FÜR ÖSTERREICH: Weitere Informationen: Merck Gesellschaft mbH, Zimbagasse 5, 1147 Wien, Tel.: 01/576 00-0
Abbildung 0

CIBIS II - Cardiac Insufficiency Bisoprolol Study
Abbildung 1: Bisoprolol fumarate (2:1) is a racemate and as a derivative of phenoxyaminopropa-nol it belongs to the class of therapeutic substances known as ß-blockers. Bisoprolol fumarate is very freely soluble in water and freely soluble in ethanol and chloroform. The molecular weight is 383.48, the white crystalline substance melts at 101°C.


Keywords: Betablocker,  Bisoprolol,  CIBIS-II,  Concor,  Studie

CIBIS II - Cardiac Insufficiency Bisoprolol Study - Objectives
Abbildung 2: Bisoprolol proved to be the compound with the highest ß1-selectivity in all in vitro and in vivo studies and in all animal species investigated. One measure of ß1-selectivity is the ratio of the constants of inhibition (ci) for the ß1- and ß2-receptor. The constants of inhibition of the ß-blockers bisoprolol, atenolol, betaxolol and propranolol were determined in ligand-binding studies using rat parotid gland (mainly occupied by ß1-receptors) and rat reticulocytes (mainly occupied by ß2-receptors) in human plasma: using a non-specific radiolabelled ligand, the ß1- and ß2-receptors of the rat parotid gland and reticulocytes were completely occupied. This cell suspension was then mixed with the plasma of volunteers pretreated with different ß-blockers. The non-specific radioligand was now displaced from the receptor by addition of this serum enriched with ß-blockers. Constants of inhibition of a characteristic magnitude for each ß-blocker and receptor type could be determined from these tests; the smaller the ci-value, the higher the affinity of the ß-blocker for the receptor type concerned. The ratio of ci/ß1 to ci/ß2 was 1:75 for bisoprolol, 1:35 for atenolol and betaxolol, 1:20 for metoprolol, and 1.8:1 for propranolol. Bisoprolol therefore proved to be the ß-blocker with the highest ß1-selectivity in this model as well.


Keywords: Betablocker,  Bisoprolol,  CIBIS-II,  Concor,  Studie

CIBIS II - Cardiac Insufficiency Bisoprolol Study - Main inclusion criteria
Abbildung 3


Keywords: Betablocker,  Bisoprolol,  CIBIS-II,  Concor,  Einschlusskriterien,  Studie

CIBIS II - Cardiac Insufficiency Bisoprolol Study - Design
Abbildung 4: Receptor occupancy detected by an in vitro incubation of plasma samples with a ß-adrenoceptor preparation allows for a prediction of the relative extent of ß-adrenoceptor antagonistic effects in man. In this study the time course of plasma concentration after a single oral dose of 100 mg of bisoprolol - a dosage far beyond the therapeutic dose range - was compared with the ß-adrenoceptor occupancy of the two adrenoceptor subtypes in an ex-vivo/in-vitro assay. 24 hours after the administration of 100 mg bisoprolol, there was no longer any ß2-adrenoceptor occupancy detected in the plasma samples. Up to that time, plasma levels far exceeded the normal therapeutic range. Therefore an occupancy of the ß2-receptors is practically not to be expected under therapeutic conditions. 36 to 60 hours after a single oral dose of 100 mg of bisoprolol, plasma concentrations similar to a steady state condition after once daily dosage of 10 mg were found. At an 80 % occupancy of ß1-receptors, there was no occupancy of ß2-receptors seen with bisoprolol, whilst under 200 mg of atenolol (slide 4) when there was a maximum occupancy of ß1-receptors of 80%, 25% of ß2-receptors were occupied as well. Occupancy of the ß1-receptors with bisoprolol is in the range of approximately 80-30 % for the therapeutic dose range of 5-10 mg.


Keywords: Betablocker,  Bisoprolol,  CIBIS-II,  Concor,  Design,  Studie

CIBIS II - Cardiac Insufficiency Bisoprolol Study - Characteristics (I)
Abbildung 5


Keywords: Betablocker,  Bisoprolol,  CIBIS-II,  Concor,  Patientencharakteristik,  Studie

CIBIS II - Cardiac Insufficiency Bisoprolol Study - Characteristics (II)
Abbildung 6


Keywords: Betablocker,  Bisoprolol,  CIBIS-II,  Concor,  Patientencharakteristik,  Studie

CIBIS II - Cardiac Insufficiency Bisoprolol Study -Survival
Abbildung 7


Keywords: Betablocker,  Bisoprolol,  CIBIS-II,  Concor,  Diagramm,  Studie,  Ãœberleben

CIBIS II - Cardiac Insufficiency Bisoprolol Study - Analysis of time to death
Abbildung 8


Keywords: Betablocker,  Bisoprolol,  CIBIS-II,  Concor,  Diagramm,  Mortalität,  Studie

CIBIS II - Cardiac Insufficiency Bisoprolol Study - Secondary endpoints
Abbildung 9


Keywords: Betablocker,  Bisoprolol,  CIBIS-II,  Concor,  sekundärer Endpunkt,  Studie

CIBIS II - Cardiac Insufficiency Bisoprolol Study - Mortality by baseline findings
Abbildung 10


Keywords: Betablocker,  Bisoprolol,  CIBIS-II,  Concor,  Diagramm,  Mortalität,  Studie

CIBIS II - Cardiac Insufficiency Bisoprolol Study - Main results at a glance
Abbildung 11


Keywords: Betablocker,  Bisoprolol,  CIBIS-II,  Concor,  Hospitalisation,  Mortalität,  Resultat,  Studie

CIBIS II - Cardiac Insufficiency Bisoprolol Study - Conclusions
Abbildung 12


Keywords: Betablocker,  Bisoprolol,  CIBIS-II,  Concor,  Resultat,  Studie