ABSTRACT
Authors consider causes of low efficiency of antidote therapy and ways of pharmacological tolerance management during medical treatment of organophosphate poisoning. One of the promising ways is a preventive antidote on the base of enzyme agents and allosteric modulators of a cholinesterase activity. Authors showed a expediency of a study of new acetylcholinesterase reactivators, its compositions and ways of drug delivery. Authors specified ways of searching for anticonvulsants from classes of quick-closing benzodiatines and NMDA-antagonists. Authors defined ways of improvement of methods of special antidotes delivery with targeted transport system. Authors made an assumption about the necessity of symptomatic treatment.
Subject(s)
Anticonvulsants/therapeutic use , Antidotes/therapeutic use , Chemical Warfare Agents/poisoning , Drug Delivery Systems/methods , Drug Resistance/drug effects , Organophosphate Poisoning/drug therapy , Acetylcholinesterase/metabolism , Humans , Organophosphate Poisoning/enzymology , Receptors, N-Methyl-D-Aspartate/agonistsABSTRACT
The effect of memantine administration has been studied on the model of mice poisoning with an anticholinesterase compound. It is established that the memantine action is due to its influence on the cholinesterase activity in the brain, blood plasma, and erythrocytes in addition to its NMDA-blocking action. Memantine promotes oxime-induced erythrocyte enzyme reactivation on the model of mice poisoning with anticholinesterase compound (0.8 LD50).
Subject(s)
Anticonvulsants/pharmacology , Cholinesterase Reactivators/pharmacology , Memantine/pharmacology , Organophosphate Poisoning/drug therapy , Acetylcholinesterase/metabolism , Animals , Anticonvulsants/metabolism , Brain/drug effects , Brain/enzymology , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/poisoning , Cholinesterase Reactivators/metabolism , Erythrocytes/drug effects , Erythrocytes/enzymology , Isoflurophate/poisoning , Lethal Dose 50 , Male , Memantine/metabolism , Mice , N-Methylaspartate/antagonists & inhibitors , N-Methylaspartate/metabolism , Organophosphate Poisoning/blood , Oximes/metabolismABSTRACT
The kinetics of oxime-induced reactivation of malathion-inhibited cholinesterase has been experimentally studied in vitro. It is shown that oximes do not restore the activity of inhibited butyrylcholinesterase. Acetylcholinesterase reactivation peak (5-mins long) was found to take place upon introduction of dipyroxime (32.5%), pralidoxime (18%), carboxyme (16%) at a concentration of 2.5 x 10(-4) mol/l or toxogonine (26%) at a concentration of 5 x 10(-4) mol/l. Toxogonine demonstrated the maximum affinity to phosphorylated enzyme, while dipyroxime is characterized by a high reactivity with respect to oxime. Significant reactivating ability of these preparations (kR -2300 mol(-1) min(-1) makes them promising solution for the treatment of malathion intoxication.
Subject(s)
Acetylcholinesterase/chemistry , Antidotes/chemistry , Butyrylcholinesterase/chemistry , Cholinesterase Inhibitors/chemistry , Cholinesterase Reactivators/chemistry , Malathion/chemistry , Animals , Enzyme Activation , Erythrocytes/chemistry , Erythrocytes/enzymology , Horses , Kinetics , Obidoxime Chloride/chemistry , Pralidoxime Compounds/chemistry , Solutions , Torpedo , Trimedoxime/chemistryABSTRACT
The tolerance of five central muscarinic receptor antagonists has been studied in experimental animals. According to the effect on orientation-exploratory reaction, drugs were arranged in the following order of increasing toxicity: procyclidine < trihexiphenidyl < benactizine < atropine < scopolamine. For the same therapeutic index, trihexiphenidyl and benactizine were characterized by the maximum tolerance (TD50/ED50 > 10) in mice. Scopolamine and atropine exhibited anticonvulsant activity at doses exceeding the threshold values by a factor of 6.3 and 3.9, respectively. For procyclidine, the average anticonvulsant dose was threefold lower than the threshold value. Benactizine and procyclidine had maximum tolerance levels in rats. The TD50/ED50 ratio for these drugs was greater than 3 (against 0.5 - 0.7 in groups treated with trihexiphenidyl, atropine and scopolamine).
Subject(s)
Anticonvulsants/pharmacology , Maximum Tolerated Dose , Muscarinic Antagonists/pharmacology , Animals , Male , Mice , RatsABSTRACT
The effect of an angiotensin receptor II antagonist (losartan) on the model acute renal failure (ARF) induced by severe ethylene glycol poisoning at 2/3 LD50 has been studied in rats. It is established that losartan administration (20 mg/kg for 72 h) produces a significant (4-fold) increase in the animal death rate, which is associated with ARF transition to a decompensation stage. Pronounced changes in the qualitative and quantitative composition of diurnal diuresis, more than 8-fold increase in the creatinine level, and 18-fold increase in the blood urea have been observed. Thus, the administration of losartan to ethylene glycol poisoned rats causes more pronounced degeneration of proximal tubule epithelium and destruction of glomeruli. It is concluded that the use of losartan for the treatment of ARF is inexpedient.
Subject(s)
Acute Kidney Injury/chemically induced , Acute Kidney Injury/drug therapy , Angiotensin II Type 1 Receptor Blockers/pharmacology , Ethylene Glycol/poisoning , Losartan/pharmacology , Acute Kidney Injury/metabolism , Acute Kidney Injury/pathology , Animals , Diuresis/drug effects , Glomerular Mesangium/metabolism , Glomerular Mesangium/pathology , Kidney Tubules, Proximal/metabolism , Kidney Tubules, Proximal/pathology , Male , Rats , Rats, WistarABSTRACT
Combined administration of caffeine and ketorolac (NSAID) is accompanied by all possible types of drug interaction. Side effects of the drug combination are mostly due to the action of ketorolac and manifested by decompensated renal failure and progressive endotoxemia within 3 - 7 days after single administration of drugs. Thus, the amplification of ketorolac effects by caffeine must be taken into consideration in prescribing NSAIDs.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Caffeine/adverse effects , Drug Incompatibility , Ketorolac/adverse effects , Renal Insufficiency/chemically induced , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Caffeine/administration & dosage , Drug Interactions , Ketorolac/administration & dosage , Male , RatsABSTRACT
The antioxidant properties of sulfur-containing substances have been experimentally studied in vitro. Unithiol exhibits a wide spectrum us radicals. For this reason, unithiol can be considered, along with ascorbic acid, as a universal drug for the reduction of free radical reactions.
