regulators of gut motility function, while primary afferent neurons and CNS play essential roles in induction of visceral hypersensitivity – no explanation was provided as to how mild mucosal inflammation causes dysfunction in cells far removed. Accumulating evidence shows that mild mucosal inflammation in IBS patients is in physiological range. It has little deleterious effects on cells within its own environment and therefore it is unlikely to affect cells in the muscularis externa. This review discusses the disconnect between the focus on mild/low-grade mucosal inflammation and the potential mechanisms and molecular dysfunctions in smooth muscle cells, myenteric neurons, and primary afferent neurons that may underlie IBS
Zhao, Wenting; Pang, Qin; Xu, Ruixue; Liu, Jianwen; Liu, Shengfa; Li, Jian; Su, Xin-zhuan
Leucocytozoon parasites infect many species of avian hosts, including domestic chicken, and can inflict heavy economic loss on the poultry industry. Two major species of Leucocytozoon parasites have been reported in China, L. sabrazesi and L. caulleryi, although L. sabrazesi appears to be more widespread than L. caulleryi in southern China. The traditional method for detecting Leucocytozoon infection is microscopic examination of blood smears for the presence of mature gametocytes in circulation, which may miss infections with low parasitemia (gametocytemia) or immature gametocytes. Here we developed a PCR-based method to monitor L. sabrazesi infections at seven sites in four provinces of China after testing two PCR primer pairs based on parasite mitochondrial cytochrome b (cytb) and cytochrome c oxidase III (coxIII) genes. We compared the results of PCR detection with those of microscopic observation. As expected, the PCR assays were more sensitive than microscope examination in detecting L. sabrazesi infection and were able to detect parasite DNA after gametocytes disappeared in the blood stream. Using these methods, we investigated monthly dynamics of L. sabrazesi in chickens from a free-range farm in Xiamen, Fujian province of China, over one year. Our results showed that chickens were infected with L. sabrazesi year-round in southern China. Finally, we tested several compounds for potential treatment of Leucocytozoon infections, including primaquine, ketotifen, clomipramine hydrochloride, desipramine hydrochloride, sulfaquinoxaline, and pyrimethamine. Only primaquine had activity against L. sabrazesi gametocytes. Our results provide important information for controlling parasite transmission in southern China and disease management. PMID:27571513
Iwasaki, N; Sakaguchi, J; Ohashi, T; Takahara, E; Ogawa, N; Yasuda, S; Koshinaka, E; Kato, H; Ito, Y; Sawanishi, H
A simple method of transforming classical antihistaminics into nonsedative antiallergic agents with strong effects in rat models is described. Various [4-(diphenylmethoxy)piperidino]- (series A), [4-(diphenylmethyl)piperazinyl]-(series B) and [4-(diphenylmethylene)piperidino]alkanoic acid derivatives (series C) were synthesized and examined for antiallergic activities and effects on the central nervous system (CNS), in comparison with the corresponding N-methyl derivatives (1a--c). N-Alkylcarboxylic acids (5a--c) showed stronger inhibitory effects on compound 48/80-induced lethality in rats than the corresponding N-methyl derivatives (1a--c). In particular, N-alkylcarboxylic acids (5a) in series A exhibited approximately 100-fold stronger inhibitory effects than 1a, and were the least effective in prolonging the sleeping time on hexobarbital-induced anesthesia in mice in all series. As a result of chemical modification in series A, it was found that introduction of a methyl group at the para-position on one benzene ring in the (diphenylmethoxy)piperidine system effectively reduced CNS side-effects without reducing antiallergic activity. (+)-3-[4-[(4-Methylphenyl)phenylmethoxy]piperidino]propionic acid ((+)-5l), an optically active isomer of 5l, exhibited a stronger antiallergic effect (ED50 = 0.17 mg/kg, p.o.) than ketotifen and terfenadine in the 48 h homologous passive cutaneous anaphylaxis (PCA) test, and moreover exhibited no CNS side-effects, such as prolongation of the sleeping time on hexobarbital-induced anesthesia, at an oral dose of 30 mg/kg. Compound (+)-5l was thus proved to be a promising candidate as a nonsedative antiallergic agent.
Casares Alonso, I; Cano Garcinuño, A; Blanco Quirós, A; Pérez García, I
Asthma is one of the most prevalent chronic diseases with effective treatment in paediatrics. The aim of this study is to describe the paediatric prescribing of anti-asthmatics in Castilla-León, analyzing its geographic variability and temporal evolution. An analysis was made of prescriptions dispensed in pharmacies of R03 therapeutic subgroup (anti-asthmatic agents), and the active ingredients mepyramine and ketotifen, prescribed in children less than 14 years of age in the Castilla-León health service from 2005 to 2010 in Primary Care. Data is presented in prescribed daily doses per thousand inhabitants per day (PDHD) for each active ingredient being calculated raw rates and age-adjusted to the variables health area, type of health zone and year of study. A total of 462,354 prescriptions of anti-asthmatic agents were dispensed to a population of 1,580,229 persons/year. There was wide variation between areas in the type and intensity of anti-asthmatic agents used, partly explained by differences in the prevalence of asthma. Montelukast predominated as controller drug in most of them (PDHD 3.1 to 7.7), being similar the consumption intensity in the three types of health zones (PDHD 4.7 to 4.8). The annual variability was low. The study describes the paediatric prescribing pattern of anti-asthmatic agents in Castilla-León between 2005-2010. It shows wide geographical variation, as well as inadequacies regarding current recommendations of asthma treatment. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.
Kato, Yukiko; Izukawa, Takeshi; Oda, Shingo; Fukami, Tatsuki; Finel, Moshe; Yokoi, Tsuyoshi; Nakajima, Miki
Recent observations revealed that human UDP-glucuronosyltransferase (UGT) 2B10 catalyzes N-glucuronidation of amine-containing compounds. Knowledge of the substrate specificity and clinical significance of UGT2B10 is still limited. The purpose of this study was to expand the knowledge of UGT2B10 substrates and to evaluate its significance in drug clearance. Using recombinant UGT2B10, we found that it catalyzes the N-glucuronidation of amitriptyline, imipramine, ketotifen, pizotifen, olanzapine, diphenhydramine, tamoxifen, ketoconazole, and midazolam. These are drugs that were previously reported to be substrates for UGT1A4 or UGT1A3, and that contain in their structure either tertiary aliphatic amines, cyclic amines, or an imidazole group. UGT2B10 was inactive in the glucuronidation of desipramine, nortriptyline, carbamazepine, and afloqualone. This group of drugs contains secondary or primary amines, and these results suggest that UGT2B10 preferably conjugates tertiary amines. This preference is partial because UGT2B10 did not conjugate the tertiary cyclic amine in trifluoperazine. Kinetic analyses revealed that the affinity and clearance of UGT2B10 for amitriptyline, imipramine, and diphenhydramine are significantly higher than the corresponding values of UGT1A4 and UGT1A3, although the Vmax values of UGT1A4 toward these drugs are considerably higher. These findings suggest that UGT2B10 plays a major role in the N-glucuronidation of these drugs at therapeutic concentrations. These results are also supported by inhibition studies with nicotine and hecogenin. In conclusion, this study expands the understanding of the substrate specificity of UGT2B10, highlighting its preference for tertiary amines with higher affinities and clearance values than those of UGT1A4 and UGT1A3.
Shah, Neil; Tan, Hui-leng; Sebire, Neil; Suri, Ranjan; Leuven, Ku
There is increasing evidence to suggest the presence of chronic inflammation in the gastrointestinal (GI) tract of cystic fibrosis (CF) patients. Some CF patients continue to have very severe gastrointestinal symptoms despite conventional CF treatment. In our center, these patients are managed in a CF gastroenterology clinic, jointly with a pediatric gastroenterologist. A number have required GI endoscopy and biopsy. The aim of our study was to characterize these patients and determine whether endoscopy and biopsy changed their management. We reviewed all the patients seen in the CF gastroenterology clinic from 2004 to 2009, who had GI endoscopies performed. The GI symptoms these patients were experiencing included abdominal pain, nausea and vomiting, rectal bleeding, failure to thrive, loose stools, and constipation. Twelve patients had GI endoscopies with mucosal biopsies performed. The median [interquartile range (IQR)] age at referral to the CF gastroenterology clinic was 4 years [0.9-8]. Their body mass index (BMI) was 15.2 [13.7-15.5]. Twenty-five percent were homozygous delta F508. Two patients had previously had meconium ileus as neonates requiring surgical intervention. One other patient had needed abdominal surgery for intussusception. Ninty-two percent were pancreatic insufficient, 25% were chronically infected with Pseudomonas aeruginosa and 17% were on regularly 3 monthly intravenous antibiotics. Of the 10 patients who were able to perform spirometry, FEV1 was 101% [67-125] predicted. Nine of the 12 patients had evidence of mucosal inflammation in their biopsies, including duodenitis with eosinophilic infiltrate, chronic non-specific inactive gastritis, enteropathy with partial villous atrophy, and non-specific colitis. Immunosuppressive and anti-inflammatory therapies were commenced in these nine patients, including prednisolone, azathioprine, methotrexate, ketotifen, mesalazine, and sulfasalazine as well as the use of parenteral nutrition and
El-Kousy, N; Bebawy, L I
Atomic absorption spectrometry (AAS) and colourimetric methods have been developed for the determination of pizotifen (I), ketotifen (II) and loratadine (III). The first method depends on the reaction of the three drugs (I); (II) and (III) with cobalt thiocyanate reagent at pH 2 to give ternary complexes. These complexes are readily extracted with organic solvent and estimated by indirect atomic absorption method via the determination of the cobalt content in the formed complex after extraction in 0.1 M hydrochloric acid. It was found that the three drugs can be determined in the concentration ranges from 10 to 74, 12 to 95 and 10 to 93 microg ml(-1) with mean percentage recovery of 99.71+/-0.87, 99.70+/-0.79 and 99.62+/-0.75%, respectively. The second method is based on the formation of orange red ion pairs as a result of the reaction between (I); (II) and (III) and molybdenum thiocyanate with maximum absorption at 469.5 nm in dichloromethane. Appropriate conditions were established for the colour reaction. Under the proposed conditions linearity was obeyed in the concentration ranges 3.5-25, 5-37.5 and 2.5-22.5 microg ml(-1) with mean percentage recovery of 99.60+/-0.41, 100.11+/-0.43 and 99.31+/-0.47% for (I): (II) and (III), respectively. The third method depends on the formation of radical ion using 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ). The colour formed was measured at 588 nm for the three drugs (I); (II) and (III), respectively. The method is valid in concentration range 10-80 microg ml(-1) with mean percentage recovery 99.75+/-0.44, 99.94+/-0.72 and 99.17+/-0.36% for (I); (II) and (III), respectively. The proposed methods were applied to the analysis of pharmaceutical preparations. The results obtained were statistically analysed and compared with those obtained by applying the official and reference methods.
Wüthrich, B; Hofer, T
The treatment of food allergies is logically based on strict elimination of causative allergens. While it is easy to eliminate food which is infrequently consumed, it is more difficult to manage an allergy involving regularly consumed foods, especially where patients have to eat away from home for professional reasons. The creation of elimination diets for milk, eggs, and mould and yeast allergies is discussed. In raw food and vegetable allergy the act of cooking is often sufficient to denature the allergen as it is unstable to heat. Follow-up investigations show that some 50% of children achieve cure spontaneously by strict elimination diet, especially in regard to milk allergy. In our own 173 (mainly adult) patients with food allergy, some 2/3 reported after 3-5 years that a strict elimination diet had to be followed, since otherwise prompt relapse of allergic symptoms was noted. About 1/3 of patients, mainly with milk, cheese or egg allergy, can hope for spontaneous desensitization by appropriate diet. This is demonstrated by a case history with disappearance of IgE antibodies. Should this fail to occur, oral desensitization with milk or egg-white extracts offers an effective therapy. The practice of hyposensitization with foodstuffs is illustrated by examples and tabulation of immunologic parameters. In raw food or vegetable allergy, which is often associated with birch or mugwort pollinosis, improvement or even complete cure can be expected in about 1/3 of cases by systematic desensitization of pollinosis. On the other hand, the therapy and prognosis of food allergy involving extreme and polyvalent sensitivities, especially to spices, or with multifactorially induced symptoms, is more problematic. In these cases a strict elimination diet should be followed by continuous prophylactic/symptomatic treatment with antianaphylactic substances such as cromoglicinic acid (Nalcrom) - especially in gastrointestinal food allergies - or with ketotifen (Zaditen) or
Carbone, Simona E.; Wattchow, David A.; Spencer, Nick J.; Hibberd, Timothy J.; Brookes, Simon J. H.
Excitatory and inhibitory junction potentials of circular smooth muscle cells in guinea pig ileum and colon are suppressed 30–90 min after setting up in vitro preparations. We have previously shown this “unresponsive” period is associated with a transient loss of dye coupling between smooth muscle cells, which subsequently recovers over the ensuing 30–90 min; junction potentials recover in parallel with dye coupling (Carbone et al., 2012). Here, we investigated which components of dissection trigger the initial loss of coupling. Intracellular recordings were made from circular muscle cells of guinea pig ileum with micropipettes containing 5% carboxyfluorescein. After allowing 90–120 min for junction potentials to reach full amplitude, we re-cut all 4 edges of the preparation more than 1 mm from the recording sites. This caused a reduction in the amplitude of IJPs from 17.2 ± 0.7 mV to 9.5 ± 1.5 mV (P < 0.001, n = 12) and a significant reduction in dye coupling. Both recovered within 60 min. We repeated this experiment (n = 4), recording both 1 and 4 mm from the cut edge: both sites were equally affected by re-cutting the sides of the preparation. Equilibrated preparations were stretched to 150% of their original length, this had no significant effect on junction potentials or dye coupling. Setting up preparations in low calcium solution did not prevent the initial suppression of IJPs and dye coupling. Application of 3 μM indomethacin (n = 3), 10 μM ketotifen (n = 4) or 10 μM forskolin during dissection did not prevent the suppression of IJPs and dye coupling. If dissection damage was reduced, by leaving the mucosa and submucosa attached to the circular muscle, IJPs showed less initial suppression than in preparations where the layers were dissected off. We conclude that physical damage to the gut wall triggers loss of gap junction coupling and neuromuscular transmission, this is not due to stretch, influx of calcium ions, release of prostaglandins or
Cloning and characterization of four rabbit aldo-keto reductases featuring broad substrate specificity for xenobiotic and endogenous carbonyl compounds: relationship with multiple forms of drug ketone reductases.
Endo, Satoshi; Matsunaga, Toshiyuki; Arai, Yuki; Ikari, Akira; Tajima, Kazuo; El-Kabbani, Ossama; Yamano, Shigeru; Hara, Akira; Kitade, Yukio
Multiple forms of reductases for several drug ketones were isolated from rabbit liver, but their interrelationship and physiologic roles remain unknown. We isolated cDNAs for four aldo-keto reductases (AKR1C30, AKR1C31, AKR1C32, and AKR1C33), which share high amino acid sequence identity with the partial sequences of two rabbit naloxone reductases. The four recombinant enzymes reduced a variety of carbonyl compounds, including endogenous α-dicarbonyls (e.g., isatin and diacetyl), aldehydes (e.g., farnesal and 4-oxo-2-nonenal), and ketosteroids. They differed in specificity for drug ketones and ketosteroids. Although daunorubicin and befunolol were common substrates of all of the enzymes, AKR enzymes specifically reduced naloxone (AKR1C30, AKR1C32, and AKR1C33), metyrapone (AKR1C32 and AKR1C33), loxoprofen (AKR1C31 and AKR1C32), ketotifen (AKR1C30), and naltrexone and fenofibric acid (AKR1C33). AKR1C30 reduced only 17-keto-5β-androstanes, whereas the other enzymes were active toward 3-, 17-, and 20-ketosteroids, and AKR1C33 further reduced 3-keto groups of bile acids and 7α-hydroxy-5β-cholestanes. In addition, AKR1C30, AKR1C31, AKR1C32, and AKR1C33 were selectively inhibited by carbenoxolone, baccharin, phenolphthalein, and zearalenone, respectively. The mRNAs for the four enzymes were ubiquitously expressed in male rabbit tissues, in which highly expressed tissues were the brain, heart, liver, kidney, intestine, colon, and testis (for AKR1C30 and AKR1C31); brain, heart, liver, kidney, testis, lung, and adrenal gland (for AKR1C32); and liver and intestine (for AKR1C33). Thus, the four enzymes correspond to the multiple drug ketone reductases, and may function in the metabolisms of steroids, isatin and reactive carbonyl compounds, and bile acid synthesis.
Castillo, Mayret; Scott, Neil W; Mustafa, Mohammad Z; Mustafa, Mohammed S; Azuara-Blanco, Augusto
reference lists of review articles and relevant trial reports for details of further relevant publications. We included randomised controlled trials (RCTs) comparing topical antihistamine and mast cell stabilisers, alone or in combination, with placebo, no treatment or to any other antihistamine or mast cell stabiliser, or both, that examined people with seasonal or perennial allergic conjunctivitis, or both. The primary outcome was any participant-reported evaluation (by questionnaire) of severity of four main ocular symptoms: itching, irritation, watering eye (tearing), and photophobia (dislike of light), both separately and, if possible, by an overall symptom score. We considered any follow-up time between one week and one year. Two review authors independently extracted data and assessed risk of bias. Disagreements were resolved by discussion among review authors and the involvement of a third review author. We followed standard methodological approaches used by Cochrane. We identified 30 trials with a total of 4344 participants randomised, with 17 different drugs or treatment comparisons. The following antihistamines and mast cell stabilisers were evaluated in at least one RCT: nedocromil sodium or sodium cromoglycate, olopatadine, ketotifen, azelastine, emedastine, levocabastine (or levocabastine), mequitazine, bepotastine besilate, combination of antazoline and tetryzoline, combination of levocabastine and pemirolast potassium. The most common comparison was azelastine versus placebo (nine studies).We observed a large variability in reporting outcomes. The quality of the studies and reporting was variable, but overall the risk of bias was low. Trials evaluated only short-term effects, with a range of treatment of one to eight weeks. Meta-analysis was only possible in one comparison (olopatadine versus ketotifen). There was some evidence to support that topical antihistamines and mast cell stabilisers reduce symptoms and signs of seasonal allergic conjunctivitis when