ABSTRACT
The present pharmacological test results characterize soquinolol (5-[3-tertiary butylamino-2-hydroxypropoxy]-2-formyl-1,2,3,4- tetrahydroisoquinoline mucate, We 704, Sertum) as a highly potent non-subtype-selective beta-adrenergic receptor blocker, which is devoid of any intrinsic sympathomimetic activity. Its localanaesthetic activity (membrane stabilizing effect) is very weak. It also shows good enteral efficacy and long duration of action. In binding studies with heart (Ki beta 1 = 3.25 nmol/l) and lung membranes (Ki beta 2 = 0.85 nmol/l) its binding profile was found to be similar to that of propranolol. Soquinolol inhibits the isoprenaline-induced tachycardia (EC50% = 48 micrograms/l) in the guinea-pig Langendorff heart in vitro to the same degree as propranolol. However, in the conscious dog soquinolol's beta 1-adrenergic blocking activity (ED 50%) on intravenous injection (5.5 micrograms/kg) and oral administration (5.8 micrograms/kg) is about twice as great as that of pindolol and 19 times (i.v.) or 138 times (p.o.) greater than that of propranolol. These results suggest 95% enteral efficacy for soquinolol (pindolol 88%, propranolol 13%). The differences in soquinolol's and propranolol's efficacy detected in vitro and in vivo are partially attributable to differences in their kinetic properties namely the lower protein binding and the higher distribution volume of soquinolol. In the conscious dog, soquinolol inhibits beta 1-(ED 50% = 4.0 micrograms/kg) and beta 2-receptors (ED 50% = 2.7 micrograms/kg) at dose levels which do not differ significantly.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Adrenergic beta-Antagonists/pharmacology , Isoquinolines/pharmacology , Tetrahydroisoquinolines , Adrenergic beta-Antagonists/metabolism , Animals , Binding Sites , Dogs , Guinea Pigs , Heart/drug effects , Isoproterenol/antagonists & inhibitors , Isoquinolines/metabolism , Lung/drug effects , Pindolol/pharmacology , Propranolol/pharmacology , Rats , Rats, Inbred Strains , Tachycardia/chemically inducedABSTRACT
Analytical methods of determination, investigations of stability and the behaviour of the substance in artificial gastric and intestinal fluids are the bases for the formulation of an oral preparation of 14-hydroxy-3beta-[4-O-methyl-alpha-L-rhamnopyranosyl)oxy]-14beta-bufa-4,20,22-trienolide (meproscillarin, Clift). The problems of developing a stable form, the maintenance of uniform content and the bioavailability are discussed.
Subject(s)
Cardiac Glycosides/administration & dosage , Administration, Oral , Biological Availability , Cardiac Glycosides/analysis , Chemical Phenomena , Chemistry, Physical , Densitometry , Drug Stability , Solubility , Spectrophotometry, Ultraviolet , Tablets , Time FactorsABSTRACT
The stability of bufadienolides in artificial gastric and intestinal fluids was investigated at different pH-values as a function of incubation time using proscillaridine, proscillaridine-3'-methylether and proscillaridine-4'-methylether. These glycosides were completely stable on pH 3.0--8.5 during the investigated time interval of 1 h. At lower pH-values cleavage of the glycosidic bond occurred. At pH 1.0 73% of proscillaridine, 33% of proscillaridine-3'-methylether and 41% of proscillaridine-4'-methylether were decomposed. At pH 2.0 only about 10% decomposition of these compounds could be detected. These experiments show that the stability of proscillaridine in gastric juice is comparable with the stability of digitalis glycosides and digoxin derivatives. The stability of methylated proscillaridine derivatives in artificial digestion fluids, however, proved to be superior to any orally administered cardiac glycoside.
