Synthesis and properties of tetra(hexa)hydropyrazolo [1,2-a]pyrido[3,4-d]pyridazine derivatives.

The synthesis of tetra(hexa)hydropyrazolo[1,2-a]pyrido[3,4-d]pyridazine derivatives (14-21) and the results of pharmacological screening are described in this paper. All compounds tested were non-toxic and showed a significant analgesic action. The analgesic effects were associated with the suppression of the spontaneous locomotor activity. Furthermore most of the synthesized compounds displayed a weak antimycobacterial action in the preliminary screening.

Lead levels in body fluids of workers of an automobile factory with clinically diagnosed arterial hypertension.

The aim of the study is the evaluation of lead levels in body fluids in a chosen study group with diagnosed arterial hypertension employed in a car factory. The study was carried out on workers diagnosed with various stages of arterial hypertension who had been subjected to long-term lead exposure at different workplaces. The examination of the patients included medical history, physical examination and biochemical tests of blood and urine, following routine in the laboratory diagnosis in order to assess medical condition in terms of subclinical symptoms of lead exposure. Mean values of the lead level in blood and urine of studied population are insignificantly higher than in the control group. The obtained results seem insufficient to confirm the effect of occupational exposure to lead in subthreshold doses on the development of arterial hypertension, and are within the recommended hygienic standards.

The effects of citicoline and/or MK-801 on survival, neurological and behavioral outcome of mice exposed to transient hyperglycemia and oligemic hypoxia.

UNLABELLED: The effects of citicoline and/or low dose of MK-801 (sufficient to prevent the development of seizures) on survival, neurological and behavioral recovery following transient hyperglycemic-oligemic-hypoxic insult have been evaluated in mice. Neurological recovery was assessed semi-quantitatively on the third and the 10th day after the insult, and behavioral tests evaluating spontaneous locomotor activity, motor coordination and spontaneous alternation performance were performed on day 10. Neither drug given alone did influence survival rate, but the combination of MK-801 and higher citicoline dose decreased mortality on day 10. Behavioral performance was markedly compromised by the insult. Citicoline, but not MK-801, slightly but significantly improved behavioral outcome in all three tests. CONCLUSION: when brain ischemic insult is complicated with acute hyperglycemia, post-treatment with citicoline combined with MK-801 in low anti-convulsive dose improves survival and neurological recovery, and citicoline but not MK-801 enhances behavioral recovery.

2-deoxyglucose enhances epileptic tolerance evoked by transient incomplete brain ischemia in mice.

The aim of the study was to assess the influence of chronic treatment with a non-metabolisable glucose analogue, 2-deoxyglucose (2-DG) at a 150 mg/kg dose on long-term epileptic tolerance (ET) evoked by 30 min bilateral carotid artery clamping (BCCA) in mice. The effects of protein synthesis inhibition with cycloheximide (CHX), given in three daily doses of 2.5 mg/kg starting either 1 day before (peri-insult regimen) or 1 day after the priming insult (post-insult regimen), on ET development was also studied. Seizures were induced 14 days after BCCA with 3.5 mg/kg of bicuculline; this dose (CD97) evokes convulsions in 97% of normal untreated mice. BCCA resulted in decreased mortality, prolonged latency to the onset of generalised convulsions and decreased overall seizure score. CHX given in the post-insult regimen did not influence, while the peri-insult regimen abolished, all signs of BCCA-evoked ET. 2-DG treatment of sham-operated animals resulted in a moderate but significant decrease in mortality rate and a tendency toward a lower seizure score. BCCA combined with 2-DG treatment resulted in a marked decrease in mortality rate, as well as reduction in all indicators of seizure susceptibility. CHX abolished the antiepileptic effects of BCCA alone, as well as BCCA combined with 2-DG, while it did not influence the 2-DG-related decrease in mortality. We conclude that the development of BCCA-induced epileptic tolerance, as well as unmasking antiepileptic effects of 2-DG by BCCA, is dependent on protein synthesis.

The evaluation of noise level in different points of urban area.

The aim of the study was measuring noise intensity in the selected points of traffic routes in the city of Lublin. Investigations were carried out at 11 points located in the centre of the city and at escape roads. Noise value levels showed variable intensity, the highest being observed in the morning and afternoon hours. The highest mean level of noise intensity was recorded at the crossing of Solidarnosci Avenue and Sikorskiego Street, and the lowest in Narutowicza Street.

Delta aminolevulinic acid urinary excretion in rural region inhabitants.

The purpose of the work was to estimate to what extent the inhabitants of a typical agricultural region are exposed to the influence of lead compounds. 132 people at the age of 9 to 74 were included in the research. Urinary delta aminolevulinic acid (ALA) excretion was determined. The highest excretion of ALA was observed among the examined who were up to 18 years old, while the lowest was among those who were above 60 years old. These differences, however, were not statistically significant.

Vitamin E influence on selected parameters in rats after ochratoxin A intoxication.

The aim of the research was to evaluate vitamin E influence on ochratoxin A (OTA) toxicity based on analysis of selected parameters of white and red cell system in rats. The animals were divided into groups: I--control, II--treated with OTA, III--treated with OTA and vitamin E. In group II a significant decrease in the values of hematocrit, hemoglobin level, red and white cell counts was observed. In group III an average hematocrit, hemoglobin level were significantly lower than in control group, nevertheless they were higher than in group II.

The evaluation of intensity of traffic noise in different points of town routes.

The aim of the study was measuring noise intensity in the selected points of traffic routes in the town of Lublin. Investigations were carried out at 11 points located in the centre of the town and at escape roads. Noise value levels showed variable intensity, the highest being observed in the morning and afternoon hours. The highest mean level of noise intensity was recorded at the crossing of Solidarnosci Avenue and Sikorskiego Street, and the lowest in Narutowicza Street.

Synthesis and in vivo pharmacology of new derivatives of isothiazolo[5,4-b]pyridine of Mannich base type.

Recently we reported on 2H-4,6-dimethyl-2-[(4-phenylpiperazin-1-yl)methyl]-3-oxo-2,3-dihydroisothiazolo[5,4-b]pyridine (V), which exhibited high anorectic action in animal models as a result of stimulation of serotoninergic system. This paper describes the synthesis of the series 3-5 of analogues of V prepared from 2-hydroxymethyl-4,6-dimethylisothiazolopyridine (2) and corresponding 4-substituted-piperazines(piperidines) or tetrahydroisoquinoline. The 12 compounds obtained were screened in standard CNS tests in in vivo (mice and rats). In contrast to V, none of its analogues showed serotoninergic activity, whereas several of these compounds were found to be active as weak to moderate analgesic agents. According to X-ray and molecular modeling studies the different pharmacological profile of V and its o-OCH3 analog 3a, taken as an example, should be referred back to the conformational restriction incorporated by the o-substitution rather than effects of different lipophlicity or basicity of these compounds.

Effect of adenosine A1 and A2 receptor stimulation on hypoxia-induced convulsions in adult mice.

Clinical observations indicate that seizures induced by hypoxia are common kind of convulsive activity in both infants and elderly patients. The occurrence of seizure episode during hypoxia is important risk factor of epilepsy development in the future. Experimental hypoxia was obtained by exposure of adult (20-23 g) Albino Swiss mice to spontaneous breathing in gas mixture composed of 5% oxygen and 95% nitrogen. The latency time to convulsive activity was determined. Single sublethal episode of seizures induced by hypoxia (HS) resulted in higher susceptibility to pentetrazol (PTZ), bicuculline (BCC), N-methyl-D-aspartic acid (NMDA) but not in electrically induced convulsions. Adenosine A1 receptor agonist, R(-)N6-(2-phenyl-isopropyl)adenosine (R-PIA) (0.01; 0.05; 0.1 mg/kg, i.p.) prolonged the latency to HS-induced convulsions. A1 receptor antagonist, 8-cyclopentyltheophylline (CPT), reversed the protective action of R-PIA. A2 receptor agonist, N(6)-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)]ethyladenosine (DPMA), only at the highest dose (5 mg/kg i.p.) prolonged the latency time to convulsive activity. This effect was only partially reversed by A2 antagonist 3,7-dimethyl-1-propargylxanthine (DMPX). Administered immediately after episode of HS R-PIA diminished the higher susceptibility to PTZ, BCC, NMDA at 3rd day after HS, while DPMA appeared to be ineffective. These results confirm the important role of adenosine A1 receptor agonist in protection against acute and chronic epileptogenic effect of hypoxia. The role of adenosine A2 receptors seems to be of minor importance.

Brain tolerance and preconditioning.

In this review article the authors describe a phenomenon of "brain tolerance" which represents transient resistance of brain tissue to a lethal insult established by preconditioning with a mild insult of short duration. Tolerance evoked by brief ischemia resembles transient ischemic attack(s) (TIA) often preceding full-blown ischemic stroke in a clinical setting. A series of recent studies have described another relevant phenomenon termed "chemical preconditioning". Several substances interfering with cellular energy metabolism applied in subtoxic doses may provide protection against lethal insults of a different type. For example, 3-nitropropionic acid (3-NP), antibiotics erythromycin and kanamycin, acetylsalicylic acid, and 2-deoxyglucose have been shown to evoke tolerance. Recently, we have reported that NMDA receptor antagonists and 2-deoxyglucose used at relatively low doses were potent agents to potentiate the protective anticonvulsant effect induced by transient brain mild ischemia. Further studies are expected to prove similar action of these drugs in other experimental models. Based on the accumulated experimental and clinical data the brain tolerance subsequently reinforced by pharmacological intervention might become a successful prophylactic strategy against serious brain insults in patients.

The role of opioid receptors in hypoxic preconditioning against seizures in brain.

Preconditioning is defined as an adaptive mechanism produced by short periods of hypoxia/ischemia, resulting in protection against subsequent ischemic insult, and development of seizures. Results of the present study demonstrate that an episode of normobar hypoxia reduces the susceptibility to convulsions induced by pentylenetetrazol (PTZ) 30 min, 24 h, as well as 4 and 7 days later. Administration of morphine showed similar effects after 24 h. Naloxone, given before ischemic preconditioning, as well as morphine, blocked the development of the protection. Administration of D-Ala-Met-enkephalin-Gly-ol (DAMGO - a selective mu-opioid receptor agonist), as well as trans-3, 4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl) cycloexilbenzeneacetamide ethane sulfonate] (U-69,593 - a selective kappa-opioid receptor agonist), mimicked the effects of hypoxic preconditioning (HPC). (-)-N-(Cyclopropylmethyl)-4,14-dimethoxymorphinan-6-one (cyprodime - a selective mu-opioid receptor antagonist, as well as nor-binaltorphimine dihydrochloride (nor-BNI - selective kappa-opioid receptors antagonist), given before HPC as well as before respective opioid receptor agonists, blocked the development of the protection. This study provides evidence that mu- and kappa-opioid receptors are involved in HPC against seizures in the brain.

The influence of MK-801 on bicuculline evoked seizures in adult mice exposed to transient episode of brain ischemia.

The aim of the study was to examine the role of NMDA receptors in modulation of protective effect against bicuculline toxicity after transient brain ischemia in mice. Animals were exposed for 30 min to bilateral clamping of the common carotid arteries (BCCA) in anaesthesia. MK-801 was administered intraperitoneally in two paradigms: a) acute treatment: twice, 1.0 mg/kg; 1 hour before clamping and 6 hours after re-circulation and b) chronic treatment: 0.1 mg/kg; started 24 hours after re-circulation and continued once daily for 13 days, the last injection was administered 24 hours before seizure induction. 14 days after BCCA, the animals were injected with bicuculline (3.5 mg/kg s.c). A significant decrease in seizure susceptibility could be observed in BCCA treated mice compared with sham-operated controls. Acute treatment with MK-801 did not affect seizure activity both in sham and BCCA mice. Chronic treatment with the drug potentiated anticonvulsant effect of brain ischemia but had no influence on seizure activity in sham-operated mice. The analysis of GABA content in brain tissue performed 14 days after BCCA showed a moderate increase in vehicle-treated mice and significant elevation after chronic treatment with MK-801. It can be suggested that NMDA receptors are not involved in the induction of a protective effect against bicuculline toxicity after transient brain ischemia. The prolonged treatment with low doses of MK-801 may potentiate a developed process in a mechanism of chemical preconditioning.

The effect of CGP-40116 on pilocarpine evoked seizures in mice exposed to transient episode of brain ischemia.

The objective of the study was to examine the role of N-methyl-D-aspartate (NMDA) receptors in the modulation of a brain tolerance after a transient cerebral ischemia. Adult mice were exposed for 30 min to bilateral clamping of common carotid arteries (BCCA) under anaesthesia. The competitive NMDA antagonist CGP-40116 was administered intraperitoneally (i.p.) in two experimental paradigms, (a) acute treatment: twice, 4.0 mg/kg; 1.5 h before the clamping of vessels and 6 h after re-circulation and (b) chronic treatment in a dose of 1.0 mg/kg; started 24 h after re-circulation and continued once daily for 13 days with the last injection 24 h before the induction of convulsions. Seizures were evoked with pilocarpine (400 mg/kg, i.p.) 14 days after BCCA. The preliminary study showed that BCCA induced protection against pilocarpine toxicity. The acute treatment with CGP-40116 partially diminished the anticonvulsant phenomenon. In contrast, the chronic treatment with the drug led to a marked potentiation of the effect. The whole brain gamma-aminobutyric acid (GABA) analysis performed 14 days after BCCA showed a moderate increase in vehicle-treated mice and a significant elevation after chronic treatment with CGP-40116. It can be concluded that NMDA antagonists may exert the opposite effects on the brain tolerance against pilocarpine toxicity after BCCA. The acute treatment with CGP-40116 diminished its induction while the chronic low-dose treatment enhanced a brain tolerance, possibly through the mechanism of chemical preconditioning.

Synthesis and preliminary screening of derivatives of 2-(4-arylpiperazin-1-ylalkyl)-3-oxoisothiazolo[5,4-b] pyridines as CNS and antimycobacterial agents.

We have synthesized several new isothiazolopyridines possessing a side chain at the isothiazole ring typical, among others, for trazodone or NAN-195. Representatives of the novel isothiazolopyridines were examined for acute toxicity and in several commonly used CNS tests in mice and for arterial blood pressure in rats. Three of the five compounds tested showed significant analgesic activity. The most active compound (3b) exhibited analgesic action in the "writhing" test in a dose 1/1280 of LD50 (LD50 = 1135.5 mg/kg) after administration i.p. to mice. Additionally, the compounds described here and related isothiazolopyridines obtained previously were evaluated against Mycobacterium tuberculosis H37Rv at 12.5 micrograms/ml in in vitro assays. Seven of the nineteen compounds tested showed 100% inhibition of that mycobacterium.

Synthesis and pharmacological properties of 1-(4-substituted)butyl derivatives of amides of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimi dine-5 -carboxylic acid.

The synthesis of 1-(4-substituted)butyl derivatives of amides of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimid ine-5- carboxylic acid and the results of the preliminary pharmacological screening are described in this paper. Some of them showed a weak analgesic action and caused suppression of the spontaneous locomotor activity of mice.

Synthesis of some N-substituted 3,4-pyrroledicarboximides as potential CNS depressive agents.

As a continuation of our work on N-[4-aryl(heteroaryl)piperazin-1-ylalkyl]-3,4-pyrro ledicarboximides, which were characterized by strong analgesic activity and CNS depressive action, several novel N-substituted 3,4-pyrroledicarboximides were prepared and eleven representatives were examined in a series of in vivo CNS tests. A few of these compounds displayed a similar profile of biological selectivity to that of 3,4-pyrroledicarboximides described previously; their structure-activity relationships are discussed.

The influence of CGP-40116 on bicuculline evoked seizures in mice exposed to transient episode of brain oligemia.

To assess the role of NMDA receptors in the modulation of a brain tolerance after a transient cerebral mild ischemia, adult mice were exposed for 30 min to bilateral clamping of the common carotid arteries (BCCA) under pentobarbital anaesthesia. The competitive NMDA antagonist CGP-40116 was administered intraperitoneally (i.p.) in two experimental paradigms: a) acute treatment: twice, 4.0 mg/kg; 1.5 hour before the clamping of vessels and 6 hours after re-circulation and b) chronic treatment in a dose of 1.0 mg/kg; started 24 hours after re-circulation and continued once daily for 13 days with the last injection 24 hours before the induction of convulsions. Seizures were evoked with bicuculline (3.5 mg/kg, i.p.) 14 days after BCCA. Transient brain oligemia induced protection against bicuculline toxicity. The acute treatment with CGP-40116 only partially diminished the anticonvulsant phenomenon. In contrast, the chronic treatment with the drug markedly potentiated the effect. It can be concluded that NMDA receptors only partially participate in the induction of a protective effect against bicuculline toxicity after BCCA. The chronic treatment with low doses of the NMDA antagonist may enhance the brain tolerance, possibly due to the chemical preconditioning.

Effect of MK-801 on pilocarpine-evoked seizures in mice exposed to transient incomplete brain ischemia.

The aim of the study was to examine the role of NMDA receptors in the modulation of brain tolerance after transient cerebral ischemia. Adult mice were exposed for 30 min to bilateral clamping of common carotid arteries (BCCA) under anaesthesia. The non-competitive NMDA antagonist, MK-801 was administered intraperitoneally (ip) in two experimental paradigms: a) acute: twice at 1.0 mg/kg; 1 h before the clamping of the vessels and 6 h after re-circulation; b) chronic at a dose of 0.1 mg/kg, started 24 h after recirculation and continued once daily for 13 days with the last injection 24 h before the induction of convulsions. Seizures were evoked with pilocarpine (400 mg/kg, ip) 14 days after BCCA. It was found that transient incomplete brain ischemia induced protection against pilocarpine toxicity. The acute treatment with MK-801 did not diminish the anticonvulsant action of the procedure. In contrast, the chronic treatment with the drug led to a marked potentiation of the effect. In conclusion, it can be suggested that studied NMDA receptor antagonist used at relatively low dose may enhance the brain tolerance activated after a transient ischemic episode.

Synthesis and pharmacological screening of some N-(4-substituted-piperazin-1-ylalkyl)-3,4-pyrroledicarboximides.

As an extension of our previous work we describe the synthesis and pharmacological investigation of a new series of derivatives of pyrrole-3,4-dicarboximide possessing the 4-substituted-piperazin-1-ylalkyl group linked to the imide nitrogen. The products were evaluated for acute toxicity, and effectiveness in a series of CNS and arterial blood pressure tests. The preliminary pharmacological screening was determined in animal models. Several compounds demonstrated moderate to high analgesic activity in the 'writhing syndrome' test (5f-1/640 LD50). Some of the structure-activity relationships are also discussed.