The assessment of percutaneous absorption of molecules is a very important step in the evaluation of any dermal or transdermal drug delivery system. In order to perform percutaneous drug absorption studies, it is essential that the methods are standardized and that the integrity of the skin is monitored and maintained to ensure that the data obtained are valid and relevant. Reproducible data on percutaneous absorption in humans are as well required to predict the systemic risk from dermal exposure to chemicals, such as hazardous substances at the workplace, agrochemicals and cosmetic ingredients. In vitro and animal models provide important tools for screening a series of drug formulations, evaluation of skin permeation enhancing properties and mechanism of action of the carrier systems and estimation of rank of skin transport for a series of drug molecules. In this review, we have summarized in vitro testing of skin absorption using static Franz-type diffusion cells.

Basic part of the current standard treatment of organophosphate (OP) agent poisoning is administration of cholinesterase reactivators. It includes different types of oximes with a similar basic structure differing by the number of pyridinium rings and by the position of the oxime group in the pyridinium ring. Oximes hydrolytically cleave the organophosphates from acetylcholinesterase (AChE), restoring enzymatic function. This reactivation of AChE is dependent on the type of the agent and, on the reactivator used. From the common oximes, mono- and bisquaternary pyridinium oximes are more or less frequently used in clinical practice such as pralidoxime, obidoxime, trimedoxime, and HI-6. Though there are data on a good therapeutic effects of reactivators, some attempts to undermine the role of reactivators as effective antidotes against OP poisoning have been made. Some arguments on the necessity of their administration following OP poisoning are discussed with the aim to resolve the question on their effective use, possible repeated administration in the treatment of OP poisoning, their peripheral and central effects including questions on their penetration through the blood brain barrier as well as a possibility to achieve their effective concentration for AChE reactivation in the brain. Reactivation of cholinesterases in the peripheral and central nervous system is described and it is underlined its importance for the survival or death of the organism poisoned with OP. An universality of oximes able to reactivate AChE inhibited by all OP is questioned and trends (molecular modelling using neural network, structure-activity relationship, combination of reactivation and anticholinergic properties in one molecule) for future research are characterized.

Highly toxic organophosphorus inhibitors of acetylcholinesterase referred as nerve agents are considered to be among the most dangerous chemical warfare agents. The oximes represent very important part of antidotal medical countermeasures. They are used to reactivate the nerve agent-inhibited acetylcholinesterase. Despite long-term research activities, there is no single, broad-spectrum oxime suitable for the antidotal treatment of poisoning with all organophosphorus agents. Therefore, the development of new structural analogues of currently available oximes should continue to increase the effectiveness of antidotal treatment of poisoning by organophosphorus compounds. The review describes the development of new structural analogues of currently available oximes and the evaluation of their potency to counteract the acute toxicity of some nerve agents (tabun, cyclosarin) in comparison with commonly used oximes (pralidoxime, obidoxime, trimedoxime, HI-6).

Oximes in combination with atropine, are an integral part of the treatment of acute intoxications with organophosphorus insecticides or with the nerve agents such as tabun, sarin, soman, cyclosarin or VX. Organophosphorus compounds are extremely potent inhibitors of the enzyme acetylcholinesterase (AChE, 3.1.1.7). The pharmacological action of oximes is multiple: they are able to reactivate the inhibited AChE, but they affect acetylcholine release in peripheral and central cholinergic synapses, allosterically modulate the muscarinic receptors in peripheral and central synapses, and influence the nicotinic receptor-associated ion-channels. In our study, we have determined the acute toxicity of different structures of oximes after intramuscular application in mice. The acute toxicity of oximes is crucial for the assesment of a dose applied as a treatment for organophosphorus intoxications. We have tested 7 oximes of different structures (HS-6, K033, BI-6, MMB-4, K048, HI-6 and obidoxime ) and during our experiments we have observed the intoxication process including typical signs of intoxication, and times of death. K033 was the most toxic oxime with an LD50 of only 48 mg/kg, while the least toxic oxime - HI-6 - has an LD50 value of 671 mg/kg. All the oximes tested were of the bispyridinium type, with different length or shape of the connecting chain and positions of oxime groups at the pyridinium rings. All these structural features play an important role in biological activity of these compounds performed by their acute toxicity as well as by their reactivation potency.

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