Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Patent
1996-07-30
1999-08-17
Brouillette, D. Gabrielle
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
424448, A61F 1300
Patent
active
059390956
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a transdermal therapeutic system and to a process for the combined transdermal application of physostigmine and scopolamine for the prophylaxis and preliminary treatment of poisoning caused by highly toxic organophosphorus cholinesterase inhibitors, in particular soman. In particular, the present invention is to provide pharmaceutical formulations releasing suitable active substances without detrimental side effects in a controlled manner for the prophylactic treatment of poisonings caused by organophosphorus cholinesterase inhibitors.
BACKGROUND OF THE INVENTION
The group of organophosphorus cholinesterase inhibitors include certain esters of phosphoric acid derivatives, e.g., nitrostigmine (=diethyl-(4-nitrophenyl)-thiophosphate), better known under the names Parathion or E 605, but they also include tabun, as well as the phosphonic acid derivatives sarin, soman and VX.
Among other things cholinesterase-inhibiting phosphoric esters are used as insecticides in agriculture. Since they have a toxic effect on human beings too, the staff working in agriculture is subject to a basic hazard to life and limb; this is true all the more since these organic phosphoric esters can also be absorbed via the skin. As compared to insecticides, the compounds tabun, sarin, soman and VX which belong to the group of the so-called nerve warfare agents are distinguished by a particularly high toxicity. All of these compounds are more or less strong inhibitors of acetylcholinesterase, an enzyme which physiologically blocks the effect of the transmitter acetylcholine released at certain nerve endings. Most of the symptoms of poisoning caused by cholinesterase inhibitors are produced by an inundation with endogenic acetylcholine.
The basic drug therapy of such a poisoning consists in the administration of the parasympatholytic atropine, blocking the exceeding muscarinic acetylcholine effects (e.g., increase of secretion in the respiratory system, bronchospasm, inhibition of the central nervous respiratory drive). There is no suitable antagonist available to normalize the exceeding nicotinic acetylcholine actions (e.g., inhibition of the impulse transmission at the synapses of motorial nerves to the respiratory musculature and to other skeletal muscles up to a complete peripheral motor paralysis). The peripherally caused myoparesis can only be compensated by oximes, e.g., pralidoxime (PAM) or obidoxime (Toxogonin.RTM.) whose mechanism of action consists in a reactivation of the inhibited acetylcholinesterase.
However, this post-exposure therapy is not sufficient to ensure survival after poisoning with the double LD.sub.50 of soman (LD.sub.50 =dose which is lethal for 50% of the exposed subjects). The probability of survival after a soman poisoning increases only when a pretreatment with a carbamate, e.g., pyridostigmine or physostigmine, has taken place prior to the poison exposure, and when additionally the conventional antidote-therapy with atropine and an oxime is started immediately on occurrence of the first symptoms of the poisoning. The requirement with respect to the carbamate used in the pretreatment is that it should not have significant undesired effects at the highest possible, lasting protective action, in particular it must not impair reaction capacity.
Some of the organophosphorus cholinesterase inhibitors are distinguished by the fact that they split off alkyl residues after accumulation to the acetylcholinesterase, thus stabilizing the bond ("aging"). The aged esterase inhibitor complex cannot be reactivated by oximes. In case of poisonings caused by the nerve warfare agent soman, aging already occurs after 2 to 5 minutes. The therapy with atropine and oximes can considerably be improved by a preliminary treatment with indirect parasympathomimetics, e.g., carbamic acid esters, such as pyridostigmine and physostigmine.
Carbamic acid esters inhibit the acetylcholinesterase in a manner similar to that of phosphoric acids. However, the bond is of a shorter duration and completely re
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Asmussen Bodo
Hille Thomas
Muller Walter
Brouillette D. Gabrielle
LTS Lohmann Therapie-Systeme GmbH
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