Ba 679 BR, a novel long-acting anticholinergic bronchodilator.

The use of anticholinergics in antiobstructive therapy is well established in pulmonary medicine. We sought to improve the duration of action of inhaled antimuscarinics. A newly developed compound, Ba 679 BR (abbreviated Ba 679) proved to be a highly potent muscarinic antagonist in guinea pig tracheal rings. Its binding to human receptors (Hm1, Hm2, Hm3) was characterized by KD-values in the 10(-10) M concentration range. Assessment of the dissociation rate of complexes of labelled Ba 679 and human muscarinic receptors revealed very slow dissociation in comparison to ipratropium. The half-lives in hours were: Ba 679-Hm3: 34.7, -Hm1: 14.6, -Hm2: 3.6; ipratropium-Hm3: 0.26, -Hm1: 0.11, -Hm2: 0.035. The duration of action in vivo was determined by means of acetylcholine-induced bronchospasms in dogs following inhalation of the drugs. Ba 679 demonstrated a significantly longer duration of protection than an equipotent dose of ipratropium. The plasma levels following inhalation in dogs declined rapidly and are unlikely to reflect the duration of the pharmacological activity. In summary, Ba 679 represents a novel type of antimuscarinic bronchodilator with a long duration of action, most likely due to its slow dissociation from Hm3-receptors. In addition, the drug showed "kinetic receptor subtype selectivity" by having a more rapid dissociation from Hm2 than from Hm1 and Hm3 receptors.

Bronchospasmolytic effect of oxitropium bromide following powder inhalation in anaesthetized dogs.

A marked and long-lasting bronchospasmolytic effect without any cardiovascular side effects has been demonstrated in anaesthetized dogs following inhalation of 0.1 mg oxitropium bromide, with glucose as vehicle, administered as powder in powder inhaler capsules.

His bundle electrography in the dog. Normal values and findings with verapamil.

An exact analysis of the intracardiac conducting system can be performed by the His bundle electrography. It allows a differential representation of individual parts of this system and, therefore, a more accurate determination of the site of action of compounds. Today this method belongs to the diagnostic routine in large cardiologic centres. However, His bundle electrography is seldom applied in experimental pharmacology. Our control values of 97 anaesthetized dogs under non-stimulated conditions are as follows: PA time = 41 +/- 1 ms, AH time = 66 +/- 2 ms, HV time = 37 +/- 1 ms; under stimulated conditions: PA = 40 +/- 1, AH = 88 +/- 2, HV = 36 +/- 1, QRS = 51 +/- 1 ms, sinus node recovery time (SNRT) = 1087 +/- 26 ms, corrected sinus node recovery time (CSNRT) = 370 +/- 17 ms, effective refractory period of the atrium = 267 +/- 8 ms, and of the AV node = 266 +/- 8 ms, functional refractory period of the atrium = 276 +/- 8 ms, and of the AV node 345 +/- 7 ms. With intravenous injections of 0.03 and 0.1 mg/kg verapamil, only a tendency to prolongation of the AH time, CSNRT and the refractory parameters was achieved. Immediately after 0.3 mg/kg verapamil given as i.v. injection or infusion over a period of 5 min, heart rate was increased and sinus node recovery time was shortened transitorily. After the rapid disappearance of these effects, AH time was prolonged while PA, HV and QRS remained unaffected, also under stimulated conditions. All refractory periods measured were prolonged significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological effects of a combination of fenoterol hydrobromide and ipratropium bromide.

The bronchospasmolytic and cardiovascular effects of fenoterol hydrobromide and ipratropium bromide alone and in combination were investigated using metered aerosols in guinea pigs and dogs and intravenous injection in dogs. The additive effect of the combination on bronchospasmolysis could be demonstrated. The slight cardiovascular side-effects of fenoterol hydrobromide alone were reduced to an insignificant level with the combination administered as a metered aerosol, but were still present when the combination was administered parenterally. Ipratropium bromide in both forms of administration had no effect on the cardiovascular system.

Metabolic effects of various beta-adrenoceptor blocking agents in rats and dogs.

Koe 3290 (N-[3-cyano-4-[3-[(1, 1-dimethyl-2-propynyl)amino]-2-hydroxypropoxy] phenyl]-2-methyl-propionamide), Koe 4299 (N-[3-cyano-4-(3-tert-butylamino-2-hydroxypropoxy)phenyl]-hexanamide+ ++ hydrochloride), Koe 4302 (N-[3-cyano-4-[3-[(1, 1-dimethyl-2-propynyl)amino]-2-hydroxypropoxy]phenyl]-hexanamid e hydrochloride) and the well-known compounds propranolol, bunitrolol, atenolol and acebutolol inhibit isoprenaline-stimulated increase of the concentration of free fatty acids (FFA) in the plasma of rats and dogs. In rats, most of the cardioselective blockers (Koe 3290, Koe 4299, Koe 4302, acebutolol) diminish isoprenaline-stimulated lactate, after s.c. injection, in a dose range higher than that required to reduce FFA. With the exception of atenolol, these substances show a relative selectivity between antilipolytic and antiglycolytic activity in favour of the antilipolytic effect. The non-cardioselective substances, propranolol and bunitrolol, either do not or only slightly differentiate between the inhibition of FFA and that of lactate. In dogs, after i.v. injection, only Koe 3290 and acebutolol have a relative metabolic selectivity similar to that seen in rats, but the other beta-adrenoceptor antagonists, with and without cardioselectivity, do not differentiate between the inhibition of isoprenaline-stimulated FFA, and that of lactate and glucose. In contrast, a greater antiglycolytic effect is often seen. Interspecies differences between the rat and the dog and variations among the drugs tested are discussed in detail. Koe 3290 is the only highly cardioselective drug with marked antilipolytic activity which markedly differentiates, in both rats and dogs, between the inhibition of FFA and carbohydrates. This substance, therefore, would appear to offer some additional advantages in the therapy of myocardial ischemia.

Pharmacological effects and determination of the morphological distribution of powder aerosols containing fenoterol hydrobromide and ipratropium bromide.

The bronchospasmolytic effects of fenoterol hydrobromide and ipratropium bromide, with some cardiovascular side effects by fenoterol, and the topographic morphological distribution of the powder aerosol particles in the respiratory tract were clearly demonstrated with the aid of ethidium-induced fluorescence in anaesthetised dogs.

[Asymmetrical synthesis of (R)(-) and (S)(+)-etilefrine by enantioselective hydrogenation and the effects of enantiomers in an animal experiment]. / Asymmetrische Synthese des (R)(-)- und (S)(+)-Etilefrins durch enantioselektive Hydrierung und die Wirkungen der Enantiomere im Tierexperiment.

The enantiomers of etilefrine (Effortil) were produced by enantioselective hydrogenation. The optical purity was determined by conversion with (+)-[(R)-tetrahydrofurfuryl-(1S)-camphor-10-sulfonate] to N-[(R)-tetrahydrofurfuryl]-etilefrine and subsequent separation of the diastereomers by HPLC. An animal experiment showed that the (R)(-)-enantiomer is more effective.

Haemodynamic and electrophysiologic actions of alinidine in the dog.

Alinidine (St 567, 2-[N-allyl-N-(2,6-dichlorophenyl)-amino]-2-imidazoline), the N-allyl derivative of clonidine which causes a specific bradycardia at the sinus node, has been investigated for cardiovascular effects. In a total of 7 mongrel dogs anaesthetized with piritramide and respirated with nitrous oxide 1.5 mg/kg alinidine was injected intravenously and 2 hr later, long before subsidence of the effects, a further dose of 3 mg/kg was given. Heart rate was reduced by both doses (-38, -50% of control) while arterial blood pressure decreased slightly only with 3 mg/kg (-13%). Cardiac output (thermodilution) was diminished (-33, -54%) and total peripheral resistance increased (+48, +101%). Simultaneously contractility (dp/dtmax.; -27, -46%), cardiac volume work (-34, -60%), tension time index (-23, -38%) and coronary sinus blood flow (electromagnetic flowmeter) decreased (-22, -48%). These results suggest a reduction in myocardial oxygen demand as is confirmed by the detection of reduced myocardial oxygen consumption (-14, -44%). Oxygen content of the coronary venous blood remained unchanged. In contrast to cardiac output and femoral artery flow (-37, -37%) renal blood flow was not affected. In another group of 9 dogs anaesthetized with pentobarbitone His bundle EG and ECG were reported. Alinidine (1.5 mg/kg i.v.) prolonged the A-H interval under spontaneous contraction (+65%) as well as at atrial pacing with 120 stimuli/min (+64%), thus pointing to a retarded AV conduction. Two hr after the drug administration bradycardia and A-H prolongation were still fully developed. The intervals P-A, H-V and the QRS complex were not influenced. In 4 further dogs atrial pacing rate was increased in stages up to 300 stimuli/min and the maximal ventricular follow frequency determined. Alinidine (1.5 mg/kg i.v.) reduced the maximal follow frequency from 215 to 125 beats/min (-43%). This effect is considered as a consequence of the retarded conduction in the AV node.