Testing efficiency transfer codes for equivalence.

Four general Monte Carlo codes (GEANT3, PENELOPE, MCNP and EGS4) and five dedicated packages for efficiency determination in gamma-ray spectrometry (ANGLE, DETEFF, GESPECOR, ETNA and EFFTRAN) were checked for equivalence by applying them to the calculation of efficiency transfer (ET) factors for a set of well-defined sample parameters, detector parameters and energies typically encountered in environmental radioactivity measurements. The differences between the results of the different codes never exceeded a few percent and were lower than 2% in the majority of cases.

Effect of enkephalin analogues Tyr-D-Ala-Gly-Phe-Cys(Et) and Tyr-D-Ala-Gly-Phe-Cys(Bu) on prolactin and growth hormone release in rats.

The effect of natural Met-enkephalin and its analogues Tyr-D-Ala-Gly-Phe-Cys(Et) (I) and Tyr-D-Ala-Gly-Phe-Cys(Bu) (II) on serum rat prolactin and rat growth hormone levels in male rats has been studied. Met-enkephalin and both analogues increased serum growth hormone and prolactin concentration, analogue I being the most potent. Enkephalin analogue I, with isosteric isomer of methionine in Met-enkephalin, and analogue II with butyl residue showed a lower stimulatory effect than natural Met-enkephalin. Stimulatory effect of analogues I and II on prolactin and growth hormone release was found to be reversed by a simultaneous treatment with the opiate antagonist naloxone.

Binding characteristics of the dopamine agonist/antagonist [3H]terguride (transdihydrolisuride) in the rat striatum.

The binding properties of [3H]terguride were studied in various regions of the rat brain. The highest density of [3H]terguride binding sites was found in the striatum and tuberculum olfactorium. In the striatum, the binding was saturable, stereoselective and of a high affinity. There was a good correlation between the inhibition of [3H]terguride and [3H]spiperone bindings by various dopaminergic agents. Drugs with affinity to another type of receptors did not displace [3H]terguride binding in the striatum; only SCH 23390 was effective. The experiments indicate a certain affinity of the ligand to D-1 receptors. Nevertheless, [3H]terguride appears to have an affinity to D-2 receptors in the striatum and, thanks to its dopamine agonistic/antagonistic profile, would be useful in the further study of dopamine receptors.

Effect of a spirocyclic cyclodipeptide derivate of MIF on passive avoidance behavior and amnesia in rats.

Cyclo (1-amino-1-cyclopentane-carbonyl-L-alanyl)-c(Acp-Ala), a derivative of MIF (prolyl-leucyl-glycinamide) affected passive avoidance behavior of rats when administered at different phases of the step-through type of experimental paradigm. c(Acp-Ala) given s.c. or orally in a 1 mg/kg dose increased avoidance latencies not only when administered before, or immediately after the shock trial but also when given before the pretraining trial, i.e. at the first exposure of animals to the experimental situation without shock treatment. The notion is discussed, that it is the influence of c(Acp-Ala) on processing of information received during the pretraining trial that manifests itself in the facilitation of avoidance response. The drug appears to have a long-term action since it was active when given 20 h before the pretraining trial or the shock trial or the test of retention. c(Acp-Ala) when administered immediately after the shock trial, attenuated amnesia in rats induced by electroconvulsive shock (ECS).

To what extent can results of experimental studies be extrapolated in predicting adverse side effects of drugs in man?

A new potential antiinflammatory substance serves as an example that substantiates the necessity of carrying out concurrent comparative pharmacokinetic and biotransformation studies of new drugs in experimental animals and man during the preclinical research stage, with adherence to all safety precautions. Such a procedure will facilitate the choice of an animal model that approaches human metabolism and pharmacokinetics as closely as possible. This serves in the further development of the test drug, and thus enhances the validity of the transfer of experimental data to man, especially from the toxicological aspect.

Lisuride and transdihydrolisuride: differences in action on central dopaminergic functions in dependence on the location and the state of receptors.

The effects of apomorphine, lisuride and 9, 10 transdihydrolisuride (TDHL) were compared on two models of rotating rat. In rats with 6-hydroxydopamine (6OHDA) induced unilateral lesions, all three drugs evoked contralateral rotation. By contrast, in rats with unilateral electrolytical lesions of the striatum, only apomorphine and lisuride acted as agonists. TDHL did not cause any circling and inhibited rotation induced by apomorphine and lisuride. In other experiments the effects on body temperature was examined. All three drugs lowered the rectal temperature in normal mice; however, only apomorphine and--to some extent--lisuride reversed the hypothermia induced by reserpine. Both lisuride and TDHL inhibited the hypothermia reversal induced by apomorphine. The presented results are interpreted in terms of lower intrinsic activities of TDHL and lisuride in comparison with apomorphine. The lower intrinsic activity is manifested as partial agonist or antagonist type of action in dependence on the location and the state of receptors.

The use of striatal dopaminergic supersensitivity for the evaluation of drugs with possible antidyskinetic properties.

An animal model of tardive dyskinesia was used for the evaluation of potential antidyskinetic properties of the neuropeptide L-Prolyl-L-Leucyl-glycinamide (PLG) and related drugs: cyclo[glycine-(1-amino-1-cyclopentane) carbonyl]--c(CPC-Gly) and cyclo[alanine-(1-amino-1-cyclopentane) carbonyl]--c(CPC-Ala). Dopaminergic supersensitivity was induced by repeated administration of the neuroleptic drug isofloxythepin. Isofloxythepin (5 mg/kg/day po) after the withdrawal increased Bmax of 3H-spiperone striatal binding sites, significantly decreased HVA level in the striatum and induced tolerance to the cataleptic effects challenged by perphenazine. PLG, c(CPC-Gly) and c(CPC-Ala) counteracted supersensitive responses of isofloxythepin. The use of c(CPC-Gly) and c(CPC-Ala) in the prevention of tardive dyskinesia is proposed.

Effect of beta-casomorphin and its analogue on serum prolactin in the rat.

The effects of exogenous opioid peptides beta-casomorphin Tyr-Pro-Phe-Pro-Gly-Pro-Ile and its analogue Tyr-Pro-Gly-Pro-Phe-Pro-Ile (analogue I) were found to increase prolactin level in plasma after intraperitoneal injection. Analogue I was more potent. This effect of beta-casomorphin and analogue I were blocked by an opioid antagonist, naloxone. These results indicate that the exogenous opioid peptides (exorphins) may participate in the regulation of prolactin secretion. The similarity of analogue I with enkephalin structure was discussed.

Bar-pressing for water reward: effects of nootropic drugs and peptides on discrimination learning in rats.

Rats maintained on 23-hr water deprivation were first trained to bar-press for continuous water reinforcement and then to discriminate between regularly alternating periods (24 sec) during which time a light signal was either on and each response was reinforced or the light was off and bar-presses were not rewarded. The following drugs were injected s. c. prior to the sessions of discriminative learning: piracetam, 1-(4-Methyl-piperazinocarbonylmethyl)-2-pyrrolidone/hydrogen maleate (VUFB 13763), N alpha-glycyl-glycyl[8-lysine]des-9-glycinamide-vasopressin (DG-Trigly-LVP) and an analog of MIF, EUC-Leu-beta-Ala-NH2 (EUC, 2-oxoimidazolidine-1-carboxylic acid). None of the drugs influenced the total number of bar-pressing (sum of reinforced and non reinforced responses). Piracetam (100 mg.kg-1), VUFB 13763 (40 mg.kg-1) and EUC-Leu-beta-Ala-NH2 (1 mg.kg-1) improved the performance of rats on the discrimination learning task, DG-Trigly-LVP slowed the rate of acquisition.

Induction of dopaminergic supersensitivity after a single dose of the neuroleptic isofloxythepin.

The development of dopaminergic supersensitivity was evaluated, after single oral administration of the long-acting neuroleptic drug isofloxythepin, in nigrostriatal and tuberoinfundibular system in the rat. Isofloxythepin (5 mg/kg orally) increased concentration homovanillic acid (HVA) in the striatum for up to 24 h after administration, whereas a significant decrease below control values was found after 4-5 days. A similar biphasic effect appeared in behavior, since there was an enhancement of apomorphine stereotypy 4-5 days after administration of isofloxythepin (5 and 10 mg/kg orally). Both findings agree with the hypothesis of development of nigrostriatal dopaminergic supersensitivity at long intervals after isofloxythepin. On the other hand, the increase in prolactin (PRL) secretion induced by isofloxythepin indicated only the blocking action of this drug on dopamine receptors in the tuberoinfundibular system, and provided no evidence for tuberoinfundibular dopaminergic supersensitivity after neuroleptic treatment. It is concluded that a single dose of isofloxythepin is capable of inducing dopaminergic supersensitivity in the nigrostriatal system, but not in the tuberoinfundibular system.

Passive avoidance behavior: opposite effects of oxytocin analogs with agonist and antagonist properties.

Deamino-6-carba-oxytoxin (dC60), a potent oxytocin analog considered to be resistant to some of the physiologically significant enzymic systems, and N-alpha-acetyl-[2-O-methyltyrosine]oxytocin (AMTO), an analog acting as a competitive inhibitor of oxytocin on the rat uterus, were studied in rats trained in a passive avoidance task. Subcutaneous administration of dC60 (5-50 microgram . kg-1) during different phases of the passive avoidance learning paradigm attenuated avoidance latencies; the results indicated that the drug induced state-dependent learning. AMTO (5-20 microgram . kg-1) enhanced avoidance latencies when administered subcutaneously before training trials and/or before retention test trials. This effect occurred in both males and females. The analogs did not influence exploratory behavior in open field. The results suggest that oxytoxin, in contrast to vasopressin, may impair memory processes. However, both analogs failed to influence the passive avoidance response when administered after training. This finding indicates that dC60 and AMTO did not influence the mechanism of memory consolidation whereas vasopressin and oxytoxin had a marked effect.

Pharmacological properties of a potent neuroleptic drug octoclothepin.

Octoclothepin, 8-chloro-1-(4-methylpiperazino)-10,11-dihydrodibenzo (b,f) thiepin, is a very potent neuroleptic drug with pronounced central antidopaminergic and antiserotonin actions. In most animal experiments, its plharmacological profile resembles that of perphenazine. Octoclothepin reveals an intensive central depressant action in a series of observational and instrumental procedures in rodents. Its active oral doses are within the range of 0.54 to 2.2 mg kg-1 in mice and of 0.1 to 4.8 mg kg-1 in rats. Octoclothepin possesses high cataleptogenic and anti-apomorphine activities in rats; it is able to exert full protection against apomorphine-induced emesis in dogs after the dose of 0.1 mg kg-1 s.c. Octoclothepin reduces some actions and toxicity of d,l-amphetamine and phenmetrazine in rodents. In the rat corpus striatum, octoclothepin in doses of 0.5 and d1.5 mg kg-1 s.c. reduces the DA level and raises the HVA and DOPAC levels significantly. Octoclothepin has antihistamine, antiserotonin and antianaphylactoid actions, it exhibits a high protection against the lethal action of adrenaline and noradrenaline in mice and rats, respectively. Acute toxicological data in mice, rats, rabbits and dogs are given. Clinical antipsychotic effectiveness of octoclothepin has been verified in a large population of psychiatric patients.