Effect of recombinant neutral endopeptidase (EC 3.4.24.11) on neuropeptide-mediated nasal fluid secretion and plasma exudation in the rat.

The nasal mucosa harbors sensory nerves containing neuropeptides such as substance P (SP), which are released by capsaicin. The neuropeptides are degraded by peptidases, e.g., neutral endopeptidase (NEP) that is present in the nasal mucosa. We studied the effect of enzymatically active recombinant NEP (rNEP) on neuropeptide-evoked secretion of nasal fluid and plasma exudation in rats. rNEP administered intranasally (i.n.) reduced the capsaicin-evoked nasal fluid secretion but failed to reduce the secretion evoked by SP (exogenous) under the experimental conditions used. rNEP reduced the increase in nasal plasma exudation evoked by capsaicin (endogenous neuropeptides). Because rNEP reduced neuropeptide-mediated nasal fluid secretion and plasma exudation in the rat, we suggest that peptidase activity in the nasal mucosa will determine the magnitude of the response to locally released neuropeptides.

Influence of azelastine and some selected drugs on mucociliary clearance.

The effect of azelastine and some selected compounds on ciliary beating frequency (CBF) was investigated in vitro using human mucosal samples and in vivo using anesthetized guinea pigs. Further influence of azelastine on mucus secretion was evaluated in mice and on mucociliary clearance in anesthetized rabbits. Azelastine influenced the ciliary beating frequency neither in vitro nor in vivo. Azelastine, similarly to salbutamol, ambroxol, and bromhexine, increased mucus secretion measured by the tracheal output of phenol red. Azelastine dose-dependently enhanced mucociliary clearance measured by elimination of 99mTc-labeled erythrocytes in rabbits. The activity of azelastine proved to be about 10 times stronger than that of bromhexine. Since the ciliary activity remained unchanged under the influence of azelastine, it is likely that azelastine increases the mucociliary clearance by enhancing bronchial secretion. It is possible that the observed increase in mucociliary clearance may contribute to the beneficial effect of azelastine in the treatment of respiratory diseases.

Protective property of azelastine against histamine challenge of rhinal mucosa in domestic pigs.

In anaesthetized domestic pigs a filter paper sampling technique was applied to estimate basal and histamine induced nasal secretion. Histamine (0.2 mg/nostril) increased secretion more than twofold, a dose of 2 mg/nostril more than 10 fold. Intranasally instilled azelastine (A-5610, CAS 58581-89-8) prevented this histamine induced rhinorrhea without reduction of basal secretion. The protective effect remained for more than 2 h even when histamine challenge was repeated.

Influence of various adrenergic compounds on plasma potassium levels in conscious dogs and anaesthetized domestic pigs.

The influence of various compounds with affinity to beta-adrenoceptors on plasma potassium levels was investigated in conscious dogs and anaesthetized pigs. There was a marked fall, amounting to about 1 mmol/l following salbutamol and pirbuterol but nearly no effect following dobutamine and xamoterol. In dogs the hypokalaemic effect of salbutamol was augmented when prazosin was additionally applied. It is concluded, that the plasma potassium level is reduced mainly by beta 2-adrenoceptor stimulation. Blocking of alpha-adrenoceptors enhanced this effect and should therefore be avoided when beta 2-agonists are used therapeutically.

Effects of the novel beta-adrenergic partial agonist alifedrine on cardiac performance in dogs with acute ischemic left ventricular failure.

Acute ischemic left ventricular failure was induced in dogs by coronary embolization with plastic microspheres, resulting in reduced cardiac output (CO), increased left ventricular end-diastolic pressure (LVEDP), pulmonary capillary pressure (PCP), and total peripheral resistance (TPR). Intravenous (i.v.) administration of alifedrine, a beta-adrenergic partial agonist (0.3 mg/kg as bolus and 0.3 mg/kg/h as infusion), significantly improved performance of the failing heart. Left ventricular contractility was increased up to 50%, heart rate (HR) up to 28%, and CO up to 30%. LVEDP, PCP, and TPR were markedly decreased. Myocardial oxygen consumption was increased only to a minor degree despite the positive inotropic effect; coronary flow was augmented up to 26%. Thus, alifedrine in this model markedly improved left ventricular function by balanced stimulation of the myocardium and reduction of pre- and afterload.

Young domestic pigs for the cardiovascular assessment of inotropic drugs. Comparison with dogs.

A comparison is made of cardiovascular response to cardiotonic drugs in young domestic pigs and dogs, and the use of pigs as an alternative to dogs in cardiovascular investigations is described.

[General pharmacologic studies on the analgesic flupirtine]. / Allgemeine pharmakologische Untersuchungen mit dem Analgetikum Flupirtin.

In the present study the general pharmacological properties of ethyl-N-[2-amino-6-(4-fluor-phenylmethylamino)pyridin-3-yl]carbama te (flupirtine, D 9998), a structural new analgesic, are described. In several tests with mice flupirtine shows a centrally depressant component of action. However, regarding undesirable side effects as ataxia, inhibition of motor activity etc. this action is, with respect to the analgesic effective doses less pronounced than those of comparable analgesics, for instance phenacetin. In relatively low doses flupirtine antagonizes tremor induced by oxotremorine in mice. This activity is probably not caused by a central anticholinergic action, because other anticholinergic effects have not been observed. It should be pointed out that flupirtine antagonizes the morphine-induced tail phenomenon in mice in relatively low doses. This action obviously differentiates flupirtine from opiates. Up to high doses flupirtine does not cause catalepsia in mice, consequently its centrally depressant activity does not resemble that of reserpine and also is not comparable with those of neuroleptic agents. The corneal and pinnal reflexes are not influenced by flupirtine and the righting reflex is slightly delayed in high doses. The anticonvulsive activity of flupirtine observed in the pentetrazol shock test (mouse) after high doses probably cannot be considered to occur within the analgesic dose range. Inhibition of amphetamine toxicity in mice observed in doses near the hypnotic doses may be caused by non-specific effects. In vitro tests with isolated trachea or ileum of guinea pigs show that flupirtine possesses no or very weak antagonism against histamine-induced spasms. In spasms caused by barium chloride flupirtine shows a weak musculotropic-spasmolytic activity. Investigations on the circulatory system of dogs do not indicate any incompatibilities with flupirtine. No evidence of antiarrhythmic activity was found in rats. Flupirtine has no local anesthetic activity in mice but some weak effects on the cornea of rabbits. Like several other analgesics flupirtine shows in rats a reversible antidiuretic action including sodium and chloride retention which is of relatively short duration and is not observed in long-term studies in rats and dogs. In contrast to many stronger antiinflammatory compounds, flupirtine does not possess ulcerogenic activity in rats up to high doses. A minimal inhibition of intestinal motility (mouse) is observed only in doses higher than the analgesic effective doses.

[The pharmacology of a new cardiosteroid, a partially synthetic derivative of the aglycone hellebrigenin (acrihellin)]. / Zur Pharmakologie eines neuen Kardiosteroids, einem partial-synthetischen Derivat des Aglykons Hellebrigenin (Acrihellin).

3 beta,5,14-Trihydroxy-19-oxo-5 beta-bufa-20,22-dienolide 3-(3-methylcrotonate) (acrihellin, D 12 316) is according to chemical structure and pharmacological effects a semisynthetic compound of the aglycon hellebrigenin. It is characterized as a cardiosteroid. In isolated organ (Langendorff heart) the positive inotropic effect proved to be stronger in comparison to digoxin. Also in dogs and cats acrihellin increases the contractile force of the myocardium; especially in failing canine heart, it increases the force of contraction (strain-gauge) and velocity of pressure rise (dp/dt max). In classical glycoside test on cat (Hatcher's dose) acrihellin is more effective than digoxin and methyldigoxin on weight basis, equivalent on a molar basis. The therapeutical index of acrihellin is like that of methyldigoxin. In cats and dogs, the compound is absorbed rapidly and almost completely, especially when administered intraduodenally. Herein it is comparable to methyldigoxin, better than digoxin. In cats acrihellin shows a decay rate of 26%. In all investigations performed in order to study central nervous effects after single administration of therapeutical doses no central side-effects could be detected in contrast to methyldigoxin.

[Investigations on the general effects of tinofedrine on heart and blood circulation (author's transl)]. / Untersuchungen zur allgemeinen Herz- und Kreislaufwirkung des Tinofedrin.

In anesthetized dogs, (+)-(R)-alpha ((S)-1-[(3,3-di-3-thienylallyl)amino]-ethyl)-benzylalcohol hydrochloride (tinofedrine hydrochloride, D 8955) causes a remarkable increase of cardiac output by positive inotropic and chronotropic stimulation of the heart and simultaneous reduction of peripheral vascular resistance. The effect is antagonized by beta-adrenergic blocking drugs. In comparison with typical beta-agonists (e.g., orciprenaline) tinofedrine at inotropically equieffective doses, has a much weaker effect on the heart rate. Measurement of tissue blood flow by radioactive tracer microspheres after tinofedrine exhibited a rather homogeneous increased perfusion in all parts of the brain, as well as myocardium, kidneys and liver. In coronary circulation tinofedrine causes vasodilation so that in a therapeutic dose range increased work load is equalized by a sufficient myocardial supply. Tinofedrine itself neither caused a disturbance of heart rhythm nor worsened aconitine-induced arrhythmias in anesthetized rats. Simultaneous application of digoxin or diazepam did not influence the action of tinofedrine; there was no evidence of any incompatibility of such combinations. Experiments with a possible metabolite (l-norephedrine) showed that it is not involved in the action of tinofedrine.

[Pharmacological effect of tinofedrine on cerebral and peripheral hemodynamics in the dog (author's transl)]. / Pharmakologische Wirkung von Tinofedrin auf die zerebrale und periphere Hämodynamik des Hundes.

l-(+)-alpha-(1-[(3,3-Di-3-thienylallyl)amino]-ethyl)-benzyl alcohol hydrochloride (Tinofedrine, D 8955, Novocebrin), a new drug, synthetized in our research laboratories, has been tested in dogs with regard to the improvement of cerebral and peripheral blood flow. Direct electromagnetic flow measurement at the vertebral artery as well as 133xenon wash-out method showed a strong and long-lasting increase of cerebral and femoral blood flow following intravenous as well as oral administration. No decrease of activity was observed after repeated intravenous application. Comparative studies with several standard drugs of the same field of indication proved a remarkable superiority of tinofedrine in our experimental conditions.

[Compound with bronchospasmolytical activity from the chemical class of beta-phenylethyl-aminoalkyl-xanthines (author's transl)]. / Pharmakologische Untersuchungen der neuen Substanz Reproterol mit bronchospasmolytischer Wirkung aus der Substanzklasse der beta-Phenyläthyl-aminoalkyl-xanthine

1. 7-(3-[2-(3,5-Dihydroxyphenyl)-2-hydroxy-ethylamino]-propyl)-theophylline (reproterol, D 1959, Bronchospasmin) was developed as a bronchospasmolytic agent from the structure class of the phenylethyl-aminoalkyl-xanthines. 2. The pharmacological effects characterize reproterol as a bronchospasmolytic with preferential impact on the adrenergic beta2-receptors. 3. In the therapeutic dose range, reproterol stands out because of its nearly non-existent cardiovascular or central nervous side effects. Effects of over and above pharmacodynamically effective doses as well as toxic ones may be reversed with beta1-receptor blockers.