Pharmacological evaluation of ifosfamide and its enantiomers in laboratory animals.

Some pharmacological properties of commercial racemic ifosfamide (Holoxan) and its D- and L-enantiomers were compared in experiments on mice and rats. Although values of acute toxicity and some results of subchronic treatment revealed better parameters of L-form in comparison to racemic mixture, distinct hepatotoxic effects and thrombocytopenia noted in the course of prolonged treatment seem to be the important factors limiting therapeutic usefulness of levorotatory form.

comparison of pharmacological properties of cyclophosphamide and its enantiomers.

Comparison of pharmacological properties of commercial racemic Cyclophosphamide and its D- and L-enantiomers was performed in experiments on mice and rats. Acute toxicity, behavioral screening tests and the effects of subchronic treatment (influence on body mass, the increase of the mass of internal organs, mortality, morphology of peripheral blood, biochemical investigations of blood plasma, microscopic evaluation of liver and bladder) were taken into account. Summarized results revealed the most pronounced toxicity of D-cyclophosphamide.

Comparison of subacute toxicity of rubidomycine and its four derivatives.

In experiments carried out on Albino-Swiss mice we tried to compare some pharmacological properties of standard compound-rubidomycin with its 4 newly synthetized derivatives. DR-16 appeared to be more toxic compound than rubidomycin and DR-19 was found to possess the lowest toxicity.

Comparison of some properties of rubidomycine and its four derivatives.

In the experiments performed on Albino-Swiss mice and Wistar rats it was found that newly synthesized anthracyclines were less toxic and possessed similar pharmacological properties as rubidomycine. Only in some tests their activity was weaker or sometimes different.

A role of some central neurotransmitter systems in the mechanism of electroconvulsive shock action.

Behavioral effects of electroconvulsive shock (ECS) on the neurotransmitter systems were studied in relation to the mechanism of action. Repeated ECS, applied to rats, enhanced the behavioral response to dopaminergic, serotonergic and opiate agonists and attenuated the behavioral effects to GABA-ergic antagonists. The same ECS schedule did not significantly alter the behavioral response to alpha 2- and beta-adrenergic agonists and apomorphine-induced stereotypy but significantly potentiated haloperidol-induced catalepsy.

Phosphonic analogues of excitatory amino acids raise the threshold for maximal electroconvulsions in mice.

2-Amino-5-phosphonopentanoic acid (100 and 200 mg/kg) and 2-amino-7-phosphonoheptanoic acid (50-200 mg/kg i.p.) significantly elevated the threshold for maximal electroconvulsions in mice, the latter being more effective in this respect.

Modification of the anticonvulsant activity of 2-amino-5-phosphonovalerate by agents affecting different neurotransmitter systems.

The effects of atropine (5 mg/kg), baclofen (10 mg/kg), gamma-hydroxybutyrate (300 mg/kg), gamma-butyrolactone (100 mg/kg) and muscimol (1 mg/kg) upon the action of 2-amino-5-phosphonovalerate (APV; an antagonist at receptors for N-methyl-D-aspartate) on the threshold current for seizures induced by electroshock, were studied in mice. Neither APV, up to 100 mg/kg, nor the other agents produced any significant increase in the convulsive threshold when tested alone. Muscimol had no effect on the action of APV (50 and 100 mg/kg) and the combination of APV with the subthreshold doses of atropine, baclofen, gamma-hydroxybutyrate and gamma-butyrolactone resulted in a clearcut anticonvulsant action.

Preliminary pharmacological investigation on 38 aminophosphonic acids and their derivatives.

Central pharmacological properties of 38 aminophosphonic acids and their derivatives, mostly newly synthesized, were investigated on mice and rats. Acute toxicity, neurotoxic activity, influence on spontaneous locomotor activity, body temperature, electrogenic and pentetrazol convulsions, on cerebral GABA level were tested. The most active compounds were (in a decreasing order of activity): 2-amino-7-phosphonoheptanoic, 2-amino-5-phosphonovaleric, 2-amino-8-phosphonooctanoic, 2-amino-2-methyl-3-methylphosphonopropionic, and 3-amino-3-hydroxy-5-phosphonovaleric acid.

The effect of stimulation and blocking of histamine H2 receptors on the turnover of the serotonin in different parts of the alimentary tract and the brain of the rat.

In the experiments performed on Wistar rats it was found that histamine (0.05 and 0.5 mg/kg i.

Effects of electroconvulsive shock on central GABA-ergic mechanisms.

A single electroconvulsive shock (ECS) has no influence on seizures induced by picrotoxin and bicuculline, although it decreases the level of GABA in the cortex. A repeated ECS (once daily for 7 days) does not change the level of GABA in the cortex, brain stem, and cerebellum, but depresses seizures induced by both compounds. It prolongs the time of their occurrence and decreases their intensity.

Effects of morphine and naloxone on pilocarpine-induced convulsions in rats.

Systemic administration of morphine hydrochloride (MF; 5-80 mg/kg; i.p.) in rats enhanced the epileptogenic potential of pilocarpine hydrochloride (PIL) in a dose-dependent manner.

Injections of picrotoxin and bicuculline into the amygdaloid complex of the rat: an electroencephalographic, behavioural and morphological analysis.

Bicuculline methiodide (0.5-3 nmol) and picrotoxin (0.5-4 nmol) were injected uni- or bilaterally into the rat amygdala and the resulting behavioural, electroencephalographic and morphological alterations were studied.

Effects of pentagastrin and oxyphenonium on the levels of serotonin and 5-hydroxyindoleacetic acid in different parts of the digestive tract, blood and brain of rats.

In the experiments of Wistar rats it was found that pentagastrin in a dose of 0.6 microgram/kg decreased the level of serotonin and increased that of 5-HIAA in the stomach wall, and in a dose of 3 micrograms/kg it had no effect on these parameters, while in a dose of 6 micrograms/kg it decreased only the serotonin level. Oxyphenonium 0.

Effects of excitatory amino-acid antagonists on the anticonvulsant action of phenobarbital or diphenylhydantoin in mice.

The effects of L-glutamic acid diethyl ester (GDEE), D,L-alpha-aminoadipic acid (alpha-AA) and D,L-2-aminophosphonovaleric acid (APV) on the anticonvulsant action of phenobarbital and of diphenylhydantoin were studied in mice against electroconvulsions. Anticonvulsants were administered intraperitoneally 60 min and amino-acid antagonists 30 min before the test, by the same route. Neither GDEE (up to 400 mg/kg) nor alpha-AA (up to 100 mg/kg) were found to affect the seizure threshold whilst APV (100 and 200 mg/kg) raised the threshold moderately from 6.

Effects of histamine and H1 and H2-receptor antagonists on wet-dog-shake episodes in rats induced with tranylcypromine and 5-methoxytryptamine.

Intraperitoneally administered tranylcypromine and 5-methoxytryptamine induced in rats the so called wet-dogs-shake behaviour. Histamine injected intraventricularly had no effect on the number or episodes of this behaviour during the first 40 minutes of observation. On the other hand, dimaprit in doses of 5 micrograms/rat injected also intraventricularly increased the number of these episodes.

Effects of histamine and H1 and H2-receptor antagonists on the wet-dog-shaking episodes in rats induced with lithium chloride.

In the experiments carried out on Wistar rats it was demonstrated that histamine administered intraventricularly had no effect on the number of wet-dog-shaking episodes induced with lithium chloride. Thenalidine and antazoline, antagonists of the H1 receptor, and cimetidine and ranitidine, antagonists of the H2 receptor reduced the number of shaking episodes proportionally to the dose. These results may suggest that the reduction of the number of shaking episodes induced with lithium chloride was connected with blockade of histamine receptors, although an indirect effect of H1 and H2-receptor antagonists on the serotoninergic and cholinergic systems cannot be ruled out.

Effects of histamine and cimetidine on the levels of serotonin and 5-hydroxyindoleacetic acid in various parts of the digestive tract and in the blood and brain of rats.

In the investigations on male Wistar rats it was demonstrated that histamine (0.05 and 0.5 mg/kg) decreased the serotonin level, without affecting the level of 5-HIAA in the stomach and duodenum.

Differential effects of baclofen, gamma-hydroxybutyric acid and muscimol on the protective action of phenobarbital and diphenylhydantoin against maximal electroshock-induced seizures in mice.

This study was designed to compare the effects of baclofen (a GABAB agonist), muscimol (a GABAA agonist) and gamma-hydroxybutyric acid on the protective action of phenobarbital (PB) and diphenylhydantoin (DPH) against electroshock-induced convulsions. All drugs were given intraperitoneally, muscimol being also injected intraventricularly in a dose of 50 ng per mouse. It was found that both baclofen and gamma-hydroxybutyric acid potentiated the anticonvulsant activity of phenobarbital, being ineffective regarding the action of diphenylhydantoin.