RESUMO
OBJECTIVES: In this work, we hypothesized whether galantamine could interact with the cholinergic anti-inflammatory pathway and modulate immunity this way. BACKGROUND: Galantamine is a drug used for the therapy of Alzheimer disease. The drug inhibits enzyme acetylcholinesterase in the central nervous system, which causes better availability of neurotransmitter acetylcholine. METHODS: In the experiment, we immunized BALB/c laboratory mice by keyhole limpet hemocyanin (KLH) in combination with galantamine in a dose 0.02-0.5 mg/kg. The animals were sacrificed from 1 to 7 days after the substances applications and plasma was collected in order to examine immunochemical markers by enzyme-linked immunosorbent assay. RESULTS: We found significant drop in production of immunoglobulins and interleukin (IL) 4 level while IL2, IL4 and tumour necrosis factor α remained unaltered for the whole experiment. We infer that galantamine causes better availability of acetylcholine also in blood system, where the neurotransmitter interacts with nicotinic acetylcholine receptors on macrophages and initiates cholinergic anti-inflammatory pathway. CONCLUSIONS: In a conclusion, galantamine can cause lower efficacy of vaccination or immunity response to an infectious disease and the phenomenon should be taken into consideration in the current therapy (Tab. 1, Fig. 2, Ref. 24).
Assuntos
Acetilcolinesterase/sangue , Doença de Alzheimer/imunologia , Anti-Inflamatórios/farmacologia , Inibidores da Colinesterase/sangue , Galantamina/farmacologia , Hemocianinas/farmacologia , Acetilcolina/sangue , Animais , Interações Medicamentosas , Ensaio de Imunoadsorção Enzimática , Feminino , Imunoglobulinas/sangue , Mediadores da Inflamação/sangue , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Receptores Nicotínicos/efeitos dos fármacosRESUMO
Freund´s complete adjuvant (FCA) is a mean used for improving immunization efficacy in experiments and veterinary medicine. Despite high efficacy, it is not used in human vaccination due to number of adverse effects. Arthritis can be an example of a typical adverse consequence. In this work, we decided to investigate the link between oxidative stress and inflammation in animals exposed to FCA. BALB/c mice received either saline or FCA in doses 10-50 µl and were euthanized from one to three days after infection. Interleukins (IL) IL-2, IL-4 and tumor necrosis factor α (TNF-α) were determined in plasma. Ferric reducing antioxidant power (FRAP), malondialdehyde by thiobarbituric acid reactive substances assay (TBARS), reduced glutathione (GSH) and caspase-3 were measured in livers, muscles and other organs. We determined significant effect of FCA on TBARS and GSH in the livers. Beside this, TBARS were altered in muscles as well. Inflammation was confirmed by increased level of TNF-α. Taking the results into account, we infer that the harmful effect of FCA is mediated not only by inflammation but also by oxidative. This should be considered when pathological consequences of FCA are scored.
Assuntos
Adjuvantes Imunológicos/farmacologia , Citocinas/efeitos dos fármacos , Adjuvante de Freund/farmacologia , Glutationa/efeitos dos fármacos , Fígado/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Caspase 3/efeitos dos fármacos , Caspase 3/metabolismo , Citocinas/metabolismo , Feminino , Glutationa/metabolismo , Inflamação , Interleucina-2/metabolismo , Interleucina-4/metabolismo , Fígado/metabolismo , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Músculo Esquelético/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Understanding the mechanism of action of organophosphates (OP)/nerve agents -- irreversible acetylcholinesterase (AChE, EC 3.1.1.7) inhibition at the cholinergic synapses followed by metabolic dysbalance of the organism -- two therapeutic principles for antidotal treatment are derived. The main drugs are anticholinergics that antagonize the effects of accumulated acetylcholine at the cholinergic synapses and cholinesterase reactivators (oximes) reactivating inhibited AChE. Anticonvulsants such as diazepam are also used to treat convulsions. Though there are experimental data on a good therapeutic effects of reactivators, some attempts to underestimate 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. Their distribution patterns and some metabolic and pharmacological effects are described 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. Metabolization and some other effects of oximes (not connected with AChE reactivation) are discussed (e.g. forming of the phosphonylated oxime, parasympatholytic action, hepatotoxicity, behavioral changes etc.). An universality of oximes able to reactivate AChE inhibited by all OP is questioned and therefore, needs of development of new oximes is underlined.
Assuntos
Antídotos/uso terapêutico , Reativadores da Colinesterase/farmacocinética , Colinesterases/efeitos dos fármacos , Neurotransmissores/farmacocinética , Compostos Organofosforados/farmacocinética , Oximas/farmacocinética , Praguicidas/farmacocinética , Acetilcolina/análise , Antídotos/administração & dosagem , Antídotos/química , Barreira Hematoencefálica/efeitos dos fármacos , Reativadores da Colinesterase/administração & dosagem , Reativadores da Colinesterase/química , Reativadores da Colinesterase/uso terapêutico , Diazepam/uso terapêutico , Humanos , Estrutura Molecular , Neurotransmissores/intoxicação , Intoxicação por Organofosfatos , Oximas/administração & dosagem , Oximas/química , Praguicidas/química , Convulsões/tratamento farmacológicoRESUMO
Tacrin, its 7-methoxy-(MEOTA) and 7-hydroxy-(HYOTA) derivatives were i.m. administered to rats in a dose of 1.2 x LD50 and acetylcholinesterase (blood, hippocampus, frontal cortex, basal ganglia, septum and diaphragm) or butyrylcholinesterase (liver) activities were detected. The inhibitory effect of the examined substances in vivo decreased in the following order: tacrin HYOTA > MEOTA. The marked inhibition of the enzymes studied following administration of all three compounds in the frontal cortex could suggest importance of this structure for action of these drugs.
Assuntos
Acetilcolinesterase/metabolismo , Encéfalo/enzimologia , Butirilcolinesterase/metabolismo , Tacrina/farmacologia , Acetilcolinesterase/sangue , Animais , Gânglios da Base/enzimologia , Butirilcolinesterase/sangue , Feminino , Lobo Frontal/enzimologia , Hipocampo/enzimologia , Fígado/enzimologia , Músculos/enzimologia , Ratos , Ratos Wistar , Tacrina/análogos & derivadosRESUMO
The influence of some anticholinergic drugs (atropine, benactyzine, biperiden, scopolamine) on the efficacy of antidotal treatment to eliminate soman (O-pinacolyl methylphosphonofluoridate)-induced disturbance of respiration and circulation and to protect experimental animals poisoned with supralethal dose of soman (1.5 x LD(50)) was investigated in a rat model with on-line monitoring of respiratory and circulatory parameters. While the oxime HI-6 in combination with atropine prevented soman-induced changes in monitored physiological parameters insufficiently and very shortly, the combination of HI-6 with benactyzine or biperiden is able to prevent soman-induced alteration of respiration and circulation much more longer. Nevertheless, only rats treated with HI-6 in combination with scopolamine were fully protected against the lethal toxic effects of soman within 2 h following soman challenge. Our findings confirm that anticholinergic drugs with the strong central antimuscarinic activity, such as benactyzine, biperiden and especially scopolamine, seem to be more effective adjuncts to HI-6 treatment of severe acute soman-induced poisoning than atropine.
Assuntos
Antídotos/farmacologia , Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/toxicidade , Reativadores da Colinesterase/farmacologia , Soman/toxicidade , Animais , Antídotos/normas , Atropina/farmacologia , Atropina/normas , Benactizina/farmacologia , Benactizina/normas , Biperideno/farmacologia , Biperideno/normas , Pressão Sanguínea , Reativadores da Colinesterase/normas , Eletrocardiografia , Frequência Cardíaca , Masculino , Antagonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/normas , Oximas , Compostos de Piridínio/farmacologia , Compostos de Piridínio/normas , Ratos , Escopolamina/farmacologia , Escopolamina/normasRESUMO
The influence of pretreatment with the drug mixture (pyridostigmine, benactyzine and trihexyphenidyle), and antidotal treatment (the oxime HI-6 in combination with benactyzine) on respiration, circulation and survival of experimental animals poisoned with supralethal doses of soman (2 x LD50) was investigated in a rat model with on-line monitoring of respiratory and circulatory parameters. Untreated soman poisoning caused rapid respiratory depression, progressive bradycardia and a short-term increase in the mean arterial pressure, followed immediately by hypotension. The poisoned rats died on average within 10 min from respiratory and circulatory insufficiency. A cholinergic-anticholinergic pretreatment alone partially prevented changes in monitored physiological variables, caused by soman, but only for a few minutes; post-poisoning treatment with antidotes, also alone, had similar effects. The rats died on average within 30 min from respiratory and circulatory failure. When rats were pretreated by the drug mixture and treated by antidotes, respiration as well as circulation were completely restored and the rats survived at least 120 min following soman challenge. The results of the investigation suggest that cholinergic-anticholinergic pretreatment seems able to enhance the efficacy of antidotal treatment in restoring respiratory and circulatory changes induced by soman.
Assuntos
Antídotos/farmacologia , Colinérgicos/farmacologia , Antagonistas Colinérgicos/farmacologia , Inibidores da Colinesterase/toxicidade , Soman/toxicidade , Animais , Combinação de Medicamentos , Eletrocardiografia/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Respiração/efeitos dos fármacosRESUMO
Acetylcholinesterase activity in rat blood was continuously monitored following O-ethyl-S-(2-dimethylaminoethyl)-methylphosphonothioate intoxication (p.o.) alone and in combination with atropine and the reactivators trimedoxime, obidoxime and methoxime. Decrease of acetylcholinesterase activity was not influenced by atropine alone but following treatment with a combination of atropine with the reactivators mentioned, an increase (reactivation) of the blood enzyme was demonstrated. This increase was highest for the combination atropine-trimedoxime and the lowest for the combination atropine-obidoxime.
Assuntos
Acetilcolinesterase/sangue , Reativadores da Colinesterase , Intoxicação por Organofosfatos , Oximas/farmacologia , Acetiltiocolina/metabolismo , Animais , Atropina/farmacologia , Feminino , Ratos , Ratos EndogâmicosRESUMO
Toxicities expressed as LD50 values of 2-dialkylaminoalkyl-(dialkylamido)-fluorophosphates for rats and mice (i.m. administration) were determined. Rats were more sensitive to these compounds than mice: LD50 values varied from 17 (rats) to 1222 (mice) micrograms/kg. LD50 values at different routes of administration (i.v., i.m., s.c., p.o. and p.c.) for one derivative of this group, 2-dimethylaminoethyl-(dimethylamido)-fluorophosphate, were determined. Depending on the route of administration, LD50 values varied from 11 (i.v.) to 190 (p.o.) micrograms/kg for rats and from 27.6 (i.v.) to 222 (p.o.) micrograms/kg for mice, respectively. Percutaneous toxicity in rats only (LD50 = 1366 micrograms/kg) was determined.
Assuntos
Hidrocarbonetos Fluorados/toxicidade , Animais , Vias de Administração de Medicamentos , Feminino , Dose Letal Mediana , Camundongos , Fosfatos/toxicidade , RatosRESUMO
1 The effect of pharmacological pretreatment (pyridostigmine, benactyzine and trihexyphenidyle), designated Panpal, and antidotal treatment (the oxime HI-6 plus benactyzine) in soman poisoning was investigated in a rat model with on-line monitoring of respiratory and circulatory parameters. 2 Soman poisoning caused a high decrease in respiratory rate as well as minute respiratory volume and an increase in mean arterial pressure from 30-120 min following soman challenge. Soman at sublethal dose also significantly inhibited acetylcholinesterase activity in diaphragm and various brain parts. 3 Panpal pretreatment as well as antidotal treatment were effective in improving the respiratory and circulatory function disturbed by soman without the ability to increase significantly soman-inhibited acetylcholinesterase activity in all brain parts studied. 4 The efficacy of combined Panpal pretreatment and antidotal treatment against sublethal soman poisoning was not different from the efficacy of Panpal pretreatment or antidotal treatment alone. 5 The results of this investigation suggest that Panpal pretreatment as well as antidotal treatment are able to restore respiratory and circulatory function in soman-poisoned rats without significant reactivation of brain acetylcholinesterase.
Assuntos
Antídotos/uso terapêutico , Benactizina/administração & dosagem , Benactizina/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Doenças do Sistema Nervoso Central/induzido quimicamente , Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/toxicidade , Reativadores da Colinesterase/uso terapêutico , Frequência Cardíaca/efeitos dos fármacos , Compostos de Piridínio/uso terapêutico , Brometo de Piridostigmina/administração & dosagem , Respiração/efeitos dos fármacos , Soman/toxicidade , Triexifenidil/administração & dosagem , Acetilcolinesterase/metabolismo , Animais , Encéfalo/enzimologia , Doenças do Sistema Nervoso Central/tratamento farmacológico , Diafragma/enzimologia , Quimioterapia Combinada , Eletrocardiografia , Masculino , Oximas , Ratos , Ratos WistarRESUMO
Chemical terrorism is a new threat to the security of mankind, which scale essentially exceeds the impact of use of the most modem firearms. At present time all over the world threats from different radical elements to use radioactive materials, potent poisonous substances and pathogenic microorganisms for terrorist purposes became more frequent. High-toxic chemical substances can fall in terrorist hands through wide range of sources. Potentially misused types of chemical compounds are discussed in this article.
Assuntos
Substâncias para a Guerra Química/intoxicação , Guerra Química , Terrorismo , HumanosRESUMO
The aim of this study was to demonstrate changes in acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities, tyrosine aminotransferase activity (TAT) and plasma corticosterone level, neuroexcitability and behavior following 24 hours and 4 weeks of soman sublethal inhalation exposure at low level. AChE activity in erythrocytes and BuChE activity in plasma was decreased (dependent on the concentration of soman) 24 h and 4 weeks after the exposure. Similar decrease in AChE activity in different brain parts was observed. One of stressogenic parameters (TAT) was changed after 24 h exposure only. 4 weeks after the exposure, these parameters (corticosterone and TAT) were in the range of normal values. Behaviour of experimental animals was changed 24 h after the exposure persisting 4 weeks after the exposure as well as neuroexcitability.
Assuntos
Acetilcolinesterase/metabolismo , Comportamento Animal/efeitos dos fármacos , Butirilcolinesterase/metabolismo , Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/toxicidade , Colinesterases/metabolismo , Soman/toxicidade , Tirosina Transaminase/metabolismo , Acetilcolinesterase/sangue , Animais , Encéfalo/enzimologia , Butirilcolinesterase/sangue , Colinesterases/sangue , Corticosterona/sangue , Diafragma/enzimologia , Eritrócitos/enzimologia , Feminino , Cobaias , Exposição por Inalação , Dose Letal Mediana , Fígado/enzimologia , Tirosina Transaminase/sangueRESUMO
1. The changes of cholinesterase activity in rabbit blood, peripheral tissues and the central nervous system following transfusion of erythrocytes with soman inhibited acetylcholinesterase we were demonstrated. 2. After incubation with soman for 0.5 or 24 h, erythrocytes without acetylcholinesterase activity were injected to intact rabbits and cholinesterase activity in the erythrocytes, plasma, diaphragm, liver and various parts of the brain were evaluated 24 h following blood-transfusion. 3. When erythrocytes were incubated with soman for 24 h, no changes of cholinesterase activity in the rabbit following blood-transfusion were observed with an exception of erythrocyte acetylcholinesterase. 4. When erythrocytes were incubated with soman for 0.5 h, a significant decrease in cholinesterase activity in the erythrocytes, plasma, diaphragm and liver following blood-transfusion was found. These data show that soman is able to release from erythrocytes and inhibit cholinesterase activities not only in vitro but also in vivo although the significant inhibition of cholinesterase activities by soman was only observed in the peripheral compartment.
Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Colinesterases/metabolismo , Transfusão de Eritrócitos , Eritrócitos/enzimologia , Soman/farmacologia , Acetilcolinesterase/sangue , Animais , Encéfalo/enzimologia , Butirilcolinesterase/metabolismo , Substâncias para a Guerra Química/farmacocinética , Diafragma/enzimologia , Eritrócitos/metabolismo , Fígado/enzimologia , Masculino , Coelhos , Soman/farmacocinéticaRESUMO
3-Nitropropionic acid as well as 3-nitro-1-propanol and its beta-D-glucopyranoside (miserotoxin) are the plant and fungal toxins reported to interrupt mitochondrial electron transport resulting in cellular energy deficit. These nitrotoxins induce neurological degeneration in ruminants and humans. 3-Nitropropionic acid-intoxicated rats serve as the animal model for Huntington's disease.
Assuntos
Glucosídeos , Micotoxinas , Plantas Tóxicas , Propanóis , Propionatos , Animais , Glucosídeos/química , Glucosídeos/toxicidade , Humanos , Micotoxinas/química , Neurotoxinas/química , Neurotoxinas/toxicidade , Nitrocompostos , Extratos Vegetais/química , Extratos Vegetais/toxicidade , Propanóis/química , Propanóis/toxicidade , Propionatos/química , Propionatos/toxicidadeRESUMO
Toxicities expressed as LD50 values of O-alkyl S-(2-dialkylaminoethyl) methyl phosphonothiolates in different species and different routes of administration were determined. Rats were more sensitive to these compounds than mice, rabbits and guinea-pigs were more sensitive than mice and rats. The most sensitive to these compounds were dogs. LD50 values varied in a wide range, however, a decrease of toxicity was observed in the following rank: i.v., i.m., s.c., i.p., p.o. and p.c., respectively. Depending on the route of administration, LD50 values varied from 5 g/kg (i.m., dogs) through tens of microgram/kg for the most part of compounds and routes of administration to hundreds, rarely thousands of g/kg (some chemicals, p.c. administration).
Assuntos
Substâncias para a Guerra Química/toxicidade , Compostos Organotiofosforados/toxicidade , Animais , Cães , Cobaias , Camundongos , Compostos Organotiofosforados/administração & dosagem , Coelhos , RatosRESUMO
Macrophages play an important role in the immune system. They also participate in multiple processes including angiogenesis and triggering of inflammation. The present study summarizes pieces of knowledge on the importance of macrophages in disease, especially the inflammation. Special attention is paid to the cholinergic anti-inflammatory pathway (CAP) associated with the nicotinic acetylcholine receptor (nAChR) and the parasympathetic nervous system. The current pharmacological effectiveness in suppressing the inflammation in general and the septic shock in particular, is limited. CAP was discovered recently and it seems to be a suitable target for the development of new drugs. Moreover, available drugs binding to either nAChR or acetylcholinesterase (AChE) are candidates for either an inhibition or enhancement of CAP. Though the current scientific databases do not include all necessary data on the association of CAP with body functions and the research is quite intensive, the objective of the present review is to introduce the current trends and to critically evaluate CAP and macrophage-associated pathways.
Assuntos
Colinérgicos/química , Inflamação/imunologia , Macrófagos/imunologia , Acetilcolinesterase/metabolismo , Corticosteroides/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/uso terapêutico , Colinérgicos/uso terapêutico , Infecções por HIV/imunologia , Infecções por HIV/patologia , Humanos , Inflamação/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Receptores Nicotínicos/metabolismoRESUMO
Current treatment of organophosphorus poisoning, resulting in overstimulation and desensitization of muscarinic and nicotinic receptors by acetylcholine (ACh), consists of the administration of atropine and oxime reactivators. However, no versatile oxime reactivator has been developed yet and some mortality still remains after application of standard atropine treatment, probably due to its lack of antinicotinic action. In our study, we focused on the interesting non-acetylcholinesterase property of oximes, i.e. antinicotinic effect of reactivators. Two standard reactivators (HI-6, obidoxime) and two new compounds (K027 and K203) were chosen for in vitro (patch clamp) and in vivo (nerve-evoked muscle contraction) testings. Both examinations showed antinicotinic effects of the reactivators. In vitro inhibition of acetylcholine-evoked currents by obidoxime, HI-6 and K203 was equivalent while K027 was less potent. Similar order of potency was observed by the in vivo examinations. We thus confirm previous in vitro results, which describe antinicotinic effects of oxime reactivators, and furthermore, we show in vivo antagonism of oxime reactivators exerted by the inhibition of ACh effect on the nicotinic receptor in the neuromuscular junction. Taking together, the effects of tested oxime reactivators indicate an antagonism on both embryonic and adult form of the muscle nicotinic receptors.
Assuntos
Reativadores da Colinesterase/farmacologia , Antagonistas Nicotínicos/farmacologia , Oximas/farmacologia , Receptores Nicotínicos/fisiologia , Animais , Reativadores da Colinesterase/química , Relação Dose-Resposta a Droga , Masculino , Antagonistas Nicotínicos/química , Cloreto de Obidoxima/farmacologia , Oximas/química , Compostos de Piridínio/química , Compostos de Piridínio/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
The antidotal treatment of organophosphorus poisoning is still a problematic issue since no versatile antidote has been developed yet. In our study, we focused on an interesting property, which does not relate to the reactivation of inhibited acetylcholinesterase (AChE) of some oximes, but refers to their anti-muscarinic effects which may contribute considerably to their treatment efficacy. One standard reactivator (HI-6) and two new compounds (K027 and K203) have been investigated for their antimuscarinic properties. Anti-muscarinic effects were studies by means of an in vitro stimulated atrium preparation (functional test), the [(3)H]-QNB binding assay and G-protein coupled receptor assay (GPCR, beta-Arrestin Assay). Based on the functional data HI-6 demonstrates the highest anti-muscarinic effect. However, only when comparing [(3)H]-QNB binding results and GPCR data, K203 shows a very promising compound with regard to anti-muscarinic potency. The therapeutic impact of these findings has been discussed.
Assuntos
Reativadores da Colinesterase/farmacologia , Oximas/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Animais , Reativadores da Colinesterase/metabolismo , Estimulação Elétrica , Frequência Cardíaca/efeitos dos fármacos , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Oximas/metabolismo , Oxotremorina/análogos & derivados , Oxotremorina/farmacologia , Compostos de Piridínio/metabolismo , Compostos de Piridínio/farmacologia , Quinuclidinil Benzilato/metabolismo , Ratos , Ratos Wistar , Receptores Acoplados a Proteínas G/metabolismoRESUMO
The oxime reactivator K112 is a member of the new group of xylene linker-containing AChE reactivators. Its cholinergic properties could be of importance at OP poisoning and are not related to the AChE reactivation that has been studied. It has been found that, despite of reactivating potency, this compound has additional effects. These cholinergic effects include a weak inhibition of AChE (IC(50)=43.8 ± 4.88 µM), inhibition of binding to the porcine muscarinic M2 receptor (IC(50)=4.36 µM) and finally, the inhibition of HACU (68.4 ± 9.9%), a key regulatory step in the synthesis of ACh. The inhibition of the binding of (3H)-HC-3 (64.7 ± 4.7%) and the influence on the membrane fluidity have also been observed. Blocking properties of K112 on the muscarinic receptors have been revealed in the in vitro experiment (rat urinary bladder) and in the in vivo experiment (rat heart BPM) as well. All these cholinergic properties could significantly contribute to the antidotal effect of K112 at the poisoning by the organophosphates.
Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Reativadores da Colinesterase/farmacologia , Oximas/farmacologia , Compostos de Piridínio/farmacologia , Animais , Inibidores da Colinesterase/química , Reativadores da Colinesterase/química , Relação Dose-Resposta a Droga , Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Técnicas In Vitro , Fluidez de Membrana/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/enzimologia , Intoxicação por Organofosfatos , Oximas/química , Intoxicação/tratamento farmacológico , Intoxicação/enzimologia , Ligação Proteica , Compostos de Piridínio/química , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptor Muscarínico M2/antagonistas & inibidores , Proteínas Recombinantes/antagonistas & inibidores , Suínos , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/enzimologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/enzimologiaRESUMO
The poisoning with organophosphorus compounds represents a life threatening danger especially in the time of terroristic menace. No universal antidote has been developed yet and other therapeutic approaches not related to reactivation of acetylcholinesterase are being investigated. This review describes the main features of the cholinergic system, cholinergic receptors, cholinesterases and their inhibitors. It also focuses on the organophosphorus nerve agents, their properties, effects and a large part describes various possibilities in treatments, mainly traditional oxime therapies based on reactivation of AChE. Furthermore, non-cholinesterase coupled antidotal effects of the oximes are thoroughly discussed. These antidotal effects principally include oxime interactions with muscarinic and nicotinic receptors.