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7-methoxytacrine (MEOTA) is a reversible inhibitor of acetylcholinesterase and it belongs to a group of drugs, which are known as activators of cognitive functions and could be useful in the therapy of some neurodegenerative disorders such as Alzheimer’s disease. The lower toxicity is its advantage in comparison with tacrine. L-carnitine (CRT) was used to increase penetration of MEOTA through the blood brain barrier in rat. ³H-MEOTA was administered intravenously (5 mg/kg), orally (5 and 0.5 mg/kg) or intramuscularly (100 mg/kg) to rats in order to evaluate its pharmacokinetic properties. The intramuscular administration was chosen for the biodistribution study, where MEOTA was administered in two groups of rats: one group was administered only with MEOTA and the second group was administered CRT (300 mg/kg) orally for 3 consecutive days before MEOTA. Levels of MEOTA Were assessed in blood and in the brain tissue samples. In the next experimental step it was evaluated inhibition of acetylcholinesterase (AChE) activity in separate brain areas following administration of MEOTA in interaction with CRT. The results showed that MEOTA crossed blood brain barrier and its levels in the brain were weakly increased after CRT repeated administration. On the other hand the repeated administration of CRT enhanced significantly the inhibiting effect of 7-MEOTA on the brain AChE activity. A comparison of the brain tissue levels of MEOTA under the influence of CRT with the inhibiting eflect on the AChE activity in the brain showed that the higher inhibiting effect of MEOTA on AChE activity with CRT is not caused by a global increasing of its concentration in the brain tissue, but it is probably due to an interaction of MEOTA and CRT on active centre of the corresponding enzyme.

The integrity of the human genome is constantly threatened by exogenous or endogenous genotoxic agents that cause DNA damage. The ionizing radiation (IR)-induced DNA double-strand breaks (DSBs) are considered as the most deleterious forms of DNA damage which could lead to genomic instability and to cancer development, if left unrepaired. The DNA damage response (DDR) is comprised of a network of proteins that cooperate to regulate cell cycle progression and repair of DNA lesions. Our understanding of molecular basis of repair processes and of functions of repair proteins, as well as understanding of chromatin modifications may provide new possibilities in improvement of cancer management. Phosphorylation of histone variant H2AX at serine 139 (γ-H2AX) and formation of γ-H2AX repair foci seems to be the most sensitive DNA damage marker in the chromatin flanking the free DNA double-stranded ends in DSBs. Monitoring of γ-H2AX levels can serve for early indication of cancer development, as biomarker of cancer therapy efficiency or as a biodosimetric marker of radiation exposure.

Anatoxin-a(s) is a guanidinemethyl phosphate ester isolated from the freshwater cyanobacterium (blue-green algae) Anabaena flos-aquae strain NRC 525-17. Previous work has shown anatoxin-a(s) to be a potent irreversible inhibitor of electric eel acetylcholinesterase (AChE, EC 3.1.1.7). Anatoxin-a(s) has been shown to be an active site-directed inhibitor of AChE, which is resistant to reactivation by oximes because of the enzyme-oxime adduct formation. In vivo pretreatment with physostigmine and high concentrations of pyridine 2-aldoxime methochloride (2-PAM) were the only effective antagonists against a lethal dose of anatoxin-a(s). Anatoxin-a(s) is very toxic and it is produced by cyanobacteria during its blooms. Purified toxin has an LD₅₀ (i.p) of approximately 20-50 μg/kg body weight in mice. Toxicoses associated with cholinesterase-inhibiting anatoxin-a(s) have been observed in humans, animals, birds and fish. Anatoxin-a(s) induces clinical signs of hypercholinergic preponderance, such as salivation, lacrimation, urinary incontinence, defecation, convulsion, fasciculation, and respiratory arrest.

The authors discuss an issue of demographic aging, heterogeneity of seniors, specific needs and questionable issues in seniors with mental disorders hospitalized at the Department of Gerontopsychiatry. The seniors with a psychiatric morbidity dependent on institutional care usually stand at the fringe interest of the society, even research does not pay a proper attention to them. From the point of financial costs, the gerontopsychiatry is incredibly underpaid area - there is a lack of money for both reconstruction and modernization of obsolescent gerontopsychiatric departments of mental homes. A guardian of the human rights has repeatedly warned about these conditions. The medical and social problematics of complex care for psychiatric senior patients itself brings specific difficulties as well as specific challenges which the authors called The Ten Commandments of seniors hospitalized on the gerontopsychiatric bed. The authors openly touch hot issues of institutional gerontopsychiatric care - unvoluntary hospitalizations, use of restrictive measures in gerontopsychiatry, pharmacotherapy of psychomotoric unrest states, disability for providing legal actions and compulsory treatment. Newly, the authors point out a quality of provided care in gerontopsychiatry and emphasize the issue of burnout which negatively influences just the quality of care in gerontopsychiatry and lives of gerontopsychiatric workers as well.

Chlorine trifluoride is nonflammable, corrosive, and nearly colourless gas with a sweet odour. This compound is extremely reactive. Chlorine trifluoride is hazardous chemical highly irritating the skin, eyes, and mucous membranes. There are no valid human studies in which well characterized exposure to inhalation of ClF3 is related to systemic effects but data from inhalation experiments in laboratory rats and dogs indicate that eyes and respiratory tract are the target organs following acute and repeated exposure to chlorine trifluoride. The current OSHA permissible exposure limit (PEL) for chlorine trifluoride is 0.1 ppm of air as a ceiling limit. Concentrations above 10 ppm are reportedly intolerable.

Colorimetric detectors based on recognition capability of acetylcholinesterase (AChE) are a suitable tool for fast but sensitive detection of nerve agents and some pesticides based on AChE inhibition. In this review article, basic biochemical methods appropriate for colorimetric estimation of AChE enzymatic activity are presented. Moreover, the available matrices suitable for construction of dipsticks and chemical as well as physical immobilization protocols for AChE binding on matrice surface are described, too. Detehit and ChP-71 are indicated as typical colorimetric detectors for assay of nerve agents.

Organophosphorus pesticides are toxic compounds commercialized for protection of agricultural commodities as well as pertinent disinfection. Pesticides utilization is regulated in the Czech Republic by laws, the similar effort is obvious throughout the whole European Union. Regulation of pesticides utilization is current trend. This review study is focused on presentation of active substances and some important parameters including toxicity mechanisms.

The harmful effect of organophosphates and carbamates on natural enzymes from the group of cholinesterases can be employed for analytical purposes. The biosensors based on cholinesterases as biorecognition components were used for an analysis of organophosphates and carbamates several times. In this review article, some enzyme reaction visualizations as well as immobilization procedures have been compared as important parameters of biosensor construction.

The ability of the examined compounds to create ion pairs with the selected anionic dyes, allows their determination by the method of extraction spectrophotometry in the visible radiation. These ion pairs are extractable with an organic solvent immiscible with water. The procedure is based on protonisation of the studied compounds in acidic environment, and consequently their extraction in the form of associate with the anion of the acid dye into the organic phase, in this case in chloroform.Mentioned methods of analysis may be advantageously used for simple and express determination of fentanyl, alfentanil and remifentanil.

The objective of the experiment was to verify that HI-6 dimethanesulphonate (HI-6 DMS) is able to penetrate the skin in amounts sufficient to protect against organophosphate poisoning using a rat model. HI-6 2Cl is a major component of Transant, a transdermal patch, used as a protective agent against organophosphate intoxication in the Czech and Slovak armies, although there is little evidence that HI-6 would penetrate the skin in sufficient amounts. HI-6 DMS at a total amount of 127 mg or 635 mg was applied as a buffer solution on the Transant patch which was fixed on the back of the rat. Two, seven or twenty-four hours later, rats were sacrificed and blood samples were collected to determine the levels of HI-6 in plasma by HPLC on reversed phase with isocratic elution and UV/VIS detection. HI-6 was not detectable in plasma samples of animals exposed to 127 mg of HI-6 DMS. The highest levels of HI-6 (20.6 ± 18.8 ng/ml) were found in plasma of animals exposed to 635 mg of HI-6 DMS 2 hours after patch application, whereas after 7 or 24 hours the levels were very low. Based on these results, the ability of HI-6 DMS to penetrate the skin is discussed and some possibilities of improving the transdermal penetration are suggested.

On the 20^th September, 2013, Czech medical community received a very sad announcement of the death of Professor Radana Königová, a prominent personality in the Czech medicine and whole society, respected authority within the international burns and medical societies. She passed away in the hospital where she had worked for more than 51 years, until the very last days, before orthopedic surgery she had had to undergo. Unfortunately, she did not return to her "second home", the Prague...

Personnel decontamination belongs to one of the crucial measurements performed to personnel's protection within hazard management after either employment of Weapons of Mass Destruction or leakage of Toxic Industrial Materials. Suitable personnel, technical and material conditions corresponding to current demands and trends are necessary to create its realization in this area. Knowledge gained within solution problems of personnel decontamination, casualty decontamination, immobile people decontamination, decontamination of personnel weapons, selected Individual Protective Equipment, personnel garments, accoutrements and other materials with the usage of modular elements are summarized in this paper. A conceptual proposal of solution of a mobile decontamination system for personnel decontamination is also stated in this paper.

Traditionally, the 16th national conference in a row on "Nutrition and Health" with international participation was held in the spa house Beethoven in Teplice on 18 - 19 September, 2012. The Teplice conference is the largest home conference focused on nutrition hygiene and primary prevention referred to a food intake. This year 40 specialists from the Czech Republic and Slovakia participated there. Specialities were represented mainly by physicians, nutritional therapists and regional hygiene stations workers. The Czech Medical Association, Third Faculty of Medicine, Charles University in Prague and the Health Institute located in Ústí nad Labem were in charge of organization of the conference. Within two conference days, 26 special oral presentations were delivered and 16 posters ...

18^th Interdisciplinary Czech-Slovak Toxicology Conference

In this study, 21 structurally diverse drugs with examined central nervous system penetration were used for prediction of blood-brain barrier penetration using HPLC-UV instrument. Drugs' chromatographic capacity factors were measured by the immobilized artificial membrane presented by phosphatidylcholine column. The correlation between chromatographic capacity factor, octanol-water partition coefficient (log P) and molecular polar surface area (PSA) were determined at the physiological pH. The correlation factor 0.6677 with respect to log P and 0.7199 in reference to PSA was assigned. The developed in vitro prediction method may be used as a screening tool for blood-brain barrier penetration of drugs with passive transport mechanism.

External application of seabuckthorn oil (Hippophae rhamnoides L.) is difficult due to its liquid state in spite of its benefits for damaged skin. In order to overcome this inadequacy the semisolid emulsion with seabuckthorn oil was prepared. Previous research showed that this emulsion possessing an enhanced structure with liquid crystals showed a higher wound healing potential than seabuckthorn oil. The aim of this investigation was to characterize suitability of this emulsion for topical use. The emulsion was prepared by combining emulsifiers that form liquid crystals. Two different quantities of seabuckthorn oil were incorporated. Samples were prepared with 10% and 40% of seabuckthorn oil. Organoleptic characteristics were estimated visually and by smearing samples on a thin glass plate. Type of emulsion was determined by a conductometric method, while a pH value of the emulsion was measured by a pH meter. Samples of seabuckthorn emulsion were orange, semisolid, shiny, easily spreadable on skin, and the smear on the glass plate was homogeneous. There was an absence of smell and the emulsion could be rinsed by water after the application on skin, which is a desired characteristic of oil/water emulsions. Results of an electrical conductivity confirmed that an outer phase is water. Samples possesed an acceptable pH value for an external topical use. This research confirmed that constituents and a method used were suitable for preparing semisolid emulsion with seabuckthorn oil. Organoleptic properties, a pH value and a type of obtained emuslion appear to be adequate for topical use.

Organophosphorous compounds cause fatal intoxication based on inhibition of acetylcholinesterase, an essential enzyme of neurosynapses and neuromuscular junctions. There is an obvious need to develop appropriate treatment against them due to their application in agriculture and chemical industry or their misuse in terrorist or war attack.In the Czech army some medicaments have been established to be used against this poisoning; Obidoxime, Methoxime, Atropine and Benactyzine. In present in vitro study we focused on potential cytotoxic and genotoxic effect evaluation of these drugs by the clonogenic and comet assay, respectively.Obtained results show that oximes exhibit pronounced toxic effect, namely obidoxime in term of genotoxicity and methoxime in term of cytotoxicity.

Non-lethal weapons are a combat means and weapon systems which put a human being out of combat action or other purposeful activity by causing physical or mental disablement. If chemical agents are the means of temporary incapacitation, these substances are known as non-lethal chemical agents and weapons based on this principle are known as non-lethal chemical weapons. A temporary incapacitation without a serious damage to health is a primary effect of these weapons. In this article the development of non-lethal chemical weapons is discussed in relation to the Convention on Prohibition of Chemical Weapons.

Group G streptococci (GGS) are commonly regarded as commensals because they are often found in association with the normal flora of human and animal pharynx, skin, gastrointestinal and urogenital tract. In recent years, they have been reported with increasing frequency as a cause of variety of human infections, such as endocarditis, arthritis, meningitis, pharyngitis and sepsis. GGS infections have manifestinations similar to those caused by S. pyogenes. They express several virulence determinants initially identified in S. pyogenes, such as M protein, streptokinase, streptolysins O and S, C5a peptidase and hyaluronic acid capsule. The human isolates of beta-haemolytic GGS include the anginosus group and S. dysgalactiae ssp. equisimilis. S. canis is important animal pathogen.

This review deals with the smokeless tobacco products, their use, composition, systemic and oral diseases associated with it. It is evident that smokeless tobacco is carcinogenic to human and causes various systemic and oral diseases. One of the major cancers caused by smokeless tobacco use is oral cancer and other oral diseases like leucoplakia, dental caries, smokeless keratosis, and other negative influences of smokeless tobacco on oral cavity including staining of teeth, bad breath, mouth sores, attrition and abrasion. This review also tries to describe the possible tobacco cessation intervention in dental office.

This work describes the possibilities of using food as an element of bioterrorist activity. At the present time the infection or contamination of food products is considered to be easier than the use of aerosols in bioterrorist attacks. Terrorists can use food in their attacks which can cause casualties but can also provoke fear and panic, a reduction in confidence or even distrust of the authorities. The efiect of bioterrorist activity on food producers can cause a constant reduction of production and sales which can lead to significant material losses.

Central anticholinergic syndrome evoked by some incapacitating chemical agents from the family of anticholinergics is possible to treat with some reversible centrally active inhibitors of acetylcholinesterase. In this paper the view of anticholinergic incapacitating agents and their biological effects is summarize as well as a survey of inhibitors of acetylcholinesterase which may be used as antidotes against intoxication by incapacitating chemical agents. The position of 7-methoxytacrine as very effective and little toxic antidote is discussed.

Detergent-based mixtures and pure surfactants used as decontaminants in mass casualty scenarios were investigated for their acute 24 h toxicity. Commercial detergents Neodekont^TM, Argos^TM, Dermogel^TM, and FloraFree^TM were tested in male Wistar rats after percutaneous, peroral and intramuscular administration. Pure surfactants althosan MB, sodium alkylbenzene sulphonate, triton X, benzyl dimethyl dodecyl ammonium chloride, and N-dodecyl pyridinium bromide were investigated in male ICR mice. Estimated LD₅₀ of surfactants varied from < 100 mg.kg^-1 (i.m.) to more than 2000 mg.kg-1 (p.o, p.c.) in mice. All detergents tested in rats were rather less toxic (LD₅₀ > 6 ml.kg^-1), thus could be considered as safe if used as external skin decontaminant or if low volume is accidentally ingested.

This review describes a drug target for cancer therapy, family of phosphatidylinositol-3 kinase related kinases (PIKKs), and it gives a comprehensive review of recent information. Besides general information about phosphatidylinositol-3 kinase superfamily, it characterizes a DNA-damage response pathway since it is monitored by PIKKs.

The most complex topic is represented by operative treatment of type IV lesions of rotator cuff. Palliative arthroscopic resection of rotator cuff did not produce optimal results. We thus intend to evaluate the newly implemented surgical techniques at our department.Fifty-six patients with type IV rotator cuff lesions were treated surgically between October 2007 and December 2010. In 6 patients, combined operations had to be performed because of their pathology, and these were not included in detailed evaluation. The population selected for detailed evaluation of new surgical techniques included 50 patients (mean age: 59 years, range: 41-73 years). The patients were randomized into two subpopulations, each formed by 25 people. Both subpopulations can be considered representative and comparable.All operations were performed in the "beach-chair" position in general anesthesia or/and in interscalenic block. After type IV lesion was diagnosed, the prespecified surgical procedure followed - partial muscle transfer of subscapularis muscle tendon (Karas) or partial non-anatomic rotator cuff reconstruction (Burkhart). The results were evaluated after 6 months using the modified Constant Functional Score. The following parameters were assessed: sex, age, side of the operation, dominance of the limb, Constant Functional Score pre-operatively and post-operatively, subjective and objective evaluation, pain, activities, movement and muscle strength, Constant Score improvement, improvement in its individual items and subitems, pain pre-operatively and post-operatively.In older patients with type IV lesions, we have good experience with Karas method while in younger and more active patients, Burkhart method seems to be more useful.

Postdoctoral studies - development of new methods and evaluation of compound pharmacokinetics parameters & Postdoctoral studies -Position focused on synthetic work

Intracellular pathogen F. tularensis is a causative agent of tularemia disease and belongs to the most hazardeous pathogen worldwide, categorized by the Center for Disease Control and Prevention, USA (CDC) as a category A agent. However, no safe and licensed vaccine for prevention a F. tularensis infection is available for vaccination. Tularemia is manifested by several forms depending on a route of infection and virulence of a F. tularensis strain. Essential to a development of the disease is the ability to infect, survive and proliferate inside the mononuclear phagocytes, such as macrophages or dendritic cells. Therefore, this review will discuss aspects of F. tularensis intracellular fate within host macrophages, modulate host signaling pathways to benefit Francisella infection and finally, summarize bacterial determinats involved in the process of phagosomal escape and intracellular replication.

Riot control agents are highly potent sensory irritants of relatively low toxicity that produce dose and time-dependent acute site-specific toxicity. These compounds have been referred to as transient incapacitating agents or as lacrimators, and in common parlance they are known as "tear gases". These compounds interact pharmacologically with sensory nerve receptors associated with mucosal surfaces and the skin at the site of contamination, resulting in localized discomfort or pain with associated reflexes. This biological response, e.g. ocular irritation, results in pain in the eye and excess reflex lacrimation and blepharospasm. Riot control agents have both civil and military applications and have been classified as either military chemicals or chemical warfare agents. Non-lethal or less lethal weapons have become increasingly popular for law enforcement use when confronting dangerous, combative individuals in the field, include riot control agents. Many incapacitating agents were developed during the Cold War. Oleoresin capsicum (OC) spray, an extracted resin from Capsicum pepper plants, was first developed in the 1970s as an alternative to CS (2-chlorobenzylidene malononitrile) and CN (chloroacetophenone) agents. Most recently, a synthetic form of capsaicin, PAVA (pelargonic acid vanillylamide), gained popularity as a defensive aerosol in the early 1990s. Chemical, pharmacological, and toxicological properties of PAVA are discussed in this paper.

Searching for the universal oxime, which could be able to reactivate acetylcholinesterase inhibited by various nerve agents is still topic of high interest. In this contribution, oxime HLö-7, that was thoroughly discussed in the last decade, is evaluated . Its universality was tested in vitro using the rat brain homogenate as a source of the cholinesterases. The main members of the nerve agent family (tabun, sarin, soman, cyclosarin and VX) were used for this purpose. As shown, oxime HLö-7 was able to reactivate cholinesterases inhibited by all tested nerve agents with the exception of tabun. Hence, it could not be designated as the broad-spectrum reactivator.

Toxins are important virulence factors responsible for microbial pathogenicity. Potential applications of toxin research extend beyond simply combating microbial virulence and include the development of novel anti-cancer drugs and other front-line medicines. No less important is the use of toxins as tools in cellular biology and neurobiology. Understanding toxin molecular and cellular biology is critical for the development of new anti-toxin strategies, particularly for those with bioterrorism capability. This well worked book not only provides a general overview of toxins but elucidates in detail recent molecular approaches, achievements and refreshing perspective on the future studies of these molecules. The book is divided into nine chapters and each chapter is written by internationally respected scientists. ...