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Questionnaire

Summary of the main activities of a scientific Organisation

of the Slovak Academy of Sciences

Period: January 1, 2003 - December 31, 2006

I. Formal information on the assessed Organisation:

1. Legal name and address Institute of Experimental Pharmacology, Slovak Academy of Sciences

Dúbravská cesta 9, 841 04 Bratislava, Slovakia

2. Executive body of the Organisation and its composition

Directoriat name age years in the position

director Radomír Nosáľ 65 2004 -

deputy director Ružena Sotníková 60 2006 -

scientific secretary Michal Dubovický 40 2004 -

3. Head of the Scientific Board

Ivo Juránek

4. Basic information about the research personnel i. Number of employees with a university degree (PhD students excluded)

engaged in research and development and their full time equivalent work capacity (FTE) in 2003, 2004, 2005, 2006 and average number during the assessment period

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ii. Organisation units/departments and their FTE employees with the university degree engaged in research and development

No. FTE No. FTE No. FTE No. FTE No. FTE

organisation in whole 35 33,6 32 30,95 30 29,7 34 30,65 32,75 31,225

Biochemical pharmacology 6 6 5 5 5 5 6 5,58 5,5 5,395

Cellular pharmacology 6 5,7 6 5,7 6 5,7 6 5,7 6 5,7

Cardiovascular pharmacology 3 3 3 3 3 3 3 3 3 3

Neuropharmacology 5 4,6 4 4 4 4 5 4,25 4,5 4,2125

Smooth muscle pharmacology 7 6,3 6 5,25 4 4 4 4 5,25 4,8875

Pharmacokinetics 4 4 4 4 4 4 5 4,04 4,25 4,01

Teratology 2 2 2 2 2 2 3 2,08 2,25 2,02

Toxicology and animal breeding 2 2 2 2 2 2 2 2 2 2

Research staff2003 average200620052004

5. Basic information on the funding

i. Total salary budget1 of the Organisation allocated from the institutional resources of the Slovak Academy of Sciences (SAS) in 2003, 2004, 2005, 2006, and average amount for the assessment period

Salary budget 2003 2004 2005 2006 average

total salary budget (millions of SKK) 12,970 13,528 13,998 14,409 13,726 6. URL of the Organisation’s web site

http://www.uef.sav.sk/

1 Sum of the brutto salaries without the fund contributions.

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II. General information on the research and development activity of

the Organisation: 1. Mission Statement of the Organisation as presented in its Foundation

Charter

Article 1 of the Foundation Certificate

Basic purpose and subject of activity

1. The Institute accomplishes complex solutions in basic research in the field

of pharmacology 2. The Institute conducts scientific and research activities. 3. The Institute accomplishes scientific education according to general

mandatory legal regulations. 4. The Institute pursues scientific and research problems of the SAS and

contributes to the development of science by solving theoretically significant issues for pharmacotherapeutic practice.

Brief History of the Organisation. The Institute came into being by splitting of the Pharmacological Institute of the former Czechoslovak Academy of Sciences in 1969. In addtion to the initial structure of the Institute, in the decade of 1970-80, new departments were created and special attention has been paid to the application of modern radioisotopic methods in drug metabolism studies. Special interest was focussed on pharmacotoxicologal studies with newly synthetised potential medicinal agents on different kinds of animals, including mice, rats, guinea pigs, rabbits and dogs. All kinds of toxicological studies were performed, including acute, subacute, subchronic, chronic and long lasting studies (up to one year) applying the dose-response schedules. Parallel to toxicological examinations, teratological studies have been continuously performed in at least three species of animals: mice, rats and rabbits. All investigations were concentrated on the dose-response effects of biologically active substances, including medicinal drugs on the pregnant mother and developing fetus. Teratological studies were extended by biochemical and haematological examinations, as well as transplacental studies of the substances applied. Results from toxicological and teratological investigations became an integral part of preclinical reports for registration procedures of new drugs.

In the decade of 1980-90 the organisation of the Institute was completed and the research activities concentrated on cardiovascular, neuronal, cellular and biochemical pharmacodynamics of newly synthetised drugs and on the mechanisms of side effects of cardiovascular, immunomodulatory and chemotherapeutic drugs. Pharmacotoxicological and teratological studies used the most recent methodological approaches, both for basic and applied research and the same was true for studies in pharmacokinetics. The Institute became the leading institution in pharmacological research in Czechoslovakia and was internationally well accepted.

After 1990, the staff of the Institute was reduced by the authorities within general restrictions of SAS. In spite of these negative interferences the IEPh did not lose its standard and continued in important research activities in several attractive and up-to-date areas. Behavioural methods and techniques were introduced and elaborated for studying the effects of drugs on the central nervous system (behavioural pharmacology) as well as effects of various adverse factors on functional development of the brain (behavioural teratology).

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2. Summary of R&D activity pursued by the Organisation during the assessed period, from both national and international aspects and its incorporation in the European Research Area (max. 10 pages)

Institute of Experimental Pharmacology SAS (further only IEPh or the Institute) represents the most advanced research institution in basic and applied pharmacology in Slovakia. The present status continuously developed from the organisation of pharmacological research in former Czechoslovakia, where since 1970 IEPh was considered the most advanced and developed pharmacological research institution. Ever since the Institute has played an important role in the development of the scientific field „pharmacology“ and that also in the present state of Slovakia. An integral part of the Institute is the Department of Toxicology and Animal Breeding located at Dobrá Voda near Trnava. It is the only centre for toxicological research in and breeding of laboratory animals in Slovakia. The Department possesses the Certificate of GLP Compliance No 23/2000 issued by the Slovak National Accreditation Service for toxicity studies, carcinogenicity, care and housing of animals (in accordance with the Directive 1999/12/EC).

The research in pharmacodynamics was focussed on several areas, particularly systemic pharmacology, like cardiovascular and neuropharmacology, smooth muscle pharmacology and cellular and biochemical pharmacology. In applied pharmacology the Institute has a long tradition and is keeping in progress in teratology and pharmacological toxicology. These two areas yielded not only results in basic teratology and toxicology but provided many reports concerning studies on new drug registrations and production of drugs to be used therapeutically. A similar development holds true for the research in pharmacokinetics concerning studies in basic pharmacokinetics, particularly in the metabolism and fate of biologically active substances in the living organism. With the aim to find optimal therapeutical regimens, theoretical modelling of drug pharmacokinetics in the human and animal body has been introduced.

At present the main interest of the Institute is focussed on the study of pharmacological interventions in oxidative stress and proinflammatory reactions-induced injury of the organism. Proinflammatory reactions are integral part of pathophysiology in many syndromes like ischaemia-reperfusion during cardiovascular and neurovascular diseases, hypertension, inflammation, rheumatoid polyarthritis, immunological reactions, diabetes mellitus, cancer, etc. One of the main interests of the Institute is to develop new pharmacotherapeutic approaches to diseases associated with pro-inflammatory processes and oxidative stress. By using experimental models of individual diseases the following in vivo models have been introduced and elaborated at the Institute: transient ischaemia of the brain and spinal cord, acute trauma of the brain, renovascular hypertension, myocardial infarction, mesenteric ischaemia/reperfusion, ulcerative colitis, diabetes mellitus, adjuvant arthritis, chronic intrauterine hypoxia, perinatal asphyxia.

An integral part of R&D activities are studies in the field of biopharmaceutical (medicinal) chemistry focussed on the design and synthesis of new pyridoindole derivatives with anti-inflammatory and anti-radical properties and research of the use of hyaluronan biopolymers. Pharmacodynamic, pharmacokinetic as well as toxicological mechanisms of action of biologically active substances are investigated at body, organ, cellular, membrane, receptor and molecular levels. Potential side toxic effects of the drugs are studied using a battery of toxicity tests. These studies are performed at the Department of Toxicology and Animal Breeding located at Dobrá Voda near Trnava. Laboratory animals from the own production are used for the experiments.

The Institute pursued its R&D activities in the field of pharmacology and toxicology during the assessed period of 2003 - 2006 years both on national and international levels within the European Research Area (ERA). During the assessed period, the Institute continued in the investigation of pharmacological approaches in model diseases in which reactive oxygen species play a key role, as well as of possibilities of pharmacological intervention/prevention. Derivatives of pyridoindoles with anti-radical scavenging activity were designed, synthesised and their effects on manifestations of the model diseases tested. Therapeutically used drugs from different pharmacological groups have been characterised for their antioxidative properties (cardiovascular and immunomodulatory drugs and chemotherapeutics).

Individual scientific problems were investigated within 6 scientific projects supported by the Agency for the Promotion of Research and Development (APVV/APVT), 25 projects were

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supported by grants from the National Research Programmes, Scientific Grant Agency of the Slovak Academy of Sciences and the Ministry of Education (VEGA), and one project was supported by the Government (ŠPVV). Individual investigations were performed in cooperation with other institutes of SAS, universities, as well as other organisations. International cooperation took part within 1 project of the 6th Frame Programme of the EU (Networking of Excellence), 5 scientific programmes COST, 6 projects within interacademy treaties (cooperation with the Academy of Sciences of the Czech Republic, DAAD, Germany, the Scientific and Technical Research Council, Turkey and National Centre of Radiation Research and Technology, Atomic Energy Authority, Egyptian Academy of Sciences, Cairo, Egypt) and 1 bilateral project (cooperation with the Aristotle University, Greece). SUMMARY OF THE MOST IMPORTANT RESULTS Basic research Reactive oxygen species related diseases of the nervous system. Preclinical study of preventive and therapeutical potential of novel antiradical compounds developed in the IEPh. New antioxidants derived from the pyridoindole stobadine were investigated for their potential neuroprotective properties. In the model of brain injury induced in mice by acute neurotrauma, a significant decrease of acute impairment of sensomotoric function was observed after treatment with these substances. Accordingly, they protected transmission in CA1 neurons, extremely sensitive to reversible hypoxia. As acute toxicity of these substances assessed in mice was found to be remarkably lower than that of stobadine, an improved safety margin may be expected with the new substances. The targeted modification of the stobadine molecule resulted not only in enhancement of its antioxidant action but also in potentiation of its neuroprotective properties. This was demonstrated in central nervous system impairments induced by acute hypoxia as well as by traumatic injury. Similar protective actions were observed also with 2,3-dihydromelatonine, the chemically related new antioxidant. The synthesised pyridoindole derivatives seem to be new alternative drugs suitable for prevention and treatment of pathologies, involving oxidative stress. Their structure, synthesis, and protective actions are subject of patent protection. Aimed at their further scientific and commercial exploitation, license negotiations have been launched with a foreign partner. (The results were integrated in the most important results of basic research in the Annual Report of SAS in 2003) References:

ŠTOLC, S., POVAŽANEC, F., BAUER, V. et al. Pyridoindole derivatives with antioxidant properties, their synthesis and use in therapeutic praxis, Slovak Patent Registration PP 1321, 2003. ● GÁSPÁROVÁ, Z., ŠTOLC, S., ŠNIRC, V. Pharmacological Research. Vol. 53, (2006), p. 22-27. ● ŠTOLC, S., ŠNIRC, V., MÁJEKOVÁ, M., et al. Cellular and Molecular Neurobiology. Vol 26, (2006), p.1493-1502.

Pharmacology of vascular diabetic complications: Effect of pyridoindole antioxidants. Pyridoindole derivatives (stobadine, SMe1EC2.HCl) was found to restore the endothelium-mediated relaxation damaged by hyperglycaemia in vitro and mitigate biochemical, functional and ultrastructural changes induced by experimental diabetes. The results suggest an important role of hyperglycaemia-induced reactive oxygen species (ROS) production in mediating endothelial dysfunction in experimental diabetes and beneficial effect of antioxidants. As diabetes mellitus is associated with increased incidence of ischaemic organic damage, the influence of diabetes on intestinal and vascular injury induced by mesenteric ischaemia/reperfusion (I/R) was studied. The results documented that diabetes rendered the intestinal tissue more vulnerable to the effects of I/R, while endothelial-dependent relaxation of the superior mesenteric artery diminished by diabetes, did not further deteriorate by I/R.

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References:

SOTNÍKOVÁ, R., SKALSKÁ, S., OKRUHLICOVÁ, L., et al. General Physiology and Biophysics. Vol. 25, (2006), p.289-302. ● ZÚROVÁ-NEDELČEVOVÁ, J., NAVAROVÁ, J., DRÁBIKOVÁ, K., et al. Neuroendocrinology Letters. Vol. 27, (2006), p. 168-171. ● NOSÁĽOVÁ, V., DRÁBIKOVÁ, K., ZÚROVÁ J., et al. Neuroendocrinology Letters. Vol. 27, (2006), p.152-155.

Pharmacology of diabetic complications: Preclinical implications of novel aldose reductase inhibitors based on carboxymethylated pyridoindoles and antioxidants of Zwitterionic nature. Novel carboxymethylated hexahydro- and tetrahydropyridoindoles were designed, synthesised and characterised as bifunctional compounds with joint antioxidant/aldose reductase inhibitory activities with potential agents that could be multifactorially beneficial. The inhibitory mode, efficacy and selectivity of the novel aldose reductase inhibitors were preserved even under conditions of prolonged experimental diabetes of rats. Antioxidant activity of the novel compounds was documented in a DPPH test and in a model liposomal membrane system oxidatively stressed by peroxyl radicals. Owing to the zwitterionic nature of these compounds, the lipophilicity profile of the representative inhibitor (2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-yl)-acetic acid, showed maximal extraction yield around physiological pH 7 in water/octanol system. The principle of a molecular pump was suggested that might be responsible for the rapid uptake of this type of compounds by liposomes. The zwitterionic principle appears to offer an interesting way how to improve bioavailability of aldose reductase inhibitors bearing an acidic function and thus to improve their potential for the treatment of diabetic complications. References:

ŠTEFEK M., ŠNIRC V., DEMOPOULOS V., et al. Carboxymethyl pyridoindoles, their synthesis and use in therapeutic praxis as the inhibitors of aldose reductase and antioxidants, Slovak Patent Registration PP 98-2005. ● DJOUBISSIE, P.-O., ŠNIRC, V., SOTNÍKOVÁ, R., et al. General Physiology and Biophysics. Vol. 25, (2006), p.415-425. Pharmacology of ischaemia/reperfusion (I/R)-induced injury of intestinal and vascular tissue: beneficial action of novel compounds synthesised at the IEPh. Mesenteric I/R induced by occlusion of the superior mesenteric artery (SMA) and subsequent reperfusion initiated a series of events that resulted in a pronounced intestinal and vascular injury. The effect of I/R was expressed mainly as increased vascular permeability, with protein leakage and haemorrhagic injury of the intestine as well as impaired endothelium-dependent SMA relaxation. Vessel dysfunction was manifested by a decrease of the maximal relaxation response to acetylcholine. An increase of chemiluminescence (CL), indicative of increased ROS production, was observed in both intestinal and vascular tissue. The antioxidant stobadine was found to reduce the increased vascular permeability and the extent of small intestine injury caused by I/R, to improve biochemical alterations accompanying I/R, to protect endothelial-dependent relaxation of mesenteric arteries, and to attenuate the CL response. Similar beneficial effects, achieved by using other drugs with antioxidant properties, such as the stobadine derivative SMe1EC2.HCl, melatonin, dihydromelatonin, N-acetylcystein and antihistamines, indicate a role of ROS in these processes and may thus be a possible target in the preventive and/or therapeutic approach to I/R- induced pathologies. Reference:

NOSÁĽOVÁ, V., NAVAROVÁ, J., MIHALOVÁ, D., SOTNÍKOVÁ, R. Methods and Findings in Experimental and Clinical Pharmacology. Vol. 29, (2007), p. 1-7.

Inflammation in the development and progression of heart failure. Studies on animal models have identified the importance of inflammation in the development and progression of heart failure due to prior myocardial infarction. Tumour necrosis factor (TNF), endothelin (ET), adrenomedullin (AM) and monocyte chemoattractive protein (MCP) are known to be

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overexpressed by endothelial cells, vascular and myocardial fibroblasts, directly in the ischaemic heart. Human and porcine coronary artery vascular smooth muscle ET-receptors undergo ET(B)-selective down-regulation. Processes are mediated by ET-receptor activation and are fully reversible. The ET(A)-selective antagonists PD151242 and PD155080 significantly attenuated ET-induced proliferation in human vascular fibroblasts and BQ788 blocked down-regulation of ET-receptors in coronary vascular smooth muscle. ET(B)-receptors are markedly down-regulated in human tumourigenic cells as a result of stimulation with angiogenic and growth factors expressed in neoplastic cells. The findings suggest significantly enhanced expression of adrenomedullin (AM) mRNA in renal hypoxic cells, an increased release of AM and up-regulated AM receptors, while inhibition of glucose metabolism reduced AM expression and release, and down-regulated AM receptors in renal tubular epithelial cells References:

DŘÍMAL, J., DŘÍMAL, J.Jr., DŘÍMAL, D. Physiological Research. Vol. 55, (2006), p.535-542.

Inflammation and oxidative stress in rat adjuvant arthritis: Effect of natural and novel synthetic substances with antioxidant activity. Pyridoindoles.The prophylactic and therapeutic effect of the pyridoindoles − stobadine, SMe1.2HCl and SMe1EC2.HCl was studied on the model of adjuvant arthritis induced to male Lewis rats with intradermal injection of Mycobacterium butyricum. The pyridoindoles studied improved the arthritic parameters in the order of potency: stobadine, SMe1.2HCl and SMe1EC2.HCl. These findings were supported by decreased activity of γ-glutamyl transferase-GGT (inflammatory parameter) in the spleen and joint. In these biological samples, both new pyridoindoles were more effective than stobadine. The obtained results indicate that systemic chronic inflammation can be beneficially affected by lowering the oxidative stress by administration of anti-radical effective substances. Copper complexes. In the adjuvat arthritis model, a beneficial effect was further observed for two complexes studied - N-salicylidene-L-α-alaninato-copper(II) [complex A] and N-salicylidene-β-alaninato-copper(II) [complex B]. The anti-rheumatic activity of the compounds studied was demonstrated not only as to their capability to suppress inflammation oedema of the hind paw and to improve body weight loss but also as to inhibit the arthritis stimulated oxidation processes in spleen and liver. Yeast glucan derivatives. In the experiments involving administration of carboxymethyl (1/3)-β-D-glucan to rats with adjuvant arthritis, a substantial decline of the level of plasmatic carbonyls, a parameter indicating oxidative tissue damage during the progress of arthritic diseases, was observed. References:

BAUEROVÁ, K., PONIŠT, S., ONDREJIČKOVÁ, O., et al. Neuroendocrinology Letters. Vol. 27, (2006), p.172-175. ● BAUEROVÁ, K., VALENTOVÁ, J., PONIŠT, S., et al. Biologia. Vol. 60, (2005), p. 67-70. ● KOGAN, G., STAŠKO, A., BAUEROVÁ, K., et al. Carbohydrate Polymers. Vol. 61, (2005), p. 18-28.

Antiinflammatory, antiphagocyte and antioxidative effects of carvedilol, H1-antihistamines, serotonin and pyridoindole stobadine. Carvedilol significantly decreased chemiluminescence (CL), formation of ROS and myeloperoxidase activity in whole human blood, isolated neutrophils, as well as in cell-free systems. Interference with the oxidative burst of professional phagocytes and direct radical scavenging activity were found to be involved in carvedilol effects. In addition carvedilol interfered with the NADPH metabolic pathway and the expression of iNOS in neutrophils. Experimental results suggest the administration of carvedilol in pathological states accompanied with ischaemia/reperfusion-induced tissue damage. Pharmacological agents from the group of betaadrenoceptor blocking drugs, H1-antihistamines and stobadine suppressed in a dose dependent way the formation of ROS measured directly or indirectly by means of CL in human and animal professional phagocytes. A new method was introduced for the measurement and

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differentiation of the effect of the drugs studied on oxidative burst of phagocytes at extracellular and intracellular level by means of luminol and isoluminol. Dithiaden suppressed both the intra- and extracellular CL, while histamine was active only extracellularly. The suggestive role of serotonin on the respiratory burst of human neutrophils was verified. References:

PEČIVOVÁ, J., MAČIČKOVÁ, T., NOSÁĽ, R., et al.. Methods and Findings in Experimental and Clinical Pharmacology. Vol. 26, (2004), p. 395-398. ● NOSÁL, R., DRÁBIKOVÁ, K., JANČINOVÁ, V., et al. Inflammation Research. Vol. 54, (2005), p. S19-20. ● NOSÁĽ, R., JANČINOVÁ, V., ČÍŽ, M., et al. Scandinavian Journal of Clinical and Laboratory Investigation. Vol. 65, (2005), p.55-64. Antiaggregatory effect of selected drugs affecting cardiovascular system. The beta-adrenoceptor blocking drug carvedilol was found to exert an antiplatelet effect. The antiaggregatory activity of carvedilol was shown to be associated with reduced thromboxane formation and with altered regulation of blood platelets via the arachidonic acid pathway. Compared to other alpha-adrenoceptor blocking drugs, the effect of carvedilol was found to be more pronounced. Our results speak in favour of administering carvedilol to patients at increased risk of thromboembolic complications.

A hirudin-like fraction from salivary gland of Amblyoma variegatum (Acari –Ixodidae) is indicative of antithrombotic activity by interfering with activated human blood platelets possessing a strong antiaggregatory effect. References:

NOSÁĽ, R. Cardiovascular & Hematological Agents in Medicinal Chemistry. Vol. 4, (2006), p. 237-261. ● NOSÁĽ, R., DRÁBIKOVÁ, K., JANČINOVÁ, V., et al. Fundamental & Clinical Pharmacology. Vol.18, (2004), p. 37. ● NOSÁĽ, R., PETRÍKOVÁ, M., KAZIMÍROVÁ, M., et al. Platelets. Vol.15, (2004), p. 506-507 Cardiovascular toxicity of anti-cancer therapy. The study of contradictory tumour necrosis factor (TNF)-α and adrenomedullin (AM) surface-membrane receptor signalling on human tumour cells in culture revealed a novel proliferative mechanisms controlling AM production and thus oncogenic signaling in cells. Our findings implied that several putative inhibitors of TNF-α and AM signalling may be considered also for treatment of tumours otherwise nonresponding to cytostatic therapy. The common manifestations of cardiovascular toxicity after anti-cancer therapy with bevacizumab may include signs of cardiac ischaemia manifested by ST-segment elevation or depression, QT prolongation, hypertension, ventricular tachycardia, or depression. Thus, suddenly increased and hyperexpressed inflammatory cytokines, neurohormones and chemoattractant MCP-1 in plasma during intensive anti-cancer therapy could be the long-awaited markers of imminent cardiotoxicity. References:

DŘÍMAL, J., DŘÍMAL, J.Jr., DŘÍMAL, D. Neoplasma, Vol. 53, (2006), p.144-149. ● DŘÍMAL, J., ZÚROVÁ-NEDELČEVOVÁ, J., ET AL. Neuroendocrinology Letters. Vol. 27, (2006), p.176-179.

Pharmacological prevention of consequences of intrauterine growth restriction and perinatal asphyxia: searching for an effective intervention in animal models. During the assessed period, experimental models of intrauterine growth retardation (IUGR) and perinatal asphyxia (PA) were introduced and elaborated. The IUGR was induced pharmacologically by administration of the antiepeleptic drug phenytoin (PHT) to pregnant rats. PHT administration caused maternal and embryofoetal toxicity manifested by decreased body weight gain of pregnant rats and by decrease of placental and foetal weight accompanied by increased skeletal and visceral anomalies. Moreover, PHT administration resulted in serious neurobehavioural changes in offspring during their postnatal development (delayed neuromotor and reflex development, hyperactivity, learning deficit in water maze test). PA was induced by exposure of the rat pups to anoxia early after birth. Neonatal anoxia resulted in hyperactivity of the rats in repeated testing in an open field and slowed-down habituation in a new environment. Moreover, neonatal anoxia caused alterations in some

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biochemical variables (glutathione and lactate). Natural (melatonin, vitamin E) and synthetic (pyridoindole stobadine) antioxidants were tested for their potential protective effects. Of the substances tested only stobadine exerted protective effects on alterations caused by PHT administration and exposure to anoxia. Stobadine was able to inhibit the teratogenic effect of PHT, as manifested by an increase of foetal and placental weight and by changes of some reproductive variables (live foetuses, resorptions, pre- and postimplantation loss). Stobadine also inhibited hyperactivity of the rats induced by neonatal anoxia. Moreover, the results showed that melatonin and vitamin E can interfere with developmental processes. That was manifested by subtle neurobehavioural changes in the rat offspring treated with melatonin alone and by changes in body weight persisting up to adulthood of the rats treated with vitamin E alone. References:

DUBOVICKÝ M., MAKATSORI A., UJHÁZY E., et al. Reproductive Toxicology. Vol. 20, (2005), p. 459. ● UJHÁZY, E., SCHMIDTOVÁ, M., DUBOVICKÝ, M., et al. Neuroendocrinology Letters. Vol. 27, (2006), p.82-85. ● MACH, M., DUBOVICKÝ, M., NAVAROVÁ, J., et al. Neuroendocrinology Letters. Vol. 27, (2006), p.69-73.

Oxidative damage of a model protein and its pharmacological influence by antioxidants in vitro. Oxidative systems included in the inflammatory process, HOCl and Fenton system, were studied individually on sarcoplasmatic reticulum (SR) from rabbit skeletal muscle and on purified Ca2+-ATPase (SERCA) from the same source. In spite of the fact that all agents studied exerted antioxidant effects on SERCA injured by HOCl or by Fenton system, their effects on the function of this enzyme, measured by enzyme activity were different: protective, without any effect, or even paradoxically inhibiting. The protective effect of trolox and standardised plant extract EGb 761 on SERCA activity inhibited by HOCl was observed in vitro for the first time and represents a contribution to the study of the mechanism of the protective effect of these agents. Stobadine was for the first time found to fail to exert any protective effect and that in spite of its significant scavenging activity against HOCl. Its effect may be tissue dependent and dependent on the mode of oxidation in the given pathological state. The inhibition of SERCA induced by Fe was not prevented by antioxidants. In the type of SERCA injury affecting calcium regulating function, the radical formation may be controlled by increasing intracellular calcium level leading to decrease of ATP synthesis in mitochondria, and by this way also to decrease of oxygen radical formation. References:

HORÁKOVÁ, Ľ., ŠTROSOVÁ, M., ŠKUCIOVÁ, M. Biofactors. Vol. 23, (2005), p.1-5. ● HORÁKOVÁ, Ľ., ŠTROSOVÁ, M., ŠKUCIOVÁ, M. Biologia, Vol. 60, (2005), p.131-134. ● ŠTROSOVÁ, M., KARLOVSKÁ, J., BALGAVÝ, P., et al. Neuroendocrinology Letters. Vol. 27, (2006), p. 164-167.

QSAR on substituted hexahydro-pyridoindoles: Their free radical scavenging and antioxidant activities. New substituted hexahydropyridoindoles, structural analogues of the antioxidant agent stobadine, designed with the aim to maximise their protective effects against oxidative damage of biological tissues, were studied for their radical scavenging abilities in a system of ethanolic solution of 1,1`-diphenyl-2-picrylhydrazyl and for their lipid peroxidation inhibitory properties. On the basis of the obtained quantitative structure-activity relationship (QSAR) correlations, new structural analogues with high antioxidant activity and optimal bioavailability were designed for potential pharmacological use in prevention and treatment of free-radical related pathologies. References:

RAČKOVÁ, L., FIRÁKOVÁ, S., KOŠŤÁLOVÁ, D., et al. Bioorganic & Medicinal Chemistry. Vol. 13, (2005), p. 6477- 6484. ● RAČKOVÁ, L., ŠNIRC, V., MÁJEKOVÁ, M., et al. Medicinal Chemistry. Vol.49, (2006), p. 2543 -2548.

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Synthesis of new pyridoindole derivatives with antioxidant, neuroprotective and aldose reductase inhibitory activities. Aimed at developing new medicines with neuroprotective action based on antioxidative and/or anti-free radical mechanisms, a number of original derivatives of stobadine, the well established scavenger of oxygen free radicals, were computed, designed, synthesised, and pharmacologically studied. Then antioxidants derived from the pyridoindole stobadine revealed enhanced antioxidant, antiradical, and protective properties as well as efficacy in inhibiting enzyme aldosereductase. The beneficial and protective effects of original stobadine and its new congeners were documented in several models of diseases, involving oxidative stress. Two groups of compounds have been proposed and synthetised: 1. a group of the substitiuted hexa- and tetra-hydropyridoindoles with optimised ability to react with free radical species, and 2. a group of carboxymethyl hexa- and tetra-hydropyridoindoles with optimised inhibition activity for the enzyme aldosereductase with preserved antioxidant activity. References:

ŠTOLC, S., POVAŽANEC, F., BAUER, V., et al. Pyridoindole derivatives with antioxidant properties, their synthesis and use in therapeutic praxis, Slovak Patent Registration PP 1321, 2003. ● ŠTEFEK M., ŠNIRC V., DEMOPOULOS V.J., et al. Carboxymethyl pyridoindoles, their synthesis and use in therapeutic praxis as the inhibitors of aldose reductase and antioxidants, Slovak Patent Registration PP 98-2005.

Dynamic model of glucose – insulin interaction. A circulatory, physiologically relevant, dynamic model of glucose – insulin interaction was developed. The modelling approach used is based on the theory of dynamic systems and represents an advanced opposite to the sum of exponential modelling, which yields only a formal description of the observed behaviour of the substance under investigation, having an outward appearance but lacking in substance. The model and modelling approach represent a contribution to the current state of high-level-system-biology modelling adopted within the pharmaceutical industry with the aim to improve drug development and decision-making. References:

ĎURIŠOVÁ, M., DEDÍK, L. Basic and Clinical Pharmacology and Toxicology. Vol. 96, (2005), p. 335-342. ● DEDÍK, L., ĎURIŠOVÁ, M., PENESOVÁ, A. Klinická Farmakologie a Farmacie. Vol. 17, (2003), p. 132-138. ● DEDÍK, L., ĎURIŠOVÁ, M., PENESOVÁ, A. Klinická Farmakologie a Farmacie. Vol. 17, (2003), p. 139-144.

Applied research Department of Toxicology and Animal Breeding The Department located at Dobrá Voda near Trnava is an integral part of the Institute. It is the largest centre for toxicological research and breeding of laboratory animals in Slovakia. The Department possesses:

• Accreditation for breeding and experimentation on laboratory animals issued by the State Veterinary Administration of the Slovak Republic No 7656/02-2201

• Certificate of GLP Compliance No 23/2000 issued by the Slovak National Accreditation Service. Area of expertise: toxicity studies, carcinogenicity, care and housing of animals

• Statement of entry in the Register of Diets for Experimental Animals in the Slovak Republic No 8922

The Department produces laboratory animals (rats: Wistar - outbred, Lewis - inbred, SHR - inbred, mice: ICR - outbred, guinea pigs: TRIK-outbred, gerbils: MON agouti and black - outbred) and laboratory animal diet for rats and mice, guinea pigs and rabbits and for dogs, both for the national and international market. With the competent and experienced staff of the toxicological laboratory, experimental and consultancy services have been provided to

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industrial clients in Slovakia and abroad, regarding the development and safety assessment of pharmaceuticals, chemicals and consumer products. Toxicity studies are performed using up-to-date research techniques in compliance with GLP and OECD guidelines for testing of chemicals. The offered tests are in accordance with the Directives 1999/12/EC; 92/69 EEC; 96/54/EC; 2001/59/EC; 88/302/EEC and OECD Test Guidelines for acute toxicity (dermal, skin and eye irritation, skin sensitisation); repeated dose toxicity, subchronic and chronic toxicity. In cooperation with domestic and foreign partners, the Department performed the followed studies, during the assessed period:

1. Acute and repeated dermal toxicities of antipsoriatics (Derma Protect + Innovation, GmbH, Friedrichshafen, Germany),

2. Production of hyperimmune sera in rabbits (Biovendor, Laboratory Medicine, a.s., Brno, Czech Republic),

3. Acute toxicities of new species of magnetic nanoparticles (Institute of Experimental Physics, SAS, Košice),

4. Acute and repeated oral and dermal toxicites of the new prospective drugs (PHARMACENTRUM, s.r.o. Bratislava).

Protective effect of the substance VULM 1457, a new ACAT inhibitor. Cellular signalling mechanisms induced by the new lipid lowering drug VULM1457 (the prospective inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-CoA reductase) were investigated. Identification of specific cellular [125I]adrenomedullin (AM) binding sites on human HepG2 cells, abundantly expressing AM, production of a protective AM family of peptides in human tumourigenic cells, their proliferation and change in viability of cells were used as indicators of activation of cells and expression of surface adhesive proteins. Our experimental findings indicate reduced expression of specific AM binding sites on cells, thus documenting a significant protective effect of VULM1457, most probably related to its effects on signalling chains or to the nuclear component of hyperproliferative activation of cells. (Users: Drug Research Institute Modra a.s, Slovakofarma a.s., Léčiva, a.s., Zentiva s.r.o., Warburg-Pincus LLC.) Acute toxicities of selected magnetic nanoparticles. Related to the usage of magnetic fluids (which are developed at the Institute of Experimental Physics SAS in Košice) as a vehicle of drugs which will be administered to the organism, acute toxicity of selected fluids after peroral and intravenous treatment in mice has been established. Appropriate models (adjuvant arthritis in rats, trauma of the head in mice and hypoxic-ischaemic brain damage in gerbils) have been introduced to study pharmacodynamic effects of the model drugs in the free form compared to the drugs bound to the magnetic vehicle in in vivo conditions. (User: pharmaceutical industry, the confidential expert´s report is available on request at the IEPH). Antiaggregatory and antioxidative effect of carvedilol in vitro and in patients with congestive heart failure and diabetes mellitus. Evaluation of experimental data speaks in favour of the administration of carvedilol in pathological states accompanied with ischaemia/reperfusion-induced tissue damage. Collaborative investigation with clinicians confirmed the suggestion of a beneficial effect of carvedilol in patients suffering from congestive heart failure and diabetes mellitus type 2. In these patients, carvedilol therapy reduced the concentration of reactive oxygen species in blood, decreased activation of blood platelets and improved their quality of life. The limited duration of the project did not enable extensive and long-term monitoring of the patients; therefore the investigation will be continued despite the formal termination of the study. (User: 1st Department of Medicine of the Faculty Hospital, Bratislava). Reference:

DRÁBIKOVÁ, K., JANČINOVÁ, V., NOSÁĽ, R., et al. Neuroendocrinology Letters.. Vol. 27, (2006), p. 138-140.

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International cooperation Effect of stobadine on leukocyte function in experimental diabetes. In a model of experimental diabetes in rats, the effect of the antioxidant stobadine on the ability of leukocytes to produce reactive oxygen species was investigated. Diabetic rats revealed significantly decreased chemiluminiscence of the whole blood after stimulation by phorbol myristate. Treatment of diabetic rats with stobadine for 10 weeks prevented the depression of the chemiluminiscence response. The results showed that stobadine was effective in the prevention of impairment of leukocyte free radical release function in diabetic rats. (Cooperation with the Scientific and Technical Research Council, Turkey, the results were integrated in the most important results of international cooperation in the Annual Report of SAS in 2004) Reference:

DEMIRYUREK, A.T., KARASU, C., STEFEK, M., STOLC, S. Pharmacology. Vol. 70, (2004), p.1-4.

Effect of stobadine on neuropathic changes in the reproductive system of diabetic male rats. Experimentally diabetic rats in an 8-month chronic diabetes model showed significant decrease in contractility of the isolated vas deferens elicited by electrical field stimulation as well as a significant increase in the contractile response of the vas deferens to exogenous noradrenaline, when compared with control rats. Administration of stobadine dipalmitate reverted both parameters towards control values. The results point to the ability of the antioxidant stobadine to prevent degenerative changes seen in diabetic sympathetic nerves of the vas deferens and are suggestive of antioxidants as therapeutic agents in reproductive system disability of male diabetics. (Cooperation with the Scientific and Technical Research Council Turkey, the results were integrated in the most important results of international cooperation in the Annual Report of SAS in 2005) Reference:

GÜNEŞ, A., CEYLAN, A., SARIOGLU, Y., ŠTEFEK, M., et al. Fundamental & Clinical Pharmacology. Vol. 19, (2005), p. 73-79.

Mathematic modelling of vessel responses in vitro. Vascular responsiveness to biologically active substances is commonly investigated by measurement of responses of vessels and registration of the responses on analogous recorders. Subsequently, descriptive variables of the responses are determined by manual evaluation of registered profiles. Such evaluation is inaccurate and poorly reproducible. Hence there is an increasing need for computational evaluation procedures. Thus techniques for automatic measurement and digital recording of vessel responses to biologically active substances and for mathematical modelling of the underlying processes were developed. (Cooperation within BioSim - A Network of Excellence 6th FP and COST projects) References:

DEDÍK, L., ĎURIŠOVÁ, M., SVRČEK, V., et al. Methods and Findings in Experimental and Clinical Pharmacology. Vol. 25, (2003) p.441-45. ● GRUNDMANN, M., DEDÍK, L., ĎURIŠOVÁ, M., et al. Therapeutic Drug Monitoring. Vol. 25, (2003), p. 97. ● CHAUBAL, M.V., DEDÍK, L., ĎURIŠOVÁ, M., BRULEY, D.F. Advances in Experimental Medicine and Biology. Vol. 566.(2005), p. 389-395.

Oxidative degradation of synovial hyaluronans: a pathological event in arthritic joints, effective pharmacological intervention with antioxidants in vitro. The degradation of an essential component of the synovial fluid – hyaluronan – was investigated. From the potential degradative species the main attention was payed to the combination of copper(II) ions and ascorbate under aerobic conditions. The combination of Cu(II) and physiological ascorbate caused a relevant degradation of high-molar-mass hyaluronan. This degradative model was used for searching the effectiveness of various drugs/antioxidants which are used in treating

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joint inflammation. (Cooperation between DAAD Germany and SAS, the results were integrated in the most important results of international cooperation in the Annual Report of SAS in 2006) Reference:

ŠOLTÉS L., MENDICHI R., KOGAN G., et al. Biomacromolecules. Vol. 7, (2006), p. 659-668.

Antioxidative properties of medicinal agents and endogenous inhibitors. Alterations in neutrophil oxidative burst by blood platelets. Scientific cooperation was focussed on the analysis of the effects of betaadrenoceptor blocking drugs and H1- antagonists on the production and formation of ROS and RNS in cell-free systems and on the analysis of these medicinal compounds in oxidative stress in phagocytes and blood platelets with respect to the suppression of chemiluminescence (extra- intracellular level), generation of superoxide, peroxyl, hydroxyl and peroxide radicals and myeloperoxidase liberation as well as their anti-inflammatory activity. The analysis of serotonin, serotonin-substituents and SSRI (selective serotonin reuptake inhibitors) were studied with respect to their antiradical effects in cell cultures and special attention was focussed on the formation of iNOS. (Slovak-Czech Scientific and Technical Cooperation between the Department of Cellular Pharmacology IEPH SAS and Department of Pathophysiology of Free Radicals, Institute of Biophysics Academy of Sciences of the Czech Republic) References:

JANČINOVÁ,V., DRÁBIKOVÁ,K., NOSÁĽ, R. et al.Thromb Res. Vol.109, (2003), p. 293-298. ● PEČIVOVÁ, J., MAČIČKOVÁ,T., ČÍŽ, M., et al. Physiological Research. Vol. 53, (2004), p. 97-102. ● NOSÁĽ, R., JANČINOVÁ, V., ČÍŽ, M., et al. Scandinavian Journal of Clinical and Laboratory Investigation. Vol. 65, (2005), p.55-64. Ferritin oxidation and proteasomal degradation: Protection by antioxidants. The accumulation of oxidatively damaged proteins is a well-known hallmark of ageing and several neurodegenerative diseases including Alzheimer´s, Parkinson´s and Huntigton´s diseases. Protective effects of the vitamin E derivative Trolox, the pyridoindole derivative stobadine and of the standardised extracts of flavonoids from the bark of Pinus Pinaster Pycnogenol® and from leaves of Ginkgo biloba were studied on moderately damaged ferritin. The effects of the above mentioned antioxidants on PC 12 cells oxidised by hydrogen peroxide were studied. All antioxidants increased the viability of hydrogen peroxide-treated PC 12 cells. Correlations between viability increase induced by antioxidants and the content of oxidation products of proteins and lipids were studied in concentrations of antioxidants most effective in preventing cell death. Concentrations of antioxidants with a large effects on viability of PC 12 cells were not effective in preventing oxygen radical induced injury of proteins. Antioxidants prevented the oxidative injury of lipids more effectively than that of proteins. (Cooperation with the Research Institute for Environmental Medicine at the Heinrich-Heine-University Duesseldorf, Germany) References:

VOSS, P., HORÁKOVÁ L., JAKSTADT, M., et al. Free Radical Research. Vol. 40, (2006), p. 673-683. ● HORÁKOVÁ, L., LICHT A., SANDIG G., et al. Archives of Toxicology. Vol. 77, 22-29, 2003.

(For detailed information see other parts of the Questionnaire and relevant Annual Reports)

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3. Concept of R&D activity of the Organisation for the next four years (max. 5 pages)

Main interests and research activities of the IEPh SAS are focussed on pharmacological intervention in oxidative damage and oxidative stress accompanying inflammatory reactions of the organism.

III. Partial indicators of the main activities: 1. Research output

i. List of the selected publications documenting the most important results of basic research. Total number of publications in the whole assessed period should not exceed the average number of the research employees

1. DEDÍK, L. - ĎURIŠOVÁ, M. - SVRČEK, V. - VOJTKO, R. - KRISTOVÁ, V. - KRIŠKA. M.

Computer-based methods for measurement, recording, and modeling vessel responses in vitro: A pilot study with noradrenaline. In Methods and Findings in Experimental and Clinical Pharmacology. Vol. 25, no. 5 (2003), p. 441-445.

2. HORÁKOVÁ, Ľ. - LICHT, A. – SANDIG, G. – JAKSTADT, M. – ĎURAČKOVÁ, Z. – GRUNE, T. Standardized extracts of flavonoids increase the viability of PC12 cells treated with hydrogen peroxide: effects on oxidative injury. In Archives of Toxicology. Vol. 77, (2003), p. 22-29.

3. JANČINOVÁ, V. – DRÁBIKOVÁ, K. – NOSÁĽ, R. – PETRÍKOVÁ, M. – ČÍŽ, M. – LOJEK, A. – DANIHELOVÁ, E. Inhibition of FMLP-stimulated neutrophil chemiluminescence by blood platelets increased in the presence of the serotonin-liberating drug chloroquine. In Thrombosis Research. Vol. 109, (2003), p. 293-298.

4. OKRUHLICOVÁ, Ľ.- UJHÁZY, E.- MACH, M.- SOTNÍKOVÁ, R.- TRIBULOVÁ, N.- GULLER, L.- DUBOVICKÝ, M. Effect of prenatal phenytoin administration on the fine structure of rat myocardium and aorta. Pathology Research and Practice. Vol. 199, no.10 (2003) p. 677-685.

5. PUCOVSKÝ, V. – MOSS, R.F. – BOLTON, T.B.: Non-contractile cells with thin processes resembling interstitial cells of Cajal found in the wall of guinea-pig mesenteric arteries. Journal of Physiology-London. Vol. 552, no. 1 (2003), p. 119-133.

6. BELEVYCH, A.E. - JURÁNEK, I. - HARVEY, R.D. Protein Kinase C Regulates Functional Coupling of β1-Adrenergic Receptors to Gi/o-Mediated Responses in Cardiac Myocytes. In FASEB Journal. Vol. 18, no. 15 (2004), p. 367-369.

7. DEMIRYUREK, A.T.- KARASU, C.- ŠTEFEK, M.- ŠTOLC, S. Effect of stobadine on leukocyte free radical generation in streptozotocin-diabetic rats: comparison with vitamin E. In Pharmacology. Vol. 70, no. 1 (2004), p.1-4.

8. KYSEĽOVÁ, Z. - ŠTEFEK, M. - BAUER, V. Pharmacological prevention of diabetic cataract. Review. In Journal of Diabetes and its Complications. Vol. 18, no. 2 (2004), p.129-140.

9. MACH, M. – GRUBBS, R.D. – PRICE, W.A. – PATON, S. – LUCOT J.B. Behavioral changes after acetycholinesterase inhibition with pyridostigmine in mice. In Pharmacology Biochemistry and Behavior. Vol. 79, no. 3 (2004), p. 533-540.

10. PEČIVOVÁ, J. – MAČIČKOVÁ, T. – ČÍŽ, M. - NOSÁĽ, R. – LOJEK, A. Effect of stobadine on opsonized zymosan stimulated generation of reactive oxygen species in human blood cells. In Physiological Research. Vol. 53, no. 1 (2004), p.97-102.

11. RAČKOVÁ, L.- MÁJEKOVÁ, M.- KOŠŤÁLOVÁ, D.- ŠTEFEK, M. Antiradical and antioxidant activities of alkaloids isolated from Mahonia aquifolium. Structural aspects. In Bioorganic & Medicinal Chemistry. Vol. 12, no. 17 (2004), p. 4709-4715.

12. ĎURIŠOVÁ, M. - DEDÍK, L. New mathematical methods in pharmacokinetic modeling. In Pharmacology & Toxicology. Vol. 96, (2005), p. 335-342.

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13. HORÁKOVÁ, Ľ. - ŠTROSOVÁ, M. - ŠKUCIOVÁ, M. Oxidative injury of rabbit skeletal muscle sarcolasmic reticulum Ca2+-ATPase induced by Fe2+/H2O2/ascorbate system. Preventive effects of antioxidants. In Biofactors. Vol. 23, (2005), p. 1-5.

14. JURÁNEK, I. – BEZEK, Š. Controversy of free radical hypothesis: Reactive oxygen species – Cause or consequences of tissue injury. In General Physiology and Biophysics. Vol. 24, no. 3 (2005), p. 263-78.

15. KOGAN, G. - STAŠKO, A. - BAUEROVÁ, K. – POLOVKA, M. – ŠOLTÉS, L. –BREZOVÁ, V. – NAVAROVÁ, J. – MIHALOVÁ, D. Antioxidant properties of yeast (1→3)-β-D-glucan studied by electron paramagnetic resonance spectroscopy and its activity in the adjuvant arthritis. In Carbohydrate Polymers. Vol. 61 (2005), p. 18-28.

16. KYSEĽOVÁ, Z. – GAJDOŠÍK, A. – GAJDOŠÍKOVÁ, A. – ULIČNÁ, O. – MIHALOVÁ, D. – KARASU, C. – ŠTEFEK, M. Effect of the pyridoindole antioxidant stobadine on development of experimental diabetic cataract and on lens protein oxidation in rats: comparison with vitamin E and BHT. In Molecular Vision. Vol. 11, (2005), p.56-65.

17. KYSEĽOVÁ, Z. – GARCIA, S.J. – GAJDOŠÍKOVÁ, A. – GAJDOŠÍK, A. – ŠTEFEK, M. Temporal relationship between lens protein oxidation and cataract development in streptozotocin-induced diabetic rats. In Physiological Research. Vol. 54, no. 1 (2005), p.49-56.

18. MAKATSORI, A. – DUBOVICKÝ, M. – UJHÁZY, E. – BAKOŠ, J. – JEŽOVÁ, D. Neuroendocrine changes in adult female rats prenatally exposed to phenytoin. In Neurotoxicology and Teratology. Vol 27, no. 3 (2005), p.509-514.

19. NOSÁĽ, R. - JANČINOVÁ, V. - ČÍŽ, M.- DRÁBIKOVÁ, K. - LOJEK, A. - FÁBRYOVÁ, V. Inhibition of chemiluminescence by carvedilol in the cell-free system, whole human blood and blood cells. In Scandinavian Journal of Clinical and Laboratory Investigation. Vol. 65, no.1 (2005), p.55-64.

20. RAČKOVÁ, L. – FIRÁKOVÁ, S. – KOŠŤÁLOVÁ, D. – ŠTEFEK, M. – ŠTURDÍK, E. – MÁJEKOVÁ, M. Oxidation of liposomal membrane suppressed by flavonoids: Quantitative structure-activity relationship. In Bioorganic & Medicinal Chemistry. Vol. 13, no. 23, (2005), p. 6477-6484.

21. ŠTEFEK, M. – KYSEĽOVÁ, Z. – RAČKOVÁ, L. – KRIŽANOVÁ, Ľ. Oxidative modification of rat eye lens proteins by peroxyl radicals in vitro: protection by the chain-breaking antioxidants stobadine and Trolox. In Biochimica et Biophysica Acta. Vol. 1741, no. (1-2) (2005), p.183-190.

22. BAUEROVÁ, K. – PONIŠT, S. – ONDREJIČKOVÁ, O. KOMENDOVÁ, D. – MIHALOVÁ, D. Association between tissue gamma-glutamyl-transferase and clinical markers of adjuvant arthritis in Lewis rats. In Neuroendocrinology Letters. Vol 27 (Suppl 2) (2006), p. 172-175.

23. DJOUBISSIE, P.-O. - ŠNIRC, V. - SOTNÍKOVÁ R. - KYSEĽOVÁ Z. - SKALSKÁ, S. – GAJDOŠÍKOVÁ A. - GAJDOŠÍK A. - JAVORKOVÁ V. - VLKOVIČOVÁ J. - VRBJAR N. - ŠTEFEK M. In vitro Inhibition of Rat Lens Aldose Reductase by (2-Benzyl-2,3,4,5-Tetrahydro-1H-Pyrido[4,3-B]Indole-8-yl)-Acetic Acid in Enzyme Preparation Isolated from Diabetic Rats. In General Physiology and Biophysics. Vol. 25, no 4 (2006), p.415-425.

24. DRÁBIKOVÁ, K. - JANČINOVÁ, V. - NOSÁĽ, R. – SOLÍK, P.- MURÍN, J.- HOLOMÁŇOVÁ, D. On the antioxidant activity of carvedilol in human polymorphonuclear leukocytes in vitro and ex vivo. In Neuroendocrinology Letters. Vol. 27, Suppl.2, (2006), p. 138-140.

25. DŘÍMAL, J. – DŘÍMAL, J.JR – DŘÍMAL, D. Hypoxic stress-enhanced expression and release of adrenomedullin (AM) and up-regulated AM receptors, while glucose starvation reduced AM expression and release and down-regulated AM receptors in monkey renal cells. In Physiological Research. Vol. 55, no.5 (2006), p. 535-542.

26. DŘÍMAL, J. – ZÚROVÁ-NEDELČEVOVÁ, J. – KNEZL, V. –SOTNÍKOVÁ, R. –NAVAROVÁ, J. Cardiovascular toxicity of the first line cancer chemotherapeutic agents: doxorubicin, cyclophosphamide, streptozotocin and bevacizumab. In Neuroendocrinology Letters. Vol. 27, Suppl.2 (2006), p.176-179.

27. GAJDOŠÍKOVÁ, A. – GAJDOŠÍK, A. – KONERACKÁ, M . – ZÁVIŠOVÁ, V. – ŠTVRTINA, S. – KRCHNÁROVÁ, V. – KOPČANSKÝ, P. – TOMAŠOVIČOVÁ, N. – ŠTOLC, S. – TIMKO, M.

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Acute toxicity of magnetic nanoparticles in mice. In Neuroendocrinology Letters. Vol. 27, Suppl 2 (2006), p. 96 – 99.

28. GÁSPÁROVÁ, Z. - ŠTOLC, S. - ŠNIRC, V. In vitro physiological evidence of enhanced neuroprotective and antioxidant action of 2,3-dihydromelatonin: a melatonin analogue. In Pharmacological Research. Vol. 53, no.1 (2006), p.22-27.

29. KNEZL, V. - KYSEĽOVÁ, Z. - ZÚROVÁ, J. - NAVAROVÁ, J. – TRIBULOVÁ, N. - DŘÍMAL, J. Effect of acetylcholine and ischaemia/reperfusion injury on the heart with STZ-induced experimental diabetes. In Neuroendocrinology Letters. Vol. 27, Suppl. 2 (2006), p.144-147.

30. MÁJEKOVÁ, M. – KOPRDA, V. – BOHÁČIK, Ľ. – BOHOV, P. – HADGRAFT, J. – BEZÁKOVÁ, Ž. – MÁJEK, P. Skin permeation of acyl derivatives of stobadine. In Drug Delivery. Vol. 13, no.1 (2006) p. 51-54.

31. NAVAROVÁ, J. - SCHMIDTOVÁ, M. - UJHÁZY, E. - DUBOVICKÝ, M. - MACH, M. Selected biochemical variables in a model of neonatal anoxia in rats. In: Neuroendocrinology Letters. Vol. 27, Suppl. 2, (2006), p.78-81.

32. NOSÁĽ, R. Antiplatelet and antileukocyte effects of cardiovascular, immunomodulatory and chemotherapeutic drugs. In Cardiovascular & Hematological Agents in Medical Chemistry. Vol. 4, (2006), p.237-261.

33. NOSÁĽOVÁ, V. - DRÁBIKOVÁ, K. - ZÚROVÁ J. – JANČINOVÁ, V. – OKRUHLICOVÁ, L. - SOTNÍKOVÁ, R. Ischaemia/reperfusion-induced organ injury in diabetes caused by low dose streptozotocin. In Neuroendocrinology Letters. Vol. 27, Suppl. 2, (2006), p.152-155.

34. RAČKOVÁ, L. – ŠNIRC, V. – MÁJEKOVÁ, M. - MÁJEK, P. – ŠTEFEK, M.. Free radical scavenging and antioxidant activities of substituted hexahydropyridoindoles. Quantitative structure-activity relationships. In Journal of Medicinal Chemistry. Vol.49, no. 8 (2006) p.2543-2548.

35. ŠOLTÉS, L. – MENDICHI, R. – KOGAN, G. – SCHILLER, J. – STANKOVSKÁ, M. - ARNHOLD, J. Degradative Action of Reactive Oxygen Species on Hyaluronan. In Biomacromolecules. Vol. 7, no. 3 (2006), p. 659-668.

36. SOTNÍKOVÁ, R. - SKALSKÁ, S. - OKRUHLICOVÁ, L. - NAVAROVÁ, J. - KYSEĽOVÁ, Z. - ZÚROVÁ, J. - ŠTEFEK, M. – HOZOVÁ, R. – NOSÁĽOVÁ, V. Changes in the function and ultrastructure of vessels in the rat model of multiple low dose streptozotocin-induced diabetes. In General Physiology and Biophysics. Vol. 25, n. 3 (2006), p.289-302.

37. ŠTOLC, S. – ŠNIRC, V. - MÁJEKOVÁ, M. – GÁSPÁROVÁ, Z. – GAJDOŠÍKOVÁ, A., - ŠTVRTINA, S. Development of the New Group of Indole-Derived Neuroprotective Drugs Affecting Oxidative Stress. In Cellular and Molecular Neurobiology. Vol 26, no 7-8 (2006), p.1493-1502.

38. UJHÁZY, E. - SCHMIDTOVÁ, M. - DUBOVICKÝ, M. - NAVAROVÁ, J. -BRUCKNEROVÁ, I. - MACH, M. Neurobehavioural changes in rats after neonatal anoxia: effect of antioxidant stobadine pretreatment. In Neuroendocrinology Letters. Vol. 27, Suppl. 2, (2006), p.82-85.

39. ZÚROVÁ-NEDELČEVOVÁ, J . - NAVAROVÁ, J. - DRÁBIKOVÁ, K. - JANČINOVÁ, V. - PETRÍKOVÁ, M. - BERNÁTOVÁ, I. - KRISTOVÁ, V. - ŠNIRC, V. - NOSÁĽOVÁ, V. - SOTNÍKOVÁ, R. Participation of reactive oxygen species in diabetes-induced endothelial dysfunction. In Neuroendocrinology Letters. Vol. 27, Suppl. 2, (2006), p. 168-171.

ii. List of monographs/books published abroad

Chapters:

1. DEDÍK L. - ĎURIŠOVÁ M. Advanced system-approach based methods for modeling biomedical systems. In: Lecture Series on Computer and Computational Series I, for International Conference of Computational Methods in Science and Engineering

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2004, ICCMSE 2004, Athens, (Simos, T.E. (ed.), Brill Academic Publishers, (2004) p. 246-251.

2. CHAUBAL, M.V. - DEDÍK, L. - ĎURIŠOVÁ, M. - BRULEY, D.F.: Modeling behavior of protein C during and after subcutaneous administration In: OXYGEN TRANSPORT TO TISSUE XXVI: Series: Advances in experimental medicine and biology. New York: Springer - Verlag, 2005 Vol.566. ISBN 038725062X. p. 389-395.

3. KOGAN, G. – ŠOLTÉS, L. – STERN, R. – SCHILLER, J. – MENDICHI, R. Hyaluronic acid: Its function and degradation in in vivo systems. In: Atta-ur-Rahman (ed.) Studies in Natural Products Chemistry (Vol. 35 Bioactive Natural Products, Part D), Elsevier, Amsterdam (2006)

iii. List of monographs/books published in Slovakia Chapters:

[1] NAVAROVÁ, J. – UJHÁZY, E. – MACH, M. – OKRUHLICOVÁ, Ľ. – SOTNÍKOVÁ, R. – DUBOVICKÝ, M. – DYTRICHOVÁ, V. Administration of phenytoin during gravidity – its effect on offsprings. In ŠVEC, P., TOMO I. Biomedicínske štúdie. Bratislava: Slovenská biologická spoločnosť pri SAV, 2003. ISBN 80-968314-5-3. p.57-61.

[2] SOTNÍKOVÁ, R. - NOSÁĽOVÁ, V. – MIHALOVÁ, D. – SZŐCS, K. – NAVAROVÁ, J. Lokálne a vzdialené poškodenie vyvolané mezenterickou ischémiou/reperfúziou. In ŠVEC, P., TOMO I. Biomedicínske štúdie Bratislava: Slovenská biologická spoločnosť pri SAV, 2003. ISBN 80-968314-5-3. p.78-82.

[3] UJHÁZY, E. – MACH, M. – DUBOVICKÝ, M. – NAVAROVÁ, J. – BRUCKNEROVÁ, I. – JURÁNEK, I. In ŠVEC, P., TOMO I. Biomedicínske štúdie Bratislava: Slovenská biologická spoločnosť pri SAV, 2003. ISBN 80-968414-5-3. p.73-77.

[4] TRIBULOVÁ, N., KNEZL,V: Myocardial gap junctions and cardiac arrhythmias In Experimental Hypertension and Ischemic Heart Disease Ed. L Bacharova, J.Kyselovic a J.Slezak Veda Publishing House SAS Bratislava 2005, pp219-234.

[5] FIALOVÁ, M. – ŠMÍDOVÁ, S. – MACSALIOVÁ, A. – KNEZL, V. – DLUGOŠOVÁ, K. – OKRUHLICOVÁ, Ľ. – WEISMANN, P. – DŘÍMAL, J. – TRIBULOVÁ, N.: Beneficial effects on N-3 polyunsaturated fatty acids on aged hypertensive rat hearts. In Potential therapeutic targets in cardiovascular and other diseases Ed.: N. Tribulova and Ľ.Okruhlicova, VEDA, Bratislava 2006, p. 34-36.

[6] KNEZL, V. – TRIBULOVÁ, N. – OKRUHLICOVÁ, Ľ. – SLEZÁK, J. – STYK, J., DŘÍMAL, J. – MANOACH, M.: Thyroid hormones modulate occurence and termination of ventricular fibrillation by both genomic and nongenomic actions. In Potential therapeutic targets in cardiovascular and other diseases Ed.: N. Tribulova and Ľ.Okruhlicova, VEDA, Bratislava 2006, p. 57-59.

[7] TRIBULOVÁ, N. – SEKI, S. – KAPLAN, P. – BABUŠÍKOVÁ, E. - KNEZL, V. – MOCHIZUKI, S. – MANOACH, M.: Heart cell Ca2+ handling is involved in initiation persistance and termination of fatal arrhythmias. In: Potential therapeutic targets in cardiovascular and other diseases Ed.: N. Tribulova and Ľ.Okruhlicova, VEDA, Bratislava 2006, p. 67-70.

[8] DJOUBISSIE, O.P. – ŠNIRC, V. – RAČKOVÁ, L. – MÁJEKOVÁ, M. – SOTNÍKOVÁ, R. – ŠTEFEK, M. Carboxymethylated pyridoindoles as aldose reductase inhibitors: Enzyme kinetics and selectivity. In Pokroky vo farmakológii v Slovenskej Republike. Ed. Peter Mačura PEEM, Bratislava 2006, ISBN 80-89197-49-3. p.47-50.

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[9] SOTNÍKOVÁ, R. – ZÚROVÁ, J. – BERNÁTOVÁ, I. Rozdiely v odpovedi mezenterickej artérie normotenzných a spontánne hypertenzných potkanov na dlhodobý sociálny stres. In Mechanizmy regulácie krvného tlaku a ich poruchy. Bratislava: Bernátová I., Kristek F., Pecháňová O., Török J. (eds.). Univerzita Komenského Bratislava, 2006. ISBN 80-223-2243-1. p.61-69.

[10] ZÚROVÁ, J. - NAVAROVÁ, J. - KYSEĽOVÁ, Z. - ŠNIRC, V. -NOSÁĽOVÁ, V. - SOTNÍKOVÁ, R. Štúdium endotelovej dysfunkcie na experimentálnom modeli mierneho diabetu: Vplyv antioxidantu SMe1EC2. In Pokroky vo farmakológii v Slovenskej republike. Bratislava: Švec P., Kyselovič J., Mátyas Š. (eds.), Peter Mačura-PEEM, 2006. ISBN 80-89197-49-3. p. 27-31.

iv. List of other scientific outputs specifically important for the Organisation

I. On-line publications:

[1] BELEVYCH, A.E. - JURÁNEK, I. - HARVEY, R.D. Protein Kinase C Regulates Functional Coupling of β1-Adrenergic Receptors to Gi/o-Mediated Responses in Cardiac Myocytes. In FASEB Journal. Vol. 17, no. 15 (2003), p. U134-U152. Online.

[2] MACH, M. - DUBOVICKY, M. - NAGOAKA, M. – LUCOT, J.B. Behavioral similarities and differences between acetylcholinesterase inhibitors in mice. Program No. 163.11. 2006 Neuroscience Meeting Planner. Atlanta, GA: Society for Neuroscience, 2006. Online.

[3] MÁJEKOVÁ, M. – ŠNIRC, V. – ŠTOLC, S. – BEZÁKOVÁ, Ž.– SOTNÍKOVÁ, R. The alpha1-adrenolytic and structural evaluation of new pyridoindole derivatives. In Central European Journal of Medicine. Vol. 1, no. 4. (2006), p.370-378. Online.

[4] DRÁBIKOVÁ, K.-JANČINOVÁ, V.-NOSÁĽ, R.-PEČIVOVÁ, J.-MAČIČKOVÁ, T.-TURČÁNI, P. Inhibitory effect of stobadine on FMLP-induced chemiluminescence in human whole blood and isolated polymorphonuclear leukocytes. In Luminescence, Online.

[5] PEČIVOVÁ, J.- MAČIČKOVÁ, T. - LOJEK, A. - GALLOVÁ, L. - ČÍŽ, M. - NOSÁĽ, R.-HOLOMÁŇOVÁ, D. In vitro effect of carvedilol on professional phagocytes. In Pharmacology. Vol. 79, No. 2, (2007), p. 86-92, Online.

[6] DEDÍK, L. - ĎURIŠOVÁ, M. – PENESOVÁ, A.: Model for evaluation of data from oral glucose tolerance test. In Klinická Farmakologie a Farmacie, 2003; 17: 139-14 Online.

II. The Institute is a regular organiser and co-organiser of the Interdisciplinary Slovak and Czech Toxicological Conferences. There were 4 conferences organised by the Institute during the assessed period.

III. Scientific cooperation in the field of applied research which resulted in expert ´s reports:

1. Acute and repeated dermal toxicities of antipsoriatics (Derma Protect + Innovation, GmbH, Friedrichshafen, Germany),

2. Production of hyperimmune sera in rabbits (Biovendor, Laboratory Medicine, a.s., Brno, Czech Republic),

3. Acute toxicities of new species of magnetic nanoparticles (Institute of Experimental Physics, SAS, Košice),

19

4. Acute and repeated oral and dermal toxicites of the new prospective drugs (PHARMACENTRUM, s.r.o. Bratislava).

v. Table of research outputs Table Research outputs shows research outputs in number of specified entries; these

entries are then divided by FTE employees with a university degree (from Tab. Research

staff) for all Organisation at the respective year; finally these entries are divided by the

total salary budget (from Tab. Salary budget).

num

ber

No.

/ FT

E

No.

/ sa

lary

bud

get

num

ber

No.

/ FT

E

No.

/ sa

lary

bud

get

num

ber

No.

/ FT

E

No.

/ sa

lary

bud

get

num

ber

No.

/ FT

E

No.

/ sa

lary

bud

get

num

ber

aver

aged

num

ber

per y

ear

av. N

o. /

FTE

av. N

o. /

sala

ry

budg

et

chapters in monographs, books published abroad

1 0,03 0,08 1 0,03 0,07 1 0,03 0,07 1 0,03 0,07 4,0 1,0 0,03 0,07

chapters in monographs, books published in Slovakia

3 0,09 0,23 0 0,00 0,00 1 0,03 0,07 6 0,20 0,42 189 2,50 0,13 0,29

CC publications 37 1,10 2,85 24 0,78 1,77 42 1,41 3,00 64 2,09 4,44 167 41,8 1,34 3,04

scientific publications indexed by other databases (specify)

0 0,00 0,00 0 0,00 0,00 0 0,00 0,00 0 0,00 0,00 0 0,0 0,00 0,00

scientific publications in other journals 33 0,98 2,54 17 0,55 1,26 23 0,77 1,64 6 0,20 0,42 79 19,8 0,63 1,44

publications in proc. of international scientific conferences

35 1,04 2,70 41 1,32 3,03 28 0,94 2,00 85 2,77 5,90 189 47,3 1,51 3,44

publications in proc. of nat. scientific conferences

0 0,00 0,00 0 0,00 0,00 0 0,00 0,00 0 0,00 0,00 0 0,0 0,00 0,00

active participations at international conferences

58 1,73 4,47 48 1,55 3,55 52 1,75 3,71 51 1,66 3,54 209 52,3 1,67 3,81

active participations at national conferences 10 0,30 0,77 12 0,39 0,89 6 0,20 0,43 3 0,10 0,21 31 7,8 0,25 0,56

total

Research outputs

2003 2004 2005 2006

20

vi. Renormalized publications2 Renormalized publications = number of CC publications in the given year times

authorship’s portion of the Organisation times the journal impact factor in 2005 divided by

the median impact factor in the research field

num

ber

No.

/ FT

E

No.

/ sa

lary

bud

get

num

ber

No.

/ FT

E

No.

/ sa

lary

bud

get

num

ber

No.

/ FT

E

No.

/ sa

lary

bud

get

num

ber

No.

/ FT

E

No.

/ sa

lary

bud

get

Renormalized publications 16,5 0,49 1,27 16,4 0,53 1,21 17,2 0,58 1,23 28,1 0,92 1,95

2006

Renormalised publications

2003 2004 2005

viii. List of patents and patent applications

Number: WO 03-091284 AI, CO7K 14/815 Authors: Nuttall P.A., Kazimirová M., Takac P., Trimnell A.L., Labuda M., Nosáľ, R., Jančinová V., Petriková M. Name: Anticoagulants Owner: Evolutec Limited, The Magdalen Centre, Oxford Science Park, Oxford OX4 4GA, GB Number: 1321-2003. Authors: Štolc, S. ,Považanec F. , Bauer, V. , Májeková, M. , Wilcox A.L. , Šnirc, V. , Račková, L. Sotníková, R. , Štefek, M., Gáspárová, Z., Gajdošíková, A., Mihalová, D., Alfoldi, J. Name: Pyridoindole derivatives with antioxidant properties, the way of their production and use in medicinal practice. Owner: The Institute of Experimental Pharmacology, SAS.

Number: PP 98-2005 Authors: Štefek M., Šnirc V., Demopoulos V., Djoubissie P., Račková L., Májeková M., Karasu C. Name: Karboxymetylated pyridoindoles, the way of their production and use in medicinal practice as inhibitors of the aldosareduktase and antioxidants. Owner: The Institute of Experimental Pharmacology, SAS. Number: EP1272530 B1, September 2006 Authors: Šoltés L., Steiner B., Machová E., Kogan G., Bystrický S., Mendichi R., Bauer V., Mach M., Alföldi J., Stratilová E. Name: Clathrate complexes formed by hyaluronic acid derivatives and use thereof as pharmaceuticals Owners: Fidia Farmaceutici, S.p.A., Abano Terme, Italy, a ÚEFa SAV, Bratislava, Slovakia.

2 This information is required only from the Organisations of the Section 2 of the Slovak Academy of Sciences.

21

ix. Supplementary information and/or comments on the scientific output of the Organisation

2. Responses to the scientific output

Table Citations shows specified responses to the scientific outputs; these entries are

then divided by the FTE employees with a university degree (from Tab. Research staff)

for all Organisation at the respective year; finally these entries are divided by the total

salary budget (from Tab. Salary budget).

num

ber

No.

/ FT

E

No.

/ sa

lary

bud

get

num

ber

No.

/ FT

E

No.

/ sa

lary

bud

get

num

ber

No.

/ FT

E

No.

/ sa

lary

bud

get

num

ber

No.

/ FT

E

No.

/ sa

lary

bud

get

num

ber

aver

aged

num

ber

per y

ear

av. N

o. /

FTE

av. N

o. /

sala

ry

budg

et

Web of Science 202 6,0 15,6 302 9,8 22,3 383 12,9 27,4 426 13,9 29,6 1313 328,3 10,5 23,9

SCOPUS 27 0,8 2,1 27 0,9 2,0 42 1,4 3,0 44 1,4 3,1 140 35,0 1,1 2,5

(specify Database 1) 0 0,0 0,0 0 0,0 0,0 0 0,0 0,0 0 0,0 0,0 0 0,0 0,0 0,0

in monographs, conf. proceedings and other publications abroad

3 0,1 0,2 4 0,1 0,3 15 0,5 1,1 8 0,3 0,6 30 7,5 0,2 0,5

in monographs, conf. proceedings and other publications in Slovakia

0 0,0 0,0 0 0,0 0,0 0 0,0 0,0 0 0,0 0,0 0 0,0 0,0 0,0

Citations

total2002 2003 2004 2005

22

i. List of 10 top-cited publications and number of their citations in the assessment period

1. BAUEROVÁ, K. – BEZEK, Š. Role of reactive oxygen and nitrogen species in etiopathogenesis of rheumatoid arthritis. In General Physiology and Biophysics. Vol. 18, Sp. Iss., (1999), p. 15-20. Citations: 40 2. ŠTOLC, S.: Indole derivatives as neuroprotectants. In Life Sciences. Vol. 65, no. 18-19, (1999), p. 1943-1950. Citations: 26 3. BAUER, V. – BAUER, F.: Reactive oxygen species as mediators of tissue protection and injury. In General Physiology and Biophysics. Vol. 18, Sp. Iss. SI, 1999, p. 7-14. Citations: 25 4. MIŠÍ ́K, V. - MIYOSHI, N -, RIESZ, P. EPR spin-trapping study of the sonolysis of H2O/D2O mixtures: Probing the temperatures of cavitation regions. In Journal of Physical Chemistry. Vol. 99, no. 11 (1995), p. 3605-3611. Citations: 19 5. KOVÁCS, P. - JURÁNEK, I. - STANKOVIČOVÁ, T. - ŠVEC, P. Lipid peroxidation during acute stress. In Pharmazie. Vol. 51, no. 1 (1996), p. 51-53. Citations: 18 6. HORÁKOVÁ, Ľ. - ŠTOLC, S. Antioxidant and pharmacodynamic effects of pyridoindole stobadine. In General Pharmacology. Vol. 30, no. 5 (1998), p. 627-638. Citations: 17 7. SOTNÍKOVÁ, R. Investigation of the mechanism underlying H2O2- evoked contraction in the isolated rat aorta. In General Pharmacology. Vol. 31, no. 1 (1998), p. 115-119. Citations: 14 8. ŠOLTÉS, L. Aminoglycoside antibiotics – two decades of their HPLC bioanalysis. In Biomedical Chromatography. Vol. 13, no. 1 (1999), p. 3-10. Citations: 12 9. ŠTOLC, S. – VLKOLINSKÝ, R. – PAVLÁSEK, J. Neuroprotection by the pyridoindole stobadine: A minireview. In Brain Research Bulletin. Vol. 42, no. 5 (1997), p. 335-340. Citations: 10 10. VLKOLINSKÝ, R. – ŠTOLC, S.: Effect of stobadine, melatonin, and other antioxidants on hypoxia/reoxygenation-induced synaptic transmission failure in rat hippocampal slices. In Brain Research. Vol. 850, no. 1-2 (1999), p. 118-126. Citations: 10

ii. List of top-cited authors from the Organisation (at most 10 % of the research employees) and their number of citations in the assessment period

1. Svorad Štolc 152 2. Vladimír Mišík 110 3. Ľubica Horáková 99 4. Ladislav Šoltés 91

23

iii. Supplementary information and/or comments on responses to the scientific output of the Organisation

Based on mutual coollaboration with the Department of Experimental Cardiology, Eppendorf University Hospital, Hamburg, Germany and Emory University, Atlanta, Georgia, USA, numerous best cited publications have been published. The co-author from the IEPh SAS was Katalin Szöcs. Her total number of citations for the assessed period is 566. Katalin Szöcs was also awarded by the LITA Agency for the citations in period of 2002-2004 in the field of natural sciences.

3. Research status of the Organisation in the international and national context

• International/European position of the Organisation i. List of the most important research activities documenting international

importance of the research performed by the Organisation, incl. major projects (details of projects should be supplied under Indicator 4). Collective membership in the international research organisations, in particular within the European Research Area

1. Biosimulation – a new tool in drug development (Project 6th FP-NoE)

2. In vitro and in vivo pharmacological studies of neuroprotective action of new compounds in oxidative stress (Project of the COST Program, Action B10)

3. Modelling in drug development (Project of the COST Program, Action B15)

4. Advanced approach to mathematical modelling in development of antiparasitic drugs (Project of the COST Program, Action B22)

5. Physiologically based pharmaco-toxicokinetics and dynamics (Project of the COST, Action B25)

6. Lipid peroxidation associated disorders (Project of the COST, Action B35)

7. Antioxidative properties of cationic amphiphilic drugs and endogene substances from blood platelets (Cooperation with the Institute of Biophysics, The Academy of Sciences, The Czech Republic)

8. Alteration of neutrophil oxidative burst by blood platelets (Cooperation with the Institute of Biophysics, the Academy of Sciences, the Czech Republic)

9. Antioxidative and antipahgocytic properties of chemical and natural compounds and drugs (Cooperation with the Institute of Biophysics, Academy of Sciences, Czech Republic)

10. Protective and Therapeutic Effect of Antioxidants in Injury Induced by Environmental Pollutants and/or Gamma Radiation (Cooperation with The National Center of Radiation Reserach and Technology, Atomic Energy Authority, Egyptian Academy of Sciences, Cairo, Egypt)

11. Comparative study of the degradation of high-molecular-weight hyaluronan by the action of myeloperoxidase or by the direct action of hypochlorite/hypobromite (Cooperation with DAAD, Germany)

24

12. Antioxidants and aldose reductase blockade in prevention of late diabetic complications: study on new pyridoindole derivatives (Cooperation with The Scientific and Technical Research Council, Turkey)

13. Computational design and preparation of 2,6-difluoro-4-pyrrol-1-yl-phenol derivatives as non-carboxylic acid aldose reductase inhibitors: Preclinical implications for pharmacological prevention of diabetic complication (Cooperation with Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, Greece)

14. Strengthening the ministries of health, enviroment and forests, and agriculture and rural affairs to harmonise and implement legislation in the field of Good laboratory practice for non-clinical health and environmental protection (Cooperation with the Institute for normalization, metrology and probation of the Slovak republic in training of Turkish scientists in Good Laboratory Practice)

15. Acute and repeated dermal toxicities of the antipsoriatics (Cooperation with the Derma Protect + Innovation, GmbH, Friedrichshafen, Germany)

16. Production of hyperimmune sera in rabbits (Cooperation with the Biovendor, Laboratory Medicine, a.s., Brno, Czech Republic)

17. Effect of newly synthesised beta-blocators with antioxidant and antiradical properties on activity of human neutrophils and blood platelets (Cooperation with the Institute of Human Pharmacology and Toxicology, Faculty of Pharmacy, Veterinary and Pharmaceutical University, Brno, Czech Republic)

18. Cardiovascular pharmacology (Cooperation with the Department of Experimental Cardiology, Eppendorf University Hospital, Hamburg, Germany)

19. Behavioral pharmacology of acetylcholinesterase inhibitors (Cooperation with Wright State University, Boonshoft School of Medicine, Department of Pharmacology and Toxicology, Dayton, Ohio, USA )

20. Study of perinatal asphyxia on transgenic mouse model (Cooperation with the University Clinic for Child Health Care, AKH, Wien, Austria)

ii. List of international conferences (co-) organised by the Organisation

1. 1st European Workshop on the Analysis of Phagocyte Functions, Brno, Czech

Republic, September 7-9, 2003.

2. 8th Interdisciplinary Czech and Slovak Toxicological Conference, Praque, Czech Republic, Septemeber 3-5, 2003.

3. International Regulatory Workshop on Bioequivalence and Dissolution, Bucharest,

Romania, December 4-5, 2003.

4. 9th Interdisciplinary Slovak and Czech Toxicological Conference, Píla-Častá, Slovakia, Septemeber 15 – 17, 2004.

5. 10th Interdisciplinary Czech and Slovak Toxicological Conference, Olomouc, Czech

Republic, September, 14 -16, 2005.

6. 55th Pharmacological Days, Section: Reactive oxygen species in physiology, pathophysiology and pharmacology. Hradec Králové, Czech Republic, August 31 – September 2, 2005.

25

7. 11th Interdisciplinary Slovak and Czech Toxicological Conference, Trenčianske

Teplice, Slovakia, June 5 – 7, 2006.

8. 2nd European Workshop on the Analysis of Phagocyte Functions. Brno, Czech Republic, June 14-17, 2006.

iii. List of international journals edited/published by the Organisation

[1] Biologia, Vol. 60, Supplement 17, Slovak and Czech toxicology integrated into the European Research Area. Eds. Navarová, J., Ujházy, E., Zemánek, M., Bratislava 2005, pp. 1-160.

[2] Neuroendocrinology Letters, Vol. 27, Suppl. 2, (December 22), pp. 1-186, 2006, Eds.

J. Navarová, E. Ujházy, M. Mach a M. Zemánek, Sweden. iv. List of edited proceedings from international scientific conferences and

other proceedings

1.

9th Interdisciplinary Slovak-Czech Toxicological Conference. Programme and Abstracts, 15-17 September 2004, Píla – Častá. Ed. M. Dubovický, J.Navarová, E.Ujházy. Bratislava: Institute of Experimental Pharmacology, SAS, 2004, 100 p.

2.

2Slovak and Czech toxicology in the European Union: Abstracts of the 11th Interdisciplinary Slovak-Czech Toxicology Conference June 5-7, 2006, Trenčianske Teplice, Slovakia. Ed. J. Navarová, E. Ujházy, M. Dubovický, M. Mach. Bratislava: Institute of Experimental Pharmacology SAS, 2006. 70 p. ISBN 80-969474-1-9.

• National position of the Organisation i. List of selected most important national projects (Centres of Excellence,

National Reference Laboratories, Agency for the Promotion of Research and Development (APVV/APVT), National Research Programmes, Scientific Grant Agency of the Slovak Academy of Sciences and the Ministry of Education

(VEGA), and others)

Centre of Excellence 1. Biotechnological Centre of the Slovak Republic BITCET (the Institute is the member

of the consortium) National Research Programmes

1. New materials and components in submicrometer technology. Material development by mineral technologies and mechanochemical and chemical procedures (coordinator: S. Štolc)

26

APVT/APVV 1. Aging and diseases related to reactive oxygen species. Preclinical study of their

prevention and treatment by new drugs of IEPh SAS with antiradical properties (coordinator: S. Štolc)

2. Molecular Mechanisms of Action of New Drugs Interfering with Oxidative Stress – the

Important Factor in Etiopathogenesis of Numerous Diseases (coordinator: S. Štolc) 3. Contribution to sanation of the middle and aged population. Carvedilol in the

treatment of cardiovascular and cerebrovascular diseases (coordinator: R. Nosáľ)

4. Role of bioflavonoids in prevention of social stress-induced hypertension (investigator: R. Sotníková)

5. Effect of immunostimalators and their combination with methotrexate on adjuvant

arthrithis in rats (investigator: K. Baureová)

6. Protection of the heart against malignant arrhythmias and functional failure (investigator: Vladimír Knézl)

VEGA

1. Effects of antioxidants and substances affecting the immune system studied on animal models of rheumatoid arthritis and osteoarthritis (principal investigator: K. Bauerová)

2. Effects of antioxidants and substances affecting the immune system studied on in vivo model of adjuvant arthritis (principal investigator: K. Bauerová)

3. New computerized methods for analysis of fate and effect of biologically active substances (investigator: M. Ďurišová)

4. A Novel Target of the Antiproliferative Therapy: Mitogenic Peptides and their Maladaptive Cell Signaling Mechanisms. Rationale for the Use of Specific Antagonists in Hyperproliferative Vascular Remodelation and in Chronic Heart Failure (principal investigator: J. Dřímal)

5. Molecular modelling and desing of endothelin receptor (investigator: J. Dřímal)

6. Study of the mechanisms of natural polyphenolic and synthetized pyridoindole antioxidants and their possible synergistic effects (principal investigator: Ľ. Horáková)

7. Oxidative injury of Ca2+- ATPase from sarcoplasmic reticulum of rabbit muscle (SERCA) in the conditions of in vitro, in cell cultures and in vivo. Preventive effects of pyridoindole and polyphenolic antioxidants (principal investigator: Ľ. Horáková)

8. Antihypoxic, antiarrhythmic and cardioprotective effects of newly-synthesised pyrido-indole derivatives (principal investigator: I. Juránek)

9. Mechanisms and transferability of resistance to important groups of antibiotics in clinical isolates of Gram-negative bacilli and Gram-positive cocci (investigator: T. Mačičková)

10. Incidence, transferability and mechanisms of resistance against antiinfection substances in clinical isolates of pathogenic microorganisms causing nosocomial infections (investigator: T. Mačičková)

11. Antiplatelet and antioxidative properties of cationic amphiphilic drugs. Studies at cellular and subcellular level (principal investigator: R. Nosáľ)

27

12. Pharmacology of antiplatelet and antioxidant substances: cardiovascular and immunomodulatory drugs (principal investigator: R. Nosáľ)

13. The study of the biological activity of salivary gland and intestine extracts from saprophagous flies and their utilization in curying of non-healing wounds (investigator: J. Pečivová)

14. Inhibition of a peroxidative damage of cell membranes in model human skin in the presence of natural polyfenolic antioxidants. Structure-activity relationships (principal investigator: L. Račková)

15. Effects of antioxidants with indol structure on injures caused by reactive oxygen species on smooth muscles of gut, airways and vessels (principal investigator: V. Nosáľová)

16. Ischaemia and reperfusion in experimental diabetes type 2 and possibilities of pharmacological management (principal investigator: R. Sotníková)

17. The interaction of stress and genetic factors in the etiology of high blood pressure and behavioral failure: the role of nitric oxide (investigator: R. Sotníková)

18. Pharmacological management of diabetic complications – angiopathies and neuropathies (investigator: R. Sotníková)

19. Hyaluronan – a relevant probe in testing the anti-oxidative properties of antiinflammatory and antirheumatic drugs as well as of natural and synthetic antioxidants (principal investigator: L. Šoltés)

20. Antioxidants and aldose reductase blockade in prevention of late diabetic complications: study on new pyridoindole derivatives (principal investigator: M. Štefek)

21. Carboxymethylated pyridoindoles as inhibitors of aldose reductase with antioxidant activity: preclinical implications for pharmacological prevention of diabetic complications (principal investigator: M. Štefek)

22. New drugs with antiradical action for prevention and treatment of some nervous system impairments. Synthesis and action. (principal investigator: S. Štolc)

23. Study of neuroprotective effects of new pyridoindole antioxidants (principal investigator: S. Štolc)

24. Study of the preventive effect of new pyridoindole antioxidants and melatonine on intrauterine hypoxia and neonatal anoxia induced changes in rats (principal investigator: E. Ujházy)

25. Contribution to prevention and treatment of behavioural disorders induced by hypoxic-ischaemic damage of the brain in perinatal period: experimental model of asphyxia and usage of antiradical and antioxidant substances (principal investigator: E. Ujházy)

ii. List of national scientific conferences (co)-organised by the Organisation 1. The Institute co-organised “Memorial of Prof. Švec”, scientific meeting for young

pharmacologists, November 13, 2003, Pharmaceutical Faculty of CU, Bratislava.

2. 7th Congress of the Slovak Pharmaceutical Society, September 9-11, 2004, Nitra.

iii. List of national journals published by the Organisation

28

iv. List of edited proceedings of national scientific conferences/events

• International/European position of the individual researchers i. List of invited/keynote presentations at international conferences, documented

by an invitation letter or programme

1. Ďurišová, M. System approach based method for analysis glucose-insulin control system. Joint Steering Meeting of BioSim-NoE, 6th FP-EU, Hvidøre, Denmark, 6th – 8th August 2005

2. Ďurišová, M. New methods for modeling drug fate in the body. 34th Conference on Synthesis and Analysis of Drugs, Brno, Czech Republic, 12.9.-14.9. 2005.

3. Juránek, I. Reactive oxygen species – cause or consequence of tissue injury? 10. MEDZIODBOROVÁ ČESKO-SLOVENSKÁ TOXIKOLOGICKÁ KONFERENCIA TOXCON 2005, Olomouc, 14.-16.9.2005, Czech Republic

4. Juránek, I. Vasodilatory responses under hypoxic condition: role of PGI2 and NO. 4TH INTERNATIONAL SYMPOSIUM ON NITRIC OXIDE, NITRIC OXIDE – BASIC REGULATIONS AND PHARMACOLOGICAL INTERVENTIONS. Tučepi, Croatia.

5. Navarová, J. Antioxidants and protection of organism against oxidative damage under experimental conditions. 10. MEDZIODBOROVÁ ČESKO-SLOVENSKÁ TOXIKOLOGICKÁ KONFERENCIA TOXCON 2005, Olomouc, 14.-16.9.2005, Czech Republic

6. Nosáľ, R. 34th Annual Meeting of the EHRS, May 11-14, 2005, Ljubljana, Slovenia.

7. Nosáľ, R. Lodz Platelet Conference, June 25-28, 2006, Lodz, Poland.

8. Štolc, S. Nové pyridoindoly ako protektíva biologických tkanív proti oxidatívnemu stresu. 34. KONFERENCE SYNTÉZA A ANALÝZA LÉČIV 2005 „NOVÉ SMĚRY VE VÝZKUMU LÉČIV“, Brno, ČR, 12.-14.9.2005.

9. Štolc, S. Development of the new group of indole-derived neuroprotective drugs affecting oxidative stress. 5th INTERNATIONAL SYMPOSIUM ON EXPERIMENTAL AND CLINICAL NEUROBIOLOGY 2005, Stará Lesná, SR, Sept. 19-22, 2005.

10. Štolc, S. New Group of Indole-derived Neuroprotective Drugs Interacting With Oxidative Stress. CEI, IBRO-CEERC & FENS EAST-EUROPEAN SYMPOSIUM „CENTRAL AND PERIPHERAL SYNAPTIC TRANSMISSION“,Varna, Bulgaria, October 5-9, 2005.

11. Ujházy E. Vývinová toxikológia – integrálna časť hodnotenia bezpečnosti nových liečiv. 10. MEDZIODBOROVÁ ČESKO-SLOVENSKÁ TOXIKOLOGICKÁ KONFERENCIA TOXCON 2005, Olomouc, 14.-16.9.2005, Česká republika.

ii. List of employees who served as members of the organising and/or programme committees for international conferences

1. Monika Červená

29

2. Michal Dubovický 3. Viera Dytrichová 4. Mária Ďurišová 5. Jozef Janšák 6. Ivo Juránek 7. Magdaléna Kouřilová 8. Tatiana Mačičková 9. Mojmír Mach 10. Jana Navarová 11. Radomír Nosáľ 12. Miroslava Schmidtová 13. Ružena Sotníková 14. Svorad Štolc 15. Eduard Ujházy

iii. List of employees who served as members of important international scientific bodies (e.g. boards, committees, editorial boards of scientific journals)

Viktor Bauer Member of the Editorial Board of the Természet Világa and Colecta Clausiana Member of the Editorial Board of the General Physiology and Biophysics (Veda, Bratislava) Mária Ďurišová Member of the Editorial Board of the Journal „Klinická farmakologie a farmacie“ published in the Czech Republic Jana Navarová Guest Editor, Neuroendocrinology Letters, Sweden. Mojmír Mach Guest Editor, Neuroendocrinology Letters, Sweden. Radomír Nosáľ Member of the International Committee and National Secretary of the European Histamine Research Society Member of the International Committee the European Platelet Group Field Editor, Neuroendocrinology Letters, Sweden Ružena Sotníková Field Editor General Physiology and Biophysics (Veda, Bratislava) Milan Štefek Field Editor, General Physiology and Biophysics, VEDA Bratislava Svorad Štolc Delegate of IUPHAR Council Member of Working Group No.1 Neuroprotection and Repair, COST ACTION B10 Brain Damage and Repair Field Editor General Physiology and Biophysics (Veda, Bratislava) Eduard Ujházy Guest Editor, Neuroendocrinology Letters, Sweden.

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iv. List of international scientific awards and distinctions

Zuzana Kyseľová Prize of the Pfizer for the best scientific publication in 2004: KYSEĽOVÁ, Z. – ŠTEFEK, M. – BAUER, V.: Pharmacological prevention of diabetic cataract. Review. In Journal of Diabetes and its Complications. Vol. 18, no. 2 (2004), p.129-140. (2,345-IF2003)

Prize of of the publisher SERVIER for the best scientific publication in 2005: KYSEĽOVÁ, Z. – GAJDOŠÍK, A. – GAJDOŠÍKOVÁ, A. – ULIČNÁ, O. – MIHALOVÁ, D. – KARASU, Ç. – ŠTEFEK, M. Effect of the pyridoindole antioxidant stobadine on development of experimental diabetic cataract and on lens protein oxidation in rats:comparison with vitamin E and BHT. In Molecular Vision. Vol. 11, no 6 (2005), p.56-65. Jana Navarová “European Teratology Society” - SCIENTIST AWARD for the Best Poster Presentation at the 32nd European Teratology Society Conference, Thessaloniki, Greece, 2004. Honorable mention and acknowledgement for long-term international cooperation in the field of toxikological sciences (by the Czech Society for Experimental and Clinical Pharmacology and Toxicology of the Czech Medical Society of J. E. Purkyně), 2006 Eduard Ujházy Honorable mention and acknowledgement for long-term international cooperation in the field of toxikological sciences (by the Czech Society for Experimental and Clinical Pharmacology and Toxicology of the Czech Medical Society of J. E. Purkyně), 2006

• National position of the individual researchers i. List of invited/keynote presentations at national conferences documented by an invitation letter or programme

ii. List of employees who served as members of organising and programme committees of national conferences

Katarina Bauerová

Svorad Štolc

iii. List of employees serving in important national scientific bodies (e.g. boards, committees, editorial boards of scientific journals)

Viktor Bauer Member of the Editorial Board of the Bratislava Medical Letters Secretary of the Slovak Pharmacology Society Michal Dubovický

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Member of the Committee of the Slovak Toxicology Society SETOX Member of the Committee of the Slovak Society for the Science on Laboratory Animals Andrej Gajdošík President of the Slovak Society for the Science on Laboratory Animals Member of the Committee of the Slovak Toxicology Society SETOX Alena Gajdošíková Member of the Committee of the Slovak Society for the Science on Laboratory Animals Viera Jančinová Member of the Committee of the Slovak Pharmacology Society Jana Navarová President of the Slovak Toxicology Society SETOX Mojmír Mach Member of the Committee of the Slovak Society for the Science on Laboratory Animals Member of the Committee of the Slovak Toxicology Society SETOX Radomír Nosáľ Member of the Committee of the SAVOL Svorad Štolc Member of the Committee of the Slovak Pharmacology Society Eduard Ujházy Member of the Committee of the Slovak Pharmacology Society Member of the Committee of the Slovak Toxicology Society SETOX Member of the Committee of the Slovak Society for the Science on Laboratory Animals

iv. List of national awards and distinctions

Svorad Štolc Medal of PhMr. V. J. Žuffa by the Committee of the Slovak Pharmaceutical Society, 2004.

Zuzana Kyseľová The 3rd place in the Competition of young scientific workers up to 35 years (2005)

Katalin Szöcs The award of the LITA Agency for the citations in period of 2002-2004 in the field of natural sciences.

Eduard Ujházy Honour Plaque of J. Jessenius for the credit of medical sciences, Slovak Academy of Sciences, 2006 Bronze Medal for the credit of Slovak Medical Society, Bratislava, 2006

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Supplementary information and/or comments documenting international and national status of the Organisation

Magdalena Majekova attended the CEC-WYS seminar (January 2006) on Responsible Conduct of Research and Scientific Communication and received a certificate. Štefan Bezek Member of the Commission of the Scientific Grant Agency of the Slovak Academy of Sciences and the Ministry of Education (VEGA) Ladislav Šoltés Member of the Commission of the Scientific Grant Agency of the Slovak Academy of Sciences and the Ministry of Education (VEGA) Svorad Štolc Member of the Commission of the Scientific Grant Agency of the Slovak Academy of Sciences and the Ministry of Education (VEGA) In 2004 and 2005, the Institute was the seat of the Scholastic Society of the SAS.

4. Project structure, research grants and other funding resources

• International projects and funding i. List of major projects within the European Research Area – 5th and 6th Framework Programme of the EU, European Science Foundation, NATO, COST, INTAS, CERN, etc. (here and in items below please specify: type of project, title, grant number, duration, funding, responsible person in the Organisation and his/her status in the project, e.g. coordinator, principal investigator, investigator)

1. Projekt 6th FP-NoE Biosimulation – a new tool in drug development LSHB-CT-2004-005137 12/2004-11/2009 2004: 150 000 Sk (SR), 2005: 1 092 674 Sk (SR), 2006: 300 000 Sk (SR), 757 268 Sk (EU) Maria Ďurišová – principal investigator 2. Project of the COST Program, Action B10 In vitro and in vivo pharmacological studies of neuroprotective action of new compounds in oxidative stress MVTS COST B10 11/2002-07/2004 2003: 80 000 Sk (SR), 72 000 Sk (EU), 2004: 25 000 Sk (SR), 30 000 Sk (National Coordinator) Svorad Štolc – principal investigator 3. Project of the COST Program, Action B15 Modelling in drug development MVTS COST B15 11/1998-07/2004 2003: 80 000 Sk (SR), 64 000 Sk (EU), 2004: 40 000 Sk (SR), 20 000 Sk (National Coordinator), 66 300 Sk (EU),

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Mária Ďurišová – principal investigator 4. Project of the COST Program, Action B22 Advanced approach to mathematical modelling in development of antiparasitic drugs MVTS COST B22 02/2003-02/2007 2003: 80 000 Sk (SR), 40 000 Sk (EU), 2004: 80 000 Sk (SAV), 20 000 Sk (National Coordinator), 66 450 Sk (EU), 2005: 50 000 Sk (SR), 2006: 100 000 Sk (SR) Mária Ďurišová – investigator 5. Project of the COST, Action B25 Physiologically based pharmaco-toxicokinetics and dynamics MVTS COST B25 04/2005-05/2009 Not funded Mária Ďurišová – principal investigator 6. Project of the COST, Action B35 Lipid peroxidation associated disorders MVTS COST B35 06/2006-06/2010 Not funded Ľubica Horáková – principal investigator ii. List of other international projects incl. funding 1. Project based on Interacademy Treaties (Cooperation with the Institute of Biophysics, Academy of Sciences, the Czech Republic) Antioxidative properties of cationic amphiphilic drugs and endogene substances from blood platelets 049/198 01/2002-12/2003 2003: 23 000 Sk Radomír Nosáľ – principal investigator 2. Project based on Interacademy Treaties (Cooperation with the Institute of Biophysics, Academy of Sciences, the Czech Republic) Alteration of neutrophil oxidative burst by blood platelets 131 01/2004-12/2005 2004: 28 000 Sk, 2005: 28 000 Sk Radomír Nosáľ – principal investigator 3. Project based on Interacademy Treaties (Cooperation with the Institute of Biophysics, The Academy of Sciences, the Czech Republic) Antioxidative and antipahgocytic properties of chemical and natural compounds and drugs SK-CZ-06606 01/2006-12/2007 34 000 Sk Radomír Nosáľ – principal investigator

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4. Project based on Interacademy Treaties (Cooperation with The National Center of Radiation Reserach and Technology, Atomic Energy Authority, Egyptian Academy of Sciences, Cairo, Egypt) Protective and Therapeutic Effect of Antioxidants in Injury Induced by Environmental Pollutants and/or Gamma Radiation 11/2003-12/2006 Not funded Svorad Štolc – principal investigator 5. Project based on Interacademy Treaties (Cooperation with DAAD, Germany) Comparative study of the degradation of high-molecular-weight hyaluronan by the action of myeloperoxidase or by the direct action of hypochlorite/hypobromite 01/2005-12/2006 Not funded, based on reciprocity Ladislav Šoltés – principal investigator 6. Project based on Interacademy Treaties (Cooperation with the Scientific and Technical Research Council, Turkey) Antioxidants and aldose reductase blockade in prevention of late diabetic complications: study on new pyridoindole derivatives 01/2004-12/2006 Not funded, based on reciprocity Milan Štefek – principal investigator 7. Bilateral project (Cooperation with Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, Greece) Computational design and preparation of 2,6-difluoro-4-pyrrol-1-yl-phenol derivatives as non-carboxylic acid aldose reductase inhibitors: Preclinical implications for pharmacological prevention of diabetic complication GRE02 01/2005-06/2007 2005: 80 000 Sk, 2006: 80 000 Sk Milan Štefek – principal investigator

iii. List of other important projects and collaborations without direct funding 1. Cooperation with the Institute for Normalisation, Metrology and Probation of the Slovak republic in training of Turkish scientists in Good Laboratory Practice Strengthening the ministries of health, enviroment and forests, and agriculture and rural affairs to harmonise and implement legislation in the field of Good laboratory practice for non-clinical health and environmental protection TR/2004/IB/EC/06 2006-2006 Radomír Nosaľ – principal investigator

• National projects and funding i. List of projects supported by the Agency for the Promotion of Research and Development (APVV/APVT), National Research Programmes, and their funding

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APVT/APVV 1. Aging and diseases related to reactive oxygen species. Preclinical study of their prevention and treatment by new drugs of IEPh SAS with antiradical properties APVT-51-020802 09/2002-12/2005 2003: 1 937 000 Sk, 2004: 1 600 000 + 415 000 Sk (transfer from 2003), 2005: 1 080 000 Sk Svorad Štolc – coordinator

2. Contribution to sanation of the middle and aged population. Carvedilol in the treatment of cardiovascular and cerebrovascular diseases APVT-51-0296/02 01/2004-12/2006 2004: 580 000 Sk, 2005: 610 000 Sk, 2006: 776 000 Sk Radomír Nosáľ – coordinator 3. Molecular Mechanisms of Action of New Drugs Interfering with Oxidative Stress – the Important Factor in Etiopathogenesis of Numerous Diseases APVV-51-017905 05/2006-04/2009 2006: 4 082 000 Sk Svorad Štolc – coordinator 4. Role of bioflavonoids in prevention of social stress-induced hypertension APVT-51-018004 01/2005-12/2007 2006: 21 000 Sk Ružena Sotníková – investigator 5. Effect of immunostimalators and their combination with methotrexate on adjuvant arthritis in rats APVV-21-055205 05/2006-04/2009 2006: 119 000 Sk Katarína Bauerová – investigator 6. Protection of the heart against malignant arrhythmias and functional failure APVV-51-059505 05/2006-04/2009 2006: 142 000 Sk Vladimír Knezl – investigator

National Research Programmes 1. New materials and components in submicrometer technology. Material development by mineral technologies and mechanochemical and chemical procedures ŠPVV SO 51/03R 06 00/03R 06 04 07/2003-12/2005 2003: 100 000 Sk, 2004: 100 000 Sk, 2005: 100 000 Sk Svorad Štolc – principal investigator

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ii. Number of projects supported by the Scientific Grant Agency of the Slovak Academy of Sciences and the Ministry of Education (VEGA) for each year, and their funding

VEGA 2003 2004 2005 2006

number 11 12 14 15

funding (millions of SKK) 1,082 1,210 1,083 1,390

• Summary of funding from external resources

External resources 2003 2004 2005 2006 total average

external resources (millions of SKK) 3,558 4,431 4,124 10,251 22,364 5,591

external resources transfered to coooperating research organisations (millions of SKK)

0,000 0,000 0,000 2,349 2,349 0,587

ratio between external resources and total salary budget 0,274 0,328 0,295 0,711 - 0,402

overall expenditures (millions of SKK) 23,302 25,560 28,031 26,960 103,853 25,963

Supplementary information and/or comments on research projects and funding resources

Other external resources (gifts and purchases): Humboldt foundation gift in January 2003, Spectrophotometer UV-VIS: 480 270 Sk During the period 2003-2004 I Dr. M. Majekova was the Institute system network administrator free of charge and thus 2 years salary of aproximately 108 000 Sk was spared. The Institute of Zoology SAS purchased chemicals (kolagén, trombín, vápnikový ionofor A 23187) in the total sum 26 402 Sk VÚLM, a.s. Modra, Modra a Zentiva, a.s. Hlohovec gift: substances of the drugs Carvedilol, Loratadín and Ditiadén in the sum 120 000 Sk Gifts of the Institute of the Biophysics AS CZR, Brno: Centrifuge K 24: 35 000 Sk, laboratory material and chemicals: 15 000 Sk, international Journals Free Radical Research, Publisher: Taylor and Francis Ltd. : 200 000 Sk. Zeiss s.r.o. Bratislava provided free of charge services and spare parts om microscope in the sum 4 000 Sk.

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Gift of the Centre of Vascular Biology and Medicine, University Hospital of Jena, Nordhauser Strasse 78, Erfurt, 990 89 Germany: chemicals: 6 560 Sk. During the period 2003-2004 I Dr. M. Majekova was the Institute system network administratort free of charge and thus 2 years salary ofaproximately 54 000 Sk for the year 2004 (according to the recent state) was spared. Chemicals (staurosporín) from the Lambda in the sum 4 500 Sk Substrate for enzyme NAGA from the Slovak Medical University: 10 000 Sk In cooperation with the Institute of human pharmacology and toxicology, Veterinary and Pharmaceutical University, Brno, Czech Republic, laboratory material and chemical were obtained: 23 000 Sk. Gift from the Experimetria firm, holders to tensometric apparatus: 2 200 Sk Within cooperation with Derma Protect + Innovation GmbH Austria, Siemensstrasse 6, D-88048 Friedrichshafen centrifuge was purchased: 800 000 Sk Derma Protect, Germany: CO2 incubator: 400 000 Sk, nitrogen container: 200 000 Sk Wien University, washing line for animal cages: 3 250 000 Sk and rabbit cages 650 000 Sk Activities at the Department of Toxicology at Dobra Voda: Production of laboratory animals and diet for Universities: 1 250 000 Sk Imunotoxicological tests: 500 000 Sk Renting of spaces at Dobrá Voda: 284 000 Sk Total for the assessed period: 8 422 932 Sk 5. Organisation of PhD studies, other pedagogical activities

i. List of accredited programmes of doctoral studies (as stipulated in the previously effective legislation as well as in the recently amended Act on the Universities)

7.1.30 Pharmacology, in cooperation with Pharmaceutical Faculty, Comenius

University, Bratislava and Jessenius Medical Faculty, Comenius University, Martin

4.1.22 Biochemistry, in cooperation with Natural Sciences Faculty, Comenius

University, Bratislava and Faculty of Chemical and Food Technology, Slovak technical

University, Bratislava

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ii. Summary table on doctoral studies (number of internal/external PhD students; number of students who completed their study by a successful thesis defence; number of PhD students who quitted the programme)

PhD study

number of potential PhD supervisors

PhD studentsnu

mbe

r

defe

nded

thes

is

stud

ents

qui

tted

num

ber

defe

nded

thes

is

stud

ents

qui

tted

num

ber

defe

nded

thes

is

stud

ents

qui

tted

num

ber

defe

nded

thes

is

stud

ents

qui

tted

internal 6 1 1 7 2 1 8 0 0 8 2

external 1 1

supervised at external institution by the research employees of the assessed organisation

1 1 1 3

31.12.200531.12.2003 31.12.2004 31.12.2006

24,00 23,00 23,00 23,00

iii. Postdoctoral positions supported by a) external funding (specify the source)

b) internal funding - the Slovak Academy of Sciences Supporting Fund of Stefan

Schwarz

Katalin Szöcs

Zuzana Kyseľová

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iv. Summary table on pedagogical activities in undergraduate programmes for each year

Teaching 2003 2004 2005 2006

lectures (hours/year) 68 52 48 48

practicum courses (hours/year) 112 56 56 47

supervised diploma works (in total) 6 5 4 4

members in PhD committees (in total) 11 12 12 9

members in DrSc. committees (in total) 0 2 1 1

members in university/faculty councils (in total) 1 1 1 1

members in habilitation/inauguration committees (in total) 1 1 1 0

v. List of published university textbooks

vi. Number of published academic course books ŠTOLC, S. Kanály riadené ligandami a neuronálna excitabilita. s.91-148. In: Funkcie biologických membrán v bunkách živočíchov. Texty k prednáškam projektu ESF „BIOMEMBRÁNY“. ed. ÚMFG SAV, 2006, 268 p.

vii. List of joint research laboratories/facilities with the universities

viii. Supplementary information and/or comments on doctoral studies and pedagogical activities

The Institute has a long-term tradition in education in cooperation with Comenius University, Bratislava. The Institute cooperates with the Faculty of Natural Sciences, Faculty of Physical Education and Sport, Faculty of Mathematics, Physics and Informatics and Philosophical Faculty of Comenius University. The Institute provides lectures on physiology of the blood - doping control - general microbiology - experimental teratology - practical ethology - ligand methods in physiology.

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6. Direct output to the society (applications of results, popularisation and outreach activities) i. List of the most important results of applied research projects

In cooperation with domestic and foreign partners, the Department performed the followed studies, during the assessed period: Protective effect of the substance VULM 1457, a new ACAT inhibitor. Cellular signalling mechanisms induced by the new lipid lowering drug VULM1457 (the prospective inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-CoA reductase) were investigated. Identification of specific cellular [125I]adrenomedullin (AM) binding sites on human HepG2 cells, abundantly expressing AM, production of a protective AM family of peptides in human tumourigenic cells, their proliferation and change in viability of cells were used as indicators of activation of cells and expression of surface adhesive proteins. Our experimental findings indicate reduced expression of specific AM binding sites on cells, thus documenting a significant protective effect of VULM1457, most probably related to the its effects on signalling chains or to the nuclear component of hyperproliferative activation of cells. (Users: Drug Research Institute Modra a.s, Slovakofarma a.s., Léčiva, a.s., Zentiva s.r.o., Warburg-Pincus LLC.) Acute toxicities of selected magnetic nanoparticles. Related to the usage of magnetic fluids (which are developed at the Institute of Experimental Physics SAS in Košice) as a vehicle of drugs which will be administered to the organism, acute toxicity of selected fluids after peroral and intravenous treatment in mice has been established. Appropriate models (adjuvant arthritis in rats, trauma of the head in mice and hypoxic-ischaemic brain damage in gerbils) have been introduced to study pharmacodynamic effects of the model drugs in the free form compared to the drugs bound to the magnetic vehicle in in vivo conditions. (User: pharmaceutical industry). Antiaggregatory and antioxidative effect of carvedilol in vitro and in patients with congestive heart failure and diabetes mellitus. Evaluation of experimental data speaks in favour of the administration of carvedilol in pathological states accompanied with ischaemia/reperfusion-induced tissue damage. Collaborative investigation with clinicians confirmed the suggestion of a beneficial effect of carvedilol in patients suffering from congestive heart failure and diabetes mellitus type 2. In these patients, carvedilol therapy reduced the concentration of reactive oxygen species in blood, decreased activation of blood platelets and improved their quality of life. The limited duration of the project did not enable extensive and long-term monitoring of the patients; therefore the investigation will be continued despite the formal termination of the study (User: 1st Department of Medicine of the Faculty Hospital, Bratislava).

Acute and repeated dermal toxicities of antipsoriatics (Derma Protect + Innovation, GmbH, Friedrichshafen, Germany).

Production of hyperimmune sera in rabbits (Biovendor, Laboratory Medicine, a.s., Brno, Czech Republic)

Acute toxicities of new species of magnetic nanoparticles (Institute of Experimental Physics, SAS, Košice).

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Acute and repeated oral and dermal toxicites of the new prospective drugs (PHARMACENTRUM, s.r.o. Bratislava). The Institute at the Department of Toxicology and Animal breeding keeps the certified breeding of outbred and inbred lines of small laboratory animals as well as special lines, such as Spontaneuosly Hypertensive Rats. Moreover, the Institute produces the certified animal diets for rats and mice, guinea pigs and rabbits and for dogs, and it is capable to provide special experimental diets. The Institute conducts toxicological studies regarding the development and safety assessment of pharmaceuticals, chemicals and consumer products.

ii. List of the most important studies commissioned for the decision-making authorities, the government and NGOs, international and foreign organisations

- Cooperation with the Institute for Normalisation, Metrology and Probation of the Slovak Republic in training of Turkish scientists in Good Laboratory Practice Strengthening the ministries of health, enviroment and forests, and agriculture and rural affairs to harmonise and implement legislation in the field of Good laboratory practice for non-clinical health and environmental protection (No.TR/2004/IB/EC/06 of the project), 2006. Viktor Bauer - Member of the Acreditation Commission of the Government of the Slovak Republic, 2003. - Ambassador in Turkey, 2003-2006 Katarína Bauerová Deputy of Slovakia in the working groups: (2005). - Market Surveillance Operations Group A, - BSE/TSE Working Group, sekcie Medical Devices, European Commission, Brussels Tatiana Mačičková - 3 expert´s reports on drugs and clinical trials of the drugs for the ŠÚKL, 2003. Radomír Nosáľ - Expert´s report for Slovakofarma, a.s., Zolpidem (CTD EU CTD/NTA, vol.2B, Edition 20) s.46, Slovakofarma a.s., October 30, 2003 - Expert´sa report for the Drug Research Institute, Modra: Carvedin 25, (CTD EU CTD/NTA, vol.2B, Edition 20), s.66, VÚL Modra, June 29, 2005.

Ružena Sotníková - 4 expert´s reports on the drugs and clinical trials of the drugs for the ŠUKL, 2003. - Deputy of Slovakia in the Efficacy Working Party pri EMEA, Londýn, GB, 2005. - Member of the Commission for the Drugs of the Slovak Republic, 2005. Svorad Štolc - Expert ESF – European Survey on Bio-Medical Infrastructure, Neuroscience/Neurological Research, 2003. - Expert in the panel on Industrial products and technologies for the Prognosis of the development and use of science and technics until 2015, (June 2003)

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- Expert´s report for the Centre of the development of chemiacal and pharmaceutical industry. SWOT analysis in the field of chemistry and pharmacy (November 2003) - Expert of the governmental office (Úrad pre verejné obstarávanie SR), 2004. - Member of the Validation Team of the Cyclotrone Centre of the Slovak Republic, 2006. - Member of the Commission for the Scientific Degrees at the Ministery of Education, 2006. - Member of the Council for Medical Sciences of the Agency for the Promotion of Research and Development (APVV/APVT), 2006. Lucia Račková - Deputy of the Institute as a certified multiplicator of the Frame Programme EU within the project LSH Mentor Multiplier, 2006.

iii. List of the most important popularisation activities Michal Dubovický DUBOVICKÝ, M. Aj zvieratá sa musia učiť. Quark 7, 20-22, 2003.

DUBOVICKÝ, M. Radostná veda. Domino fórum 43, 20, 2003.

DUBOVICKÝ, M. Radostná veda. Domino fórum 49, 18, 2003.

DUBOVICKÝ, M. Radostná veda: O zvieratách, (ľuďoch) a agresii. Domino fórum. 18, 18, 2004.

DUBOVICKÝ, M.: Stres mozgu neprospieva. Rozhovor pre denník Pravda, XVI. ročník, č.123, 28. máj 2005, víkendová príloha, s. I-II.

DUBOVICKÝ, M.: Platforma nových vedeckých kontaktov. Tradícia medziodborových slovensko-českých toxikologických konferencií, Správy SAV, 6, ročník 42, str. 11., 2006.

DUBOVICKÝ, M.: Stres počas tehotenstva. Internetová stránka: www.mamatata.sk, 2005 http://www.mamatata.sk/index.cfm?Module=Article&Page=ShowArticle&ArticleID=2621&SectionID=2&SubSectionID=10

Radomír Nosáľ Hľadanie kľúča. Hodinka s Prof. MUDr. RADOMÍROM NOSÁĽOM, DrSc, riaditeľom Ústavu experimentálnej farmakológie SAV. Tele Plus 2005, XV ročník, č. 20, s. 24-25, redaktor I.Szabo

NOSÁĽ, R. „Rozprávanie o liekoch“, 23.11.2004, 14.00h, stanica Devín, relácia Solárium, redaktor. Ing. Jeluš, Slovenský Rozhlas

Ružena Sotníková SOTNÍKOVÁ, R. Týždeň vedy. „Veda známa - neznáma“ v ÚEFa SAV. In Správy Slovenskej akadémie vied 2004, Vol.40, no.1,p.12

R. SOTNÍKOVÁ: Budú z nich farmakológovia? Správy SAV, Vol. 42, no. 11-12, s.4, 2006.

R. SOTNÍKOVÁ organised in December 1, 2004 excursion for students of primary schools at the Institute. Block of 6 lectures: SVORAD ŠTOLC: Čo je liek a liečivo? IVO JURÁNEK: Etika práce s laboratórnymi zvieratmi, RUŽENA SOTNÍKOVÁ: Ako sa vyrába liek? EDUARD UJHÁZY: Nepriaznivé účinky liekov, MICHAL DUBOVICKÝ: Čo je teratológia?, MOJMÍR MACH: Behaviorálna farmakológia.

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Svorad Štolc ŠTOLC S. – Prvá pracovná schôdza Učenej spoločnosti SAV Správy SAV 39(11), 11, 2003.

ŠTOLC, S. Príspevok do polemiky o poskytovaní lekárenskej starostlivosti v zmysle novelizácie Zák. 140/1998 po 1.dec. 2004. In: Lekárnik, 2006, vol.11, č.1, s.7.

KHANDL, L. – LIŠKA, B. – ŠTOLC, S. Turistika a zdravie. Vyd. KST, Bratislava 2006. ISBN 80-969498-2-90. 80 str.

Eduard Ujházy UJHÁZY E. - DUBOVICKÝ M. Čo je teratológia? Quark 10, 20-21, 2003.

UJHÁZY, E.: Pomocníci pri ochrane zdravia. Fifík 4, 2005, s. 6

Interview with our scientists: Marta Moravčíková: O zajtrajšku rozhoduje včerajšok, EUROBIZNIS, 6. ročník, November 2006, str. 54-55. Written obout activities of the Institute: Vladimir Šmihula: Ocenenie práce dvoch významných farmakológov. Správy SAV, ročník 42, č. 9, str. 10., 2006. Web stránka SAV Vladimir Šmihula: Education in GLP, 2006 http://www.sav.sk/index.php?lang=sk&charset=&doc=services-news&news_no=1132 Lecture of outstanding Czech scientist Prof. MUDr. E. Syková at the Institute: „Stem cells, nanomaterials, and tissue replacements in regenerative medicine“ (September 29, 2006). http://www.sav.sk/index.php?lang=sk&charset=&doc=services-news&news_no=1090 In 2004, 2005 and 2006, the Institute organised within the European Week of Science and Technics”, Days of Open Doors at the IEPh SAS with the block of 6 popularisation lectures for the students of primary and secondary schools: SVORAD ŠTOLC: Čo je liek a liečivo? IVO JURÁNEK: Etika práce s laboratórnymi zvieratmi. RUŽENA SOTNÍKOVÁ: Ako sa vyrába liek? EDUARD UJHÁZY: Nepriaznivé účinky liekov., MICHAL DUBOVICKÝ: Čo je teratológia?, MOJMÍR MACH: Behaviorálna farmakológia. Terms: November 8, November 11, 2004 – November 8, November 11, 2005 – November 21, November 23 and November 24, 2006.

Radio Reports from the 9th toxicological conference, Pila-Častá 2004, September 15, 2004, Slovak Radio Broadcast.

iv. List of patents issued abroad, incl. revenues

Number: WO 03-091284 AI, CO7K 14/815 Authors: Nuttall P.A., KazimirovÁ M., Takac P., Trimnell A.L., Labuda M., Nosáľ, R., Jančinová V., Petriková M. Name: Anticoagulants Owner: Evolutec Limited, The Magdalen Centre, Oxford Science Park, Oxford OX4 4GA, GB

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Number: EP1272530 B1, September 2006 Authors: Šoltés L., Steiner B., Machová E., Kogan G., Bystrický S., Mendichi R., Bauer V., Mach M., Alföldi J., Stratilová E. Name: Clathrate complexes formed by hyaluronic acid derivatives and use thereof as pharmaceuticals Owners: Fidia Farmaceutici, S.p.A., Abano Terme, Italy, a ÚEFa SAV, Bratislava, Slovakia.

v. List of the patents issued in Slovakia, incl. revenues

Number: 1321-2003. Authors: Štolc, S.,Považanec F., Bauer, V. , Májeková, M. , Wilcox A.L. , Šnirc, V. , Račková, L. Sotníková, R. , Štefek, M., Gáspárová, Z., Gajdošíková, A., Mihalová, D., Alfoldi, J. Name: Pyridoindole derivatives with antioxidant properties, the way of their production and use in medicinal practice. Owner: The Institute of Experimental Pharmacology, SAS. Number: PP 98-2005 Authors: Štefek M., Šnirc V., Demopoulos V., Djoubissie P., Račková L., Májeková M., Karasu C. Name: Karboxymetylated pyridoindoles, the way of their production and use in medicinal practice as inhibitors of the aldosareduktase and antioxidants. Owner: The Institute of Experimental Pharmacology, SAS.

vi. List of licences sold abroad, incl. revenues Number: EP1272530 B1, September 2006 Authors: Šoltés L., Steiner B., Machová E., Kogan G., Bystrický S., Mendichi R., Bauer V., Mach M., Alföldi J., Stratilová E. Name: Clathrate complexes formed by hyaluronic acid derivatives and use thereof as pharmaceuticals Owners: Fidia Farmaceutici, S.p.A., Abano Terme, Italy, a ÚEFa SAV, Bratislava, Slovakia.

vii. List of licences sold in Slovakia, incl. revenues

viii. List of contracts with industrial partners, incl. revenues Acute and repeated dermal toxicities of antipsoriatics (Derma Protect + Innovation, GmbH, Friedrichshafen, Germany), revenue: 1 400 000 Sk Production of hyperimmune sera in rabbits (Biovendor, Laboratory Medicine, a.s., Brno, Czech Republic), revenue: 500 000 Sk Acute and repeated oral and dermal toxicites of the new prospective drugs (PHARMACENTRUM, s.r.o. Bratislava), revenue: not yet funded.

ix. List of research projects with industrial partners, incl. revenues

Protective effect of the substance VULM 1457, a new ACAT inhibitor. (Users: Drug Research Institute Modra a.s, Slovakofarma a.s., Léčiva, a.s., Zentiva s.r.o., Warburg-Pincus LLC.), revenue: 150 000 Sk

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x. Summary of outreach activities

Outreach activities 2003 2004 2005 2006 total

studies for the decision sphere, government and NGOs, international and foreign organisations 13 2 6 6 27

articles in press media/internet popularising results of science, in particular those achieved by the Organization 5 2 4 8 19

appearances in telecommunication media popularising results of science, in particular those achieved by the Organization

0 2 0 0 2

public popularisation lectures 0 18 12 18 48

xi. Supplementary information and/or comments on applications and popularisation activities

The IEPh accomplished first steps for implementation of the EU act REACH – Registration, Evaluation, and Authorisation of Chemicals, issued by the European Commission, within the Slovak Republic, for the purposes of safety evaluation of all chemicals that could affect humans. Particularly, ways of possible involvement of the Institute and its specialised Department at Dobra Voda in the REACH implementation have been suggested and several applied research and technological project proposals have been prepared for funding.

7. Background and management. Staffing policy and implementation of findings from previous assessments

i. Summary table of personnel

Personnel 2003 2004 2005 2006

all personel 63 57 57 64

research employees from Tab. Research staff 35 32 30 34

FTE from Tab. Research staff 33,6 30,95 29,7 30,65

averaged age of research employees with university degree 51 53 53 54

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ii. Professional qualification structure

Number of 2003 2004 2005 2006

DrSc. 6 7 7 7

PhD / CSc. 17 20 20 20

Prof. 2 2 2 2

Doc./Assoc. Prof. 1 2 2 2

iii. Status and development of research infrastructure incl. experimental, computing and technical base (description of the present infrastructure, premises, and material and technical resources. Infrastructure, instrumentation and major technical equipment necessary for the achievement of the objectives specified in the research Concept)

The Institute is situated partially in the building of the Chemical Instituite of SAS and in the building of Experimental Animal Facility, both located at the Slovak Academy of Sciences campus at Patronka, Bratislava. An integral part of the Institute, the Department of Toxicology and Animal Breeding, is located at Dobrá Voda, near Trnava. The Department possesses:

• Accreditation for breeding and experimentation on laboratory animals issued by

the State Veterinary Administration of the Slovak Republic No 7656/02-2201 • Certificate of GLP Compliance No 23/2000 issued by the Slovak National

Accreditation Service (in accordance with the Directive 1999/12/EC). Area of expertise: toxicity studies, carcinogenicity, care and housing of animals

• Statement of entry in the Register of Diets for Experimental Animals in the Slovak Republic No 8922.

All experiments are conducted using laboratory animals from own production. Own animal

diet is produced as well. Animals and diets are produced also for other domestic as well as foreign partners. The Institute is regularly exports high quality laboratory guinea pigs to Austria. Distribution of the products is ensured by own transport car certified to transport laboratory animals.

The Institute has standard technical equipment which enables to conduct pharmacological and biochemical experiments and studies. The Institute possesses the Certificate for Work with Radioisotopes and Certificate for Work with Toxic and Very Toxic Substances. The Institute has its own scientific library. Each scientific worker has its own PC connected to internet. The PC network was reconstructed in 2005. For the further development of pharmacology and toxicology the Laboratory of cell cultures was established. During the assessed period the Institute obtained new instrumentation and technical equipment wich will be necessary for the achievements of the objectives specified in the research Concept (CO2 incubator, cytoflowmeter, luminometer, ultracentrifuge, HP liquid scintilation spectrometer, liquid nitrogen container, computerised system for animal behaviour analysis).

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iv. Status and development of bibliographic resources, activities of the Organisation’s library and/or information centre

There is a scientific library at the Institute with 7006 librarien units (2006), 8 subsribed scientific journals (5 from abroad). Number of loans: 2003: 3098, 2004: 2219, 2005: 1934, 2006: 2438 The data of the library are involved in the database of the Central Library of SAS “Register of publication activity of the SAS”. The library provides: - lending services from own librarian fund, - lending services from other libraries by means of MVS and MMVS systems, - reprographical services (xerocopies, PDF databases, SCAN), - exchanging information and consultation services.

v. Describe how the results and suggestions of the previous assessment were taken into account

Suggestion of the previous assessment was to improve technical equipment of the Institute. During the assessed period the followed up-to-date instruments and technical equipment necessary for further development of pharmacology and toxicology at the Institute were obtained: CO2 incubator, cytoflowmeter, luminometer, ultracentrifuge, liquid nitrogen container, HP liquid scintilation spectrometer, computerised system for animal behaviour analysis. The PC network was recontructed during the assessed period. The Laboratory of Cell Cultures has been established.

vi. Supplementary information and/or comments on management, research infrastructure, and trends in personnel development

Trends in personal development: In 2007, the Institute created 2 new positions for post doctorand fellows. A new position, deputy director for management of commercial and expertise activities was established. The Institute will apply for accreditation of new PhD study program “toxicology” in cooperation with the Veterinary University in Košice. It enables to educate new toxicologists with perspective to employ them at the Department of Toxicology at Dobrá Voda near Trnava. The Institute prepared projects for extension of research and commercial activities at the Toxicology Department to employ new perspective scientific workers as well as technical assistants for the purposes to conduct toxicity studies and to contribute to reduction of high unemployment in the Trnava Region.

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Other information relevant to the assessment The IEPh SAS is the only institution in basic and applied pharmacology in former Czecho-Slovakia and at present represents the leading institution in the research field in Slovakia. It plays an important role in the development of the scientific discipline pharmacology in Slovakia. An integral part of the Institute is the Department of Toxicology and Animal Breeding located at Dobrá Voda near Trnava. It is the only centre in Slovakia for toxicological research and breeding of small laboratory animals possessing the Certificate of GLP Compliance No 23/2000 issued by the Slovak National Accreditation Service for toxicity studies, carcinogenicity, care and housing of animals.