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A double-blind comparative study was performed to investigate the usefulness of ketotifen syrup as compared with clemastine syrup in 284 patients with atopic dermatitis. The clinical efficacy of ketotifen was significantly superior to that of clemastine. Ketotifen alleviated not only pruritus but also other dermatologic symptoms.
A validated method for determination of total amount of ketotifen (unchanged and conjugated) in human plasma has been presented. An enzyme hydrolysis of conjugated ketotifen was conducted with combination of beta-glucuronidase and arylsulfatase. After the enzyme hydrolysis a solid-phase extraction was applied as a cleaning step. The quantitative determination by gas chromatography with mass-spectrometry detection (GC-MS) was performed. Pizotifen has been used as an internal standard. A reliable hydrolysis as well as a satisfactory accuracy, improved precision in the linear region from 0.500 to 10.0 ng/ml plasma, limit of detection of 0.010 ng/ml and prolonged capillary column life have been achieved.
In several clinics we carried out a comparative double-blind study of ketotifen (HC) in 260 patients with perennial rhinitis in order to reveal the clinical efficacy, safety and usefulness. We administered two different doses of HC (0.5 mg X 2 and 1 mg X 2 daily), clemastine fumarate, CF (1.34 mg X 2 daily) and their placebos. The active drugs were always given in combination with their placebos during a period of 4 weeks. The results indicated that HC, especially HC 1 mg X 2, was superior to CF in efficacy and usefulness. Side-effects were mild and the frequency in which they occurred was similar to CF. In contrast to CF, HC showed an efficacy not only in sneezing and nasal discharge but also in nasal obstruction as well.
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Experimental studies have indicated that the central histaminergic system plays an important role in the inhibition of seizures through the stimulation of histamine H1 receptors. H1 receptor antagonists, including classical antiallergic drugs, occasionally may induce convulsions in healthy children and patients with epilepsy. The purpose of this study was to investigate the effects of antazoline and ketotifen (two H1 receptor antagonists) on the anticonvulsant activity of antiepileptic drugs against maximal electroshock (MES)-induced convulsions in mice. The following antiepileptic drugs were used: valproate, carbamazepine, diphenylhydantoin and phenobarbital. In addition, the effects of antiepileptic drugs alone or in combination with antazoline or ketotifen were studied on long-term memory (tested in the passive avoidance task) and motor performance (evaluated in the chimney test), acutely and after 7-day treatment with these H1 receptor antagonists. The influence of antazoline and ketotifen on the free plasma and brain levels of the antiepileptics was also evaluated. Antazoline (at 0.5 mg/kg), given acutely and after 7-day treatment, significantly diminished the electroconvulsive threshold. Similarly, ketotifen, after acute and chronic doses of 8 mg/kg markedly reduced the threshold for electroconvulsions. In both cases, antazoline and ketotifen were without effect upon this parameter at lower doses. Antazoline (0.25 mg/kg) significantly raised the ED50 value of carbamazepine against MES (both, acutely and after 7-day treatment). Furthermore antazoline (0.25 mg/kg) also reduced the anticonvulsant activity of diphenylhydantoin, but only after repeated administration, without modifying the brain and free plasma level of this drug. Moreover, valproate and phenobarbital did not change their protective activity when combined with antazoline. Ketotifen (4 mg/kg) possessed a biphasic action, acutely it enhanced the anticonvulsant action of carbamazepine and phenobarbital while, following 7-day treatment, reduced the antiseizure activity of carbamazepine. Ketotifen did not affect the free plasma or brain levels of antiepileptics tested. Only acute antazoline (0.25 mg/kg) applied with valproate impaired the performance of mice evaluated in the chimney test. Ketotifen (4 mg/kg) co-administered with conventional antiepileptic drugs impaired motor coordination in mice treated with valproate, phenobarbital or diphenylhydantoin. Acute and chronic antazoline (0.25 mg/kg) alone or in combination with antiepileptic drugs did not disturb long-term memory, tested in the passive avoidance task. Similarly, ketotifen (4 mg/kg) did not impair long-term memory, acutely and after 7-day treatment. However, valproate alone or in combination with chronic ketotifen (4 mg/kg) worsened long-term memory. The results of this study indicate that H1 receptor antagonists, crossing the blood brain barrier, should be used with caution in epileptic patients. This is because antazoline reduced the protective potential of diphenylhydantoin and carbamazepine. Also, ketotifen reduced the protection offered by carbamazepine and elevated the adverse activity of diphenylhydantoin, phenobarbital and valproate.
BACKGROUND: Ketotifen fumarate is a topical antiallergic combination mast-cell stabilizer and antihistamine indicated for the temporary prevention of ocular itching due to allergic conjunctivitis. Desloratadine is a systemic antihistamine indicated for the treatment of seasonal and perennial allergic rhinitis. OBJECTIVE: The purpose of this study was to compare the efficacy of ketotifen 0.025% ophthalmic solution instilled in the eye, desloratadine 5-mg tablets taken orally, and their combination for prevention of the signs and symptoms of allergic rhinoconjunctivitis, as induced by the conjunctival allergen challenge (CAC) model. METHODS: This was a randomized, double-masked, placebo- and active-controlled, single-center clinical trial. At visit l, the dose of allergen necessary to elicit a qualifying allergic reaction was determined for subjects meeting the entry criteria. At visit 2, the allergen dose determined at visit 1 was confirmed, and all subjects who had a qualifying ocular and nasal allergic reaction were randomized to 1 of 3 treatment groups: ketotifen ophthalmic solution and placebo tablet, desloratadine tablet and placebo eyedrop, or ketotifen and desloratadine. Subjects were instructed to instill 1 drop into each eye twice daily and take 1 tablet with water once daily at the same time as the morning eyedrop for approximately 4 weeks. At visit 3, subjects brought in their medication and were given 1 drop of the eyedrop bilaterally and 1 tablet with water. Bilateral CAC was performed 2 hours after administration of medication. Using standardized scales, subjects rated ocular itching at 3, 5, and 7 minutes after CAC; ocular tearing and eyelid swelling at 10, 15, and 20 minutes after CAC; and nasal signs and symptoms (sneezing, rhinorrhea and postnasal drip, pruritus, and nasal congestion) at 10, 20, 30, 40, and 50 minutes after CAC. The investigator graded ocular redness and chemosis at 10, 15, and 20 minutes after CAC. At all visits, subjects were offered an anti-allergy eyedrop to relieve any immediate ocular discomfort caused by CAC. RESULTS: One hundred two subjects were screened-82 (55 women, 27 men; mean age, 42.8 years [range, 21-70 years]) were randomized to treatment, and 80 completed the study. Subjects in the group that received ketotifen (n = 27) and the group that received ketotifen with desloratadine (n = 26) had significantly lower mean itching scores compared with those in the group that received desloratadine alone (n = 27) at all time points (P </= 0.05). Total ocular redness, calculated by summing the mean redness scores for each of the 3 vessel beds, was significantly lower in the ketotifen group than in the other treatment groups at most time points (P </= 0.05). All treatments attenuated nasal symptoms; no statistically significant differences were noted between treatment groups, with the exception of the 50-minute time point, at which combination treatment was significantly more effective than ketotifen alone (P </= 0.05). The proportion of subjects who requested relief drops after CAC was significantly lower in both the ketotifen alone and combination treatment groups compared with the desloratadine alone group (P = 0.004). CONCLUSIONS: Ketotifen ophthalmic solution significantly decreased the signs and symptoms of ocular and nasal allergic rhinoconjunctivitis. The addition of ketotifen to the oral desloratadine regimen improved the overall antiallergic efficacy of both medications.
The antiallergic drug ketotifen is chiral due to a nonplanar seven-membered ring containing a keto group. Earlier studies have revealed glucuronidation at the tertiary amino group as a major metabolic pathway in humans. Chemical synthesis of glucuronides from racemic ketotifen now led to four isomers separable by HPLC of which two each could be ascribed to (R)-(+)- and (S)-(-)-ketotifen by synthesis from the enantiomers. According to (1)H NMR analysis of the (S)-ketotifen N-glucuronides, the conformation of the piperidylidene ring differs between the two isomers. Enzymatic hydrolysis with Escherichia coli beta-glucuronidase proceeded at a lower rate with the slower eluting (S)-ketotifen glucuronide than with the three other isomers. On incubation of the ketotifen enantiomers (0.5-200 microM) with human liver microsomes in the presence of UDP-glucuronic acid and Triton X-100, the N-glucuronides of (R)-ketotifen were produced with an apparent K(M) 15 microM and V(max) 470 pmol/min/mg protein. The two (S)-ketotifen glucuronides were formed by two-enzyme kinetics with K(M1) 1.3 microM and K(M2) 92 microM and V(max) values of 60 and 440 pmol/min/mg protein. After ingestion of 1 mg of racemic ketotifen, 10 healthy subjects excreted in urine 17 +/- 5% of the dose in the form of N-glucuronides. The (R)-ketotifen glucuronide isomers contributed one-sixth only, whereas the remainder consisted primarily of the (S)-ketotifen glucuronide isomer, which eluted last. Differential hydrolysis or membrane transport may be responsible for the discrepancy between N-glucuronide isomer ratios in vitro and in vivo.
OBJECTIVE: The present in vivo study evaluates the potential use of ketotifen, a tricyclic antihistaminic drug, in treatment of Sudanese patients with uncomplicated Plasmodium falciparum malaria (19-38 years). METHODS: Four groups of patients (each has 15) were randomly selected and treated by chloroquine (25mg/kg wt) in comparison with regimen combinations of ketotifen (0.13 mg/kg body wt) with chloroquine, ketotifen with Fansidar (33.3mg/kg body wt) and ketotifen with both chloroquine and Fansidar. RESULTS: Prior to treatment all patients had a parasite density that varied from 1 x 10(3)-3.46 x 10(4)/mL blood. On day 2, the highest level of parasitaemia was recorded in patients treated with chloroquine only. Other patients had a significantly lower parasitaemia (P<0.05) with an average range of 111-243 parasites/300 leucocytes. On day 3 no parasites were detected in groups treated by ketotifen and Fansidar or by ketotifen in combination with Fansidar and chloroquine. The mean time of parasite clearance was minimum (<32 h) amongst patients that had chloroquine administered with ketotifen alone or with both Fansidar and ketotifen. The cumulative percentage of cases with recrudescence was >39% in groups that had the chloroquine regimen alone or the combination of chloroquine with ketotifen. A single case of recrudescence was also diagnosed on day 28 in the group treated with ketotifen plus fansidar but no recrudescence occurred in the group treated with the combination of the three drugs. CONCLUSION: This study indicates the possible role of ketotifen in treatment for falciparum malaria particularly when administered in combination with chloroquine and fansidar.
BACKGROUND: Ketotifen blocks histamine H(1) 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.
BACKGROUND: Ketotifen is an antihistamine which may be used to treat asthma. Since administering inhaled therapy to younger children can be difficult, an oral agent such as ketotifen offers potential advantages. OBJECTIVES: The objective of this review is to determine, whether ketotifen alone or in combination with other co-interventions results in better control of asthma in children with asthma and/or wheezing and examine its safety profile. SEARCH STRATEGY: We searched the Cochrane Airways Group register of trials (based on MEDLINE, EMBASE, CINAHL and handsearched respiratory journals) and reference lists of articles. The latest search was carried out in October 2002. SELECTION CRITERIA: Clinical studies had to be randomised-controlled and double-blinded, comparing oral ketotifen with placebo in children with asthma and/or wheeze for at least eight weeks at a dose not less than one mg daily. DATA COLLECTION AND ANALYSIS: Two reviewers independently performed selection of trials, quality assessment and data extraction; a third reviewer was included in the consensus process if necessary. MAIN RESULTS: A total of 26 relevant studies involving 1826 participants were included in this review. Children's age ranged from 4 months to 18 years and ketotifen was given between 10 and 32 weeks. The proportion of children able to reduce or stop their bronchodilator use within 12 to 16 weeks of treatment was significantly higher in the ketotifen group (relative risk 2.39, 95% CI 1.64 to 3.48) based on four trials; this result was statistically significant in a subgroup of two trials with well described and adequate method of blinding. Statistically significant beneficial effects of ketotifen were also observed in the following secondary outcomes: efficacy evaluated by physician (10 trials) and parents/patients (7 trials), asthma symptom score (4 trials), asthma exacerbations (2 trials), and reduction in use of oral steroids (4 trials). However, sub-group analyses of trials with well described and adequate method of blinding was only significant for the outcome asthma symptom score and non-significant for the remaining secondary outcomes. Reported side effects were more frequent in the ketotifen group (sedation: 21%, weight gain: 27%) than in the placebo group (sedation: 12%, weight gain: 17%). REVIEWER'S CONCLUSIONS: Evidence from randomised controlled trials indicates that ketotifen alone or in combination with other co-interventions improves control of asthma and wheezing in children with mild and moderate asthma. However due to the high proportion of children with atopy in some trials the results cannot necessarily be generalised to all asthmatic children. The benefit is obtained at the cost of minor side effects, namely sedation and weight gain. The validity of this conclusion is limited by the low reported, methodological quality of included trials.
Ketotifen is a compound with strong anti-anaphylactic and anti-histaminic properties both in experimental mental animals and man. In this paper pharmacological experiments are presented which show that these two activities are independent. In the rat, the two actions of ketotifen differ markedly in their time course. The ability of ketotifen to prevent a passive cutaneous anaphylactic reaction is of short duration and is already abolished at times when the compound still fully prevents the cutaneous reaction to histamine. Two anti-histamines, clemastine and mepyramine, were compared with ketotifen. All three compounds prevented the wheal and flare induced by intracutaneous administration of histamine, but only ketotifen also prevented passive cutaneous anaphylaxis. Accordingly, concomitant administration of the anti-histamine clemastine with ketotifen resulted in enhanced histamine-blocking effects but did not influence the anti-anaphylactic action of ketotifen. Finally, clemastine and mepyramine differed from ketotifen in their activities in a model of anaphylactically-induced bronchospasm. Ketotifen prevented the bronchospasm, dyspnea and respiratory arrest in dose-dependent fashion, while the two reference anti-histamines were virtually inactive.
Ketotifen is a tricyclic drug with a wide spectrum of pharmacological effects. We studied the actions of ketotifen on the mechanical activity of isolated segments of guinea-pig ileum, guinea-pig colon and mouse colon. In the guinea-pig ileum ketotifen induced small contractions and inhibited the contractions induced by carbachol and by electric field stimulation. Responses to bradykinin (in the absence or in the presence of atropine 1 microM) were similarly inhibited by ketotifen, with an IC50 of 23 microM. In the guinea-pig colon ketotifen evoked non-cholinergic contractions with a pD2 of 4.5, but still it inhibited responses to bradykinin (IC50 = 75 microM). Ketotifen relaxed the unstimulated mouse colon with a pD2 of 4.2. This effect persisted in the presence of propranolol and phentolamine (each 10 microM). Incubation of the mouse colon with the nitric oxide synthase inhibitors NG-nitro-L-Arginine methyl ester hydrochloride (L-NAME), or L-NG-nitro-arginine (L-NNA) (100-500 microM) did not alter the inhibitory action of ketotifen. The histamine H1 receptor antagonist chlorpheniramine (5 microM) or the nerve blocker tetrodotoxin (1 microM) did not alter the inhibitory effects of ketotifen. It is concluded that the actions of ketotifen are mediated by a non-cholinergic, non-histaminergic mechanisms.
OBJECTIVE: The purpose of this study was to compare the relative efficacy and clinical performance of olopatadine hydrochloride 0.1% ophthalmic solution and ketotifen fumarate 0.025% ophthalmic solution in the conjunctival antigen challenge model. METHODS: This was a prospective, randomized, double-masked, contralaterally controlled, single-center, antigen challenge study. Of the 53 subjects screened, 32 were enrolled and completed the study. The study comprised 3 visits. Primary efficacy variables were ocular itching (assessed at visits 2 and 3) and subject satisfaction (assessed at visit 3). Tolerability variables were slit-lamp findings (all visits), visual acuity (all visits), ocular comfort after drug instillation (visit 3), and adverse events (visits 2 and 3). At visit 1, the antigen concentration that elicited a positive ocular allergic response was determined, and this concentration was confirmed at visit 2. Subjects graded itching on a 5-point scale at 3, 5, and 10 minutes postchallenge. The scores from this visit were used as baseline scores and compared with scores from visit 3 to determine drug efficacy. At visit 3, subjects were randomly assigned to 2 treatment groups. Group A received 1 drop of olopatadine in the right eye and I drop of ketotifen in the left eye. Group B received 1 drop of olopatadine in the left eye and 1 drop of ketotifen in the right eye. Following drug instillation, the subjects assessed the comfort level in each eye. Twelve hours after instillation, subjects were challenged with the antigen concentration that elicited a positive response at the previous visits. Itching was subjectively graded at 3, 5, and 10 minutes postchallenge. Subjects were asked to choose which therapy they were more satisfied with. RESULTS: Twelve hours after administration, efficacy scores for olopatadine were significantly higher than those for ketotifen at 3 and 5 minutes postchallenge (1.84 and 1.75 vs 1.25 and 1.34; P < 0.05). Olopatadine-treated eyes were rated significantly more comfortable than those treated with ketotifen immediately after drug instillation (1.25 vs 2.09; P < 0.05) and 12 hours later, as measured by patient ratings of ocular comfort. Of the 22 subjects who had a preference, 16 (73%) were more satisfied with olopatadine than with ketotifen. CONCLUSIONS: Olopatadine is more effective than ketotifen in reducing the itching associated with allergic conjunctivitis in the antigen challenge model. Olopatadine caused less ocular discomfort than ketotifen and was preferred by approximately 3 times as many patients as was ketotifen.
The objective of the present study was to determine the efficacy of ketotifen (Zaditen), an effective antiasthmatic drug, in preventing indomethacin-induced gastroduodenal mucosal injury in a two-arm prospective, randomized, double-blind, controlled and open study. Thirty healthy volunteers with endoscopic normal-appearing mucosa were randomly treated, double-blindly, for 1 week with either placebo or ketotifen, 2 mg twice daily. On day 7 indomethacin, 50 mg three times daily, was added. Two subjects, one from each group, were withdrawn from the study owing to non-compliance. Ten additional subjects received ketotifen, 2 mg twice daily, 24 h before indomethacin administration, in an open manner. A second endoscopy was performed 24 h after indomethacin was initiated. Mucosal damage in the stomach and duodenum (hemorrhages, erosions, ulcers) was scored in accordance with Lanza et al. or counted numerically. Adverse reactions were documented. Ketotifen reduced indomethacin-induced gastric mucosal damage, reducing the mean gastric lesion score from 2.85 +/- 0.20 in the placebo-treated group to 1.86 +/- 0.36 and in the subjects pretreated with ketotifen for 7 days. Ketotifen protected (lesion score < or = 1) 6 of 14 subjects pretreated for 7 days, whereas none of the 14 placebo-treated subjects were protected. Ketotifen had no statistically significant protective effects in the duodenum. In the open study lesion scores of patients pretreated with ketotifen for 24 h were similar to those pretreated for 7 days. Ketotifen is effective in the reduction of indomethacin-induced acute gastric mucosal injury. Further studies are required to verify these data in a more relevant clinical setting.
The protective effect of ketotifen was examined by an open assessment trial in 261 asthmatics of variable types, a double blind trial comparing ketotifen and inert placebo in 189 asthmatics of extrinsic type including pure atopic asthma and asthma with atopic and infectious components (mixed type or combined type), and a double blind trial comparing ketotifen and disodium cromoglycate (DSCG) by double placebo technique in 132 asthmatics of a pure atopic type. The open clinical assessment trial suggested that ketotifen was most effective in atopic asthmatics having moderate and severe as well as mild asthmatic episodes. Efficacy increased with prolonged administration; 1 mg twice daily was better than a 1 mg daily dose. In the placebo-controlled double blind trial, the efficacy of ketotifen was demonstrated by the reduction of concomitant anti-asthmatic therapy. The results of the double blind trial comparing ketotifen and DSCG are not fully reported. However, preliminary data showed that the efficacy of both drugs was equivalent or that ketotifen was slightly superior to DSCG. Safety of ketotifen was confirmed by the three trials, transient day-time sedation being the major side effect of this agent. In conclusion, ketotifen is a promising drug for the prophylaxis of asthma.
BACKGROUND: Ketotifen fumarate blocks histamine1 (H1) receptors, stabilizes mast cells, and acts as an eosinophil inhibitor (decreases chemotaxis and activation of eosinophils). OBJECTIVE: To assess the efficacy of ketotifen 0.025% ophthalmic solution in the prevention of symptoms of allergic conjunctivitis, using the conjunctival allergen challenge model. METHODS: This was a single-center, double-masked, randomized, placebo-controlled, contralateral-eye comparison, allergen challenge trial conducted in the United States. Subjects were randomized to receive ketotifen 0.025% in one eye and placebo in the other. At visits 1 and 2, allergen challenges were performed to determine the allergen concentration eliciting a qualifying reaction for each subject. At the 3 subsequent visits, subjects received 1 drop of ketotifen 0.025% ophthalmic solution in one eye and vehicle solution as placebo in the other eye 15 minutes (visit 3), 6 hours (visit 4), and 8 hours (visit 5) before allergen challenge. The primary efficacy measure was the subject's rating of itching at 3, 7, and 10 minutes after challenge. RESULTS: Of the 89 subjects randomly assigned to masked trial medication at visit 3, 72 completed the study. At visits 3, 4, and 5, mean itching scores were significantly better for ketotifen-treated eyes at all postchallenge time points, compared with placebo (P<.001). Also at visits 3, 4, and 5, ketotifen was statistically superior to placebo in reducing ocular hyperemia at all postchallenge time points (P<.05). CONCLUSIONS: Ketotifen was safe and statistically effective in reducing ocular itching and hyperemia associated with allergic conjunctivitis. Ketotifen's rapid onset of action (within 15 minutes) and extended duration of action (at least 8 hours) make it a valuable treatment for allergic conjunctivitis.
PURPOSE: To investigate the effect of the antihistamine ketotifen on multidrug resistance in human breast cancer cells and doxorubicin toxicity in mice. METHODS: Clonogenicity assays were used to test the effect of ketotifen on human multidrug resistant breast cancer cell lines exposed to chemotherapeutic agents. Flow cytometry was used to measure accumulation of doxorubicin in cells. Fluorimetry was used to measure accumulation of doxorubicin in cardiac tissues. Histological analysis and toxicity studies in mice were used to test the effect of ketotifen on doxorubicin-induced toxicity. RESULTS: Ketotifen was found to restore the sensitivity of P-glycoprotein-overexpressing multidrug-resistant MCF-7/adr cells to doxorubicin, mitoxantrone, VP-16 and vinblastine, but not to methotrexate or camptothecin. Ketotifen, however, was unable to restore sensitivity of BCRP-overexpressing MCF-7/mx cells or MRP-overexpressing MCF-7/vp cells to mitoxantrone or VP-16, respectively. In vivo, pretreatment of mice with ketotifen caused an increased accumulation of doxorubicin in cardiac tissue, consistent with a block in drug clearance. However, unlike verapamil, ketotifen pretreatment did not enhance doxorubicin toxicity but in fact provided protection, both at the level of cardiac tissue damage and in terms of survival. CONCLUSIONS: Taken together, these observations show that ketotifen is unique in its ability both to reverse multidrug resistance due to P-glycoprotein overexpression and to provide cardioprotection to doxorubicin.
We studied the effect of ketotifen, an oral antiallergic and antihistaminic drug, on the airway and cutaneous responses to platelet-activating factor (PAF) in a double-blind, randomized, and crossover study in six normal subjects. Ketotifen (three doses of 2 mg taken during a 14-hour period before PAF) did not alter PAF-induced bronchoconstriction and did not prevent the accompanying flushing and coughing. The transient neutropenia (74.5 +/- 4.8% fall; p less than 0.001) and rebound neutrophilia (104 +/- 55% rise) induced by PAF were not affected by ketotifen. On the day placebo was received, airway responsiveness to methacholine increased after PAF exposure with the concentration needed to cause a 40% fall in baseline partial expiratory flow rate (PC40), decreasing from 69.2 mg/ml (geometric standard error of the mean, 2.69) to 23.3 mg/ml (2.34) on day 3 (p less than 0.001). Ketotifen had no effect, because on the day ketotifen was administered, mean PC40 also decreased from 52.7 mg/ml (2.5) to 21.5 mg/ml (2.14) (p less than 0.01). In the skin, ketotifen reduced the flare area (from 8.05 +/- 3.60 to 1.14 +/- 0.29 cm2; p less than 0.05) and the wheal volume (from 0.068 +/- 0.010 to 0.045 +/- 0.008 cc; p = 0.02) induced by intradermal PAF (200 ng). Cutaneous responses to histamine (1 microgram) were significantly inhibited. Thus, the bronchoconstriction and bronchial hyperresponsiveness induced by PAF are not inhibited by ketotifen. Ketotifen inhibits PAF-induced wheal and flare in the skin, which is probably histamine dependent. The airway effects of PAF are unlikely to be mediated by histamine release.