Reduction of arthrofibrosis utilizing a collagen membrane drug-eluting scaffold with celecoxib and subcutaneous injections with ketotifen.

The dense formation of abnormal scar tissue after total knee arthroplasty results in arthrofibrosis, an unfortunate sequela of inflammation. The purpose of this study was to use a validated rabbit model to assess the effects on surgically-induced knee joint contractures of two combined pharmacological interventions: celecoxib (CXB) loaded on an implanted collagen membrane, and subcutaneously (SQ) injected ketotifen. Thirty rabbits were randomly divided into five groups. The first group received no intervention after the index surgery. The remaining four groups underwent intra-articular implantation of collagen membranes loaded with or without CXB at the time of the index surgery; two of which were also treated with SQ ketotifen. Biomechanical joint contracture data were collected at 8, 10, 16, and 24 weeks. At the time of necropsy (24 weeks), posterior capsule tissue was collected for messenger RNA and histopathologic analyses. At 24 weeks, there was a statistically significant increase in passive extension among rabbits in all groups treated with CXB and/or ketotifen compared to those in the contracture control group. There was a statistically significant decrease in COL3A1, COL6A1, and ACTA2 gene expression in the treatment groups compared to the contracture control group (P < .001). Histopathologic data also demonstrated a trend towards decreased fibrous tissue density in the CXB membrane group compared to the vehicle membrane group. The present data suggest that intra-articular placement of a treated collagen membrane blunts the severity of contracture development in a rabbit model of arthrofibrosis, and that ketotifen and CXB may independently contribute to the prevention of arthrofibrosis. Statement of clinical significance: Current literature has demonstrated that arthrofibrosis may affect up to 5% of primary total knee arthroplasty patients. For that reason, novel pharmacologic prophylaxis and treatment modalities are critical to mitigating reoperations and revisions while improving the quality of life for patients with this debilitating condition.

In vivo enhancement of transdermal absorption of ketotifen by supersaturation generated by amorphous form of the drug.

The enhancing effect of supersaturation generated by amorphous ketotifen in silicone pressure-sensitive adhesive matrices (PSA) on the transdermal absorption was evaluated in vivo using hairless rats, and it was compared with the increase of drug amount in skin tissues. The duration of the enhancing effect was also investigated in relation to the time how long supersaturation was maintained in PSA. PSA containing crystalline ketotifen (PSA-Crystalline) and that containing amorphous ketotifen (PSA-Amorphous) were prepared by the solvent casting method using n-hexane and dichloromethane, respectively. In vivo transdermal absorption was evaluated by measuring the amount of ketotifen in PSAs, the stratum corneum, and viable skin tissues after administration of PSAs on abdominal sites of hairless rats. The amount of ketotifen absorbed into the systemic circulation was calculated by subtracting the drug amount in whole skin tissues from the amount of the drug released from PSAs, then it was monitored for up to 23 h. In both types of PSA, a constant absorption rate was maintained for up to 23 h after 7-h lag time. The enhancement factor of PSA-Amorphous against PSA-Crystalline was approximately 7, which was in good agreement with the difference of drug amount in viable skin tissues. Time course of the drug amount in PSA-Amorphous suggested that the supersaturated level was gradually decreased after 10h, but the decline of the driving force from PSAs was supplemented by the drug release from the skin depot resulting in the constant absorption rate up to 23 h. These results suggest the usefulness of amorphous ketotifen to obtain enhanced transdermal absorption.

Anti-inflammatory pharmacotherapy for wheezing in preschool children.

Accumulating evidence indicates that there are at least two phenotypes of wheezing in preschool years with distinct natural history. Frequent wheezing in the first 3 years of life with risk factors for asthma (e.g., eczema, maternal asthma) predicts symptoms in older age, while infrequent viral-associated wheezing without risk factors for asthma has a benign prognosis. This systematic review summarizes evidence on the use of anti-inflammatory medications in preschool children with wheezing. Literature search was performed using Medline and the Cochrane Library. Retrieved articles were critically appraised. Episodic use of high-dose inhaled corticosteroids (>1,600 mcg/day of beclomethasone) may ameliorate severity of intermittent viral-associated wheezing. Maintenance inhaled corticosteroids can control symptoms in children with frequent wheezing associated with risk factors for asthma. Inhaled corticosteroids do not alter the natural history of wheezing even when started early in life and could have a negative impact on linear growth rate. Short courses of oral corticosteroids have been proposed as an effective measure to control exacerbations of symptoms although there is little evidence supporting their use. Some studies support the administration of non-steroidal anti-inflammatory medications (leukotriene pathway modifiers, cromones, methylxanthines) for mild frequent wheezing. Maintenance inhaled corticosteroids is the most effective measure for controlling frequent wheezing in preschool children, especially when accompanied by risk factors for asthma. This treatment does not affect the natural history of wheezing, although deceleration of linear growth rate is the most commonly recognized systemic adverse effect.

Effect of antihistamine eye drops on the conjunctival provocation test with Japanese cedar pollen allergen.

BACKGROUND: Approximately 16.2% of the Japanese population suffer from cedar pollinosis, with various manifestations such as ophthalmic, laryngo-pharyngeal and skin symptoms in addition to nasal symptoms. Thus, the annual pollen season is an agonizing period for patients. No study has reported symptoms and their clinical courses after conjunctival provocation with purified cedar pollen allergen Cry j1 as well as suppression of these allergen-induced ocular symptoms by antihistamine eye drops. METHODS: Nine patients with Japanese cedar pollinosis who had no nasal or ocular symptoms were included in the present study, after obtaining informed consent in writing. 1) Purified cedar pollen allergen Cry j1 was instilled in the left eye and phosphate-buffered saline (PBS) in the right eye as a control. 2) Levocabastine hydrochloride ophthalmic suspension and ketotifen fumarate ophthalmic solution were respectively instilled in the left and right eyes, which were then challenged with the allergen. Ocular symptoms after provocation with the allergen were recorded through the clinical course. RESULTS: Pollen allergen-induced ocular symptoms were itching and hyperemia of the palpebral conjunctiva, and itching lasted for more than 5 hours. Moreover, preadministration of antihistamine eye drops suppressed the increases in the ocular symptom scores, eliminating itching within 1 hour. Allergen provoked not only ocular symptoms but also nasal symptoms in 77.8% of patients. CONCLUSIONS: Preadministration of antihistamine eye drops suppressed the symptoms induced by the allergen, which suggests that this is an effective early therapy for Japanese cedar pollinosis, if it is started before the pollen season. However, self-protection by patients using a mask may not be effective enough to suppress nasal symptoms during the pollen season, requiring them to additionally wear glasses to avoid exposure to the allergen.

The anti-allergic effects of a cromolyn sodium-chlorpheniramine combination compared to ketotifen in the conjunctival allergen challenge model.

PURPOSE: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: DSCG-chlorpheniramine was found to be more effective than ketotifen at preventing itching and redness in the CAC model.

Randomized, double-masked, placebo-controlled comparison of the efficacy of emedastine difumarate 0.05% ophthalmic solution and ketotifen fumarate 0.025% ophthalmic solution in the human conjunctival allergen challenge model.

BACKGROUND: Emedastine difumarate 0.05% ophthalmic solution and ketotifen fumarate 0.025% ophthalmic solution are 2 topical antiallergic agents available in the United States and other countries. Emedastine is indicated for the temporary relief of the signs and symptoms of allergic conjunctivitis. Ketotifen is indicated for the temporary relief of ocular itching caused by allergic conjunctivitis. OBJECTIVE: The purpose of this study was to compare the efficacy of these agents in the temporary relief of ocular itching due to allergic conjunctivitis. The 2 agents were compared with each other and with placebo (artificial tears) using the conjunctival allergen challenge (CAC) model. METHODS: This was a single-center, randomized, double-masked, placebo-controlled study. At visit 1, CAC was performed on eligible subjects to identify the dose required to elicit a positive allergic reaction. Subjects returned after 7 days for visit 2 to confirm the allergen dose. On day 14 (+/-3) of the study, enrolled subjects were randomized to 1 of 3 treatment groups: emedastine in I eye and placebo in the other, ketotifen in 1 eye and placebo in the other, or emedastine in 1 eye and ketotifen in the other. In 25 subjects, bilateral CAC was performed 5 minutes after study medication instillation. In a second group of 20 subjects, CAC was performed 15 minutes after medication instillation. Itching was graded according to a standardized 5-point scale (0 = none to 4 = severe itching) at 3, 5, and 10 minutes postchallenge. Differences in efficacy scores between treatments and versus placebo were compared using 2-sample t tests of equal variance. RESULTS: A total of 45 patients (mean age, 41.2 years) received treatment: 16 received emedastine in 1 eye and ketotifen in the other; 14 received emedastine in 1 eye and placebo in the other; and 15 received ketotifen in 1 eye and placebo in the other. Both emedastine and ketotifen significantly inhibited itching (P < 0.05) compared with placebo at all time points after the 5- and 15-minute CAC. Mean raw scores for the active treatments were not statistically different. The mean itching efficacy scores were also not statistically different between active treatments. No adverse events were reported in this study. CONCLUSION: The results of this study suggest that emedastine and ketotifen are not significantly different with respect to anti-itching efficacy in the CAC model of acute allergic conjunctivitis.

Major basic protein and topical administration of ketotifen in pollinosis under natural allergen provocation.

In this study we investigated the potential relation among subjective symptoms, blood eosinophil counts and the levels of major basic protein (MBP) in serum throughout the pre- to postpollen season. In addition, we compared the effects of topical administration of ketotifen on these parameters between the prophylactic treatment group (n = 10) and the postsymptomatic treatment group (n = 10). We found that (1) the levels of MBP in serum during the season were significantly higher than those before the season and (2) the levels of the above three parameters in the prophylactic treatment group were significantly lower than those in the postsymptomatic treatment group during the season. It was concluded from these results that the action of MBP may be involved in the pathogenesis of allergic rhinitis. Furthermore, for the first time we provided evidence that topical ketotifen administration could suppress the systemic upregulation of the blood eosinophil count and MBP level in subjects with pollinosis.

Seasonal variations of nasal resistance in allergic rhinitis and environmental pollen counts. III: Efficacy of antiallergic agents.

We previously reported that, in a patient with Japanese cedar pollinosis, preseasonal increase in total nasal airway resistance (NAR) possibly caused from circannual endogenous rhythm was suppressed by preseasonal systemic administration of antiallergic agent. In this study, in order to determine the influence of preseasonal use of a topical antiallergic agent and seasonal administration of a peroral antiallergic agent, we made measurement of nasal airway resistance and pollen counts under the previous respective conditions in separated years. Preseasonal high mean values of total NAR for a couple of weeks was not suppressed by the preseasonal topical administration of ketotifen nasal spray in 1992 which was a low pollen season (974/cm2). However, the patient did not complained of severe episodes of hay fever at all throughout the season. Preseasonal increases in mean values of total NAR were observed in 1993 which was a high Japanese cedar pollen season (4,875/cm2) with NAR the same as untreated seasons. This may have been because the patient was not treated with preseasonal use of peroral azelastine. On extremely high Japanese cedar pollen count days further increased NAR occurred in the patient. The patient experienced relatively severe hay fever episodes, but used no other anti-histamine nor topical steroid during the season.

[Use of vilozen and ketotifen combination for increasing the effectiveness and prevention of complications of antibiotic therapy of streptococcal infections]. / Primenenie kombinatsii vilozena i ketotifena dlia povysheniia éffektivnosti i profilaktiki oslozhnenii antibiotikoterapii streptokokkovykh infektsii.

The clinical efficacy of a vilozen and ketotifen (zaditen) combination in the treatment of streptococcal infections along with the routine therapy was studied. The use of the combination was shown advisable in the complex therapy and prevention of relapses in patients with streptococcal infections. The combined pharmacotherapy promoted better clinical indices, normalization of the immune status and a reduction in the incidence of allergic reactions to antibiotics and a decrease in sensitization to bacterial allergens.

[Ketotifen and nasal steroids in the therapy of pollinosis]. / Ketotifen i nazalni steroid u terapiji polinoze.

Thirty-five patients with seasonal pollen rhinitis due to hypersensitivity to Parietaria officinalis pollen were randomized and treated with ketotifen and with a combination of ketotifen and beclomethason diproprionate, a nasal steroid. The study was timed to cover the Parietaria off. pollination period (4 months), which was documented by the determination of air concentration of the pollen. Respiratory symptoms and additional medications were scored according to a defined control. During the peak pollen period, both groups suffered from intensified pollinosis symptoms which prompted additional medication. The increases, however, were less significant in the group treated with the combination of the two drugs, i.e. better results were obtained with the ketotifen-beclomethasone diproprionate combination than with ketotifen alone.

Asma y nifedipina: estudio comparativo del efecto profilactico de la nifedipina frente al ketotifeno y placebo en asma alergica infantil / Asthma and nifedipine: comparative study of the profilactic effect of nifedipine against ketotifen and placebo in child's allergic asthma

Se presentan los resultados de un estudio doble ciego, al azar, que compara los efectos de la nifedipina, una dihidropiridina antagonista del calcio, de amplia utilizacion cardiovascular, con los del Ketotifeno y los de un placebo; cada uno de ellos fue administrado por via oral cada 12 horas, durante 4 meses, a un grupo de 20 ninos mayores de 5 anos con asma alergica de una evolucion minima de 2 anos; el estudio se llevo a cabo en el Servicio de Alergias del Hospital Universitario San Vicente de Paul, de Medellin, Colombia, entre Julio de 1984 y Diciembre de 1986. La nifedipina produjo disminucion de la frecuecnia de las crisis en 17 pacientes (85%) y de su intensidad y duracion en 16 (80%); en esta misma proporcion (80%) se disminuyo el consumo de broncodilatadores; 18 pacientes (90%) informaron efectos beneficos de la nifedipina y la mejoria, evaluada por el medico, se hallo en 14 (70%). No hubo con la nifedipina modificaciones del pulso ni de la presion arterial ni, tampoco de 14 pruebas de funcion pulmonar; los efectos secundarios fueron minimos y autolimitados. Los resultados obtenidos con la nifedipina fueron estadisticamente semejantes a los de ketotifeno y los de ambos significativamente superiores a los logrados con el placebo(p<0.05)En conclusion: la nifedipina podria ser una alternativa en le manejo del asma alergica infantil leve o moderada, dado su comportamiento similar al del ketotifeno que es de eficacia reconocida en este campo; en un futuro los antagonistas del calcio pueden llegar a ser el tratamiento de elección del paciente asmatico si..

Between July 1984 and December 1986 a double blind randomized study was conducted at the Allergy Clinic of the Hospital Universitario San Vicente de Paúl, Medellín, Colombia, in order to compare the effects of Nifedipine, Ketotifen and placebo on allergic asthma in children; each drug and the placebo were administered orally every 12 hours for a period of 4 months to a group of 20 children. The objective was to evaluate the usefulness of Nifedipine In the prophylactic management of allergic asthma in this population and to compare it with Ketotifen, a provenly efficacious drug, and placebo. AII patients were older than 5 years and had suffered the disease for more than 2 years. Nifedipine treated patients showed a reduction in the frequency of their asthmatic crisis (17 patients; 85%) and in their intensity and duration (16 patients; 80%); a similar reduction was observed In the need for bronchodilators; 18 patients (90%) reported beneficial effects with this drug and medical evaluation confirmed Improvement In 14 (70%). These results resembled those obtained with Ketotifen and both were statistically superior to placebo (p<0.05). Pulmonary function tests, pulse rate and blood pressure did not show any significant changes. Secondary effects were minimal and self-Limited. It is concluded that Nifedipine can be an alternative drug for the treatment of mild to moderate allergic asthma in children. If calcium antagonists with higher affinity for the respiratory tract and better blocking effects are synthesized they might become the elective therapeutic choice for these patients

Use of inhaled calcium channel blocking agents in the treatment of asthma.

The inhalation of drugs that are active in the respiratory tract offers the ideal route of administration, since it results in the rapid delivery of appropriate concentrations with a much reduced risk of systemic adverse effects: Problems with regard to poor absorption from the gastrointestinal tract (sodium cromoglycate) or substantial effect on liver metabolism (verapamil) can be avoided. Certain drugs such as antihistamines and ketotifen may be more effective administered by inhalation since high concentrations with reduced unwanted effects can be achieved on the bronchial surface where, in allergic asthma, the critical initial interaction between sensitized mast cells (mucosal?) and allergen with subsequent mediator release occurs. Indeed inhaled verapamil has been shown to be effective in animal models of asthma but not in man. Systemically administered nifedipine gives partial and variable protection against induced asthma in man and its efficacy (with reduced cardiovascular effects) may well be improved by inhalation.

Therapeutic effects of a new, anti-allergic ophthalmic preparation.

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.