Pharmacologic properties of some derivatives of N-(2-carboxyphenyl)-4-phenoxyacetamide.

Three new inhibitors of prostaglandin (PG) synthetase: N-(2-carboxy-4-chlorophenyl)-phenoxyacetamide (ZR 29), N-(2-carobxy-4-chlorophenyl/-bromophenoxyacetamide (ZR-32), N-(2-carboxy-4-chlorophenyl)-4' - nitrophenoxyacetamide (ZR-35), in doses of 30-100-200 mg/kg p.o. inhibited edema in an acute inflammatory model, ZR-32 inhibited formation of granuloma. In the chronic inflammatory model, ZR-32 exerted strongest activity in the second and third weeks. ZR-32 demonstrated strong analgesic activity in the test of stimulation with electric current and in the "hot plate" test, besides antipyretic activity. Both compounds weekly irritated the gastric mucosa. In the tests applied, these compounds had no effect on the CNS. Their acute to toxicity was substantially lower than that of acetylsalicyclic aid and indomethacin.

A native whole blood test for the evaluation of blood-surface interaction: determination of thromboxane production.

The method developed to evaluate the hemocompatibility of artificial materials involves the determination of thromboxane production during the clotting of rabbit blood, in test tubes of different materials. The concentration of serum TXB2 obtained after incubation of whole blood in glass test tubes, for 40 min at 37 degrees C, averaged 416.8 +/- 23.3 ng/ml (mean +/- SE). Polymethylpentene, recognised as having a relatively poor blood compatibility, elicited 309.5 +/- 17.2 ng/ml of serum TXB2, while silicone and Avcothane, considered of better hemocompatibility, showed thromboxane levels of 276.2 +/- 28.2 and 222.9 +/- 31.5 ng/ml, respectively. These values validate the usefulness of the proposed method as a preliminary in vitro screening test of artificial materials intended for biomedical application.

[Synthesis and biological properties of various amino alcohol derivatives of xanthone]. / Synteza i wlasciwosci biologiczne niektórych aminoalkoholowych pochodnych ksantonu.

In the search for pharmacologically active derivatives of xanthone there were obtained amino alcohol derivatives of 2 methylxanthone (I-V). Effects of compounds Ia, IIa, III and IVa on the circulatory system were investigated.

Synthesis and pharmacological properties of new N-aminoalkyl-2-pyrrolidinone derivatives.

The paper describes the mode of obtaining and physico-chemical properties of new 1-(beta-hydroxy-gamma-aminopropyl)-2-pyrrolidinone derivatives and their antiarrhythmic effect and the action on the circulatory system.

Antiinflammatory activity of the new aminomethyl derivatives of 1-cyclohexyl-5-alkyl and 1-cyclohexyl-5,5-dialkylbarbituric acids.

Several new aminomethyl derivatives of barbituric acid were evaluated pharmacologically. 1-Cyclohexyl-5-piperidylmethyl-5-allylbarbituric acid and 1-cyclohexyl-3-morpholinomethyl-5,5-diallylbarbituric acid displayed antinflammatory activity in the carrageenin-edema and xylene-tests but did not produce analgesia. It has been also found that introduction of aminomethyl groups into the antiinflammatory barbituric derivatives brings about elevation of the resorption of the tested compounds.

Pharmacological properties of 3-aminoalkyl and amide derivatives of 5,5-diphenylhydantoin.

5,5-Diphenylhydantoin derivatives containing at the position 3 aminoalkyl (1, 2, 4, 5), aminohydroxyalkyl (3) and amide (6, 8) groups were synthesized. The compounds, given in a dose of 50 mg/kg, did not affect cardiac bioelectric activity and, in contrast to diphenylhydantoin, did not possess the antiarrhythmic properties and did not protect against pentetrazol seizures.

The effect of some 8-aminoalkanol derivatives of theophylline on cardiovascular system.

Novel 7,8-disubstituted theophyllines 1-6a, with chiral or achiral moiety of 1,2-aminoalcohol in position 8, were obtained as the compounds with expected activity on circulation. Preliminary evaluation of their antiarrhythmic activity and the effect on the cardiovascular system was carried out. The antiarrhythmic activity similar to that of quinidine (with ca. 20 times lower toxicity) was found only for racemic 7-beta-hydroxyethyl-8-(1'-hydroxybut-2'-yl) aminotheophylline 1 and its enantiomers 2, 3 which did not differ markedly in their efficacy. The compounds with the hydroxyethyl moiety in position 7 of theophylline (1-3, 5) showed the hypotensive effect.

Comparative studies on the amino acid derivatives of indometacin.

A series of amino acid derivatives of indometacin (IND) was investigated in regard to their protein binding and prostaglandin synthetase inhibition in vitro, and to acute toxicity, anti-inflammatory, antiedemic, analgesic actions, and the influence on the central nervous system in vivo. In biochemical tests the compounds were several times less potent than IND. They differed among themselves in the respect of toxicity, which was always much lower than that of IND. Out of eight compounds investigated N-IND-glycine (K1) and N-IND-epsilon-aminocaproic acid (K5) exerted more favorable antiedemic and analgesic action than IND did. Both the derivatives only weakly inhibited the cotton-pellet granuloma formation. K1 acted similarly to IND in the arthritis test. K1, K5 and IND similarly irritated the gastric mucosa. A modification of IND structure by introduction of glycine or epsilon-aminocaproic acid resulted in two new anti-inflammatory agents of more favorable therapeutic index in the antiedemic and analgesic action and of much lower toxicity than the reference compound.

Synthesis and some biological properties of 2-xanthonylalkyl-(alkoxy) carboxylic acids.

2-Xanthonylacetic acids 5a-5d and alpha-methyl-2-xanthonyloxyacetic acid 8 were obtained as potential anti-inflammatory compounds. Preliminary evaluation was carried out for anti-inflammatory and analgesic activity of acids 5a, 5c and 5d and for inhibition of blood platelets aggregation by compounds 5a-5d and 8. In the inhibition of carrageenin-induced rat edema the highest activity shown by acids 5a and 5c was similar to that of ketoprofen.

Synthesis and pharmacological properties of phenoxyethylpiperazine derivatives.

Salts of new 1-phenoxyethylpiperazines 1-5, their 4-amidine derivatives 6-10 and 4-phenoxyacetyl derivatives 11-15 have been obtained. Some of them were screened for their cardiovascular activity.

Synthesis of amide derivatives of 5,5-diphenylhydantoin as potential antiarrhythmic agents. I.

5,5-Diphenylhydantoin derivatives containing amide groups at the position 3 were synthesized as potential antiarrhythmic agents. The most valuable was (X) whose antiarrhythmic activity is stronger than that of phenytoin.

New derivatives of amino alcohols with antiarrhythmic activity.

Nine new N-acyl derivatives of 2-amino-1-alcohols and 1-amino-2-alcohols with a potential arrhythmic activity have been obtained. In the preliminary screening 2-[N-(7-theophyllineacetyl)-amino]-2-methyl-1-propanol, 5, was more active in the chloroform-induced arrhythmia than quinidine. Unlike to propranolol and quinidine, compound 5 in doses of 5-30 mg/kg, iv, did not prevent distortions of the cardiac rhythm evoked by adrenaline and strophanthine. When administered at the peak of arrhythmia, it did not abolish disturbances of the cardiac rhythm. Compound 5 had a low toxicity (LD50 = 3000 mg/kg, ip), did not change the control ECG curve, showed no cardiodepressive activity, and had weaker local anesthetic properties than lignocaine.

In vitro effects of mercury on platelet aggregation, thromboxane and vascular prostacyclin production.

Mercuric chloride [25-50 micrograms/ml platelet-rich plasma (PRP)] lowers the threshold concentration of arachidonic acid (AA) required for triggering rabbit platelet aggregation and causes a marked increase of thromboxane production. The metal, added as HgCl2, does not modify (50 micrograms/ml PRP) or block (100 micrograms/ml PRP) the platelet aggregation wave induced by a normal aggregating dose of AA. Whether or not AA-induced platelet aggregation takes place, a large increase in thromboxane production is observed. Methyl mercury, assayed as reference drug, induces platelet aggregation and a significant increase of thromboxane levels. Finally, HgCl2 and methyl mercury, in a concentration range of 0.125-0.5 micrograms/microliters in the incubation liquid, induce an increased prostacyclin release from rat aortic tissue.

Cyclohexyl analogues of some antiinflammatory drugs.

Some new compounds containing cyclohexyl substituents, with a structure similar or analogous to that of traditional antiinflammatory drugs, were synthesized and their antiinflammatory activity was investigated. The strongest activity was shown by alpha-(p-cyclohexylphenyl)-gamma-valerolactone W 8.

Antioxidants as agents reducing the toxicity of indomethacin.

Simulataneous oral administration of butylhydroxytoluene (BHT) (50 or 100 mg/kg) with indomethacin (IND) (3, 6 or 20 mg/kg) prevented the damaging effect of IND on the rat gastric mucosa. Butylhydroxyanisole (BHA) and nordihydroguiaretic acid (NDGA) rather potentiated than prevented the noxious action of IND. A reduction of IND toxicity without affecting its anti-inflammatory action seems to be possible to achieve by concomitant administration of IND with BHT.

Antioxidants as agents potentiating the antiinflammatory action of indomethacin.

Nordihydroguaiaretic acid inhibits prostaglandin (PG) biosynthesis in vitro (ID50=228 muM), with a slope of dose-response curve high (b=209) as compared with indomethacin (ID50=0.1 muM, b=72.1). Butylated hydroxyanisole, in contrast to inactive butylated hydroxytoluene, inhibits PG biosynthesis (ID50=107 muM, b=63). Only norihydroguaiaretic acid (100 mug, s.p.) inhibited the postcarrageenin edema of rat paw. Butylated hydroxyanisole (10 mug, s.p.) given together with a subthreshold (1 mug) dose of indomethacin inhibited the paw edema by 35%, while butylated hydroxytoluene and nordihydroguaiaretic acid produced a similar effect only when given at 10-fold higher doses. The results suggest the possibility of potentiation and prolongation of the anti-inflammatory effect of indomethacin by its simultaneous administration with an antioxidant, butylated hydroxyanisole.

Platelet responsiveness and biosynthesis of thromboxane and prostacyclin in response to in vitro cocaine treatment.

Preincubation of rabbit platelet-rich plasma with cocaine hydrochloride, at low and high concentrations, increased the platelet responsiveness to arachidonic acid, in terms of the aggregating response and the thromboxane production. The thromboxane levels released by collagen-stimulated platelets were increased after incubation with low concentrations of cocaine, while marked decreases were observed after incubation with high doses of cocaine. No effects on platelet aggregation induced by collagen and ADP were observed when low concentrations of cocaine were added; on the other hand, high doses of the anaesthetic were found to block the aggregating effects of these two agents. Specific studies showed cocaine to have an inhibitory activity on prostacyclin release when the aortic tissue was mechanically and thermically stimulated. By contrast, the prostacyclin synthesis by 'exhausted' aortic rings incubated with arachidonic acid appeared to be enhanced after addition of cocaine. These results lead us to believe that cocaine modifies both the Ca++ membrane binding and the extent of Ca++ influx, thereby increasing the permeability to arachidonic acid and altering the affinity of the membrane binding sites for the aggregating agents.