Polish journal of pharmacology and pharmacy最新文献

To investigate a possible functional interaction between 5-HT1B and 5-HT1A or 5-HT2 receptors we studied the effects of 5-HT1A selective agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and gepirone, of a 5-HT1A/5-HT2 agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) and of a putative 5-HT2 agonist (+/-)1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane (+/- DOI) on the 5-HT1B receptor-mediated hypothermia induced by m-trifluoromethylphenylpiperazine (TFMPP) (25 mg/kg) or m-chlorophenylpiperazine (m-CPP) (20 mg/kg) in mice. 8-OH-DPAT (1.25-5 mg/kg), gepirone (1.25-5 mg/kg), 5-MeODMT (2-8 mg/kg) and (+/-)DOI (0.5-2 mg/kg) reduced dose-dependently the TFMPP- or m-CPP-induced hypothermia. At the same time 8-OH-DPAT (2.5 and 5 mg/kg, but not 1.25 mg/kg) and gepirone (1.25-5 mg/kg) themselves decreased the body temperature in mice, while 5-MeODMT (2-8 mg/kg) and (+/-)DOI (0.5-2 mg/kg) did not affect it. The present results suggest that a functional interaction exists between 5-HT1B and 5-HT1A or 5-HT2 receptors.

We found previously that combined administration of imipramine, citalopram and, to a lesser extent, mianserin with MK-801, a non-competitive NMDA receptor antagonist, reduced the immobility time in the forced swimming test in rats more potently than administration of the antidepressant or MK-801 alone. In present paper we examined the effect of other antidepressants in this model. (+)-Oxaprotiline and (-)-oxaprotiline which, when given alone, showed a weak positive effect, increased the action of MK-801. Fluoxetine, inactive when given alone, markedly increased the effect of MK-801. Moreover, the positive effect after combined treatment was found in the experiments in which antidepressants and MK-801 given separately were inactive. A reduction in the immobility time was also observed in those experimental paradigms in which the locomotor activity was not increased. The effects of combined treatment with the antidepressants studied + MK-801 were antagonized by haloperidol, but not by prazosin. The obtained results indicate that mainly a dopamine mechanism seems to be involved in the synergistic action of MK-801 and the antidepressants in the forced swimming test.

A novel analog of dynorphin (1-13), D-Ala2,F5Phe4-dynorphin amide, was prepared and its pharmacological spectrum of activity was investigated. In a hot plate test on Swiss Webster and C57Bl mice, a 20 micrograms intracerebroventricular (icv) dose of the analog produced analgesia, which was greater in potency and duration than the parent dynorphin. This action of D-Ala2,F5Phe4-dynorphin amide was antagonized by the opiate receptor antagonist naloxone (2 mg/kg ip), administered either before or after the peptide. In addition to its analgesic action in mice, D-Ala2,F5Phe4-dynorphin amide produced a Straub tail and a catatonic-like state, both of which were also attenuated by naloxone. On the electrically-stimulated mouse vas deferens preparation, in vitro, D-Ala2,F5Phe4-dynorphin amide inhibited contractile activity and had an IC50 of 108.2 +/- 34.7 nM (SEM), about 4-fold weaker than that of dynorphin. This action was also attenuated by naloxone. An icv dose of 150 micrograms of D-Ala2,F5Phe4-dynorphin amide in mice, and a cumulative series of icv doses up to 2600 micrograms in anesthetized rats, failed to produce a lethal effect. No pathological changes were observed in mouse liver and kidney at 24 h after a 50 mg/kg dose of the peptide analog. In rats anesthetized with diallylbarbital (70 mg/kg ip) and urethane (280 mg/kg ip), D-Ala2,F5Phe4-dynorphin amide did not modify blood pressure, heart rate and respiratory rate. However, when mice were injected peripherally with single doses of D-Ala2,F5Phe4-dynorphin amide, convulsive episodes were produced, and lethal effects were observed with an LD50 of 60.0 mg/kg (95% confidence limits: 49.7-70.2 mg/kg) at 48 h. This action of D-Ala2,F5Phe4-dynorphin amide was not attenuated by naloxone (2.0 mg/kg, ip). Although analgesic and behavioral effects of D-Ala2,F5Phe4-dynorphin amide (e.g. Straub tail and catatonic-like state) are opiate-like, the lethal effect may be the consequence of actions of the peptide on non-opiate systems, Thus, the novel fluorinated dynorphin analog, D-Ala2,F5Phe4-dynorphin amide, may be a useful chemical tool for the study of opiate systems and their occasionally unanticipated biological or toxic actions.

A simple, rapid and sensitive high-performance liquid chromatographic method for the simultaneous determination of propafenone and 5-hydroxypropafenone in human serum is described. Method involves a single-step extraction of the drug and its metabolite with dichloromethane:2-propanol (4:1 v/v) mixture from 0.2 ml of serum. Separation of the investigated compounds on deactivated Supelcosil LC18-DB column is accomplished by ultraviolet detection at 210 nm. The limit of detection is 10 ng/ml for propafenone and 4 ng/ml for 5-hydroxypropafenone. The method is useful for the routine monitoring of propafenone and its main metabolite in serum as well as for the pharmacokinetic studies.

In an effort to develop more effective and selective V2-antagonists of arginine-vasopressin (AVP) we designed and synthesized four new analogs of this hormone. The peptides were designed in order to explore how the combination of modification of thioacids occupying position 1 and substitutions of positions 2 and 4 by D-Phe and Ile respectively, will influence their antagonistic properties. Three of the reported analogs are moderately potent V1/V2 antagonists.

The effect of selective adenosine receptor agonists on nociceptive responses of mice and rats and on morphine analgesia was investigated. All compounds used: phenylisopropyladenosine (R-PIA), adenosine ethylcarboxamide (NECA), cyclohexyladenosine (CHA) and 2-chloroadenosine (2-CADO) exhibited antinociceptive action in mice and rats in the hot-plate (56 degrees C) and tail-immersion (52 degrees C) tests. R-PIA, CHA and NECA potentiated the antinociceptive action of morphine in mice, and R-PIA and NECA--in rats. 2-CADO did not affect the morphine action in the tests.

The literature data regarding the vasoconstriction potency of natural vasopressin-like peptides are contradictory. The cumulative concentration-response curve for arginine-vasopressin (AVP), lysine-vasopressin (LVP), arginine-vasotocin (AVT), lysine-vasotocin (LVT) and phenypressin (PHP) on the isolated rat tail artery was determined. The potency rank of these peptides on the vascular smooth muscle of the rat tail artery was the following: AVP greater than LVP greater than AVT = LVT greater than PHP. The results are discussed in comparison to the data in the literature.

The effect of low doses of mechlorethamine (1-10 micrograms/kg) and levamisole (2.5 mg/kg) on humoral response of rabbits immunized twice with ovalbumin (0.1 mg/kg) was compared. It was shown that mechlorethamine given in a dose of 5 or 10 micrograms/kg potentiates the increase in the level of serum anti-ovalbumin hemagglutinins; this increase is induced both after the first and the second (after 14 days) antigen administration. Levamisole acted similarly but with much lower efficiency.

Inulin was used as a model drug for the study of factors influencing the transport of drugs across the blood-lymph barrier. The model drug was administered iv (0.75, 7.5 and 37.5 mg/kg) as a bolus and by infusion. Kinetic parameters in blood and central lymph including lymphatic bioavailability (FL) were determined. It has been found that FL is influenced (increased) by larger doses of inulin (FL extent 0.934 +/- 0.250 - 1.914 +/- 0.250), infusion concentration ratio lymph/blood in steady state was 0.941 +/- 0.013. Identical kinetic parameters were found in rats with differentiated content of total lipids in lymph (in fed and fasted group, FL were 0.861 +/- 0.167 and 0.934 +/- 0.250 respectively).

Synthesis and physicochemical and pharmacological properties of 10 analogs of 2-[2-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethoxy]N, N-diethylamino ethane (3) have been described. The compounds possess toxicity close to or lower than the parent compound--myrtecaine, have no antiarrhythmic activity but some of them (15, 16, 22, 24), similarly as compound 3, show quite strong local anesthetic action.