[New analgesically-active N'-acylated phenylpiperazines]. / Neue analgetisch wirksame N'-acylierte Phenylpiperazine.

Synthesis and pharmacodynamic properties of new analgesic active N'-acylated phenylpiperazines are described. 1-(3-Cyclohexyl-1-oxo-propyl)-4-(2-ethoxyphenyl)-piperazine (D 16 120) possesses strong non-opiate antinociceptive activity showing high therapeutic margin with respect to undesired side effects and toxicity.

[The pharmacologic effect of flupirtine, a structurally new analgesic]. / Untersuchungen zur pharmakologischen Wirkung von Flupirtin, einem strukturell neuartigen Analgetikum.

The analgesic potency of ethyl-N-[2-amino-6-(4-fluorophenylmethylamino)pyridin-3-yl]carb ama te (flupirtine, D 9998) in mice and rats in Haffner's test, electro-pain test and Randall-Selitto test (inflammation induced pain) lies between the more potent dextromoramide and methadone and the more weakly active pethidine, dextropropoxyphene, codeine, phenacetin and paracetamol. In comparison to codeine flupirtine is up to 4 times more potent, up to 2 times more active than pethidine and 4 times more potent than dextropropoxyphene in the above-mentioned methods. With one exception of inflammation induced pain, where flupirtine shows an activity of about 1 1/2 times that of phenacetin and paracetamol, both analgesics are about 10 to nearly 30 times less active than flupirtine in other above-mentioned tests. In the hot plate test flupirtine is twice as active as codeine and approximately 10 times more active than phenacetin and paracetamol. The weakest analgesic activity of flupirtine is seen in acetic acid test where it is about half as active as codein and approximately as active as dextropropoxyphene. Nevertheless, flupirtine is up to 10 times more potent than phenacetin and paracetamol. The acetic acid test is claimed to be non-specific according to our own experience and to other authors. Flupirtine is enterally absorbed at a higher degree than the other tested centrally acting analgesics. In regard to the results of various analgesic investigations in mice and rats flupirtine can be classified as a medium to strong acting analgesic. The duration of action of flupirtine is comparable to that of codeine. Experiments with flupirtine suggest that there are some convincing criteria for a pronounced central acting component of its analgesic activity. These criteria are the strong efficacy in the hot-plate and Haffner's test, in which only centrally acting analgesics show distinct effects, and the finding that flupirtine increases the pain threshold for vocalisation in rats and mice excluding a pure reflex of the spinal cord. In current experiments concerning the mode of action flupirtine exhibits a distinct central analgesic component of action. In spite of its relatively high analgesic potency which corresponds to that of opiates flupirtine does not show any other signs of opiate properties and other potent analgesics. Thus, flupirtine does not develop tolerance in mice and rats after 19 or 17 days of daily administration.(ABSTRACT TRUNCATED AT 400 WORDS)

[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.

[Pharmacokinetics and biotransformation of the analgesic flupirtine in the rat and dog]. / Untersuchungen zur Pharmakokinetik und Biotransformation des Analgetikums Flupirtin bei Ratte und Hund.

Pharmacokinetics and biotransformation of 14C-labelled ethyl-N-[2-amino-6-(4-fluorophenylmethylamino)pyridin-3-yl]carbama te maleate (flupirtine maleate, D 9998 maleate) was studied in rats and dogs. The drug was rapidly and completely absorbed after peroral administration in both species. The kinetics of the plasma levels after intravenous administration show a short distribution phase followed by an elimination phase with half-lives between 2 and 3 h. Similar half-lives were observed after peroral administration: 2.2. h in the rat and 2.6 h in the dog. Renal excretion amounts to 20% (rat) and 36% (dog) after i.v. administration, and to 22% (rat) and 35% (dog) after p.o. administration. The major part of the dose is excreted via the feces. The drug is reversibly distributed to the tissues. Similar concentrations appear in the well perfused organs. A brain/plasma concentration ratio of greater than or equal to 1 was found and is a favourable prerequisite for a centrally acting analgesic. Insight in the biotransformation pathways of 14C-flupirtine maleate was obtained by structure determination of urinary metabolites. The urinary radioactivity of the rat consisted practically exclusively of p-fluoro-hippuric acid that is generated by an oxydative metabolic degradation of flupirtine. Dog urine, too, contains this metabolite, however, accompanied by the drug excreted unchanged and by a further metabolite structurally still very similar to flupirtine. The latter metabolite is formed via acetylation of an in vivo hydrolysis product of flupirtine and retains 1/4 of the analgesic potency of flupirtine. Regarding the patterns of excretion and of biotransformation the dog represents an intermediate between rat and man.

[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.

A method for induction of cold, indomethacin and restraint ulcers in rats.

A new method has been developed for producing gastric ulcers in rats. The rapid induction of gastric lesions was achieved by a combination of the administration of indomethacin in addition to cold and restraint stressors. Ulcer indices were easily reproducible and remained constant. In addition, atropine, cimetidine and an antacid were tested for their antiulcerogenic effects with the same model. All three drugs inhibited ulcer development in a dose-dependent manner.

Synthesis of orally active cardiosteroid derivatives.

Starting from hellebrigenin, orally cardiotonic active acylcardiosteroid derivatives have been synthesized. D 12316 (acrihellin), the hellebrigenin-3 beta-dimethylacrylate, has been chosen for clinical evaluation.

[Human pharmacokinetics of theophylline and etofylline from different formulations of a cardiotonic (author's transl)]. / Zur Humanpharmakokinetik von Theophyllin und Etofyllin aus verschiedenen Zubereitungen eines Kardiotonikums.

Serum concentrations of theophylline and etofylline were analysed by a specific HPLC-method in 6 volunteers after i.v. and p.o. administration of the cardiotonic Cordalin ampoules, drops and dragees. Maximum serum concentrations were reached by theophylline an etofylline at about the same time: 1.0-1.2 h after Cordalin drops; 2.3-2.6 h after Cordalin dragees. The half-life of serum elimination was 5.0-7.2 h for theophylline and 5.5-6.9 h for etofylline. The absolute bioavailability of the two oral formulations was calculated from the areas under the serum curves. For theophylline it is complete from the dragees and 78% from drops. Etofylline, too, is highly bioavailable: 94% from the dragees, 84% from drops. From the kinetic data the conclusion can be drawn that accumulation of theophylline and etofylline will be negligible after Cordalin if administered according to prescribed directions.

[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.

[New cerebrally active basic dithienyl compounds (author's tranls)]. / Neue zerebral wirksame basische Dithienyl-Verbindungen.

A review on new cerebrally active basic dithienyl compounds related to (+)-(R)-alpha-((S)-1-[(3,3-di-3-thienylallyl)amino]-ethyl)-benzylalcohol (tinofedrine) is presented. Tinofedrine was selected out of a large number of related compounds on account of its high increase of cerebral blood flow, its improvement of heart performance, of the metabolism of the brain, and because it is well toleraded. Different routes of synthesis are discussed.

Does gastrin (pentagastrin) act directly on the parietal cell in the isolated whole stomach of the mouse?

Acid secretory effect of pentagastrin and compound 48/80 was studied in the isolated whole stomach of the mouse. Acid secretory response to compound 48/80 was inhibited by cimetidine, indicating histamine involvement in this reaction. Acid secretion stimulated by pentagastrin was not diminished after pre-treatment with compound 48/80 suggesting that gastrin releases non-mast cell histamine. Secretory response to pentagastrin was reduced in Ca++-free serosal media but not to histamine and compound 48/80. A possible pathway of gastrin will be discussed.

Distention ulcer as a model for testing of drugs for ulcerogenic side effects.

A modification of the distention ulcer was studied in albino rats and a new possibility of testing ulcerogenic side effects of drugs was described. The distention alone was not sufficient to produce lesions. The severity of ulcer lesions was highly dependent on the volume of the acid solution. Large volumes of 0.1 N HC1 evoked severe ulcers within 1 h. Small amounts of weak acid solution did not cause any ulceration. Anti-inflammatory drugs administered in therapeutic doses, which did not yet produce any ulcers in animals, increased the sensitivity of the gastric mucosa against the aggresive factor, the acid. In animals pretreated by anti-inflammatory drugs in toxic doses an earlier development of ulceration was observed by distention with acid. Stress also accelerated and aggravated the formation of distention ulcers.

[Treatment of distortions and non-traumatic conditions of pain and swelling. Double-blind trial with an analgetic and detumescent drug combination]. / Zur Behandlung von Distorsionen und nicht-traumatisch bedingten Schmerz-und Schwellungszuständen Doppelblind-Versuch mit einer analgetisch und abschwellend wirksamen Substanz-Kombination.

A combination of specifically detumescent and analgesic/antiphlogistic substances (Dolo Mobilat film tablets) was tested in a double-blind study against placebo. The active product brought about very good or good therapeutic results in approximately 78% of 50 patients suffering from distortions of joints and from painful inflammation and swelling of non-traumatic origin; the corresponding percentage obtained with the placebo was 34%. Separate evaluations of pain and swellings most relevant for their homogeneity in distortions of joints showed rates of 80% and 31%, respectively. These differences as to efficacy are highly significant (p less than 0.001). There were no symptoms of intolerance except some sporadic mild gastric complaints. In comparison with the experience made with analgesics and antiphlogistics in oral therapy the action and tolerance were judged as very good.

[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.

[The influence of tinofedrine on cerebral energy metabolism in normotensive, hypotensive and hypoxemic rats after carotis ligation (author's transl)]. / Einfluss von Tinofedrin auf den zerebralen Energiestoffwechsel von normotonen, hypotonen und hypoxämischen Ratten nach Carotis-Verschluss.

l-(+)-alpha-(1-[(3,3-Di-3-thienylallyl)amino]-ethyl)-benzyl alcohol hydrochloride (tinofedrine hydrochloride, D 8955, Novocebrin), a new cerebrally active substance, synthetized in our research laboratories, was investigated for its action on the disturbed cerebral metabolism in rats. By variation of the arterial blood pressure (normal, 100 and 70 mmHg), and O2-concentration for the artificial ventilation of 30 or 15 vol% and carotis ligation for 15, 30 and 60 min different degrees of cerebral disturbances could be induced. The glucose concentration and energy state of the brain were used as criteria of the degree of cerebral disturbance. After intravenous injection of tinofedrine such a disturbed cerebral state could be normalized partially or completely.