Synthesis and preliminary biological evaluation of gabactyzine, a benactyzine-GABA mutual prodrug, as an organophosphate antidote.

Organophosphates (OPs) are inhibitors of acetylcholinesterase and have deleterious effects on the central nervous system. Clinical manifestations of OP poisoning include convulsions, which represent an underlying toxic neuro-pathological process, leading to permanent neuronal damage. This neurotoxicity is mediated through the cholinergic, GABAergic and glutamatergic (NMDA) systems. Pharmacological interventions in OP poisoning are designed to mitigate these specific neuro-pathological pathways, using anticholinergic drugs and GABAergic agents. Benactyzine is a combined anticholinergic, anti-NMDA compound. Based on previous development of novel GABA derivatives (such as prodrugs based on perphenazine for the treatment of schizophrenia and nortriptyline against neuropathic pain), we describe the synthesis and preliminary testing of a mutual prodrug ester of benactyzine and GABA. It is assumed that once the ester crosses the blood-brain-barrier it will undergo hydrolysis, releasing benactyzine and GABA, which are expected to act synergistically. The combined release of both compounds in the brain offers several advantages over the current OP poisoning treatment protocol: improved efficacy and safety profile (where the inhibitory properties of GABA are expected to counteract the anticholinergic cognitive adverse effects of benactyzine) and enhanced chemical stability compared to benactyzine alone. We present here preliminary results of animal studies, showing promising results with early gabactyzine administration.

Analytical determination of bioactive compounds as an indication of fruit quality.

The aim of this investigation was to determine the bioactive compounds in kiwifruit as an indication of quality after extraction using methanol and ethyl acetate. Using FTIR and three-dimensional fluorescence spectroscopy and electrospray ionization/MS, the contents of polyphenols, flavonoids, flavanols, and tannins, and the level of the antioxidant activity by 2, 2-azino-bis (3-ethyl-benzothiazoline-6-sulfonic acid) diammonium salt, 1, 1-diphenyl-2-picrylhydrazyl, ferric-reducing/ antioxidant power, and cupric reducing antioxidant capacity assays were determined and compared. It was found that the methanol extracts of kiwifruit showed significantly higher amounts of bioactive acetate extracts. The cultivar Bidan, in comparison compounds and antioxidant activities than the ethyl with the classic Hayward, showed significantly higher bioactivity. For the first time, Bidan organic kiwifruit was analyzed for its antioxidant activities and compared with the widely consumed Hayward organic based on its bioactive compounds and fluorescence properties. Relatively high content of bioactive compounds and positive antioxidant and antiproliferative properties of kiwifruit determined by the advanced analytical methods justify its use as a source of valuable antioxidants. The methods used are applicable for bioactivity determination, in general, for any food products.

Concentration of bioactive compounds in mussels Mytilus galloprovincialis as an indicator of pollution.

The polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs) and organotins were analyzed in mussels Mytilus galloprovincialis from polluted and unpolluted sites from Mokpo Bay, Korea. The total PAH's concentrations (10(-3)mgkg(-1)) measured by GC-MS were in the range from 31+/-23 to 1+/-1. Among the eight PAHs the predominant ones were fluoranthene, phenanthrene and pyrene and accounted approximately 63% of the total PAHs. Among the four detected PCBs the highest content was of PCB 153, which accounted about 47% of the total PCBs. The main organotin compounds were dibutyltindichloride (DBT) and tributyltinchloride (TBT) and their composition was approximately 33% and 24%. PAHs, PCBs and organotins were found only in the mussels from polluted site. The antioxidant activity by ABTS [2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid)] test was higher in mussels from polluted than from unpolluted sites (P<0.05). It was found a correlation between the determined compounds (PAHs, PCBs and organotins) and the antioxidant activity of the mussel tissue from polluted site and the correlation coefficients were 0.96, 0.92 and 0.80, respectively. Such correlation can be explained by the properties of mussels. Since the mussel cell wall and tissues are hydrophobic, they can concentrate a number of hydrophobic pollutants like PAHs and PCBs from the marine environment by solubility rules. On the other hand, proteins are lipophilic compounds having antioxidant properties. Certain amino acid residues and thiol (-SH) groups, contained in proteins, respond to the ABTS antioxidant activity assay. Thus there may be a correlation between the total antioxidant activity of the organism and the PAH-PCB pollutants which were concentrated from its environment. The studied properties of mussels from polluted site can be used as an additional indicator of pollution.

Osmium tetroxide: a new kind of weapon.

OsO4 is a powerful oxidizer. It affects mainly the skin and mucous membranes. Although unsuitable for a large-scale terrorist attack, mainly due to its scarcity, it could be used in small-scale attacks. The small quantity contained in a vial would cause irritation to the eyes, nose, throat and skin. Combining the agent with an explosive material will probably destroy most of it, chemically. Thus, releasing the chemical without using explosives may be considerably more dangerous. Medical management is mainly symptomatic. As soon as the chemical enters the body, it rapidly reacts with the tissues in contact. Medical personnel should be aware of its poisonous effects and be equally familiar with the necessary self-protection measures and the treatment protocols.

Bromine--the red cloud approaching.

Bromine is a strong and prevalent irritating agent that can spread both as liquid and as fumes. It has a characteristic reddish-brown color. The mainstay of the medical management is supportive and symptomatic therapy that should be given as soon as possible to prevent further damage. Medical personnel, especially the emergency department staff, should be familiar with its health effects, including the safety precautions needed when caring for casualties following such an exposure.

[Cyanides--treatment beneath the shade of terror].

Although the use of cyanides as warfare agents has not been documented since the Iran-Iraq war in the 1980s, there are rising fears of cyanide being used by terrorists. An Al-Qaeda terror plot to use cyanide gas in the London Underground was foiled in 2002. The threat of similar events becomes more imminent in light of the terror attacks in our country and worldwide, accompanied by statements and threats by fundamentalist leaders to employ chemical weapons. Therefore, mass-intoxication with cyanides is not merely a hypothetical scenario. The treatment of cyanide poisoning is under constant evaluation and there is no international consensus on the subject. The medical treatment of victims at the scene and in hospitals should be rapid and efficient. Current treatment dictates establishing an intravenous line and a slow rate of administration of antidotes. Both demands are not feasible in this specific mass casualty event. The clinical signs of cyanide poisoning are complex, variable and not necessarily obvious for the medical team. There is great interest in reconsidering the existing treatment protocols for cyanide intoxication in light of current research. This review describes the mechanisms of cyanide toxicity, clinical signs of exposure, and current treatment protocols in use worldwide. On the basis of this evidence we suggest a medical treatment protocol for a mass casualty event caused by cyanide.

[Political poisoning with dioxins--a weapon of chemical "disgracefulness"].

The recent attempt to poison Ukrainian President, Viktor Yuschenko with dioxins, raised public concern regarding this toxic chemical. In industrial countries, there is a constitutive exposure of humans to dioxin compounds, which are formed as by-products in manufacturing processes of various chlorinated organic chemicals and in waste incinerators. Dioxins are extremely stable in the environment and have a low turnover rate in the body--sometimes they are detected years after the original exposure. Of the dioxins, the most notoriously famous is the TCDD (2,3,7,8 tetrachlorodibenzo-p-dioxin). Dioxins exhibit high acute toxicity in various animal species. Humans, however, are considered less susceptible and so far there were no reported deaths following acute dioxin poisoning. Nevertheless, numerous adverse health effects are attributed to dioxin exposure. The most prominent is the chloracne--an acute acneiform eruption, usually appearing on facial skin. There is a solid evidence base that some dioxins are carcinogens. Other long-term deleterious effects of dioxin include: immunosuppression, effects on reproduction, impairments in developmental, neurological and cognitive functions in infants, increased risk for diabetes and cardiovascular diseases and various hormonal alterations. The action of dioxins resembles that of hormones, since their toxicity is mostly receptor-mediated. Dioxins manifest their toxicity in extremely low concentrations. Although there are compounds that exhibit their biological activity at even lower dose range (e.g. nerve gases), this potency of dioxins is considered extraordinary, since there is an every-day exposure to dioxins through environmental vectors mostly via the food chain. Until now, there is no antidotal cure for dioxins, but only symptomatic treatment combined with techniques that accelerate its excretion rate from the body.

Pharmacologic prophylaxis against nerve agent poisoning.

Nerve agent poisoning is characterized by the rapid progression of toxic signs, including hypersecretions, tremor, convulsions and profound brain damage. In the political arena of today's world, the threat of nerve agent use against military troops has prompted armies to search for prophylactic protection. The two main strategies for prophylaxis include biological scavengers that can bind or cleave nerve agents before they react with acetylcholinesterase, and antidotes as prophylactic treatment. Pyridostigmine is the current pretreatment for nerve agent poisoning and is in use by most of the armed forces in Western countries. However, since pyridostigmine barely crosses the blood-brain barrier it provides no protection against nerve agent-induced central injury. Pyridostigmine is ineffective when administered without post-exposure treatment adjuncts. Therefore, other directions for prophylactic treatment should be explored. These include combinations of carbamates (reversible AChE inhibitors) and central anticholinergics or NMDA receptor antagonists, benzodiazepines or partial agonists for benzodiazepine receptor, and other central AChE inhibitors approved for Alzheimer's disease. The transdermal route is an alternative way for delivering the prophylactic agent. Administration of prophylaxis can be extended also for civilian use during wartime.

Adverse reaction to atropine and the treatment of organophosphate intoxication.

Atropine is the drug of choice for treatment of organophosphate nerve agent and insecticide intoxication and has been used for this indication for several decades. Adverse reactions to atropine may occur, and are of two types: toxic and allergic. Toxic reaction, the most common form, results from the anti-muscarinic effects of the drug. Since it is most probably related to interpersonal variation in sensitivity to atropine, toxic effects may appear at the usual therapeutic doses. The second type, allergic reaction, includes local manifestations, usually after the administration of eyedrops, and systemic reaction in the form of anaphylaxis. Since most patients manifest only a mild reaction, allergy testing is not performed and the prevalence of allergy to atropine is therefore not known. Severe allergic reaction to atropine is rare, as evidenced by the small number of case reports in the literature despite the drug's extensive use. Alternative anti-muscarinic drugs recommended for OP poisoning include glycopyrrolate and scopolamine. Glycopyrrolate is a peripheral anti-muscarinic drug that has been studied in comparison to atropine for many clinical indications, while scopolamine is an anti-muscarinic drug with both peripheral and central effects. An acceptable alternative regimen for patients with proven allergy to atropine is a combination of glycopyrrolate with centrally active drugs such as benzodiazepines or scopolamine.