Polish journal of pharmacology and pharmacy最新文献

The antitumor activity of subtherapeutical dose of cisplatin and vitamin C combinations was studied against murine Dalton's lymphoma in vivo. The sequence-dependent synergistic antitumor effect of vitamin C and cisplatin was shown to lead to the regression of the tumor resulting in a significant increase in the host survivals with tumor free hosts. Decrease in tumor pH noted in the treated tumor bearing mice and involvement of host's immune system could be an important step in this sequence-dependent antitumor activity of vitamin C and cisplatin.

Peptide YY (PYY) is a recently discovered polypeptide which has been proposed as physiological inhibitor of pancreatic exocrine secretion. The purpose of this study was to evaluate the effects of exogenous PYY on pancreatic blood flow and oxygen consumption. In anesthetized dogs, the superior pancreatico-duodenal artery blood flow (SPBF), pancreatic microcirculatory blood flow (PBF) and pancreatic oxygen consumption (PVO2) were determined. Control values for SPBF, PVO2 and PBF averaged 43.3 ml/min, 1.8 ml/min, and 57.5 ml/min/100g of tissue, respectively. Following iv injection of PYY at doses of 200 and 400 pmol/kg the values of SPBF decreased by 12 +/- 1% and 22 +/- 2%, respectively. PVO2 was reduced by those doses of PYY by 9 +/- 1 and 17 +/- 3%, respectively. PBF was also reduced by 16 +/- 2 and 34 +/- 2%, respectively after those doses of PYY. Pretreatment with phentolamine reversed the blood flow and PVO2 responses to PYY because SPBF, PVO2 and PBF were significantly increased above the control level. However, after additional pretreatment with propranolol the pancreatic vascular and metabolic responses to PYY were abolished. The above pancreatic responses to PYY were also significantly reduced after acute adrenalectomy. The experimental data indicate that adrenergic pathway is involved in the mechanism of action of PYY on the pancreatic circulation.

The hypoxic radiosensitizer 1-(2-hydroxy-3-methoxypropyl)-2-chloro-4-nitroimidazole [P40] was investigated for its mutagenic activity in bacterial Ames test as well as for genotoxic activity in micronucleus assay in vivo. This nitroimidazole showed the weak mutagenicity towards TA100 strain (base pair substitution) and towards TA98 strain (frameshift) only in the highest concentration. P40 induced also a significant increase in the frequency of micronucleated polychromatic erythrocytes (PCEs) at the doses of 0.6 mg/g and 1.2 mg/g. The maximum time response was at 48 h. The decrease of percentage of PCEs suggested the possible cytotoxicity on bone marrow cells after treatment with P40. Positive results in this battery short-term tests provide evidence of clastogenic activity of P40.

Six new 5(1H)oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylic ethyl esters bearing an aromatic substituent in position 1 or 2 were obtained. Pharmacological studies on the central action of these derivatives were carried out on mice and rats. The highest activity showed compounds 1 and 2 which produced analgesic effects in mice.

The response of GABA-modulin to various doses of diazepam and muscimol was used as an index of the sensitivity of central benzodiazepine and GABA-A receptors, respectively. Diazepam and muscimol induced a dose-dependent increase in cytosol GABA-modulin activity in rat nucleus accumbens, hippocampus and cerebellum. A single dose of ethanol (1 g/kg po) potentiated the action of diazepam and muscimol. Prolonged treatment with ethanol (5 g/kg/day for 21 days) did not affect the action of diazepam. In contrast, the effect of muscimol was greatly reduced. In the rats pretreated for 21 days with ethanol five times higher doses of muscimol than in control group were necessary to induce a statistically significant increase of GABA-modulin in the cytosol of the nucleus accumbens, hippocampus and cerebellum. Those results show that a single dose of ethanol enhances GABA-ergic transmission, whereas prolonged treatment with ethanol induces subsensitivity of GABA-A but not benzodiazepine receptors in the limbic system and in cerebellum.

The effects of C-terminal unsulfated cholecystokinin octapeptide (CCK-8US) and its fragments C-terminal heptapeptide (CCK-7), C-terminal hexapeptide (CCK-6) and C-terminal pentapeptide (CCK-5) were studied on the arterial blood pressure and the isolated rat heart. CCK-8US had only slight hypertensive and no cardiac effects. CCK-5, CCK-6 and CCK-7 had no effect on the arterial blood pressure, the cardiac contraction amplitude and the heart rate. Only CCK-7 increased coronary outflow of the isolated rat heart. CCK-8US and C-terminal fragments; CCK-7 have little effect on the circulation of the rat.

Fourteen days of treatment with 20 mg/kg/day carbamazepine (CBZ) reduced the immobility time in the behavioral "despair" test in rats. Two blockers of dopaminergic receptors: haloperidol (0.5 mg/kg) and sulpiride (100 mg/kg) antagonized the reduction of immobility caused by CBZ. The anti-immobility effect of CBZ was also counteracted by clonidine (0.1 mg/kg) an agonist of presynaptic alpha 2 adrenoreceptors and propranolol (5 mg/kg) beta-adrenolytic drug.

The effect of six 5-HT3 receptor antagonists: ondansetron (0.01-3 mg/kg ip), granisetron (0.01-1 mg/kg ip), zacopride (0.01-3 mg/kg ip), tropisetron (0.001-0.1 mg/kg ip), MDL 72222 (0.01-3 mg/kg ip) and DAU 6215 (0.01-3 mg/kg sc) were examined in the conflict drinking test (Vogel test) and in the elevated plus-maze test in rats. Ondansetron (0.1-0.3 or 1 mg/kg), zacopride (0.1-1 mg/kg) and tropisetron (0.01 mg/kg) increased the punished responding in the Vogel test and showed anxiolytic effects in the elevated plus-maze test. Their effects were limited to a narrow dose range and were not dose-dependent. Granisetron (0.1 mg/kg) exhibited an anti-conflict activity, but was ineffective in the elevated plus-maze test. MDL 72222 and DAU 6215 were ineffective in both those tests. On the other hand, diazepam (2.5-10 mg/kg), used as a reference drug, was active in either procedure and its effects were dose-dependent. These results indicate that an anxiolytic-like activity is not a common characteristic of 5-HT3 receptor antagonists. Moreover, even the anxiolytic action of drugs which were active in the experimental models used should be accepted with caution.

The effect of post-footshock injections of serotonergic agonists into the nucleus accumbens on formation of the open field deficit, has been studied in rats. It was found that the deficient open field behavior, examined 24 h after learned helplessness training, was not modified by local injection of serotonin, buspirone, ipsapirone and ICS 205 930, as well as by peripherally administered citalopram. It is concluded that accumbens serotonin system does not seem to contribute to the balance in the activity of local dopaminergic and GABAergic neurotransmitter mechanisms, previously shown to mediate some behavioral effects of stressors.

The effects of thiophosphoric acid alkaloid derivatives from Chelidonium majus L. (Ukrain, UKSR-222) on the central nervous system (CNS) of mice and rats was studied. Intraperitoneal (ip) administration of Ukrain in doses of 9.5 and 19 mg/kg for mice depressed spontaneous motor activity, decreased body temperature and potentiated the action of hexobarbital. Only in a dose of 19 mg/kg Ukrain produced analgesic action in the hot plate test. It had no protective effect against electroshock or pentetrazol-induced seizures. In rats, ip administration of Ukrain in dose of 14 and 28 mg/kg potentiated the action of amphetamine and apomorphine but had no effect on catalepsy induced by haloperidol. Ukrain used in dose 9.5, 14, 19 and 28 mg/kg antagonized the head twitches induced by 5-HTP and hyperthermia-induced by m-CPP. Biochemical studies indicated that Ukrain did not affect the NA and DA concentrations in the whole rats' brain and did not affect the 5-HT and 5-HIAA concentrations in the whole brain of rats. These findings demonstrate that the central action of Ukrain involves the stimulation of the dopaminergic system and the inhibition of the serotoninergic system.