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60 BM-1144, a novel thromboxane A2 receptor antagonist relaxes trachea guinea pig in vitro
Abstracts
J ALLERGY CLIN IMMUNOL VOLUME 105, NUMBER 1. PART 2
SUMMARY
OF EFFICACY
VARIABLES AEROBID
AT ENDPOINT NON-AEROBID
GROUP SUCCESS
RATE
FEV, 0-j Fvc 04 % PREDICTED
FE’.‘,
A.M.PEFR(UMIN) I?M.PEFR(UMIN) ALBUTEROLUSE(PUFFS/DAY) NOCTURNALAWAKENINGS QUALITYOFLIFESCORE
(/WK)
85.7 2.58 f 0.81 3.60 * 1.04 75.25 f 20.05 371.6 f 104.0 363.2 f 103.6 3.3 f 3.2 0.3kO.6 5.24i 1.1
GROUP
85.7 2.60 f 0.85 3.60 * 1.05 75.52 f 17.60 372.4 f 112.1 358.5 et 111.6 3.2 f 3.4 0.3 * 0.7 5.23 f 0.96
WlTHTHEEXCEFTIONOFSUCCESSRATE.VALUESAREEXPRESSEDAS MEANGD
CONCLUSIONS: The results of this study demonstrate that Aerobid M administered once daily is as safe and effective as bid to qid regimens of triamcinolone acetonide. beclometbasone dipropionate or fluticasone propionate. 60
BM-144, a Novel Thromboxane A2 Receptor Antagonist Relaxes Trachea Guinea Pig In Vitro Jean-Michel Do@, Xavier de Lmal, Jacques Delarge, Stephanie Rolin, Bernard Masereel Department of Medicinal Chemistry, University of Litge, av de I’hBpital, I. 4000 Litge Belgium Thromboxane A2 is an arachidonic acid metabolite produced in human platelets and vasular and bronchial endothelium. It exhibits two major potential pathological activities: stimulation of platelet function inducing platelet aggregation, vasoconstriction and bronchoconstriction. Therefore. drugs which antagonize the action or the formation of thromboxane A2 have been demonstrated to exhibit anti-thrombotic and anti-asthmatic properties. The pharmacomodulation of torasemide led to the development of a sulfonylcyanoguanidine (BM 144) which presents the same pharmacological profile of sulotroban, a thromboxane A2 receptor antagonist frequently used as reference. Indeed, BM I44 showed a marked affinity for human washed platelets tbromboxane A2 receptors labelled with [3H]SQ-29,548 (100 :O.l2pM). Since TXA2 is implicated in the regulation of hemostatic plug and thrombus formation [5], we demonstrated the anti-aggregating activity of BM I44 on human platelets with aggregating agents such as arachidonic acid (IC 50 : 9.4 @I.) and U-46619, a stable thromboxane A2 agonist (IC 50 : 13.5 @I.). This TXA2 antagonist potency has been confirmed on trachea smooth muscle. Indeed, BM I44 has been showed to relax precontracted guinea pig trachea strips by U-46619 (IC 50 = 0.006 pM).In this test, seratrodast,a thromboxaneA2 receptor antagonist marketed in japan as anti-asthma agent was shown three times more potent than our drug (IC50: 0.002 @I) Moreover, BM I44 (30 mg/kg ip) has also been demonstrated to prevent sudden death in rats (100% of protection ; n=6) induced by a lethal dose (180 pg/kg iv) of U-46619. Our results suggest that BM 144. an original thromboxane A2 receptor antagonist which lost the diuretic properties of torasemide, is a new leader in the treatment of pathologies where an overproduction of thromboxane A2 is implicated, especially asthma and thrombosis.
61
S21
Assessment of Bronchodilator Response in 2 to 5 Year Old Children Gabriel Ortiz, PA-C, Jose Venzoc MD, Roger Menendez. MD Allergy and Asthma Research Center of El Paso, El Paso, TX. Wheezing and reversible airways disease are prevalent conditions among pre.-schoolaged children. As many as50% will have experienced a wheezing attack by age 6. Yet assessmentof airfow obstruction and response to therapy in this age group remain difficult and frought with technical difficulties. Of several techniques available for measuring resistance to airflow, forced oscillation remains the most adaptable to young children and most practical for clinic use.Advances in data processing has made possible the development of a system capable of obtaining estimatesof total respiratory resistance(as impedance) quickly (in seconds) and reproducibly (CV comparable to body plethysmography).One such system is the Jaeger MasterScreen. We have used the Jaeger MasterScreen Impulse Oscillometry System (IOS) to assessthe response of pre-school aged children to bronchomodulating drugs. We report here our results using albuterol MD1 delivered via a spacer device. We performed a single-blind, placebo controlled, crossover study in IO children aged 2 to 5 years with a history of reactive airways disease,who were not receiving regular asthma therapy. They withheld all bronchcdilators for at least I2 hours prior to study.All testing was started at 0900 * I hour. Testdays were separated by at least 7 days. The children were testedwhile seatedwith neck slightly extended, lips sealed around the mouthpiece and cheeks supported with both hands. Measurements were taken during tidal breathing while the child watched cartoons on a TV screen. The 10s technique has been well characterized by Klug. Landser. and others. Briefly, random oscillations of 5-35HZ are superimposed on tidal breathing for approximately 30 seconds. Real time recordings of the mouth pressure and flow signals are used to calculate total impedance (Zrs) and its two components,resistance.(Rrs) and reactance (Xrs), using FFT techniques and previously validated algorytbms contained in the software package.Since Xrs @J5Hz haslower intraindividual and between-individual variability than Rrs and correlates best with changes in PEV 1,this parameter is used to estimatedrug responses. Mean intraindividual variability in Xrs is 25% which is comparable to SRaw. A pre/post change in Xrs of 50% is considered significant. After baseline measurements,each child received, at random, either inhaled albuterol or an identical placebo. Measurements were repeated at 5,30, 60, and 360 minutes post-treatment The mean change from baseline (s.e.) in Xrs after placebo was 9.6(3.0), 10.1(2.6), 5.1(2.9), 6.1(3.5) at each time point (p=.36). The mean change from baseline(s.e.) after active treatment was 32.7(3.8), 53.9(1.2), 47.3(5.4), and 18.1(5.8), pcO.01 vs baseline at all time periods. We conclude that: a) this is a practical and reproducible way of assessingahway responses in this age group; b) that it is well-suited for clinical as well as therapeutic research use. Supported by a Clinical Applications Research Grant from GlaxoWellcome.
J ALLERGY CLIN IMMUNOL VOLUME 105, NUMBER 1. PART 2
SUMMARY
OF EFFICACY
VARIABLES AEROBID
AT ENDPOINT NON-AEROBID
GROUP SUCCESS
RATE
FEV, 0-j Fvc 04 % PREDICTED
FE’.‘,
A.M.PEFR(UMIN) I?M.PEFR(UMIN) ALBUTEROLUSE(PUFFS/DAY) NOCTURNALAWAKENINGS QUALITYOFLIFESCORE
(/WK)
85.7 2.58 f 0.81 3.60 * 1.04 75.25 f 20.05 371.6 f 104.0 363.2 f 103.6 3.3 f 3.2 0.3kO.6 5.24i 1.1
GROUP
85.7 2.60 f 0.85 3.60 * 1.05 75.52 f 17.60 372.4 f 112.1 358.5 et 111.6 3.2 f 3.4 0.3 * 0.7 5.23 f 0.96
WlTHTHEEXCEFTIONOFSUCCESSRATE.VALUESAREEXPRESSEDAS MEANGD
CONCLUSIONS: The results of this study demonstrate that Aerobid M administered once daily is as safe and effective as bid to qid regimens of triamcinolone acetonide. beclometbasone dipropionate or fluticasone propionate. 60
BM-144, a Novel Thromboxane A2 Receptor Antagonist Relaxes Trachea Guinea Pig In Vitro Jean-Michel Do@, Xavier de Lmal, Jacques Delarge, Stephanie Rolin, Bernard Masereel Department of Medicinal Chemistry, University of Litge, av de I’hBpital, I. 4000 Litge Belgium Thromboxane A2 is an arachidonic acid metabolite produced in human platelets and vasular and bronchial endothelium. It exhibits two major potential pathological activities: stimulation of platelet function inducing platelet aggregation, vasoconstriction and bronchoconstriction. Therefore. drugs which antagonize the action or the formation of thromboxane A2 have been demonstrated to exhibit anti-thrombotic and anti-asthmatic properties. The pharmacomodulation of torasemide led to the development of a sulfonylcyanoguanidine (BM 144) which presents the same pharmacological profile of sulotroban, a thromboxane A2 receptor antagonist frequently used as reference. Indeed, BM I44 showed a marked affinity for human washed platelets tbromboxane A2 receptors labelled with [3H]SQ-29,548 (100 :O.l2pM). Since TXA2 is implicated in the regulation of hemostatic plug and thrombus formation [5], we demonstrated the anti-aggregating activity of BM I44 on human platelets with aggregating agents such as arachidonic acid (IC 50 : 9.4 @I.) and U-46619, a stable thromboxane A2 agonist (IC 50 : 13.5 @I.). This TXA2 antagonist potency has been confirmed on trachea smooth muscle. Indeed, BM I44 has been showed to relax precontracted guinea pig trachea strips by U-46619 (IC 50 = 0.006 pM).In this test, seratrodast,a thromboxaneA2 receptor antagonist marketed in japan as anti-asthma agent was shown three times more potent than our drug (IC50: 0.002 @I) Moreover, BM I44 (30 mg/kg ip) has also been demonstrated to prevent sudden death in rats (100% of protection ; n=6) induced by a lethal dose (180 pg/kg iv) of U-46619. Our results suggest that BM 144. an original thromboxane A2 receptor antagonist which lost the diuretic properties of torasemide, is a new leader in the treatment of pathologies where an overproduction of thromboxane A2 is implicated, especially asthma and thrombosis.
61
S21
Assessment of Bronchodilator Response in 2 to 5 Year Old Children Gabriel Ortiz, PA-C, Jose Venzoc MD, Roger Menendez. MD Allergy and Asthma Research Center of El Paso, El Paso, TX. Wheezing and reversible airways disease are prevalent conditions among pre.-schoolaged children. As many as50% will have experienced a wheezing attack by age 6. Yet assessmentof airfow obstruction and response to therapy in this age group remain difficult and frought with technical difficulties. Of several techniques available for measuring resistance to airflow, forced oscillation remains the most adaptable to young children and most practical for clinic use.Advances in data processing has made possible the development of a system capable of obtaining estimatesof total respiratory resistance(as impedance) quickly (in seconds) and reproducibly (CV comparable to body plethysmography).One such system is the Jaeger MasterScreen. We have used the Jaeger MasterScreen Impulse Oscillometry System (IOS) to assessthe response of pre-school aged children to bronchomodulating drugs. We report here our results using albuterol MD1 delivered via a spacer device. We performed a single-blind, placebo controlled, crossover study in IO children aged 2 to 5 years with a history of reactive airways disease,who were not receiving regular asthma therapy. They withheld all bronchcdilators for at least I2 hours prior to study.All testing was started at 0900 * I hour. Testdays were separated by at least 7 days. The children were testedwhile seatedwith neck slightly extended, lips sealed around the mouthpiece and cheeks supported with both hands. Measurements were taken during tidal breathing while the child watched cartoons on a TV screen. The 10s technique has been well characterized by Klug. Landser. and others. Briefly, random oscillations of 5-35HZ are superimposed on tidal breathing for approximately 30 seconds. Real time recordings of the mouth pressure and flow signals are used to calculate total impedance (Zrs) and its two components,resistance.(Rrs) and reactance (Xrs), using FFT techniques and previously validated algorytbms contained in the software package.Since Xrs @J5Hz haslower intraindividual and between-individual variability than Rrs and correlates best with changes in PEV 1,this parameter is used to estimatedrug responses. Mean intraindividual variability in Xrs is 25% which is comparable to SRaw. A pre/post change in Xrs of 50% is considered significant. After baseline measurements,each child received, at random, either inhaled albuterol or an identical placebo. Measurements were repeated at 5,30, 60, and 360 minutes post-treatment The mean change from baseline (s.e.) in Xrs after placebo was 9.6(3.0), 10.1(2.6), 5.1(2.9), 6.1(3.5) at each time point (p=.36). The mean change from baseline(s.e.) after active treatment was 32.7(3.8), 53.9(1.2), 47.3(5.4), and 18.1(5.8), pcO.01 vs baseline at all time periods. We conclude that: a) this is a practical and reproducible way of assessingahway responses in this age group; b) that it is well-suited for clinical as well as therapeutic research use. Supported by a Clinical Applications Research Grant from GlaxoWellcome.