pyrimidinones and pemirolast

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

Topics: Administration, Ophthalmic; Anti-Allergic Agents; Benzazepines; Conjunctivitis, Allergic; Cromolyn Sodium; Dibenzazepines; Histamine Antagonists; Humans; Hyperemia; Imidazoles; Ketotifen; Nedocromil; Olopatadine Hydrochloride; Phthalazines; Piperidines; Pruritus; Pyridines; Pyrimidinones

Abdominal aortic aneurysm (AAA) is thought to develop as a result of inflammatory processes in the aortic wall. In particular, mast cells are believed to play a central role. The AORTA trial was undertaken to investigate whether the mast cell inhibitor, pemirolast, could retard the growth of medium-sized AAAs. In preclinical and clinical trials, pemirolast has been shown to inhibit antigen-induced allergic reactions.. Inclusion criteria for the trial were patients with an AAA of 39-49 mm in diameter on ultrasound imaging. Among exclusion criteria were previous aortic surgery, diabetes mellitus, and severe concomitant disease with a life expectancy of less than 2 years. Included patients were treated with 10, 25 or 40 mg pemirolast, or matching placebo for 52 weeks. The primary endpoint was change in aortic diameter as measured from leading edge adventitia at the anterior wall to leading edge adventitia at the posterior wall in systole. All ultrasound scans were read in a central imaging laboratory.. Some 326 patients (mean age 70·8 years; 88·0 per cent men) were included in the trial. The overall mean growth rate was 2·42 mm during the 12-month study. There was no statistically significant difference in growth between patients receiving placebo and those in the three dose groups of pemirolast. Similarly, there were no differences in adverse events.. Treatment with pemirolast did not retard the growth of medium-sized AAAs.. NCT01354184 (https://www.clinicaltrials.gov).

Topics: Aged; Aged, 80 and over; Anti-Inflammatory Agents; Aortic Aneurysm, Abdominal; Double-Blind Method; Female; Humans; Male; Mast Cells; Middle Aged; Pyridines; Pyrimidinones; Ultrasonography

To evaluate the efficacy of a combined therapy with levocabastine hydrochloride ophthalmic suspension and pemirolast potassium ophthalmic solution compared to single therapy with levocabastine hydrochloride ophthalmic suspension alone.. Thirty-two allergic conjunctivitis patients were randomized to combined-treatment (n = 15) or single-treatment groups (n = 17). The improvement of subjective symptoms as well as objective findings were evaluated.. The degree of improvement was significantly higher in the combined-treatment group for lacrimation (p = 0.008) among the subjective symptoms, for conjunctival edema (p = 0.030), eyelid edema (p = 0.032) and conjunctival papilla formation(p = 0.040) among the objective findings.. Both objective assessments and subjective symptoms of allergic conjunctivitis showed the greatest improvements when patients were treated with combined therapy as compared to single-agent therapy. The enhanced benefits of combined therapy may result from these agents having different mechanisms of action.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Conjunctivitis, Allergic; Drug Therapy, Combination; Eosinophils; Female; Histamine H1 Antagonists, Non-Sedating; Humans; Leukocyte Count; Male; Middle Aged; Ophthalmic Solutions; Piperidines; Pyridines; Pyrimidinones; Treatment Outcome

We have previously shown that sensory nerve peptides contribute to the pathogenesis of pulmonary hypersensitivity reactions (HSRs) to paclitaxel in rats. Moreover, pemirolast, an antiallergic agent, reverses the HSRs to paclitaxel, although the mechanism is considered to result from the blockade of paclitaxel-induced release of sensory peptides, rather than the inhibition of histamine release. In the present study, we investigated the preventive effect of pemirolast against acute HSRs in a total of 84 patients who undertook postoperative paclitaxel plus carboplatin chemotherapy every 4 weeks for ovarian cancer. Patients were assigned to receive oral lactose (placebo) or pemirolast (10 mg), 2 hr before paclitaxel infusion. All patients received conventional premedication, including oral diphenhydramine, intravenous ranitidine and intravenous dexamethasone, 30 min before paclitaxel infusion. The HSRs that led to the discontinuance of paclitaxel infusion (grade>or=2) occurred in 5 of 42 patients in placebo group, whereas none of pemirolast-treated 42 patients showed any signs of HSRs. Plasma histamine concentrations were not changed after paclitaxel infusion in either group. Our present findings suggest that pemirolast is potentially useful for prophylaxis of paclitaxel-induced HSRs. In this respect, the use of pemirolast as premedication is expected to be beneficial to the safety management in patients who undergo chemotherapy containing paclitaxel.

Topics: Administration, Oral; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Drug Hypersensitivity; Female; Histamine Antagonists; Humans; Ovarian Neoplasms; Paclitaxel; Placebos; Pyridines; Pyrimidinones

To compare efficacy and safety between twice-daily and four-times-daily regimens of pemirolast 0.1% in allergic conjunctivitis patients.. This investigator-masked trial recruited 169 patients, with a positive skin prick test, +2 itching and hyperemia. Patients were randomized to two times daily (t.i.d.) or four times daily (q.i.d.) treatment during allergy season. Evaluation was at 0, 2 and 4 weeks, with itching and hyperemia at week 4 as the primary endpoints. Analysis used last observation carried forward (LOCF) and analysis of variance (ANOVA) for efficacy, factoring treatment and center variations. The basis of the statistical evaluation was to confirm parity between two treatments, via noninferiority hypothesis testing. A 95% confidence interval (CI) with an upper limit of < or = 0.5 was set to assess non-inferiority or to conclude if schedules were statistically similar.. B.i.d. and q.i.d. baselines were similar, respectively, for itching (2.6 and 2.8) and hyperemia (2.3 and 2.2). Week 4 itching was statistically non-inferior between treatments (1 b.i.d. versus 0.8 q.i.d.), with a mean treatment difference of 0.17 (-0.13, 0.47, Delta < or = 0.5). Week 4 hyperemia was comparable (1.2 for b.i.d. versus 1.0 for q.i.d). Week 2 scores and mean change from baseline (weeks 2 and 4), patient diary data, and investigator assessments were comparable. Both regimens were well tolerated with no differences in adverse events were observed.. B.i.d. dosing was statistically non-inferior to q.i.d. dosing with respect to itching and hyperemia. Both regimens were similarly well tolerated in allergic conjunctivitis patients.

Topics: Adolescent; Adult; Aged; Child; Conjunctivitis, Allergic; Drug Administration Schedule; Female; Histamine Antagonists; Humans; Instillation, Drug; Male; Middle Aged; Ophthalmic Solutions; Prospective Studies; Pyridines; Pyrimidinones; Seasons; Treatment Outcome

Many topical agents with similar efficacies are available for the treatment of ocular allergies. In addition to efficacy, comfort is an important criterion because it affects overall patient satisfaction, compliance, and in turn efficacy.. The goal of this study was to compare the comfort profiles of permirolast, ketorolac, cromolyn, and nedocromil ophthalmic solutions using combined results from 2 separate clinical trials.. Two clinical trials were conducted. Adults with asymptomatic eyes were included in the first study. In this single-center, 7-day, prospective, double-blind, single-dose, crossover, parallel-group study, subjects were randomized to be bilaterally dosed with pemirolast, cromolyn, or ketorolac at each of 3 visits. Study 2 was a single-center, 1-day, prospective, randomized, double-blind, single-dose, contralateral, active-control study in which subjects received pemirolast in 1 eye and nedocromil in the contralateral eye. In both studies, subjects completed a pre- and postinstillation ocular comfort questionnaire: the primary variable was overall ocular discomfort, measured on a 4-point scale original to these studies (0 = absent, 1 = mild, 2 = moderate, 3 = severe). Half-increments were permitted. Secondary variables included burning/stinging, foreign-body sensation, tearing, and photophobia.. Forty-five subjects (29 women, 16 men; mean [SD] age, 35.9 [12.6] years) were enrolled in study 1; 48 subjects (30 women, 18 men; mean [SD] age, 33.6 [10.2] years) were enrolled in study 2. In study 1, overall discomfort was significantly lower with pemirolast than with cromolyn (P = 0.001) or ketorolac (P < 0.001). In terms of overall discomfort, the number of subjects with a clinically significant increase (>/=1 unit) in score was significantly lower with pemirolast compared with ketorolac (P = 0.021). Burning/stinging and tearing were also significantly lower with pemirolast than with cromolyn (P < 0.001 and P = 0.014, respectively). Mean changes in score compared with preinstillation were consistently lower with pemirolast than with cromolyn for both burning/stinging (P < 0.001) and tearing (P = 0.014). In study 2, overall discomfort was significantly lower with pemirolast than with nedocromil (P < 0.001). The number of subjects with a clinically significant increase in overall discomfort score was significantly lower with pemirolast than with nedocromil (P = 0.007). No changes in ocular tolerability parameters were reported in either study.. In these single-dose studies, pemirolast was found to be significantly more comfortable than cromolyn, ketorolac, or nedocromil.

Topics: Administration, Topical; Adult; Anti-Allergic Agents; Conjunctivitis, Allergic; Cromolyn Sodium; Double-Blind Method; Female; Histamine Antagonists; Humans; Ketorolac; Male; Middle Aged; Nedocromil; Ophthalmic Solutions; Patient Compliance; Pyridines; Pyrimidinones; Treatment Outcome

Patients with allergic conjunctivitis may experience several debilitating symptoms, particularly ocular itching. The objective of this study was to evaluate the efficacy and safety of pemirolast potassium 0.1% ophthalmic solution (Alamast trade mark ), a novel mast-cell stabilizer, for preventing ocular manifestations of seasonal allergic conjunctivitis. A pooled analysis was performed of data derived from 2 prospective, randomized, double-masked, placebo-controlled, multicenter phase III clinical trials of pemirolast potassium 0.1% in patients with a history of allergic conjunctivitis. Patients having a positive bilateral response to conjunctival allergen challenge (CAC) with ragweed antigen (N = 274) were randomized to receive pemirolast potassium 0.1% or placebo QID, beginning approximately 1-2 weeks before the onset of ragweed season and continuing until after the first killing frost (12-17 weeks duration). Patients recorded their daily evaluations of ocular itching in a diary. After the allergy season, patients underwent a second CAC. Evaluable patients (n = 265) recorded a total of 21,491 patient-days of ocular itching data during allergy season. In every 7-day or 14-day period, patients treated with pemirolast potassium 0.1% reported more days without any ocular itching compared with patients receiving placebo. Differences favoring pemirolast potassium 0.1% were statistically significant in 63% (10/16) of all 7-day periods (p < or = 0.046) and 88% (7/8) of all 14-day periods (p < or = 0.016). After the allergy season, pemirolast potassium 0.1% was significantly superior to placebo in relieving CAC-induced ocular itching, with relief occurring as early as 3 minutes after allergen challenge (p < or = 0.034). Pemirolast potassium 0.1% was well tolerated and had a safety profile similar to that of placebo. In conclusion, pemirolast potassium 0.1% is effective and safe in preventing ocular itching in patients with allergic conjunctivitis during allergy season.

Topics: Adolescent; Adult; Aged; Child; Conjunctivitis, Allergic; Double-Blind Method; Female; Histamine Antagonists; Humans; Male; Middle Aged; Ophthalmic Solutions; Prospective Studies; Pyridines; Pyrimidinones; Treatment Outcome

Pemirolast potassium, an antiallergic agent, has preventive effects against restenosis after percutaneous transluminal coronary angioplasty (PTCA). This study investigated the mechanism of the preventive effects of pemirolast on restenosis using serial intravascular ultrasound (IVUS). Initial elective PTCA was performed in consecutive 106 patients from March 1996 through August 1997. Patients with type C lesions or graft stenosis were excluded from the study. A total of 97 patients with 110 lesions, 48 patients (56 lesions) in the pemirolast treated group and 49 patients (54 lesions) in the control group were analyzed. Restenosis was defined as a diameter stenosis of > or = 50% at follow-up study. Patients in the pemirolast group received 20 mg/day from the morning after angioplasty until the time of follow-up (mean 6 months). The lumen cross-sectional area, vessel area, plaque area, and % plaque area were measured by quantitative coronary ultrasound and compared after PTCA and at follow-up between the patients without restenosis in the pemirolast (28 lesions) and control (27 lesions) groups. There was no significant change in baseline characteristics between the 2 groups. Restenosis rate per lesion was significantly lower in the pemirolast group than in the control group (23.2% vs 44.4%, p < 0.05, respectively). After angioplasty and at follow-up study, there was no difference in lumen and vessel cross-sectional areas between the 2 groups. However, plaque and % plaque area in the pemirolast group were smaller than in the control group at follow-up study (8.9 +/- 2.3 vs 11.8 +/- 3.5 mm2, p < 0.005, 56.0 +/- 9.0% vs 64.0 +/- 10.4%, p < 0.005, respectively). These results suggest that suppression of neointimal hyperplasia is the preventive mechanism of pemirolast against restenosis after angioplasty. Pemirolast may be more effective against restenosis after coronary stenting.

Topics: Angioplasty, Balloon, Coronary; Coronary Angiography; Coronary Disease; Endosonography; Female; Follow-Up Studies; Histamine Antagonists; Humans; Male; Middle Aged; Pyridines; Pyrimidinones; Recurrence

We recently confirmed that pemirolast potassium, an antiallergic agent, markedly inhibits migration and proliferation of vascular smooth muscle cells. It has also been reported that pemirolast inhibits intimal hyperplasia in animal experiments.. To elucidate the preventive effects of pemirolast on restenosis after percutaneous transluminal coronary angioplasty (PTCA), 227 patients were enrolled in this prospective, randomized trial. A total of 205 patients who were compatible with the protocol were analyzed (pemirolast group, 104 patients with 140 lesions; control group, 101 patients with 133 lesions). Patients in the pemirolast group received 20 mg/d of pemirolast from 1 week before PTCA until the time of follow-up angiography (4 months after PTCA). Angiographic restenosis was defined as diameter stenosis >/=50% at follow-up. Restenosis rates were significantly lower in the pemirolast group than in the control group (24.0% vs 46.5% of patients, 18.6% vs 35.3% of lesions, P <.01, respectively). During 8 months of follow-up, there were no coronary events (death, myocardial infarction, coronary artery bypass surgery, or repeated PTCA) in 81.7% of the pemirolast group and in 63.4% of the control group (P =.013).. This study suggested that pemirolast would be useful in the clinical setting to prevent restenosis after PTCA.

Topics: Aged; Angioplasty, Balloon, Coronary; Cell Division; Coronary Angiography; Coronary Disease; Female; Histamine Antagonists; Humans; Male; Middle Aged; Muscle, Smooth, Vascular; Prospective Studies; Pyridines; Pyrimidinones; Secondary Prevention

The effect of a newly developed anti-allergic drug, pemirolast potassium (TBX), on the pharmacokinetics and metabolism of theophylline was investigated under steady-state conditions in seven healthy male volunteers. A sustained-release theophylline formulation (100 mg twice daily at 12 h intervals) was given as monotherapy and coadministered with TBX (10 mg twice daily at 12 h). Plasma concentration-time curves and the urinary excretion of theophylline and its major metabolites after administration of theophylline alone and after coadministration with TBX were compared. No significant adverse effects from this study were observed. There were no significant differences in the total body clearance, renal clearance and maximum concentration of theophylline between the two treatments, although coadministration of TBX significantly delayed the time to reach maximum concentration of theophylline. In the case of urinary excretion, no significant changes in the fraction of urinary excretion of theophylline and its metabolites were observed. These results indicate that TBX has little or no effect on the pharmacokinetics and metabolism of theophylline and suggest that TBX is safe for asthma patients receiving theophylline therapy for treatment of chronic obstructive airway diseases.

Topics: Adult; Delayed-Action Preparations; Drug Interactions; Half-Life; Histamine Antagonists; Humans; Liver; Male; Pyridines; Pyrimidinones; Theophylline

Pemirolast is a new oral, nonbronchodilator antiallergy medication that is being evaluated for the therapy of asthma. In this multicenter, double-blind, randomized study, 96 patients with mild asthma received pemirolast, 50 mg (n = 34); pemirolast, 25 mg (n = 31); or placebo (n = 31) BID for 6 weeks. Patients were evaluated weekly at the research centers; they maintained daily symptom diaries and measured peak expiratory flow rates twice a day. Methacholine challenge was performed at the start and end of the study. Results with pemirolast, 50 mg BID, showed statistically significant decrease in nocturnal symptoms (P = .02), in composite symptom scores (P = .02) and in bronchodilator use (P = .05) when compared with placebo. There were no statistically significant differences between treatments in pulmonary function tests or in methacholine challenge sensitivity. Pemirolast, 25 mg BID, did not differ from placebo. There were no significant adverse effects. Pemirolast, 50 mg BID, demonstrated sufficient antiasthma activity to warrant further studies in patients with more severe asthma and with higher doses.

Topics: Administration, Oral; Adolescent; Adult; Aged; Asthma; Bronchial Spasm; Chronic Disease; Double-Blind Method; Forced Expiratory Volume; Histamine Antagonists; Humans; Middle Aged; Placebos; Pyridines; Pyrimidinones

Pemirolast is a potent, long-acting, orally effective antiallergic agent evaluated for clinical activity in prevention of symptoms of seasonal allergic rhinitis. It was evaluated in a randomized, double-blind, placebo-controlled parallel group in season trials to test its safety, tolerance, and prophylactic activity. Thirty-one patients with a history of fall seasonal allergic rhinitis were treated for 6 weeks with pemirolast, 50 mg bid, or placebo beginning approximately 2 weeks before the onset of the ragweed season in Atlanta. Daily evaluation of symptom scores disclosed statistically significantly less sneezing, rhinorrhea, and stuffy nose during treatment with pemirolast. There was, however, no difference for other evaluated symptoms or for the use of rescue medicines. There were no side effects during this short study. This preliminary study indicates that pemirolast may warrant further evaluation for the treatment of allergic rhinitis.

Topics: Adolescent; Adult; Eosinophils; Female; Follow-Up Studies; Histamine Antagonists; Humans; Leukocyte Count; Male; Middle Aged; Nasal Mucosa; Pyridines; Pyrimidinones; Rhinitis, Allergic, Seasonal

To establish a novel delivery system of pemirolast potassium-loaded gellan gum in situ gel in allergic conjunctivitis therapy.. The prepared in situ gels were studied in the following aspects: in vitro gelation, in vitro release, stability, viscosity measurement, in vivo tear kinetics and pharmacodynamics.. In this study, the results showed that the viscosity of the in situ gels significantly increased when the preparation was in contact with simulated tear fluid and it also exhibited good stability in a period of three months. In vitro release showed that the release of pemirolast potassium from in situ gels had a good sustained release ability. No ocular damage or abnormal clinical signs to the cornea, iris, or conjunctivae were visible. Consistent with the in vitro studies, pemirolast potassium in situ gels were highly efficient in suppressing the inflammatory symptoms and improving the ocular bioavailability.. Pemirolast potassium ocular in situ gels are safe and promising therapeutic alternatives to the existing medications for allergic conjunctivitis therapy.

Topics: Animals; Conjunctivitis, Allergic; Drug Compounding; Gels; Mice; Mice, Inbred BALB C; Ophthalmic Solutions; Pyridines; Pyrimidinones; Rabbits; Viscosity

Topics: Animals; Antineoplastic Agents; Carboplatin; Histamine Antagonists; Humans; Nausea; Neuropeptides; Paclitaxel; Pyridines; Pyrimidinones; Substance P; Vomiting

Emesis is the most feared side effect in patients who are undergoing cancer chemotherapy. In particular, cisplatin causes severe acute and delayed emesis. Although early vomiting is well controlled by 5-hydroxytryptamine 3 (5-HT(3)) receptor antagonists, delayed-phase vomiting is not sufficiently controlled. Substance P is thought to be involved in the development of emesis, and tachykinin NK(1) receptor antagonists can inhibit delayed vomiting. We previously have reported that substance P is involved in the paclitaxel-induced hypersensitivity reaction in rats, and anti-allergic agent pemirolast reduces these reactions via inhibition of substance P release. In the present study, we investigated the effect of pemirolast on cisplatin-induced kaolin intake, which is an index of nausea/vomiting in the rat. Cisplatin (5 mg/kg, i.p.) induced kaolin intake and reduced normal feed intake from days 1 to 5 after injection. Cisplatin-induced kaolin intake was significantly reduced by co-administration of ondansetron (2 mg/kg, i.p.), a 5-HT(3) receptor antagonist, and dexamethasone (2 mg/kg, i.p.) from days 1 to 5. Similarly, pemirolast (10 mg/kg, p.o.) and the tachykinin NK(1) receptor antagonist aprepitant (10 and 30 mg/kg, p.o.) significantly reduced cisplatin-induced kaolin intake on days 3 and 4. Moreover, pemirolast at the same dose significantly reversed the cisplatin-induced increase in the cerebrospinal fluid level of substance P in rats. These results suggest that substance P is involved in cisplatin-induced kaolin intake in rats, and pemirolast reduces kaolin intake by inhibition of substance P release.

Topics: Animals; Antineoplastic Agents; Aprepitant; Biological Transport; Body Weight; Cisplatin; Dexamethasone; Eating; Kaolin; Male; Morpholines; Ondansetron; Pyridines; Pyrimidinones; Rats; Substance P

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)%, (71.1 +/- 5.1)%, respectively. The q values of A to B group and A to C group at 6 h were 3.27, 4.31, respectively (P < 0.05). The green fluorescent staining of calcein-AM indicated intracellular esterase activity was decreased after incubation with increasing concentration and longer exposure time. There was no significantly different result between each group (P > 0.05). The proportion of green staining cell of A, B and C group at 24 h were 100.0% with 50.0% concentration and were (23.2 +/- 4.6)%, (29.5 +/- 5.2)%, (31.1 +/- 5.5)% respectively with 20.0% concentration (F = 1.97, P = 0.377). (3) MTT assay: The results of the three groups revealed cell viability decreased significantly with increasing concentration and longer exposure time at all the concentrations except 0.8%. MTT values for A, B and C group at the concentration of 20.0%, at 6 h were 0.429 +/- 0.028, 0.367 +/- 0.038, 0.379 +/- 0.012 and 4% at 24 h were 0.457 +/- 0.025, 0.401 +/- 0.008, 0.387 +/- 0.012, respectively. The data for olopatadine 0.1% were significantly improved over those of ketotifen fumarate 0.025% and pemirolast potassium 0.1%. The q value of A to B group, A to C group were 3.01, 3.77 (P < 0.05) at the concentration of 20.0%, 6 h and were 3.63, 4.11 (P < 0.05) at the concentration, 24 h. There were no statistical significant results at other concentrations.. The topical ocular anti-allergic agent, olopatadine 0.1%, showed less toxic effects on human corneal epithelial cells compared to ketotifen fumarate 0.025% and pemirolast potassium 0.1%. Olopatadine 0.1% may offer a safer option to the corneal epithelium when used to treat allergic keratoconjunctivitis over an extended period of time.

Topics: Anti-Allergic Agents; Cell Membrane Permeability; Cell Survival; Cells, Cultured; Dibenzoxepins; Epithelial Cells; Epithelium, Corneal; Humans; Ketotifen; Olopatadine Hydrochloride; Ophthalmic Solutions; Pyridines; Pyrimidinones

It is still difficult to manage chronic glomerulonephritis with corticosteroids because of safety concerns, especially for patients with mild symptoms and infants. Therefore, an alternative approach is greatly required. Pemirolast potassium (CAS 100299-08-9) is an antiallergic drug with high safety.. Two glomerulonephritis rat models were prepared to examine the pharmacological actions of pemirolast potassium: one reversible model prepared with the anti-Thy-1 antibody, and another irreversible model by unilateral nephrectomy and with the anti-Thy-1 antibody. Pemirolast potassium was administered to 10 Japanese chronic glomerulonephritis patients concurrently affected by allergic rhinitis in order to examine its efficacy for mild proteinuria.. Pemirolast potassium 1 and 10 mg/kg markedly inhibited proteinuria in the reversible model. In the irreversible model, pemirolast potassium 3 mg/kg showed a significant decrease in the incidence of glomerulosclerosis. In chronic glomerulonephritis patients, pemirolast potassium, 10 mg twice daily, for 6 months, significantly reduced the severity of proteinuria.. Our research suggested the efficacy of pemirolast potassium in glomerulonephritis. A well-controlled study is considered necessary to validate pemirolast potassium as a therapeutic drug for glomerulonephritis.

Topics: Adolescent; Adult; Animals; Anti-Allergic Agents; Autoantibodies; Disease Models, Animal; Female; Glomerulonephritis; Histamine Antagonists; Humans; Kidney; Male; Middle Aged; Nephrectomy; Pilot Projects; Proteinuria; Pyridines; Pyrimidinones; Rats; Rats, Sprague-Dawley; Rats, Wistar; Rhinitis, Allergic, Seasonal; Thyroid Gland

A tetrazole ring is often used in drug discovery as a replacement for the carboxylic acid group. Previous work indicates that compounds containing a tetrazole moiety show asymmetric permeability in Caco-2 cells characteristic of an efflux transporter substrate. The aim of this study is to determine which transporters are responsible for polarization of transport of tetrazole-containing compounds in Caco-2 cells. Results indicate that only select compounds with tetrazole moieties display asymmetric transport. Three compounds (two commercial drug products and one druglike structure) were selected for further studies. Losartan appears to be primarily a P-glycoprotein (P-gp) substrate, as previously reported, but MRP inhibitors such as MK-571 and rifampicin also affect the difference between apical to basolateral and basolateral to apical transport. Pemirolast and phenyltetrazole derivative C are sensitive to P-gp inhibition, but transport seems to be mediated by one or more of the MRP family of transporters. Additionally, lowering the pH from 7.4 to 4.0 eliminates the polarization of permeability in Caco-2 cells. These studies indicate that some tetrazole compounds are susceptible to efflux, therefore caution should be used when choosing an appropriate functional group to replace carboxylic acids when synthesizing a drug candidate.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzimidazoles; Caco-2 Cells; Cell Line; Cell Membrane Permeability; Cell Polarity; Dogs; Drug Design; Humans; Hydrogen-Ion Concentration; Losartan; Membrane Transport Proteins; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Pyridines; Pyrimidinones; Structure-Activity Relationship; Tetrazoles; Transfection

To report a case of peripheral interstitial keratitis in a patient with mastocytosis.. Clinical case description and immunohistologic examination of biopsied ocular tissue.. A 22-year-old woman with biopsy-proven urticaria pigmentosa, a subset of mastocytosis, presented with an active peripheral interstitial keratitis with vascularization associated with foreign body sensation and itching. Biomicroscopy of the cornea showed deep corneal inflammatory infiltrates and midstromal vascularization adjacent to a region of superior bulbar conjunctiva, which was mildly chemotic and inflamed. Topical mast cell stabilizers and a short course of topical steroids produced dramatic resolution of the lesion. Biopsy of the erythematous conjunctiva adjacent to the area of corneal inflammation showed the presence of mast cells.. This is the first case of corneal inflammatory infiltration in a patient with mastocytosis. Therapy for this condition consists of a combination of topical mast cell stabilizers, topical steroids, and systemic antihistaminic therapy.

Topics: Adult; Corneal Neovascularization; Corneal Stroma; Female; Glucocorticoids; Histamine Antagonists; Humans; Keratitis; Mast Cells; Prednisolone; Pyridines; Pyrimidinones; Urticaria Pigmentosa

We established a new and facile model to investigate allergic mechanism and assess the effect of antiallergic compounds. Male Wistar rats were actively or passively sensitized. Active sensitization was performed by injection of both dinitrophenylated-ovalbumin (DNP-OA) and Bordetella pertussis. Nine days later, DNP-OA was injected into the right hind footpad. This antigen challenge induced a biphasic footpad swelling that consisted of an early-phase (EPR) and a late-phase response (LPR). In rats passively sensitized with rat anti-DNP-OA serum, DNP-OA induced only EPR. The EPR was suppressed by disodium cromoglycate, a mast cell stabilizer, but not by cyclosporin A, an immunosuppressant, while the LPR was suppressed by cyclosporin A. Furthermore, to investigate these two allergic responses determined by the interactions between the hapten and the carrier proteins, two distinct haptenated antigens were created. DNP-Ascaris (DNP-As) induced a marked EPR and LPR in DNP-As-sensitized rats. However, DNP-As induced only EPR in DNP-OA-sensitized rats, indicating that the usage of the same carrier protein in both sensitization and challenge was necessary for induction of LPR. These data suggest that this actively sensitization model in which EPR and LPR are functionally distinguishable should be useful for evaluating the efficacy of antiallergic compounds.

Topics: Aminopyridines; Animals; Anti-Allergic Agents; Antigens; Cromolyn Sodium; Cyclosporine; Dinitrobenzenes; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation, Preclinical; Edema; Haptens; Hindlimb; Hypersensitivity, Delayed; Male; ortho-Aminobenzoates; Ovalbumin; Passive Cutaneous Anaphylaxis; Promethazine; Pyridines; Pyrimidinones; Quinolones; Rats; Rats, Wistar

The effect of the simultaneous use of 0.025% levocabastine hydrochloride eye drops (levocabastine) and 0.1% pemirolast potassium ophthalmic solution (pemirolast) on experimental allergic conjunctivitis in rats was investigated. Levocabastine and pemirolast significantly inhibited allergic conjunctivitis compared with the control group when separately administered. In addition, the simultaneous use of both drugs inhibited allergic conjunctivitis more potently than the original activity of levocabastine or pemirolast. Furthermore, the simultaneous use of levocabastine and pemirolast also significantly inhibited increased vascular permeability induced by antigen compared with levocabastine or pemirolast alone, respectively. Levocabastine and pemirolast inhibited histamine release from the rat conjunctiva in correlation with a decrease in histamine content in tears. When levocabastine and pemirolast were simultaneously applied to the eyes, histamine release from the conjunctiva was greater than for the original activities of both drugs. Similar to histamine release from the conjunctiva, the histamine content in tears induced by the simultaneous use of both drugs was significantly decreased compared with levocabastine and pemirolast alone, respectively. A potentiating effect induced by the simultaneous use of levocabastine and pemirolast may be attributable to the antihistaminic activity of levocabastine and histamine release inhibition by levocabastine and pemirolast.

Topics: Animals; Conjunctivitis, Allergic; Drug Synergism; Drug Therapy, Combination; Histamine Release; Male; Piperidines; Pyridines; Pyrimidinones; Rats; Rats, Wistar

In the early phase response of allergic rhinitis, the nasal mucosa produces important mediators including histamine and leukotrienes.. To investigate the relationship between antigen-induced leukotriene release and histamine secretion in nasal scrapings.. Using nasal mucosal scrapings from patients sensitized to only house dust mite, we studied the time course of antigen-induced leukotriene release and its relationship to histamine release.. Cumulative peptydyl leukotriene (LT) production from nasal scrapings increased from 10 min to approximately 90 min following exposure to mite antigen. The rate of LT release was small (<5 pg/10 min) until 10 min following antigen exposure, increased to approximately 250 to 350 pg LT/10 min from 10 to 45 min post exposure, was reduced to <100 pg/10 min by 60 to 150 min, and by 180 min LT production was negligible. By contrast, histamine secretion began 30 sec after antigen exposure and was complete within approximately 10 min. Net antigen-induced LT secretion strongly correlated (R=0.72) with net antigen induced histamine secretion with a ratio of 1:8.7. In addition, net LT/ng histamine and total LT secretion correlated well with antigen-specific IgE in serum, and with the patients' symptoms.. There is a close relationship between amounts of histamine and LT secretion from antigen challenged nasal mucosa, although the time course of LT release is delayed. In the early phase response, LT are likely to be generated from mucosal mast cells, and thus, mast cell activation will provide an important therapeutic target.

Topics: Adolescent; Adult; Antigens, Dermatophagoides; Child; Female; Histamine Antagonists; Histamine Release; Humans; Leukotrienes; Male; Mast Cells; Nasal Mucosa; Pyridines; Pyrimidinones; Rhinitis, Allergic, Perennial; Time Factors; Tissue Culture Techniques

The effects of anti-allergic agents on the hypersensitivity reactions to paclitaxel, an anti-cancer agent, were examined in rats. Intravenous injection of paclitaxel (15 mg/kg) caused a marked extravasation of plasma protein in lungs and a transient decrease in arterial partial oxygen pressure (PaO(2)). The paclitaxel-induced protein extravasation was inhibited by low doses (0.1-1 mg/kg) of pemirolast or high doses (30-100 mg/kg) of cromoglycate. However, ketotifen was not effective. The decrease in PaO(2) induced by paclitaxel was also significantly reversed by pemirolast. On the other hand, the paclitaxel-induced plasma extravasation was not attenuated by a histamine H(1) blocker diphenhydramine or an H(2) blocker famotidine, but was significantly reduced by a neurokinin NK(1) antagonist LY303870 (0.5 mg/kg) and an NK(2) antagonist SR48968 (1 mg/kg). The concentrations of proteins and sensory peptides such as substance P, neurokinin A and calcitonin gene-related peptide but not histamine in the rat bronchoalveolar lavage fluid were elevated by paclitaxel injection. Both cromoglycate and pemirolast reduced the paclitaxel-induced rise in proteins and sensory peptides. Therefore, we demonstrated for the first time that sensory nerve peptides are involved in paclitaxel hypersensitivity and that an anti-allergic agent pemirolast attenuates the paclitaxel response by inhibiting the release of sensory nerve peptides.

Topics: Animals; Calcitonin Gene-Related Peptide; Dose-Response Relationship, Drug; Drug Hypersensitivity; Male; Neurokinin A; Neuropeptides; Paclitaxel; Pyridines; Pyrimidinones; Rats; Rats, Sprague-Dawley; Substance P

The preventive effect of pemirolast against restenosis after coronary stent placement was evaluated.. Eighty-four patients with 89 de novo lesions who underwent successful coronary stenting were assigned to the pemirolast group(40 patients, 45 lesions) and the control group(44 patients, 44 lesions). Administration of pemirolast(20 mg/day) was initiated from the next morning after stenting and continued for 6 months of follow-up. Quantitative coronary angiography was performed immediately after stenting and at follow-up. Angiographic restenosis was defined as diameter stenosis > or = 50% at follow-up. Intravascular ultrasound study conducted at follow-up angiography was used to measure vessel cross-sectional area(CSA), stent CSA, lumen CSA, neointima CSA(stent CSA--lumen CSA), and percentage neointima CSA(neointima CSA/stent CSA x 100%) at the minimal lumen site.. There were no significant differences in baseline characteristics between the two groups. Restenosis rate was significantly lower in the pemirolast group than in the control group(15.0% vs 34.1% of patients, 13.3% vs 34.1% of lesions, p < 0.05, respectively). The intravascular ultrasound study at follow-up(36 lesions in the pemirolast group, 33 in the control group) found no significant differences in vessel CSA and stent CSA between the two groups(17.3 +/- 2.2 vs 16.8 +/- 2.4 mm2, 8.6 +/- 1.9 vs 8.4 +/- 1.7 mm2, respectively). However, lumen CSA was significantly larger in the pemirolast group than in the control group(5.5 +/- 1.3 vs 4.4 +/- 1.1 mm2, p < 0.05). Moreover, neointima CSA and percentage neointima CSA were significantly smaller in the pemirolast group(3.1 +/- 1.1 vs 4.0 +/- 1.2 mm2, p < 0.05 and 36.2 +/- 15.9% vs 47.4 +/- 15.6%, p < 0.01).. Pemirolast has a preventive effect against restenosis after stent placement, possibly by inhibiting neointimal hyperplasia.

Topics: Aged; Angioplasty, Balloon, Coronary; Anti-Allergic Agents; Coronary Angiography; Coronary Disease; Coronary Restenosis; Coronary Vessels; Female; Humans; Male; Middle Aged; Pyridines; Pyrimidinones; Stents; Ultrasonography, Interventional

Topics: Adult; Anti-Allergic Agents; Child; Child, Preschool; Clinical Trials as Topic; Conjunctivitis, Allergic; Headache; Histamine H1 Antagonists; Humans; Ketotifen; Nedocromil; Pyridines; Pyrimidinones; Rhinitis

To investigate the development of airway hyperresponsiveness in infantile guinea pigs, animals (10 days old) were immunized twice and challenged by inhalation of 1% ovalbumin for 10 min with 7 days intervals. Similar to adult guinea pigs, infantile ones developed an increased airway responsiveness to acetylcholine 24 hr after antigen challenge. There was a marked increase in the number of total leukocytes, eosinophils and lymphocytes in bronchoalveolar lavage fluid (BALF). Suplatast tosilate (suplatast) and pemirolast potassium (pemirolast) given orally throughout the experiments suppressed the development of airway hyperresponsiveness in infantile animals. They showed similar potency in the suppression of eosinophil accumulation in BALF and lung tissue, while suplatast inhibited lymphocyte accumulation stronger than pemirolast. Collectively, the present model of airway hyperresponsiveness in infantile guinea pigs may be useful in predicting the efficacy of antiallergic agents in the treatment of asthmatic children.

Topics: Animals; Anti-Allergic Agents; Antigens; Arylsulfonates; Asthma; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Guinea Pigs; Histamine Antagonists; Leukocyte Count; Male; Ovalbumin; Pyridines; Pyrimidinones; Respiratory Hypersensitivity; Sulfonium Compounds

N-(3',4'-dimethoxycinnamoyl) anthranilic acid (tranilast), an effective anti-allergic drug, has successfully prevented restenosis in patients who have undergone percutaneous transluminal coronary angioplasty. To elucidate the mechanism of tranilast, we investigated its antagonistic effect to angiotensin II, which plays a pivotal role in the proliferation of vascular smooth muscle cells, using angiotensin II-induced contractions in human gastroepiploic artery and rabbit aorta. The possible antagonistic effects of other anti-allergic agents such as 4-( p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)-phthal azinone hydrochloride (azelastine), 9-methyl-3-( 1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyramidin-4-one potassium salt (pemirolast) and disodium cromoglycate were also compared. Tranilast dose-dependently inhibited the angiotensin II-induced contractions in human and rabbit arteries (IC50 = 3.6x10(-5) M and pD'2 = 3.69, respectively). Pemirolast showed a weak antagonistic effect to angiotensin II, but the effective concentration cannot be administered in clinical dosage. Tranilast and pemirolast had no effect on the concentration-contractile response curves for KCI and norepinephrine. Azelastine inhibited angiotensin II-, KCl- and norepinephrine-induced contractions non-specifically, while disodium cromoglycate did not affect these contractile responses. Tranilast but not azelastine showed synergistic action with 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimi dazole-7-carboxylic acid (CV- 11974) in antagonizing angiotensin II-induced contraction and the inhibitory pattern was similar to that of the non-peptide angiotensin II AT1 receptor antagonist CV-11974. These findings indicate that only tranilast possesses the unique ability to antagonize angiotensin II in clinical dosage, which may contribute at least in part to prevention of restenosis after percutaneous transluminal coronary angioplasty.

Topics: Adrenergic alpha-Agonists; Adult; Aged; Aged, 80 and over; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Anti-Allergic Agents; Anti-Asthmatic Agents; Aorta; Arteries; Cromolyn Sodium; Dose-Response Relationship, Drug; Histamine Antagonists; Humans; In Vitro Techniques; Male; Middle Aged; Muscle, Smooth, Vascular; Norepinephrine; ortho-Aminobenzoates; Potassium Chloride; Pyridines; Pyrimidinones; Rabbits; Vasoconstriction

Although acyclovir (9-(2-hydroxyethoxymethyl) guanine) is an antiviral drug that inhibits DNA polymerase of herpes virus, we have had the experience of an asthmatic patient's peak flow rate being improved by oral administration of acyclovir.. The aim of this experiment is whether acyclovir has anti-asthma effects using an asthma model in guinea-pigs.. The airway response was induced by a single inhalation of calcium ionophore A23187 (2 mg/mL). The airway obstruction was estimated by the ratio of expiration to inspiration time (E/I). The peribronchial eosinophil infiltration and eosinophil influx into bronchoalveolar lavage (BAL) fluid 7 h after the inhalation were also examined. To assess the effects of acyclovir (1, 10, and 100 mg/kg), aminophylline (20 mg/kg) and pemirolast potassium (TBX, 20 mg/kg) on A23187-induced asthmatic response, the drugs were intraperitoneally administered before the inhalation.. The immediate airway obstruction was significantly suppressed by acyclovir (10 mg/kg) and aminophylline, whereas different doses of acyclovir (1 and 100 mg/kg) and TBX showed only a small inhibitory effect on the airway obstruction. On the other hand, the peribronchial eosinophilia was most successfully inhibited by TBX. Acyclovir (10 mg/kg) and aminophylline also suppressed the eosinophilia significantly. Furthermore, acyclovir significantly suppressed eosinophil influx into BAL fluid, whereas aminophylline and TBX weakly suppressed the influx.. These results suggest that acyclovir exhibits not only antiviral but also antiasthma activity.

Topics: Acyclovir; Aminophylline; Animals; Anti-Asthmatic Agents; Antiviral Agents; Asthma; Bronchi; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Calcimycin; Eosinophils; Guinea Pigs; Histamine Antagonists; Humans; Male; Middle Aged; Peak Expiratory Flow Rate; Pyridines; Pyrimidinones; Time Factors

We previously reported that tranilast, an antiallergic agent, reduced intimal thickening after endothelial injury in rats. In this study, to verify whether or not antiallergic agents inhibit intimal thickening, we investigated the effect of pemirolast on intimal thickening after endothelial injury and compared its effect with that of tranilast. Administration of two antiallergic agents, pemirolast (0.1, 1, and 10 mg/kg, p.o.) and tranilast (300 mg/kg, p.o., daily), was begun 2 days before endothelial injury and continued until the animals were killed. Endothelial injury in the rat femoral artery was induced by a photochemical reaction between localized irradiation by green light and intravenously administered rose bengal. To evaluate intimal hyperplasia, we measured the cross-sectional area of the intima 21 days after endothelial damage. Pemirolast at doses of 0.1, 1, and 10 mg/kg reduced the intimal area to 2.10 +/- 0.33, 1.36 +/- 0.19, and 1.35 +/- 0.18 (x0.01 mm2), respectively, and tranilast showed a tendency to reduce the intimal area, which was 1.86 +/- 0.35 x 0.01 mm2, compared with findings for controls (2.83 +/- 0.49 x 0.01 mm2). In rat A10 vascular smooth-muscle cells, we investigated the effects of antiallergic agents on migration by using a modified Boyden chamber assay and on proliferation by using the bromodeoxyuridine-incorporation assay. Two antiallergic agents inhibited in a concentration-dependent manner both migration and proliferation of smooth muscle cells stimulated by platelet-derived growth factor. These results suggest that antiallergic agents directly inhibit migration of smooth-muscle cells to the intima from the media and proliferation in the intima, and that pemirolast has more potent antihyperplastic action than does tranilast. Antiallergic agents may be effective in preventing restenosis after coronary angioplasty.

Topics: Animals; Antimetabolites; Arteries; Bromodeoxyuridine; Cell Division; Cell Movement; Cells, Cultured; Endothelium, Vascular; Histamine Antagonists; Histamine H1 Antagonists; ortho-Aminobenzoates; Pyridines; Pyrimidinones; Rats; Tunica Intima

The concept of mast cell heterogeneity is well established. Recent data indicate that human conjunctival tissue mast cells and human connective tissue mast cells respond to various secretagogues in similar fashion. It is now recognized that different mast cell populations respond differently to anti-allergic drugs.. The purpose of the study is to compare the effects of three new ocular anti-allergic drugs (nedocromil, olopatadine, and pemirolast) on mediator release from the target human conjunctival mast cell population with those of cromolyn sodium. The affinity of the compounds for the histamine H1 receptor was also compared.. A monodispersed suspension of partially purified human conjunctival mast cells was prepared from cadaver conjunctival tissue. Mast cells (5 x 10(3)) were challenged with anti-human IgE in the presence or absence of test drugs, and histamine content of the cell supernatants was determined using a specific radioimmunoassay. H1 receptor binding activity was assessed using a radioligand binding assay.. Cromolyn and pemirolast (100 nM to 1 mM) failed to significantly inhibit histamine release from human conjunctival mast cells using exposure times of 1 and 15 minutes prior to challenge. Using identical nedocromil concentrations and exposure times, statistically significant (P < .05) inhibition (28%) of histamine release was observed at only the 100 microM concentration and 1-minute exposure time. In contrast, olopatadine inhibited histamine release in a concentration-dependent fashion (r = 0.891, n = 59, IC50 = 653 microM). Only olopatadine exhibited significant H1 receptor binding activity at relevant concentrations (Ki = 36 nM, n = 13).. These data indicate that olopatadine possesses anti-allergic activity in the appropriate targets for topical ocular anti-allergic drug therapy, human conjunctival mast cells. Coupled with the compound's antihistaminic activity, this suggests that olopatadine will have efficacy advantages in allergic conjunctivitis patients over the other drugs tested.

Topics: Administration, Topical; Anti-Allergic Agents; Antibodies, Anti-Idiotypic; Conjunctiva; Dibenzoxepins; Histamine Release; Humans; Mast Cells; Nedocromil; Olopatadine Hydrochloride; Pyridines; Pyrimidinones; Receptors, Histamine H1

Although many studies have suggested a relation between allergy and Ménière's disease, the pathophysiology of this condition remains controversial. The aim of this study was to clarify whether an anaphylactic reaction in the inner ear can disturb hearing and equilibrium, and whether such disturbances recur in response to repeated anaphylactic reactions. Increases in audiological threshold, nystagmus, and endolymphatic hydrops were observed in response to a single exposure to antigen administered to actively sensitized guinea pigs. The increase in audiological threshold was maximal 10 h after antigen challenge (p < 0.005) and returned to the baseline level after 7 days. Nystagmus and the increase in audiological threshold induced by antigen exposure were inhibited by prior administration of pemirolast potassium (p < 0.05), an inhibitor of chemical mediator release from mast cells. A second challenge with antigen 7 days after the first also induced an increase in audiological threshold (p < 0.05) and nystagmus. These results suggest that studies of repeated antigen challenge in actively sensitized animal models may increase our understanding of the pathophysiology of Ménière's disease.

Topics: Anaphylaxis; Animals; Cochlea; Dinitrophenols; Ear, Inner; Endolymphatic Hydrops; Guinea Pigs; Hearing Loss, Bilateral; Histamine Antagonists; Male; Nystagmus, Pathologic; Postural Balance; Pyridines; Pyrimidinones; Vaccination

An anti-allergic drug, permirolast potassium (TBX), inhibited antigen (Ag)-induced phospholipase D (PLD) activation in rat basophilic leukemia (RBL-2H3) cells. The concentration-dependent inhibitory profile for Ag-induced PLD activation was parallel to those for secretory response and inositol phosphate formation. In contrast, TBX had no effect on PLD activation caused by calcium ionophore A23187 or phorbol myristate acetate. These results suggest that TBX inhibits Ag-induced PLD activation by interfering with the signal transduction pathway upstream of Ca2+ mobilization and protein kinase C activation.

Topics: Animals; Antigens; Depression, Chemical; Enzyme Activation; Histamine Antagonists; Leukemia, Basophilic, Acute; Phospholipase D; Pyridines; Pyrimidinones; Rats; Tumor Cells, Cultured

Aggregation of high affinity IgE Fc receptors (Fc epsilon RI) on RBL-2H3 cells results in tyrosine phosphorylation of 33-, 42-, 44-, 72-, 80-, 90-, 125-kDa proteins. The 42 and 44 kDa proteins were identified as mitogen-activated protein (MAP) kinases with immunoblotting of anti-MAP kinase antibody. The effects of an antiallergic drug, pemirolast potassium (TBX) on Ag-induced protein tyrosine phosphorylation and MAP kinase activation were investigated. When RBL-2H3 cells were stimulated with Ag in the presence of TBX, tyrosine phosphorylation of three proteins (33, 42 and 44 kDa) was inhibited concentration-dependently (0.1-10 micrograms/ml). Inhibition of Ag-induced tyrosine phosphorylation of 33 kDa protein, which could be a beta subunit of Fc epsilon RI, suggests that TBX may prevent the activation of Fc epsilon RI. TBX suppressed activation of MAP kinases (42 and 44 kDa) in response to Ag as well as phorbol myristate acetate (100 nM) or calcium ionophore A23187 (500 nM), implying that the drug acts on signal transduction component(s) between the second messengers and MAP kinases. However, TBX had no effects on protein tyrosine phosphorylation and MAP kinase activation in MC3T3-E1 osteoblastic cells. These results indicate that TBX may affect Fc epsilon RI and also may act as a step distal of Ca2+ mobilization and protein kinase C activation leading to MAP kinase activation in RBL-2H3 cells.

Topics: Animals; Antigens; Calcium-Calmodulin-Dependent Protein Kinases; Enzyme Activation; Histamine Antagonists; Leukemia, Basophilic, Acute; Phosphorylation; Pyridines; Pyrimidinones; Rats; Tumor Cells, Cultured; Tyrosine

Topics: Adolescent; Adult; Antigens; Conjunctiva; Conjunctivitis, Allergic; Female; Histamine Antagonists; Histamine Release; Humans; Male; Ophthalmic Solutions; Pyridines; Pyrimidinones

To determine whether pemirolast, a new antiallergic drug, inhibits the activation of eosinophils, we investigated the effect of pemirolast on the release of leukotriene C4 (LTC4) and eosinophil cationic protein (ECP) from human eosinophils. Calcium ionophore A23187 caused both LTC4 and ECP release from human eosinophils, whereas PAF and FMLP induced only ECP release from the eosinophils. Pemirolast (10(-6) to 10(-3) M) inhibited A23187-induced LTC4 release from the eosinophils in a dose-dependent fashion with 77% inhibition at 10(-3) M. Pemirolast (10(-5) to 10(-3) M) inhibited A23187-induced ECP release from the eosinophils in a dose-dependent fashion with 42% inhibition at 10(-3) M. Pemirolast (10(-4) and 10(-3) M) also inhibited PAF-induced and FMLP-induced ECP release from the eosinophils. We conclude that pemirolast prevents the activation of human eosinophils to inhibit LTC4 and ECP release. These results suggest that pemirolast might be useful in controlling allergic diseases by inhibiting eosinophil activation.

Topics: Asthma; Blood Proteins; Calcimycin; Eosinophil Granule Proteins; Eosinophils; Humans; In Vitro Techniques; Leukotriene C4; N-Formylmethionine Leucyl-Phenylalanine; Platelet Activating Factor; Pyridines; Pyrimidinones; Ribonucleases; Secretory Rate

An antiallergic drug, pemirolast potassium (TBX) at concentrations between 0.01 and 10 micrograms/ml inhibited antigen (Ag)-stimulated degranulation in RBL-2H3 cells, which have the properties of mucosal mast cells. At the same concentrations, the drug suppressed both the formation of inositol 1,4,5-trisphosphate and the mobilization of Ca2+, indicating the prevention of phospholipase C activation. The production of 1,2-diacylglycerol and phosphatidic acid, which was mainly due to phosphatidylcholine hydrolysis, was also suppressed. Moreover, TBX reduced Ag-induced liberation of arachidonic acid, a precursor of eicosanoids, implying the inhibition of phospholipase A2. These data suggest that TBX inhibits the activation of phospholipase C, leading to decreased formation of the signal transducing molecules necessary for cell activation.

Topics: Animals; Antigens; Calcium; Histamine Antagonists; Inositol 1,4,5-Trisphosphate; Leukemia, Basophilic, Acute; Phospholipases; Pyridines; Pyrimidinones; Rats; Tumor Cells, Cultured

Phosphatidylinositol (PtdIns) is the key precursor of phosphoinositide-derived intracellular mediators. The effects of changing the rate of PtdIns synthesis on mitogenic activity of human amnion-derived WISH cells were investigated. Incubation of the cells with [3H]inositol caused a time- and dose-dependent PtdIns labeling. Exogenous Ca2+ inhibited [3H]inositol incorporation in a dose-dependent fashion; half-maximal inhibition occurred with 0.3-1.0 mM Ca2+. In contrast, removal of cytosolic Ca2+ by ionophore A23187 and 1 mM EGTA induced enhancement of the PtdIns labeling as a function of A23187 concentration, perhaps through release of inhibitory effects of endogenous Ca2+. The A23187-stimulated PtdIns labeling with [3H]inositol was not abolished by additional unlabeled inositol, suggesting that [3H]inositol labeling of PtdIns occurred mainly through de novo synthesis catalyzed by PtdIns synthase (EC 2.7.8.11). In cells with PtdIns synthase activity decreased by exogenous Ca2+, [3H]thymidine incorporation was also inhibited, while A23187 caused dose-dependent enhancement of thymidine incorporation. The changes in PtdIns synthase activity occurred in parallel with changes in mitogenic activity caused by increasing the dose of exogenous Ca2+ or A23187. A similar lowering of mitogenic activity was observed upon suppression of PtdIns synthase by pemirolast potassium (9-methyl-3-1H-tetrazol-5yl-4H-pyrido[1,2-a]pyridin-4-one potassium) via a Ca(2+)-independent mechanism. These data demonstrate that changes in PtdIns synthase activity by some agents acting via different mechanisms are associated with parallel changes in thymidine incorporation, and suggest that PtdIns production is tightly coupled to cell proliferation in human amnion cells.

Topics: Amnion; Calcimycin; Calcium; CDP-Diacylglycerol-Inositol 3-Phosphatidyltransferase; Cell Division; Cell Line; DNA; Dose-Response Relationship, Drug; Egtazic Acid; Gene Expression; Histamine Antagonists; Humans; Inositol; Magnesium; Membrane Proteins; Phosphatidylinositols; Phosphotransferases; Pyridines; Pyrimidinones; Time Factors; Transferases (Other Substituted Phosphate Groups)

The effects of a potent antiallergic drug, pemirolast (TBX), on activation of signal-transducing phospholipase C and A2, were examined in rat peritoneal mast cells. TBX at concentrations between 10(-7) and 10(-5) g/ml effectively inhibited degranulation in response to both antigen and compound 48/80. At the same concentrations the drug markedly suppressed the formation of 1,2-diacylglycerol and phosphatidic acid, and the decrease in phosphatidylinositol, suggesting the prevention of phospholipase C activation. The blockade of phospholipase A2 was suggested by the decrease in agonists-induced arachidonic acid liberation. These results indicate that TBX may exert its inhibitory effects on mast cells, at least in part, by preventing the activation of signal-transducing phospholipases.

Topics: Animals; Antigens, Helminth; Ascaris; Cell Degranulation; Cell Membrane; Exocytosis; Histamine Antagonists; Histamine Release; Mast Cells; p-Methoxy-N-methylphenethylamine; Peritoneal Cavity; Phospholipids; Pyridines; Pyrimidinones; Rats; Rats, Inbred Strains; Serotonin

The effects of 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one potassium salt (TBX), a new antiallergic drug, on histamine release from lung fragments, experimental asthma and isolated tracheal muscle were investigated in guinea pigs. TBX (10(-7) to 10(-4) g/ml) dose-dependently inhibited antigen-induced histamine release from lung fragments of guinea pigs passively sensitized with homologous IgE serum. Antigen inhalation-induced experimental asthma in passively sensitized animals was inhibited in a dose-dependent fashion by i.v. (1 to 5 mg/kg) and p.o. (10 to 100 mg/kg) administrations of TBX. In vivo bronchoconstriction by platelet-activating factor (PAF, i.v.) was also inhibited by TBX (0.3 to 10 mg/kg, i.v.). However, high concentrations of TBX (more than 3 x 10(-4) g/ml) were needed to inhibit PAF-induced platelet aggregation in vitro. With regard to the effect on isolated tracheal muscle, TBX itself at concentrations higher than 10(-5) g/ml induced dose-dependent reduction in the resting tonus, which was not affected by pretreatment with propranolol. Neither the leukotriene D4-induced contraction nor the prostaglandin F2 alpha-induced one was specifically antagonized by TBX. The results obtained indicate that TBX is an antiasthmatic agent effective in inhibiting both IgE- and PAF-induced bronchoconstriction, possibly by interfering with mediator release.

Topics: Animals; Asthma; Bronchi; Dinoprost; Guinea Pigs; Histamine Antagonists; Histamine Release; In Vitro Techniques; Lung; Male; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Platelet Activating Factor; Platelet Aggregation; Pyridines; Pyrimidinones; SRS-A; Trachea

The effects of 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one potassium salt (TBX) on type II to IV allergic reactions and immunological functions were investigated in animal models. Types II to IV allergic reactions in rodents were unaffected in vivo by TBX, even at higher doses than those capable of completely inhibiting the type I allergic reaction. However, both complement-mediated hemolysis via the classical pathway and hypotonic shock-induced hemolysis were slightly inhibited in vitro only by a high concentration of the drug (10(-4) g/ml). In the mouse system, TBX had no ability to suppress anti-hapten IgE antibody formation as well as hemagglutinin formation and to inhibit the proliferation of spleen cells induced by non-specific T and B cell mitogens. The results obtained indicate that TBX is an antiallergic drug essentially devoid of inhibitory actions on types II to IV allergic reactions and immunological functions, thus indicating that it is a specific inhibitor of type I allergic reactions.

Topics: Animals; Arthus Reaction; Cell Division; Complement System Proteins; Erythrocytes; Forssman Antigen; Guinea Pigs; Hemolysis; Histamine Antagonists; Hypersensitivity; Immunity, Cellular; Male; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Passive Cutaneous Anaphylaxis; Pyridines; Pyrimidinones; Rats; Rats, Inbred Strains; Sheep; Tuberculin Test

The ability of 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one potassium salt (TBX) to inhibit histamine release from both peritoneal exudate cells (PEC) containing mast cells and lung fragments of rats was investigated in vitro. Low concentrations of TBX dose-dependently inhibited IgE-mediated histamine release from PEC of passively sensitized animals; its IC50 was 5.1 x 10(-9) g/ml. When TBX was added simultaneously with the antigen challenge, the highest inhibition was obtained. In contrast, extension of preincubation time with the agent resulted in a marked decrease in the inhibition of histamine release. The potent inhibition of histamine release by TBX was observed equally in glucose-free as well as complete Tyrode's solution, whereas TBX reduced its inhibitory action in Ca2+-free or D2O-supplemented medium. In addition, TBX inhibited compound 48/80- but not calcium ionophore A23187-induced histamine release from normal PEC. With regard to the intracellular cyclic AMP level in normal PEC, it was significantly enhanced by a high concentration of TBX (10(-3) g/ml). TBX also inhibited antigen-induced histamine release from lung fragments of actively immunized animals. Interestingly, TBX displayed non-competitive inhibition of cyclic AMP-dependent phosphodiesterase derived from lung homogenates; its K1 value was 8.70 x 10(-4) M.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Antigens; Calcimycin; Cromolyn Sodium; Cyclic AMP; Histamine Release; In Vitro Techniques; Lung; Male; Mast Cells; p-Methoxy-N-methylphenethylamine; Peritoneal Cavity; Pyridines; Pyrimidinones; Rats; Rats, Inbred Strains

The effects of 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one potassium salt (TBX), a new antiallergic drug, on passive cutaneous anaphylaxis (PCA) mediated by homologous IgE or IgG antibody were investigated in rats and guinea pigs. TBX (i.v. and p.o.) clearly inhibited IgE- and IgGa-mediated homologous PCAs in rats, without showing any inhibition of the skin reactions caused by histamine, serotonin and bradykinin in contrast to the inhibition of prostaglandin E1-induced skin reaction. Neither adrenalectomy nor propranolol treatment modified TBX's inhibition of the former PCA. With regard to tachyphylaxis to TBX, it was demonstrable in IgE-mediated homologous PCA in rats when they were pretreated with TBX (0.5 mg/kg, i.v.), followed 60 min later by a second dose of the drug (0.05 mg/kg, i.v.). There was no cross-tachyphylaxis between disodium cromoglycate (DSCG) and TBX. Homologous PCA caused by guinea pig IgE was also inhibited in a dose-dependent fashion by i.v. and p.o. administrations of TBX, although higher doses of TBX were needed to inhibit guinea pig PCA than the rat one. Interestingly, TBX showed more potent inhibition of both rat and guinea pig homologous PCAs than DSCG or tranilast. The results obtained indicate that TBX is an orally effective antiallergic agent displaying no antagonistic actions on the chemical mediators released.

Topics: Animals; Cromolyn Sodium; Guinea Pigs; Immunoglobulin E; Immunoglobulin G; Male; ortho-Aminobenzoates; Passive Cutaneous Anaphylaxis; Pyridines; Pyrimidinones; Rats; Rats, Inbred Strains

Topics: Animals; Depression, Chemical; Female; Guinea Pigs; Histamine Release; Humans; Leukocytes; Lung; Male; Pyridines; Pyrimidinones; SRS-A

A simple and sensitive assay for quantitating 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (1; BMY 26517) in human plasma was developed using high-performance liquid chromatography with fluorescence detection. The method involves precipitation of protein and reversed-phase chromatography. The method is linear in the range of 4.3-429 ng/mL of 1, and the limit of detection is 0.4 ng/mL. The day-to-day precision values of this method at 25.7 and 386 ng/mL are 2.1 and 2.6%, respectively. The day-to-day accuracy values at these concentrations are 99.7 and 99.8%, respectively. The recovery of 1 is 98.3%.

Topics: Anti-Ulcer Agents; Chemical Phenomena; Chemistry; Chromatography, High Pressure Liquid; Drug Stability; Histamine H2 Antagonists; Humans; Pyridines; Pyridones; Pyrimidinones; Spectrometry, Fluorescence