[Evaluation of efficacy and toxicity of docetaxel (Taxotere) in patients with advanced mammary gland cancer]. / Ocena skutecznosci i toksycznosci docetakselu (Taxotere) u chorych na zaawansowanego raka gruczolu piersiowego.

Twenty women with advanced breast cancer were treated with Docetaxel. In 50% of cases partial remission with median duration of 7.1 months was obtained. The median survival time was 18 months. Stabilization of disease with median duration of 5.5 months was obtained in 45%. The median survival in this group of patients was 15.3 months. The pervious antracycline-based chemotherapy did not influenced the results. The most common side effect was neutropenia (G3 in 80% of pts) and alopecia, but the chemotherapy tolerance was satisfactory.

[Evaluation of efficacy and toxicity of PC chemotherapy (cisplatin, cyclophosphamide) administered with amifostine in patients with clinically advanced ovarian cancer]. / Ocena skutecznosci i toksycznosci chemioterapii PC (cisplatyna i cyklofosfamid) podanej pod oslona amifostyny u chorych w róznym stopniu zaawansowania klinicznego raka jajnika.

Twenty patients with advanced ovarian cancer were treated with chemotherapy PC (cisplatin 100 mg/m2, cyclophosphamide 1000 mg/m2) administered with amifostine. Sixty five percent of patients had objective response with 25% complete response rate. Tolerance of treatment was satisfactory. Only in 1 patients side effects were the reason of treatment interruption. Amifostine markedly decreases chemotherapy toxicity, mainly hematological and does not seem to influence the efficacy of chemotherapy.

Antidepressant profile of 9-methyl-2[-3-(4-phenyl-1-piperazinylpropyl)]-1,2,3,4-tetrahydro-beta- carbolin-1-one (B-193).

A potential antidepressant activity of B-193 was studied in mice and rats. In in vitro studies B-193 did not affect the uptake of NA and 5-HT. In in vivo models the tested compound did not influence the reserpine-induced hypothermia, hypoactivity and ptosis, the stimulating action of L-DOPA, the apomorphine-induced hypothermia. On the other hand, it produced a positive effect in the despair test. When given repeatedly, it evoked adaptive changes in brain neurotransmitter receptors, i.e. it decreased the density of beta-adrenoceptors and increased the number of alpha 1 ones; those changes were accompanied with functional alternations in the reactivity of those receptors: an attenuated behavioral reaction to salbutamol and enhanced aggressiveness induced by a high dose of clonidine. Furthermore, B-193 administered repeatedly enhanced hyperlocomotion induced by amphetamine but did not influence the stereotypy induced by apomorphine. These results indicate that B-193 possesses properties characteristic for atypical antidepressants.

Antiserotonin activity of 9-methyl-2-[3-(4-phenyl-1-piperazinylpropyl)]-1,2,3,4-tetrahydro -beta-carbolin-1-one (B-193).

The effect of B-193 on the central and peripheral serotonin system was studied. B-193 antagonized the head-twitches responses induced by L-5-hydroxytryptophan (L-5-HTP) in mice (ED50 = 0.75 mg/kg ip and 6.6 mg/kg po) and lysergic acid diethylamide (LSD) in rats (ED50 = 1.54 mg/kg ip) and also counteracted forepaws clonic convulsions induced by tryptamine (ED50 = 3.07 mg/kg ip). B-193 (2.5-20 mg/kg ip) antagonized dose-dependently hyperthermia induced by fenfluramine or m-chlorophenylpiperazine (m-CPP) and in a dose of 1 mg/kg iv abolished the stimulation of the flexor reflex evoked by quipazine or fenfluramine. B-193 given in a concentration of 10(-7)-10(-5) mol/l competitively inhibited contractions of the rat stomach fundus strip induced by serotonin (5-HT) (pA2 = 6.5) and the increases in blood pressure induced by 5-HT in pithed rats (ED50 = 0.17 mg/kg iv). In receptor binding studies B-193 has shown distinct affinity to 5-HT2 receptors, and alpha 1-adrenoceptors much weaker affinity to 5-HT1 receptors and alpha 2-adrenoceptors but not to beta-adrenergic, GABA-ergic or benzodiazepine receptors. Our findings demonstrated that B-193 shows potent central and peripheral antiserotonin activity.

The anti-inflammatory and analgesic activity of N-3-pyridoyltryptamine (tryptamide).

In this study we compared the antiinflammatory and analgesic properties of N-3-pyridoyltryptamine (tryptamide, TRP) with those of standard non-steroid anti-inflammatory drugs (phenylbutazone, indometacin, piroxicam and ibuprofen). Antiinflammatory properties were investigated in the carrageenin-, serotonin-, kaolin-, formalin- and xylene-induced edema tests and in the cotton pellet granuloma test. The analgesic properties were studied in the writing, hot plate and electrical stimulation tests. In the majority of the applied tests TRP reveals the activity resembling this of phenylbutazone, and several times weaker than the effect of the remaining standard drugs. The ulcerogenic effect of TRP is very weak, and its effective doses are several times higher than these of the compared substances. Hence the therapeutic indices of TRP are several times higher than these of the other examined substances. The obtained results indicate that TRP is a putative anti-inflammatory and analgesic drug, much safer that other known substances with a similar pharmacological profile.

Synthesis and anticonvulsant properties of N-methylpyridyl derivatives of m- and p-bromophenylsuccinimides.

The reaction of m- or p-bromophenylsuccinic acids with 2-aminomethylpyridines yielded respective N-methylpyridylimides 1-8. Only compounds 1 and 6 show anticonvulsant activity in the pentetrazole and electric seizures tests, but their therapeutic index is inferior to that of ethosuximide and valproic acid.

1-Pyridyl-3,4-dihydro-beta-carbolines: synthesis and central action.

1-Pyridyl-3,4-dihydro-beta-carbolines (2a-2f) were synthesized by two methods. The central action of these compounds was investigated in mice and rats using behavioral tests. The most active 6-methoxy-1-(3-pyridyl)-3,4-dihydro-beta-carboline (2e) possesses potential antidepressant properties, as it reversed the effects of reserpine (sedation, hypothermia and ptosis), potentiated the stimulation induced by levodopa given jointly with pargyline, and reduced the immobility time in the despair test. Moreover, compound 2e inhibited the spontaneous locomotor activity, evoked tremor and produced an analgesic effect.

Synthesis and pharmacological investigation of compounds containing a 2-thioxopyrrolidine-4,5-dione moiety.

The synthesis of two Schiff bases of aryl methyl ketones and ethylenediamine 1c, 1d, symmetric adducts of aryl isothiocyanates with Schiff bases 2d-2m and 2-thioxopyrrolidine-4,5-dione derivatives 4d-4m obtained by condensation of oxalyl chloride with Schiff bases of aroylthioacetic acid anilides and ethylenediamine is described. Some of 13 investigated compounds 4a, 4b, 4d-4l, 5a, 5b of 2-thioxopyrrolidine-4,5-dione type showed sedative and analgesic action.

The pharmacological profile of chlordesmethyldiazepam and other benzodiazepines.

The pharmacological profile of chlordesmethyldiazepam was studied in mice and compared with that of other benzodiazepines (diazepam, lorazepam, clonazepam, nitrazepam, oxazepam, flunitrazepam, medazepam and chlordiazepoxide). All the drugs were administered perorally and their anticonvulsive activity (antagonism towards pentetrazole-induced clonic convulsions), anxiolytic action (the four-plate test), myorelaxant activity (the rota-rod test), sedative effect (inhibition of the locomotor activity) and neurotoxic effect (abolition of the righting reflex) were estimated. Chlordesmethyldiazepam revealed an anticonvulsive action (ED50 = 0.11 mg/kg), anxiolytic activity (MED = 2 mg/kg), myorelaxant action (ED50 = 17.5 mg/kg), sedative effect (ED50 = 34 mg/kg) and neurotoxic action (NTD50 = 190 mg/kg). Considering the potency of action (ED50) in respective tests and the therapeutic indices (NTD50/ED50 ratio), chlordesmethyldiazepam in respect of its profile resembles most lorazepam and diazepam.

Synthesis of 3-phenyl-3-phenylthiopropionic acids, amides, amines and studies on their pharmacological properties.

The addition of mercaptobenzene to cinnamic acids yielded 3-phenyl-3-phenylthiopropionic acids which were then converted to the amides. The latter compounds were reduced to the amines with lithium aluminum hydride. Some of the obtained amides displayed significant biological activity.

The central action of carbamazepine as a potential antidepressant drug.

Carbamazepine (CBZ) was studied in mice and rats with regard to its antidepressant activity. CBZ did not counteract hypothermia and ptosis induced by reserpine, hypothermia evoked by apomorphine, or sedation and hypothermia induced by clonidine. CBZ shortened the immobility time in the behavioral despair test in rats (but not in mice). It attenuated hyperactivity evoked by d-amphetamine, not affecting stereotypy induced by that drug. CBZ inhibited head twitches evoked by 5-HTP, as well as the hind limb flexor reflex of the spinal rat, having no effect on its stimulation by noradrenaline and 5-hydroxytryptamine agonists. CBZ administered repeatedly did not enhance clonidine aggressiveness or d-amphetamine locomotor hyperactivity, acting differently than many antidepressant drugs. The obtained results indicate that CBZ is not similar in its action to typical and many atypical antidepressants.

Synthesis and pharmacological properties of N-arylpiperazine-N'-alkylindanes.

Ten new compounds, N-aryl substituted piperazinealkylindanes, have been synthesized. The most active one 1-(2-[4-(3-chlorophenyl)-1-piperazinyl]-ethyl)-indane (compound 9), displayed evident central serotoninolytic properties in the 5-hydroxytryptamine (5-HTP) head twitch test in mice, as well as in the tryptamine convulsions test and the quipazine-stimulated hind paw flexor reflex test in rats.

Chemistry and anti-inflammatory activity of 10-methylamino-11H-indeno[1,2-b]quinolin-11-one (MB 432) derivatives.

The synthesis and properties of several derivatives of 10-methyl-amino- 11H -indeno[1,2-b] quinolin -11-one (MB 432) were described. New compounds were examined in carrageenin edema test in rats and writhing test in mice and compared to indomethacin and MB 432. The substitution in the rings of the indeno and quinoline parts deprived the compounds tested of a strong anti-inflammatory and analgesic properties characteristic of the parent system.

Synthesis and pharmacological properties of some 7H-[1] benzothiopyrano-[3,2-c] quinolin-7-ones.

The title compounds 3a-d were prepared by intramolecular cyclization of 2-[S-(quinolyl-4)]-thiobenzoic acids 2a-d. The effects of 3a-d on the central nervous system were tested. Among the investigated benzothiopyranoquinolinones, the 2-chloro-6-methyl-derivative (3c) showed analgesic activity in the hot-plate and the writhing tests in doses over 100 mg/kg. Among known, biologically active polycyclic heterocyclic systems [1], benzothiopyranoquinolinones with variously condensed heterocyclic rings, have received little attention. 7H-[1] Benzothiopyrano [3,2-c] quinolin-7-one (3a) is an example of one of the four possible isomers in such systems. In continuation of our search for new centrally active compounds [12], we report here the synthesis and characterization of the parent system 3a and its three derivatives 3b-d. Since some thioxanthene derivatives [9] are known to be neuroleptic drugs, and few known in literature compounds [2, 13, 20] derived from the 3a system have not been tested pharmacologically for the central nervous system activity, we decided to investigate the influence of [1]-benzothiopyranoquinolinones 3a-d on the central nervous system of mice. The results of pharmacological screening are presented in this paper.

Synthesis and pharmacological activity of some 2,3-dihydrofuran-2,3-dione derivatives.

New 2,3-dihydrofuran-2,3-dione derivatives (1-11) were obtained by condensation of oxalyl chloride with Schiff bases of acetyl- or benzoylacetone and aromatic amines. These compounds showed only weak sedative action and weak analgesic effect.