Safety and efficacy of azelastine nasal spray (Astelin NS) for seasonal allergic rhinitis: a 4-week comparative multicenter trial.

BACKGROUND: Azelastine is a chemically novel investigational antiallergy drug with the ability to antagonize the effects of chemical mediators of the early- phase and late phase allergic responses suggesting its usefulness in the treatment of upper and lower airway diseases. OBJECTIVE: The objective of this 4-week, double- bind, multicenter trial was to evaluate the efficacy of azelastine nasal spray in subjects with seasonal allergic rhinitis. METHODS: Two hundred sixty-four subjects 12 years of age and older were randomized to receive either azelastine, 2 sprays/nostril qd; azelastine, 2 sprays/nostril bid; oral chlorpheniramine maleate, 12 mg bid; or placebo. The primary efficacy parameters were the changes in major and total symptom severity scores. RESULTS: Overall, across all 4 weeks of treatment, the mean percent improvements in the total and major symptom complex severity scores in both azelastine treatment groups were greater than those for the placebo group. For the azelastine 2 sprays bid group, the overall results were significant at P = .05 for the major symptom complex score and at .05 < P = .10 for the total symptom complex score versus placebo. For both azelastine treatment groups, improvements in all of the individual rhinitis symptoms were superior to those for the placebo group and, in general were clinically and statistically significant. Azelastine nasal spray was well tolerated; adverse experiences were generally application site reactions, mild to moderate, and not limiting to continued treatment. CONCLUSIONS: Azelastine nasal spray demonstrated broad clinical antirhinitis activity that for the 2 sprays/nostril bid dosage regimen was consistently clinically and statistically significant.

Duration of action of a single dose of azelastine in patients with chronic asthma.

The aim of this double-blind, multicenter trial was to determine the duration of bronchodilating activity of a single 4-mg dose of azelastine in chronic asthmatics. Eligible patients had an FEV1 of 40-79% of predicted value with demonstrated reversibility of airway obstruction. A single dose of azelastine 4 mg resulted in rapid onset of bronchodilating activity with a 12-hr duration of action as demonstrated by a clinically and statistically significant mean percent improvement in FEV1, from hours 2-12. As an overall measure of improvement in FEV1, the area under the curve was statistically significantly greater for azelastine than for placebo. Mean improvements in symptom severity in the azelastine group exceeded those for placebo at all observation points. No serious adverse experiences were associated with azelastine.

A double-blind, controlled trial to assess the safety and efficacy of azelastine nasal spray in seasonal allergic rhinitis.

BACKGROUND: Azelastine solution is a topically (nasal) administered antiallergy drug with a preclinical profile suggestive of efficacy in patients with allergic rhinitis. OBJECTIVES: The study was designed to compare the effectiveness and safety of two dosages of azelastine nasal spray (2 sprays per nostril once daily and twice daily) with that of placebo in the treatment of patients with symptomatic seasonal allergic rhinitis. METHODS: Two hundred fifty-one patients (12 years of age or older) were randomized to treatment in this 2-week, double-blind, parallel-group study. Primary efficacy variables were Major Symptom Complex (nose blows, sneezes, runny nose, itchy nose, watery eyes) and Total Symptoms Complex (Major Symptom Complex plus itchy eyes/ears/throat/palate, cough, postnasal drip). RESULTS: Patients treated with azelastine had mean percent improvements in Total and Major Symptom Complex scores that were consistently superior to placebo at each evaluation point. Overall, improvements were statistically significant (p < or = 0.05) in the Total Symptoms Complex for both azelastine groups and in the Major Symptom Complex for the twice daily group with a trend toward statistical significance for the once daily group. Azelastine was superior to placebo in improving all individual rhinitis symptoms. Adverse experiences in the azelastine groups were minor and infrequent. CONCLUSION: The results support the efficacy and safety of azelastine nasal spray in the treatment of seasonal allergic rhinitis.

Double-blind assessment of azelastine in the treatment of perennial allergic rhinitis.

Azelastine is a chemically novel multifunctional antiallergy investigational drug capable of inhibiting mast-cell activation and the synthesis and/or release of chemical mediators of the upper and lower airway inflammatory response. In previous controlled clinical trials, azelastine was shown to be effective in treating the symptoms of both seasonal allergic rhinitis and perennial allergic rhinitis. The objective of this 8-week double-blind trial was to evaluate further azelastine's efficacy and safety in improving the symptoms of perennial allergic rhinitis over a prolonged period of treatment. One hundred ninety-nine patients with symptomatic perennial allergic rhinitis were randomized to receive in a double-blind fashion azelastine, 2 mg bid, clemastine fumarate, 1.34 mg bid, or placebo bid for 8 weeks. Patients treated with azelastine had superior mean percent improvements in the total symptom complex score (nose blows, sneezes, stuffy nose, runny nose, itchy nose, and itchy eyes/ears/throat) versus placebo at each evaluation point and overall across all 8 weeks (P < .01) of the trial. Improvements in the individual symptoms of rhinitis were statistically significant (P < or = .04) for nose blows, sneezes, runny nose, itchy nose, and itchy eyes, ears, and throat. Treatment with azelastine also resulted in a clinically meaningful improvement in nasal congestion. Improvement in congestion was accompanied by a decreased requirement for backup decongestant medication. The adverse experiences were generally mild and well tolerated. Azelastine provided effective prolonged relief of the symptoms of perennial allergic rhinitis with no adverse effects that would limit its long-term use.

Effectiveness of azelastine nasal solution in seasonal allergic rhinitis.

Azelastine is a novel antiallergy medication currently under investigation for the treatment of allergic rhinitis and asthma. Pharmacologic studies in laboratory animals and in vitro model systems indicate that azelastine exerts multiple actions including modulation of airways smooth muscle response, interference with inflammatory processes, and inhibition of allergic reactions. In a previous controlled clinical trial, azelastine nasal solution (ASTELIN N.S.) demonstrated effectiveness in controlling symptoms of seasonal allergic rhinitis (SAR). The objective of this 2-week double-blind, parallel-group study was to further assess the effectiveness of azelastine nasal solution in improving allergic rhinitis symptoms. Two hundred forty-seven patients (> or = 12 years) with symptomatic SAR who satisfied a minimum symptoms score during a 1-week, single-blind, baseline evaluation period were randomized to receive azelastine 2 sprays per nostril bid, azelastine 2 sprays per nostril qd, chlorpheniramine 12 mg bid, or placebo using a double-dummy technique to insure blinding. The primary efficacy variables were changes in Major Symptom Complex (nose blows, sneezes, runny nose/sniffles, itch nose, and watery eyes) and Total Symptom Complex (Major plus itchy eyes/ears/throat/palate, cough, and postnasal drip) severity scores. Patients treated with azelastine nasal solution qd and bid had mean percent improvements in the Total and Major Symptom Complex severity scores that were clinically significant (> or = 50% improvement over placebo) after both weeks, at endpoint, and overall. The improvements for the azelastine bid group were statistically significant (P < or = .05) at all evaluation points. Adverse experiences occurred infrequently, and none was considered serious or potentially limiting to the clinical utility of the nasal solution.(ABSTRACT TRUNCATED AT 250 WORDS)

Azelastine nasal spray in the management of seasonal allergic rhinitis.

Azelastine is a novel, investigational, antiallergy medication that inhibits the generation, release, and/or end-organ activity of multiple mediators of the inflammatory process in vitro and in vivo. Azelastine is capable of inhibiting both early-phase and late-phase allergic responses in animals and humans. In this 2-day trial in patients with seasonal allergic rhinitis, we evaluated the onset of action, duration of effect, and safety and efficacy of azelastine nasal solution (Astelin N.S.) in an outdoor, highly allergenic environment. Two hundred ninety-four patients who satisfied entry criteria were randomized to azelastine 2 sprays/nostril q24h or q12h, oral chlorpheniramine maleate 12 mg q12h, or placebo in this multicenter, double-blind, parallel-group study. Rhinitis symptoms were analyzed individually and combined as total and major symptom complexes. For both azelastine treatment groups, the overall mean percent improvements in the total and major symptom complex severity scores were statistically significant (P < or = .05) versus placebo. Improvements in rhinitis symptoms were observed by the second hour after administration of azelastine and lasted up to 24 hours. The therapeutic effect of azelastine was apparent for all rhinitis symptoms, not just one or a few symptoms. Seventy-three percent of the patients treated with azelastine reported overall improvement upon global assessment of their symptoms. Adverse effects with azelastine were generally mild or moderate. Azelastine nasal spray, administered either once or twice daily, was effective in treating the symptoms of seasonal allergic rhinitis and demonstrated a rapid onset of action with a duration of response lasting 12 to 24 hours.

Peritoneal clearance of theophylline.

Clearance of theophylline was determined in 3 patients receiving maintenance theophylline during peritoneal dialysis. The average peritoneal dialysis clearance of theophylline was 11.67 ml/min. The average theophylline to creatinine clearance ratio was 0.85 representing significant clearance across the peritoneum. The amount of theophylline removed per exchange was approximately 8 mg. Charcoal or resin hemoperfusion and hemodialysis are undoubtedly the most efficient means of treating theophylline overdose. However, peritoneal dialysis appears to be a useful alternative as overdosed patients would be expected to have significantly higher serum concentrations than encountered in this study, greater gradients across the peritoneal membrane, and greater net removal of theophylline per exchange than reported here.

Altered adenylate cyclase kinetics in hyperfunctioning human parathyroid glands.

Current evidence suggests that parathyroid gland adenylate cyclase is involved in the control of parathyroid hormone (PTH) secretion. Thus, the altered control of PTH release in hyperparathyroidism may relate to altered adenylate cyclase activation. Therefore, we examined adenylate cyclase kinetics in membrane preparations from hyperfunctioning human parathyroid glands and normal human and bovine parathyroid tissues. There were no differences in the affinity for ATP between enzymes of normal and pathological tissue. However, the enzyme in 10 hyperfunctioning glands showed increased affinity for Mg++. The activation constant for Mg++ (KaMg) of adenylate cyclase in normal human glands was 10.6 +/- 2 mM, a value not different from that of normal bovine parathyroid tissue (9.5 +/- 1 mM). In contrast, the adenylate cyclase in membrane preparations from three of four hyperplastic and six of seven adenomatous human glands showed a markedly reduced KaMg, ranging from 0.85-1.64 mM and from 1.58-6.46 mM, respectively. In one adenoma and one hyperplastic gland, the Ka of the enzyme for Mg++ was close to normal. The addition of guanylylimidodiphosphate or GTP to the incubation mixture increased, in a dose-dependent manner, the apparent KaMg of the enzyme in the abnormal tissue toward normal, suggesting a defective nucleotide regulatory site in the adenylate cyclase of hyperparathyroid glands. In addition, the hyperparathyroid gland enzyme was less susceptible to inhibition by calcium, requiring 0.7-1 mM Ca++ for 50% inhibition, whereas comparable inhibition of the normal adenylate cyclase was seen at 0.22-0.28 mM Ca++. We conclude that the abnormal control of PTH secretion in hyperparathyroidism may be related, at least in part, to alterations in the characteristics of parathyroid gland adenylate cyclase.

Evidence for skeletal resistance to parathyroid hormone in magnesium deficiency. Studies in isolated perfused bone.

Hypocalcemia during magnesium (Mg) depletion has been well described, but the precise mechanism(s) responsible for its occurrence is not yet fully understood. The hypocalcemia has been ascribed to decreased parathyroid hormone (PTH) secretion as well as skeletal resistance to PTH. Whereas the former is well established, controversy exists as to whether or not Mg depletion results in skeletal resistance to PTH. These studies examine the skeletal response to PTH in normal dogs and dogs fed a Mg-free diet for 4-6 mo. Isolated tibia from normal (serum Mg 1.83+/-0.1 mg/100 ml) and experimental dogs (serum Mg 1.34+/-0.15 mg/100 ml) were perfused with Krebs-Henseleit buffer during a constant infusion of 3 ng/ml of synthetic bovine PTH 1-34 (syn b-PTH 1-34). The arteriovenous (A-V) difference for immunoreactive PTH (iPTH) across seven normal bones was 37.5+/-3%. In contrast, the A-V difference for iPTH was markedly depressed to 10.1+/-1% across seven bones from Mg-depleted dogs. These findings correlated well with a biological effect (cyclic AMP [cAMP] production) of syn b-PTH 1-34 on bone. In control bones, cAMP production rose from a basal level of 5.8+/-0.2 to 17.5+/-0.7 pmol/min after syn b-PTH 1-34 infusion. In experimental bones, basal cAMP production was significantly lower than in controls, 4.5+/-0.1 pmol/min, and increased to only 7.1+/-0.4 pmol/min after syn b-PTH 1-34 infusion. Even when PTH concentrations were increased to 20 ng/ml, cAMP production by experimental bones was lower than in control bones perfused with 3 ng/ml. Histological examination of bones from Mg-deficient dogs showed a picture compatible with skeletal inactivity. These studies demonstrate decreased uptake of iPTH and diminished cAMP production by bone, which indicates skeletal resistance to PTH in chronic Mg deficiency.

Metabolism of parathyroid hormone by fetal rat calvaria.

These studies examine the metabolism of highly purified bovine parathyroid hormone [bPTH-(1--84)] by fetal rat calvaria. Enzymatically dispersed bone cells and intact (minced) calvaria were incubated with bPTH-(1--84) and the incubation medium was analyzed for degradation of PTH by polyacrylamide gel electrophoresis. Eluates of gel slices were assayed for immunoreactive PTH (iPTH) in carboxy- and amino-terminal RIAs. Both bone preparations metabolized bPTH-(1--84). The intact hormone progessively decreased with time and carboxy-terminal iPTH fragments were evident by 5 min of incubation. In the isolated cell preparations, intact hormone was completely degraded at submaximal doses of PTH (5 X 10(-9) M), as assessed by cAMP production. Degradation was incomplete in intact calvarial preparations at all doses studied. Intact calvaria were less sensitive to PTH with regard to cAMP production. No amino-terminal fragments were detected in the medium with either cell preparation. Oxidized (biologically inactive) bPTH-(1--84) was not metabolized in these systems. These findings contrast with studies in liver and kidney preparations, where oxidized bPTH has been shown to be degraded. These findings contrast with studies in liver and kidney preparations, where oxidized bPTH has been shown to be degraded. These data suggest that biological activity may be necessary for the metabolism of intact bPTH-(1--84) by bone cells and that skeletal tissue may contribute to the immunoheterogeneity of circulating PTH in the rat.

Selective uptake of the synthetic amino terminal fragment of bovine parathyroid hormone by isolated perfused bone.

Studies from our laboratory have shown that the metabolic clearance rate of carboxy terminal immunoreactive parathyroid hormone (i-PTH) can be accounted for by extraction of i-PTH by liver and kidney. In contrast, there was no demonstrable hepatic uptake of the synthetic amino terminal bovine PTH fragment (syn b-PTH 1-34) and the kidney accounted for only 45% of the metabolic clearance rate of amino terminal i-PTH. This suggested that another major site, presumably bone, played a role in the metabolism of syn b-PTH 1-34. Extraction of i-PTH by isolated perfused bone was studied during infusion of purified bovine PTH (b-PTH) 1-84 or syn b-PTH 1-34. In five studies during infusion of syn b-PTH 1-34 the arteriovenous difference for i-PTH across bone was 36%. In contrast, no significant uptake of carboxy terminal i-PTH was observed in nine studies during infusion of b-PTH 1-84. In addition, when H(2)O(2)-oxidized (biologically inactive) syn b-PTH 1-34 was used no arteriovenous difference was observed. These findings correlated with the ability of these PTH preparations to stimulate cyclic AMP production by the perfused bone. Syn b-PTH 1-34 increased cyclic AMP production at perfusate PTH concentrations of 1-5 ng/ml, whereas b-PTH 1-84 evoked only a minimal response at concentrations of 10-20 ng/ml. We conclude that bone is a major site of metabolism of the amino terminal PTH fragment, syn b-PTH 1-34. In addition, these data suggest that cleavage of the intact hormone, with the production of amino terminal PTH fragments by peripheral organs (liver and kidney), may play a major role in the regulation of PTH effects on bone.