[Pharmacokinetics of Taurolin]. / Uber die Pharmakokinetik von Taurolin.

In order to study the pharmacodynamics of taurolin (4,4'-methylene-bis(tetrahydro-2H-1,2,4-thiadiazine-1,1-dioxide) we labelled the substance in two different ways. 3*T contained 3 atoms of 14C, of which one served as a methylene bridge between the two ring systems. 4*T was labelled with 4 14C-atoms, two for every ring within the taurinamide part. Radioactivity was counted in blood, urine, faeces and expiration air of rats. For this purpose both labelled drugs were administered p.o., i.v. and i.p. After using 3*T radioactivity was excreted mainly by expiration, independently of the way of administration. The blood radioactivity diminished very slowly after a first short period. After administration of 4*T radioactivity was found mainly in the urine and only a small portion in the expiration air. Blood radioactivity diminished here very quickly. These results were confirmed by whole-body autoradiographic studies using 3*T as well as 4*T. No plasma-binding was found using the 4*T compound.

[Testing the pharmacological activity of some synthetic cannabinoids in mice (author's transl)]. / Prüfung der pharmakologischen Wirkung einiger synthetischer Cannabinoide an der Maus.

A series of synthetic cannabinoids were tested in mice for analgesic, anticonvulsant, sedative and reserpine antagonistic properties as well as for influence on body temperature and on motor coordination and compared with the natural delta 9-tetrahydrocannabinol (delta 9-THC), delta 8-tetrahydrocannabinol (delta 8-THC) and cannabidiol (CBD). All cannabinoids were injected s.c. or i.p. in mice as solutions in olive oil. The synthetic cannabinoids, with the exception of the lipophilic ones, were less active than the natural delta 9-THC. 1',1'-dimethyl-delta 8-tetrahydrocannabinol (DM-delta 8-THC) has an analgesic ED 50 of 16 mg/kg s.c. (writhing test) and is three times more active than delta 9-THC, but also eight times less active than morphine. The lipophilic derivatives of delta 8-THC prolonged pentobarbitone narcosis and diminished locomotor activity in mice. Anticonvulsant activities could never be detected; all cannabinoids slightly diminished body temperature and antagonized weakly the hypothermia induced by reserpine. The trained capacity of remaining on the rotating rod was severely shortened for a long time after application of all cannabinoids but mainly by the lipophilic ones. The influence of derivation on the activity of delta 9-THC is discussed.

3-Chloro-4-(phenylsuccinimido)-benzenesulfonamide (GS 385), a new anticonvulsant: its quantitative determination, pharmacokinetics and metabolism using high performance liquid chromatography.

A high-performance liquid chromatographic method (HPLC) involving dual wave length detection was developed for the determination of a new anticonvulsant, 3-chloro-4-(phenylsuccinimido)-benzenesulfonamide (suclofernide, GS 385, Sulfalepsin), and three of its metabolites: 3-chloro-4-(p-hydroxyphenylsuccinimido)-benzenesulfonamide (I), 3-chloro-4-(3'-phenylsuccinamyl)-benzenesulfonamide (II) and 3-chloro-4-(2'-phenylsuccinamyl)-benzenesulfonamide (III). The concentrations of GS 385 in blood samples from epileptic patients under chronic treatment with this drug was found in the range of 8--11 micrograms/ml. Pharmacokinetic curves of GS 385 blood levels in rats receiving single doses of the drug showed a maximum concentration of 22--23 micrograms/ml 1.5 h after oral application. The quantity of GS 385 in rat feces, bile and brain was also estimated. The p-hydroxy (I) and acid (II, III) metabolites of GS 385 were detected in both rat feces and bile, whereas only the acid metabolites were found in rat urine.

[Development of new antiepileptics. IV. Anticonvulsant activity of some derivatives of 1-(p-sulfamoyl-phenyl)-pyrrolidin-2-one (author's transl)]. / Die Entwicklung neuer Antiepileptika. IV. Antikonvulsive Wirkung einiger 1-(p-Sulfamoyl-phenyl)-pyrrolidin-2-on-Derivate).

A series of derivatives of 1-(p-sulfamoyl-phenyl)-pyrrolidin-2-one were tested for anticonvulsant properties in rats and mice. The substance 1-(o-chloro-p-sulfamoyl-phenyl)-4-phenyl-pyrrolidin-2-one (1725) was found to have potent anticonvulsant activities in rats and mice against seizures induced by electroshock or pentylenetetrazol. The unsubstituted phenyl ring has to be in position 4, otherwise the activity of the product is weakened. The ortho position of the halogen atom on the N-phenyl is also important for the anticonvulsant effect; chlorine acts better than fluorine. The anticonvulsants tested also potentiate the sleeping time induced by pentobarbitone and attenuate the motor activity of mice. 1-(o-Chloro-p-sulfamoyl-phenyl)-4-phenyl-pyrrolidin-2-one (1725) has a LD50 of 1000 mg/kg p.o.; the lesser active substances generally have a LD50 greater than 5000 mg/kg p.o. Toxic effects of large doses were manifested by sedation and diarrhoea.

[Development of new antiepileptics. V. Pharmacological activity of some derivatives of sulfanilamide (author's transl)]. / Die Entwicklung neuer Antiepileptika. V. Mitteilung: Pharmakologische Wirkungen einiger Sulfanilamidderivate.

9 derivatives of sulfanilamide were tested for anticonvulsant properties against electroconvulsive shock in mice and rats and against pentylenetetrazole shock in mice. Reference standard in these tests was sulfanilamide. Their toxic, analgesic and sedative activities were also examined. The anticonvulsive activity of sulfanilamide could be enhanced by substitution of the phenyl ring with a halogen atom. Substitution of the sulfonamide group diminishes the anticonvulsant and increases the sedative activity of sulfanilamide. Detoxication of the basic substance by substitution of the aromatic amino group only little influences the anticonvulsant activity and may even enhance it. Of the tested substances, 1742 (3-chloro-4-phenacetamido-benzene-sulfonamide) exhibited the best anticonvulsant activity; slightly weaker was PB 311 (3-chloro-4-amino-benzene-sulfonamide). The ED50 for the activity against electroconvulsive shock of both substances was about 30 mg/kg p.o. in mice. The relationship between anticonvulsant activity and inhibition of the renal and cerebral carbonic anhydrase is discussed.

[Anticovulsant activity of N-(p-sulfamoyl-phenyl)-succinimide derivatives (author's transl)]. / Die Entwicklung neuer Antiepileptika. I: Antikonvulsive Wirkung von N-(p-Sulfamoylphenyl)-succinimid--Derivaten.

A series of newly synthesized N-phenyl-substituted derivatives of succinimide were screened for anticonvulsant activity. Addition of a sulfonamide group in the p-position was of great consequence for the anticonvulsant effect. Substitution of a halogen in the m- or o-position improved activity against electroshock induced seizures. Pentylenetetrazole convulsions could only be prevented by few of these substances in smaller than 200 mg/kg oral doses. Activity could be further enhanced by adding more aliphatic or aromatic groups to the succinimide ring. The lethal doses of most of the active succinimides were higher than 5000 mg/kg p.o. With sublethal doses mice sometimes become drowsy and had myoclonic seizures and/or diarrhoea. At therapeutic dose levels kinetic disturbances, potentiation of pentobarbitone hypnosis or analgesia were rarely observed.

[Development of new antiepileptics. II. Anticonvulsant effect of hydantoin derivatives]. / Die Entwicklungen neuer Antiepileptika. Teil II: Antikonvulsive Wirkung einiger Hydantoin-Derivate.

From a series of N-substituted hydantoin derivatives, 1-phenyl-3-(o-chloro-p-sulfonamide-phenyl)-hydantoin was found to exhibit the best anticonvulsant activity against electroshock seizures. This substance showed also a weak activity against pentylenetetrazole seizures, as well as minor analgesic and sedative effects. The toxic effects are negligible; the lethal dose in mice was higher than 5000 mg/kg p.o. The other tested hydantoin derivatives showed much weaker anticonvulsant activities.

[Development of new antiepileptic agents. III. Anticonvulsant activity of some derivatives of 1-(p-sulfamoylphenyl)-imidazolidinone-5 (author's transl)]. / Die Entwicklung neuer Antiepileptika. III. Antikonvulsive Wirkung einiger 1-(p-Sulfamoylphenyl)-imidazolidinon-5-Derivate).

A series of derivatives of 1-(p-sulfamoylphenyl)imidazolidinone-5 were tested for anticonvulsant properties against electroshock and pentylenetetrazole seizures. They were also screened for analgesic, sedative and toxic effects. The substances that had the best anticonvulsant activities were those with halogen substitution in the ortho position of the 1-phenylring of 1-(p-sulfamoylphenyl)-3-phenylimidazolidinone-5. Additional substitutions on the basic structure (imidazolidinone-5) or on the 3-phenylring diminished the anticonvulsant activity. The anticonvulsants are less toxic than diphenylhydantoin. Some of the substances exhibited feeble analgesic and sedative properties.

MODIFICATION OF FOOD CHARACTERISTICS WITH CELLULOSE HYDROCOLLOIDS I: Rheological Characterization of an Organoleptic Property (Unctuousness).

A number of common foodstuffs and cosmetics including butter, margarine, cheese spreads, toothpaste and an ointment have been examined in steady and oscillatory shear using the Weissenberg Rheogoniometer in order to investigate the rheological parameters giving rise to the textural property of unctuousness. Products judged organoleptically to be unctuous exhibit the characteristic rheological behavior of a modified Bingham body. It is shown that certain types of sodium carboxymethyl-cellulose (CMC) form gels which are unctuous and which enhance the unctuousness of food materials. Rheological characteristics of unctuousness are discussed in detail and the development of this property by certain CMC gels is interpreted in terms of molecular and super-molecular properties of the polymer.