Development of tolerance to pethidine in rats, pretreated or not, with beta-naphtoflavone or SKF 525 A.

Tolerance to the analgesic effect of pethidine (PD) in rats, treated with a dose of 15 mg/kg of the compound twice daily at 12 h intervals for 1-3 weeks, was assessed using both, heat and current irritating stimuli. Tolerance could be detected earlier by the current irritating method, than by the hot plate technique. Pretreatment with beta-naphtoflavone did only slightly affect the development of tolerance to the antinociceptive effect of PD. In contrast after one week of treatment with SKF 525 A PD retained its analgesic effect. The prolonged pretreatment with SKF 525 A did not prevent the development of tolerance to the analgesic effect of PD.

Effects of pethidine on central neurotransmitters: changes in the state of tolerance.

Cerebral concentrations of neurotransmitters: noradrenaline, dopamine, serotonin and GABA were assayed in male Wistar rats receiving either a single dose of pethidine, or a prolonged treatment with the drug (twice daily for 21 days, im), leading to tolerance development. In tolerant rats the GABA content in the cerebral tissue was increased, and the activity of serotonergic system (assessed from the changes in 5-hydroxyindoleacetic acid level and serotonin turnover rate) was augmented.

Studies on cyproheptadine-amphetamine interaction after pretreatment with 6-hydroxydopamine.

6-hydroxydopamine (6-OH-DA) and cyproheptadine (CPH) exerted a lowering effect on blood amphetamine (AMPH) level in rats, at the same time the content of AMPH in the brain was elevated and the simultaneously recorded stereotypy was higher than in controls. After joint premedication with 6-OH-DA and CPH, however, no cumulative effect on AMPH brain level was seen, the highest AMPH elevation in whole brain as well as in corpus striatum occurred in animals premedicated with 6-OH-DA only. In spite of that, the highest stereotypy scores were noted after joint premedication with both substances. This may indicate that CPH premedication causes a rise in AMPH stereotypy mainly by pharmacodynamic interaction, though the elevation of the content of AMPH in the brain after CPH and 6-OH-DA must be of some influence as well. A further result is worth noting. After destroying peripheral adrenergic structures by 6-OH-DA a change from a two-compartment to a one-compartment model of AMPH kinetics occurred. This indicates that these structures may play the role of the second compartment or a part of it.

Development of tolerance to benzodiazepines. II. Baclofen effect on the activity of rats during tolerance to the sedative action of nitrazepam and oxazepam.

It was demonstrated that baclofen, a GABA-ergic agent, exerted a sedative effect in rats with tolerance to the sedative action of oxazepam and nitrazepam induced by administration of these drugs during several weeks. After one dose baclofen alone reduced the motor activity of rats without potentiating the effects of benzodiazepines. During long-term administration of baclofen tolerance developed also to its sedative action.

Pharmacokinetic aspects of habituation to benzodiazepines.

In state of tolerance to the sedative effect of nitrazepam (NTZ) its pharmacokinetic properties are changed: the absorption is slowed down, the elimination, in contrast, is accelerated due to the rapid biotransformation. The NTZ content in brain tissue is increased significantly with respect to the brain levels of animals treated with a single dose of NTZ. In animals of only moderate intensity of tolerance produced by oxazepam (OX) the brain concentrations of OX are correlated with the developed tolerance.

Development of tolerance to benzodiazepines. I. Changes in the systems of central nervous system neurotransmitters during long-term administration of nitrazepam.

A purpose of the study was determination of the relationships between the brain levels of neuro-mediators: noradrenaline (NA), dopamine (DA), 5-hydroxytryptamine (5-HT) and gamma-aminobutyric acid (GABA) and the development of tolerance to the sedative and anticonvulsive action of Nitrazepam. It was found that during tolerance development the GABA level increased in the cerebral tissue and changes appeared in the activity state of the serotoninergic system.

Interaction of parachlorophenylalanine, mianserine and danitracen with amphetamine.

Three antiserotonin compounds, p-chlorphenylalanine, mianserine and danitracen, were investigated for their influence on amphetamine stereotypy in correlation with concentration of this amine in blood serum and brain tissue. A positive correlation (decrease of stereotypy as well as the concentration of amphetamine in serum and brain) was found only for danitracen. p-Chlorphenylalanine and mianserine premedication decreased serum and brain tissue concentration of amphetamine, but enhanced amphetamine stereotypy effect. It is assumed that in the mixed pharmacodynamic-pharmacokinetic interaction in the case of mianserine and p-chlorphenylalanine the pharmacodynamic component (inhibition of the serotoninergic system in CNS) prevails, whereas in the case of danitracen the pharmacokinetic effect was superior.

Investigations on the interaction between cyproheptadine and amphetamine.

The effect of cyproheptadine (CPH) given in doses of 1.25 and 5 mg/kg intraperitoneally one hour before administration of D-(+)-amphetamine (AMPH) 5 mg/kg subcutaneously was studied. A moderate increase was observed in the intensity of amphetamine-induced stereotypy and a significant rise in the number of rearings after premedication with CPH 5 mg/kg. In pharmacokinetic investigations the serum level of AMPH was found to be decreased in the animals after CPH premedication. The biological half-time of AMPH in the blood was reduced after premedication with CPH 5 mg/kg. On the other hand, the level of amphetamine rose in the brain following premedication with CPH in both doses. These results suggest that the rise in brain AMPH level could be responsible for intensification of AMPH effects induced by CPH premedication.

Cystamine effect on the pharmacokinetics of imipramine in radiation sickness.

Investigations were carried out on the effect of cystamine premedication (100 mg/kg) before irradiation with 600 R on imipramine (40 mg/kg) kinetics in male Wistar rats. It was found that cystamine prevented changes in blood imipramine level in the irradiated animals but it protected additionally the process of drug elimination from the blood (T 1/2 beta in controls = 1.67 h, in irradiated = 2.38 h, in irradiated premedicated = 4.01 h).

Studies on the effect of cystamine on imipramine metabolism in radiation sickness.

Investigations were carried out for elucidating the effect of cystamine on the metabolism of imipramine in rats irradiated with a dose of 600 R. The investigations were based on determination of desmethylimipramine, the principal metabolite of this drug. It was found that cystamine reduced the serum imipramine level to control values but had no effect decreasing the level of desmethylimipramine. It caused also no fall in the concentration of this metabolite in brain tissue and even it raised this concentration. The authors explained these findings as a result of secondary resorption of desmethylimipramine into the blood stream, and a result of changed activity of beta-glucuronidase, these mechanisms being partly responsible for the overall effect.

Pharmacokinetic interaction of psychotropic drugs. I. Divergent effect of mianserin on pharmacokinetics and pharmacodynamics of amphetamine.

Pharmacokinetics of amphetamine and stereotypy caused by this drug was studied after premedication with two doses of mianserin (2 and 10 mg/kg). High doses of mianserin depressed the amphetamine level in blood and cerebral tissue and increased the stereotypy. The results suggest that the potentiation of the action of amphetamine by mianserin is mainly due to pharmacodynamic synergism and depends on the blockade of central serotonergic receptors by mianserin.

Pharmacodynamics and pharmacokinetics of psycholeptic drugs in the course of radiation disease. Effect of premedication with metanabol on dynamics and kinetics of nitrazepam.

The effect of metanabol given to rats before irradiation (600 R) on exploring motility and cataleptic action of nitrazepam was investigated. The level of nitrazepam in the blood plasma and urine was determine. Most evident radioprotective effect of metanabol was found on 3rd day after irradiation. The drug inhibited the inhibited the increased response of the rats to the anticonvulsive action of nitrazepam and prevented the pharmacokinetic disturbances appearing in the course of radiation disease.

Pharmacodynamics and pharmacokinetics of psycholeptic drugs in the course of radiation disease.

The effect of metanabol (1 mg per kg) applicated to rats during 10 days before irradiation (600 R) on pharmacodynamics and some indices of thioridazine kinetics was investigated. It was found that the increased cataleptic action of thioridazine (20 mg per kg), during radiation disease was inhibited ater metanabol premedication. The protective effect of metanabol was found to be due to shortening of the half-life time of thioridazine (from 5.5 h in irradiated to 2.38 h in irradiated premedicated animals) as well as to lowering of thioridazine content in the brain tissue.

Pharmacodynamics and pharmacokinetics of psycholeptic drugs in the course of radiation disease. The effect of premedication with cystamine on pharmacodynamics and Pharmacokinetics of nitrazepam.

Pharmacodynamics and pharmacokinetics of psycholeptic drugs in the course of radiation disease (I). Effect of premedication with cystamine on pharmacodynamics and pharmacokinetics of nitrazepam. Acta Physiol. Pol. 1977, 28 (2): 161--168. In the experiments carried out on rats the radiation disease was evoked by exposure to 600 R. The strongest radioprotective action of cystamine was found on the 3-rd day of radiation disease. The tendency to normalization of both the pharmacodynamics (exploring mobility and anticonvulsant action) and pharmacokinetics of nitrazepam in the animals premedicated with cystamine was described.

Changes in pharmacodynamics and pharmacokinetics of psycholeptic drugs in the course of radiation disease. Effects of premedication with cystamine on dynamics and kinetics of thioridazine.

Changes in pharmacodynamics and pharmacokinetics of psycholeptic drugs in the course of radiation disease. Effect of premedication with cystamine on dynamics and kinetics of thioridazine. Acta Physiol. Pol. 1977, 28 (2): 169--179. The effect of premedication with cystamine (100 mg/kg) applied before irradiation (600 R) on exploring mobility and cataleptic action of thioridazine was investigated in rats. The levels of thioridazine in blood serum, brain tissue and in bile were determined. It was found that cystamine prevents the changes in dynamics of thioridazine action in radiation disease through abolition of disturbances in kinetics of this drug. Half-life period of thioridazine was found to be reduced and its level in the brain tissue was diminished in the irradiated, cystamine-pretreated animals in comparison with the irradiated, untreated ones.

Influence of cystamine on pharmacokinetics and pharmacodynamics of nitrazepam.

The influence of cystamine on pharmacokinetics of nitrazepam was studied. Experiments were performed on the third day after the administration of cystamine, since the author's previous investigations showed that the protective action of cystamine in radiation sickness was strongest at this time. CA premedication resulted in more rapid resorption, lower level of nitrazepam in blood, and more rapid elimination of the drug.

Influence of disorders of adrenal function of activity and pharmacokinetics of some neurotropic drugs. I. Influence of adrenalectomy on potency and pharmacokinetics of drugs.

The influence of disorders of adrenal function on pharmacodynamics and biotransformation of selected neurotropic drugs was studied. Pharmacodynamic activity of salicylamide, morphine and hexobarbital were investigated. Pharmacokinetic parameters of salicylamide and hexobarbital were determined.

Influence of adrenal dysfunction on activity and pharmacokinetics of some neutropic drugs. II. Influence of chronic premedication with dexamethasone on pharmacodynamic activity and pharmacokinetics of drugs.

The influence of long-term administration of dexamethasone on pharmacodynamic activity and biotransformation of salicylamide and hexobarbital, including their absorption, distribution and excretion, were studied. Activities of the following enzymes were also determined: beta-glucuronidase (E.C.3.2.1.31), uridinediphosphoglucose dehydrogenase (E.C.1.1.1.22), uridinediphosphoglucuronyl transferase (E.C.2.4.1.17), uridinediphosphoglucuronic pyrophosphatase (E.C.3.6.1.9), and hexobarbital oxidase.