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Biomedical subjects

Jirí Patocka

Publications and source records attributed to Jirí Patocka.

11 recordsLinked to original sources

Protein biotoxins of military significance.

There is a spectrum of several threat agents, ranging from nerve agents and mustard agents to natural substances, such as biotoxins and new, synthetic, bioactive molecules produced by the chemical industry, to the classical biological warfare agents. The new, emerging threat agents are biotoxins produced by animals, plants, fungi, and bacteria. Many types of organisms produce substances that are toxic to humans. Examples of such biotoxins are botulinum toxin, tetanus toxin, and ricin. Several bioactive molecules produced by the pharmaceutical industry can be even more toxic than are the classical chemical warfare agents. Such new agents, like the biotoxins and bioregulators, often are called mid-spectrum agents. The threat to humans from agents developed by modern chemical synthesis and by genetic engineering also must be considered, since such agents may be more toxic or more effective in causing death or incapacitation than classical warfare agents. By developing effective medical protection and treatment against the most likely chemical and mid-spectrum threat agents, the effects of such agents in a war scenario or following a terrorist attack can be reduced. Toxin-mediated diseases have made humans ill for millennia. Unfortunately, the use of biological agents as weapons of terror has now been realized, and separating naturally occurring disease from bioterroristic events has become an important public health goal. The key to timely identification of such attacks relies on education of primary care physicians, first responders, and public health officials.

Bacterial Toxins↗

New quaternary pyridine aldoximes as casual antidotes against nerve agents intoxications.

In this work, the ability of four newly synthesized oximes--K005 (1,3-bis(2-hydroxyiminomethylpyridinium) propane dibromide), K027 (1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium) propane dibromide), K033 (1,4-bis(2-hydroxyiminomethylpyridinium) butane dibromide) and K048 (1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide) to reactivate acetylcholinesterase (AChE, EC 3.1.1.7) inhibited by nerve agents is summarized. Reactivation potency of these compounds was tested using standard in vitro reactivation test. Tabun, sarin, cyclosarin and VX agent were used as appropriate testing nerve agents. Rat brain AChE was used as a source of the enzyme. Efficacies of new reactivators to reactivate tabun-, sarin-, cyclosarin- and VX-inhibited AChE were compared with the currently used AChE reactivators (pralidoxime, obidoxime and HI-6). Oxime K048 seems to be promising reactivator of tabun-inhibited AChE. Its reactivation potency is significantly higher than that of HI-6 and pralidoxime and comparable with the potency of obidoxime. The best reactivator of sarin-inhibited AChE seems to be oxime HI-6. None of the new AChE reactivators reached comparable reactivation potency. The same results were obtained for cyclosarin-inhibited AChE. However, oxime K033 is also potent reactivator of AChE inhibited by this nerve agent. In the case of VX inhibition, obidoxime and new oximes K027 and K048 seem to be the best AChE reactivators. None from the currently tested AChE reactivators is able to reactivate AChE inhibited by all nerve agents used and, therefore, the search for new potential broad spectrum AChE reactivators is needed.

Acetylcholinesterase↗

Botulism and bioterrorism: how serious is this problem?

Botulism is a potentially lethal disease caused by one of seven homologous neurotoxic proteins usually produced by the bacterium, Clostridium botulinum. This neuromuscular disorder occurs through an exquisite series of molecular events, ultimately ending with the arrest of acetylcholine release and hence, flaccid paralysis. There are three types of botulism: food, wound, and infant botulism. Most strains of the bacterium produce a potent, respiratory muscle-paralyzing neurotoxin, botulinum toxin (BTX). It can lead to death unless appropriate therapy is promptly initiated. Due to the severity and potency of BTX, its importance as a biological weapon is of major concern to public health officials. Nevertheless, BTX is also medicament.

Bioterrorism↗

Pharmacological potential of endothelin receptors agonists and antagonists.

Endothelins are potent predominantly vasoconstricting agents that act as local autocrine and paracrine mediators. Endothelin-1 is the most potent and sustained vasoconstrictor and pressor substance yet identified. Abnormalities of the endothelin system occur in a range of diseases associated with vasoconstriction, vasospasm, and vascular hypertrophy. ET receptor antagonists were until recently regarded as drugs of great promise in patients with congestive heart failure, pulmonary hypertension and others. The aim of this article is a survey of compounds that affect the endothelin receptors and clinical trials with these agents.

Cardiovascular Diseases↗

Reactivation of organophosphate-inhibited acetylcholinesterase by quaternary pyridinium aldoximes.

We investigated the relationship between the chemical structure of acetylcholinesterase (AChE; EC 3.1.1.7) reactivators and their potency in reactivating this enzyme, after prior inhibition by VX (O-ethyl-S-(2-diisopropylaminoethyl)-methylthiophosphonate), tabun, sarin, and cyclosarin. The oximes, pralidoxime (2-PAM), HI-6 [1-(2-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-2-oxa-propane dichloride], obidoxime and HS-6 [1-(2-hydroxyiminomethylpyridinium)-3-(3-carbamoylpyridinium)-2-oxa-propane dichloride] were used as representatives of the group of AChE reactivators. Rat brain AChE was used as the appropriate source of the enzyme. Our results confirm that there is no single broad-spectrum oxime suitable for the treatment of poisoning with all highly toxic organophosphorus agents.

Acetylcholinesterase↗

Reactivation of cyclosarin-inhibited rat brain acetylcholinesterase by pyridinium--oximes.

Cyclohexyl methylphosphonofluoridate (cyclosarin, cyclosin, GF) is a highly toxic organophosphate, which is resistant to conventional oxime therapy. To gain insight into the reactivation kinetics, rat brain acetylcholinesterase (AChE) was inhibited in vitro by cyclosarin (pH 8.0, 25 degrees C) and reactivated with 22 different pyridiniumoximes. Three compounds were shown to be superior to the other oximes: 4-carbamoyl-4'-[(hydroxyimino)methyl]-1,1'-(oxydimethylene)dipyridin-1-ium dichloride (HS-6), 4'-carbamoyl-2-[(hydroxyimino)methyl]-1,1'-(oxydimethylene)dipyridin-1-ium dichloride (HI-6), and 4'-carbamoyl-2-[(hydroxyimino)-methyl]-1,1'-(but-2-ene-1,4-diyl)dipyridin-1-ium dichloride (BI-6).

Acetylcholinesterase↗

Endothelins and sarafotoxins: peptides of similar structure and different function.

Endothelins are endogenous vasoactive peptides that are considered among the most potent vasoconstrictor substances known. In addition to their vascular effects, endothelins and their receptors have been shown to be present in many organs and share plenty physiological and pathophysiological functions. Sarafotoxins are natural substances from the venom of snakes genus Atractaspis, structurally and pharmacologically near to endothelins. The current minireview focuses on the chemical and molecular aspects of endothelins and sarafotoxins, and their receptors in physiological and pathophysiological processes.

Animals↗

Acetylcholinesterase and butyrylcholinesterase--important enzymes of human body.

The serine hydrolases and proteases are a ubiquitous group of enzymes that is fundamental to many critical life-functions. Human tissues have two distinct cholinesterase activities: acetylcholinesterase and butyrylcholinesterase. Acetylcholinesterase functions in the transmission of nerve impulses, whereas the physiological function of butyrylcholinesterase remains unknown. Acetylcholinesterase is one of the crucial enzymes in the central and peripheral nerve system. Organophosphates and carbamates are potent inhibitors of serine hydrolases and well suited probes for investigating the chemical reaction mechanism of the inhibition. Understanding the enzyme's chemistry is essential in preventing and/or treating organophosphate and carbamate poisoning as well as designing new medicaments for cholinergic-related diseases like as Alzheimer's disease.

Acetylcholinesterase↗

Inorganic lead toxicology.

Lead is a health hazard for all humans. Especially children under the age of six are most at risk for lead poisoning. Lead toxicity causes hematological, gastrointestinal, and neurological dysfunction. Symptoms are usually noted with blood lead greater than 2 micromoles/L. Severe or prolonged exposure may also cause chronic nephropathy, hypertension, and reproductive impairment. Lead inhibits some enzymes, alters cellular calcium metabolism, stimulates synthesis of binding proteins in kidney, brain, and bone, and slows down nerve conduction. Acute lead poisoning is relatively infrequent and results from ingestion of acid soluble lead compounds or inhalation of lead vapors but chronic exposure to low levels of the metal is still a public health issue, especially among some minorities and socioeconomically disadvantaged groups. Lead has been used since prehistoric times, and has become widely distributed and mobilized in the environment. Exposure to and uptake of this non-essential element have consequently increased. Both occupational and environmental exposures to lead remain a serious problem in many developing and industrializing countries and a public health problem of global dimensions.

Acute Disease↗

Anthrax toxin characterization.

The anthrax toxin comprises three proteins. When they work together, they can kill humans, especially after spores of the bacteria have been inhaled. One anthrax protein, called protective antigen (PA), chaperones the two other toxins into human or animal cells and shields them from the body's immune system. The second, lethal factor (LF), destroys the white blood cells that hosts send in defence. The third toxin molecule, edema factor (EF), hijacks the signaling system in the body. This disrupts the energy balance of cells and leads to them accumulating fluid and complete destroy of cells.

Animals↗

Prophylaxis against anthrax.

The paper presents fundamental knowledge concerning Bacillus anthracis and its potential terrorist misuse. The basic clinical forms are resumed with emphasis on inhalation infection from inspiration of B. anthracis spores. The AVA vaccine licensed in the United States, primary vaccination, protective efficacy of the vaccine, and adverse events are characterised. Stress is laid on pre-exposure and post-exposure prophylaxis of anthrax.

Animals↗