Comparative efficacy and safety of azelastine and levocabastine nasal sprays in patients with seasonal allergic rhinitis.

The aim of the present investigation was to compare the efficacy and tolerability of azelastine (CAS 58581-89-8) (1.12 mg/day) and levocabastine (CAS 79547-78-7) (0.4 mg/day) nasal spray administered twice daily to patients with seasonal allergic rhinitis. A total of 180 patients participated in a 4-week, double-blind, parallel group (n = 90 each) study. Symptom severity of nasal, ocular and other symptoms were recorded, out of which a total symptom score (TSS) was calculated. Physicians assessed symptoms at baseline and at days 7, 14, and 28, patients and physicians evaluated the efficacy and tolerability. After 4 weeks of treatment with azelastine the mean overall TSS was reduced from a baseline score of 18.7 to 4.2, after levocabastine from 17.8 to 5.9. Patients morning scores for treatment days 1 to 28 gave a mean total score of 212.4 for the azelastine group and 230.6 for the levocabastine group; the equivalent evening scores yielded a mean total score of 115.5 and 175.6 respectively. Global efficacy was judged by physicians as either 'very good' or 'good' for 90% of azelastine patients and for 74% of the levocabastine group; 92% of azelastine patients and 76% of levocabastine patients judged treatment to be either 'very good' or 'good'. No serious adverse events were reported, all adverse events were related to nasal symptoms. Both azelastine and levocabastine administered twice daily as a nasal spray provide effective and well tolerated symptomatic treatment of seasonal allergic rhinitis. Azelastine, however, was statistically superior in efficacy as well as in safety (PWei-Lachin < 0.0001, combined results).

Comparative efficacy and safety of nimesulide and diclofenac in patients with acute shoulder, and a meta-analysis of controlled studies with nimesulide.

Adverse events, particularly gastrointestinal, partially offset the therapeutic value of NSAIDs. The abilities of nimesulide to inhibit COX-2 preferentially and to exert other novel anti-inflammatory actions are consistent with good efficacy and safety. This is borne out by a double-blind multicentre comparison of nimesulide and diclofenac in 122 patients with acute shoulder, and by a meta-analysis of various nimesulide trials. At the end of the 14 day double-blind study, nimesulide was at least as effective as diclofenac (investigator ratings: good/very good in 79.0% of patients given nimesulide, and 78.0% with diclofenac; patient ratings: good/very good in 82.3 and 78.0% respectively). Four patients (6.5%) dropped out in the nimesulide group (two early recovery, one lack of effect, one adverse event), compared with 13 (21.7%) in the diclofenac group, due mainly to adverse events (P=0.003). Global tolerability was judged by the investigators to be good/very good in 96.8% of the nimesulide group compared with 72.9% of those given diclofenac. Judgements by the patients were 96.8 and 78.0% respectively. Both differences are highly significant statistically. The meta-analysis demonstrates that nimesulide given for 2 weeks is far more efficacious than placebo in treating osteoarthritis, and is at least comparable to other NSAIDs The benefit-risk ratio for nimesulide was better in all individual studies since 100 mg nimesulide twice daily was about equal to placebo in safety and tolerability, especially regarding gastrointestinal adverse events.

Comparative efficacy and safety of the non-steroidal anti-inflammatory drugs nimesulide and diclofenac in patients with acute subdeltoid bursitis and bicipital tendinitis.

The efficacy and tolerability of nimesulide, a non-steroidal anti-inflammatory drug (NSAID) 100 mg twice daily were compared with diclofenac 75 mg b.i.d. in short term treatment of acute shoulder (acute subdeltoid bursitis and bicipital tendinitis) in adult patients. In this double-blind (double-dummy), randomised, parallel group study over two weeks, 122 patients were included. The Mann-Whitney statistics revealed therapeutic equivalence of both treatments with a slight superiority for nimesulide. The tolerability of nimesulide, judged by investigators and patients and analysed statistically, was superior to that of diclofenac. Thus, the benefit-risk relationship was better for the test drug than for the reference drug.

Evaluation of the drug monitoring programme of azelastine hydrochloride nasal spray in the treatment of allergic rhinitis in children under 13 years of age.

The efficacy and safety of a nasal spray containing azelastine (CAS 58581-89-8; e.g. Afluon, Allergadil, Rhinolast) in the treatment of both perennial and seasonal allergic rhinitis have been evaluated in two postmarketing drug surveillance programmes (PMS) conducted in Spain. The present analysis reports on the data from a subpopulation from these studies and includes 211 children aged less than 13 years of age. In 73% of children the administered dose of azelastine was one spray puff per nostril twice daily, corresponding to the recommended daily, dosage of 0.56 mg azelastine. Patients with seasonal rhinitis were treated for a period of two weeks, those perennial rhinitis were treated for four weeks. The efficacy of the azelastine was assessed by the changes in severity of the following 10 individual symptoms of rhinitis: sneezing, nose itching, nose congestion, rhinorrhoea, smell reduction, eye itching, lachrimation, photophobia, throat itching, and coughing. Symptoms were rated according to a four-point scale: 0 = absent, 1 = slight, 2 = moderate, and 3 = severe. Both the investigators and the patients were requested to evaluate efficacy and tolerance according to a four point scale: 1 = very good, 2 = good, 3 = moderate, 4 = bad. All of the 10 clinical symptoms underwent a statistically significant and clinically relevant reduction during the treatment period. Nose itching, sneezing, and rhinorrhoea were the symptoms which completely disappeared in the highest number of patients by the end of therapy. The mean sum of all 10 symptom scores pre-treatment (baseline visit) was 11.03 while at the completion of therapy (control visit) it was 3.21. Overall, a decrease of this score was seen in 112 (98%) patients for whom complete data was available, whereas an increase was registered only in 2 (2%) cases. The mean total of the five nasal scores at the baseline visit was 7.64, and at the control visit its value measured 2.31. One hundred and twenty-one (98%) patients exhibited a decrease in the total nasal score, and only 3 (2%) demonstrated an increase. The mean total of the three ocular symptoms scores at the baseline visit was 2.25, while at the control visit its value was only 0.48. A decrease in the total ocular score was observed in 78 (62%) patients, while an increase occurred in only one patient. Overall, 85% of doctors evaluated the efficacy of the drug as "very good/good". 90% of patients did not report adverse events (AEs) during treatment with azelastine and only four patients discontinued treatment due to AEs. General tolerance was evaluated as "very good or good" by 97% of the treating physicians. Local tolerance was rated as "very good or good" by 94%. The most positive characteristics of the therapy according to the physicians were: rapid onset of action in 56% of cases, good efficacy in 46%, simple application in 44%, no sedation in 34%, and long duration of action in 22% of cases. Based upon the excellent risk-benefit assessment of this PMS, our results confirm the suitability of azelastine nasal spray in the treatment of allergic rhinitis in juvenile patients.

Efficacy and tolerability of azelastine nasal spray in the treatment of allergic rhinitis: large scale experience in community practice.

Two Spanish prospective monitoring studies evaluated efficacy and tolerability of azelastine nasal spray containing azelastine hydrochloride for allergic rhinitis. Both studies were conducted by community practitioners over two weeks (Study I) or one month (Study II). The numbers of patients recruited were 3680 (I) and 4002 (II). Of these, 56.1% (I) and 51.7% (II) had been previously treated with oral antihistamines with/without other medications. Patients rated the severity of 10 symptoms of allergic rhinitis as absent, mild, moderate or severe. Azelastine nasal spray was generally administered at a dose of one spray puff (0.14 mg) per nostril twice daily. Follow-up was after 14 days (I) or 31 days (II), when symptoms were rated and patients questioned about treatment. Assessment was by a sum score for all 10 symptoms. A symptom sum score of 16-20 occurred in 21.1% (I) and 13.7% (II) of patients before treatment and only 0.8% (I) and 0.6% (II) after treatment. A symptom sum score of 11-15 occurred in 35.9% (I) and 30.5% (II) of patients before treatment and only 2.6% (I) and 2.8% (II) after treatment. Overall, 92.3% (I) and 90.7% (II) of patients were completely free of adverse events, 7.0% (I) and 8.8% (II) experienced one and 0.7% (I) and 0.6% (II) two adverse events. The number of doctors who rated efficacy as either very good or good was 89.4% (I) and 84.6% (II). General tolerance was rated as good or very good by 97.5% (I) and 97.3% (II), and local tolerance by 93.1% (I) and 91.5% (II) of physicians, respectively. Overall, azelastine nasal spray was highly effective and very well tolerated in normal clinical practice.

Topical therapy of allergic rhinitis in childhood: Allergodil nasal spray--non-sedating in children.

The efficacy and safety of the nasally administered drug Allergodil in the treatment of allergic rhinitis were evaluated in a prospective drug monitoring programme conducted in Germany. Data from 489 children under the age 13 were included. The study was designed to gain knowledge about Allergodil in a normal clinical setting. Dosing was at the judgement of the investigator bearing in mind data sheet recommendations, i.e. one spray-puff (0.14 mg) per nostril twice daily. Patients were treated for four weeks. The occurrence of ten nasal, eye and throat symptoms was rated (0 = never, 1 = sometimes, 2 = often). All symptoms showed a statistically significant improvement at the final visit, as did the overall sums of the scores. These changes were clinically significant. Overall assessment of efficacy by the physicians and the patients was very good and good in more than 85% of patients. 70% of patients required no concomitant medication. 13.5% of patients experienced adverse events, mostly mild or moderate in severity. Safety and tolerance were assessed as very good and good in more than 97% of cases. No sedation was seen. With respect to both efficacy and safety, there were no differences between patients younger than 6 years and those aged 6-12 years. In conclusion, these results suggest that Allergodil is an effective treatment of the symptoms of allergic rhinitis in children. The subgroup of 48 young patients studied shows that Allergodil was safe and well tolerated in patients aged 2-6 years.

Bioavailability of vinpocetine and interference of the time of application with food intake.

In a pilot study based on an open cross-over design involving four phases, the relative bioavailability of the eburnamenine derivative vinpocetine (CAS 42971-09-5) was investigated in 8 healthy volunteers in relation to different times of drug administration relative to food intake. The substance was applied orally as 10 mg film tablets. The areas under the plasma concentration-time curves (AUC) amounted to 27.3 +/- 18.1 ng.h/ml (fasting) and 42.8 +/- 27.4 up to 54.3 +/- 38.4 ng.h/ml (non-fasting, intake before and after meal, resp.). The relative bioavailability under non-fasting conditions was found to be approx. 60 to 100% higher than under fasting conditions.

Biochemical evidence of platelet activation in patients with persistent unstable angina.

Thromboxane released from activated platelets and prostacyclin of the vessel wall may act as potent antagonistic modulators of platelet aggregability and coronary vascular tone. Therefore, urinary excretion of their major metabolites, 2,3-dinor-thromboxane B2 and 2,3-dinor-6-ketoprostaglandin F1 alpha, was studied in 16 patients presenting with prolonged angina at rest. The 10 patients whose condition did not improve under vigorous antianginal treatment within 48 hours exhibited higher thromboxane metabolite excretion than did the 6 patients who responded to therapy (2,208 +/- 1,542 versus 609 +/- 312 ng/g creatinine; p less than 0.001). Elevated values were also found in four of eight patients with sustained postinfarction angina. Enhanced thromboxane metabolite excretion was frequently associated with angiographic evidence of thrombus formation. When nine patients were restudied in a stable phase after 11 +/- 5 months, thromboxane metabolite excretion was consistently normal or high normal. Excretion of prostacyclin metabolites was not depressed in any patient but correlated weakly with thromboxane (r = 0.41). Thus, enhanced thromboxane production as an index of platelet activation may identify patients with active thrombus formation who could benefit most from platelet inhibitory treatment.

Inhibition of thromboxane synthetase by the imidazole derivative 3-(1H-imidazol-1-yl-methyl)-2-methyl-1H-indole-1-propanoic acid as a novel therapeutic approach to experimental myocardial ischemia.

3-(1H-imidazol-1-yl-methyl)-2-methyl-1H-indole-1-propanoic acid (UK 38.485), a novel imidazole derivative, was employed to study potential protective effects of thromboxane synthetase inhibition on ischemically stressed canine myocardium. In anaesthetized open-chest mongrel dogs (n = 5) repeated ischemia (3 min) was produced by proximal, intermittent occlusion of the left anterior descending artery. A total of 18 occlusions after therapy was analysed and compared to a total of 15 occlusions under control conditions. In each experiment 2-3 control occlusions and 3-4 occlusions under therapy were performed. The drug was applicated intravenously at a dose of 5 mg/kg body weight 30 min before the first therapy occlusion. Hemodynamics and energetics did not significantly change. The efficiency of the drug in protecting ischemically stressed myocardium was examined by the amounts of potassium, inorganic phosphate and lactate released in the first minute of reperfusion and by quantification of 02-debt and 02-repayment in the occlusion and reperfusion periods. Compared to control occlusions, premedication with UK 38.485 led to a reduced 02-debt (-39.1%; p less than 0.01) combined with a significant decrease of the release of potassium (-15.7%; p less than 0.001), inorganic phosphate (-20.2%; p less than 0.002) and lactate (-20.7%; p less than 0.01). The protective effect is suggested to be mainly due to enhanced flow to ischemic areas regarding a significant lesser reduction of myocardial blood flow and an improved oxygen uptake during ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects on prostanoid formation and pharmacokinetics of dazmegrel (UK-38,485), a novel thromboxane synthase inhibitor, in man.

The pharmacokinetics of dazmegrel (UK-38,485), a novel selective thromboxane synthase inhibitor, and its effects on in vivo prostanoid formation were studied in a 2 weeks, multiple dose, placebo controlled, double blind trial in man. The drug was well tolerated. After dazmegrel 50-200 mg p.o. peak plasma levels of 0.7-3 mu/ml were reached within 1 hr. Elimination was of first order with a half life of 0.88 +/- 0.17 hr. Platelet count and bleeding time were unchanged by all regimes of dazmegrel used (100 and 200 mg b.i.d.; 50, 100 and 200 mg t.i.d.). Serum thromboxane (TXB2) was more than 95% suppressed one hour after all doses studied, but 200 mg t.i.d. were needed suppress circadian serum TXB2 profiles more than 90% at all times. Urinary excretion of 2,3-dinor-TXB2 (TXA2-M) fell by over 90%. An increase in the excretion of 2,3-dinor-6-keto-PGF1 alpha (PGI2-M), the major metabolite of prostacyclin, was largely transient and fell short of significance at all times. The ratio of TXA2-M to PGI2-M was lowered from about 5.0 to 0.2 and sustained throughout treatment. Dazmegrel selectively blocks in vivo and ex vivo TXA2 formation. Redirection of endoperoxides from total body TXA2 formation into prostacyclin formation is only minor under basal conditions.

Preservation of myocardium in transient ischemia by the thromboxane synthetase inhibitor UK 38.485.

This study was performed to examine potential protective effects of UK 38.485, an inhibitor of thromboxane synthetase, in canine myocardium stressed by transient ischemia. On anesthetized open-chest mongrel-dogs (n = 9) repeated ischemia (3 min) was produced by proximal, intermittent occlusion of the left anterior descending artery. A total of 18 occlusions after 3 mg UK 38.485/kg body wt. and 12 occlusions after 5 mg UK 38.485/kg body wt. were compared to a total of 24 occlusions under control conditions. In each experiment, 2-3 control occlusions and 3-4 therapy occlusions were performed. The drug was applied i.v. in a dose of 3 or 5 mg/body wt. 30 min before the first therapy occlusion. In both groups, hemodynamics and energetics did not significantly change as compared to control. The efficiency of the drug in protecting ischemically stressed myocardium was examined by (a) quantification of oxygen debt and oxygen repayment in the occlusion and reperfusion periods and (b) the amounts of inorganic phosphate, lactate, and potassium released in the first minute of reperfusion. Compared to control occlusions, premedication with either 3 or 5 mg UK 38.485 led to a significantly reduced oxygen debt combined with a significant decrease of the release of inorganic phosphate, lactate, and potassium. The protective effect is suggested to be mainly due to enhanced flow to ischemic areas. Data obtained in this study suggest protective effects of the compound in the preservation of myocardium in transient ischemia and attest to the concept that thromboxane A2 may aggravate the metabolic and energetic situation of myocardium in circumstances with reduced oxygen supply.

Changes in myocardial substrate utilisation and protection of ischemic stressed myocardium by oxfenicine [(S)-4-hydroxyphenylglycine].

Potential protective effects of oxfenicine [(S)-4-hydoxyphenylglycine] in ischemic stressed canine myocardium have been studied. This compound is characterized as a drug leading to metabolic inhibition of free fatty acid (FFA) metabolism. The drug (0.06 mmol . kg-1 body weight) caused no changes in hemodynamics or energy demand (Et) but depressed myocardial oxygen consumption (MVO2) by 11% (P less than 0.02). Significant changes in FFA and lactate metabolism were observed: lactate extraction (EX) increased from 22.5-37.1 mumol/Min, extraction ratio (EXR) from 16.5-30% and oxygen extraction ratio (OER) from 24.8-38%; EX of FFA decreased from 6900-5000 nmol/min, EXR from 48.2-31.4% and OER from 59.7-46.6%. Arterial concentrations of FFA and lactate remained unchanged. EX, EXR and OER of glucose were not affected under basic conditions. In the same collective, repeated ischemia (3 min) was produced by proximal occlusion of the left anterior descending artery (LAD). The efficiency of the drug was examined by (a) the amounts of ischemia metabolites released in the early reperfusion and (b) quantification of O2-debt and O2-repayment in the occlusion- and reperfusion periods. Compared to control occlusions, premedication led to a reduced O2-debt (P less than 0.01) combined with a reduced amount of oxygen additionally taken up in the early reperfusion (P less than 0.05). Furthermore, release of potassium increased (+7.1%; P less than 0.05); release of lactate (-32%, P less than 0.001) and inorganic phosphate (-34%, P less than 0.01) decreased. These data give support to the concept that a pharmacologically induced shift of cardiac metabolism with reduction of FFA utilisation may be favourable in circumstances with limited oxygen supply.

[Beclomethasone dipropionate seasonal allergic rhinitis treatment of children. A double blind cross over study (author's transl)]. / Beclometason dipropionat bei Rhinitis pollinosa im Kindesalter. Eine gekreuzte Doppelblindstudie.

In a double-blind cross over study on 25 children with seasonal allergic rhinitis treatment with Beclomethasone dipropionate (BDP)-Aerosol was found more effective than placebo. 17 children preferred BDP, two the placebo-aerosol, while 6 had no preferrence. During a period with very high pollen concentrations in the air the effect of BDP-therapy was no longer sufficient.