RESUMO
BACKGROUND: In the present study, two structurally similar alkaloids from trees of Cinchona genus, chloroquine and cinchonine, were examined for their vasorelaxant effects in a model of phenylephrine-induced smooth muscle contractions. METHODS: Potential mechanisms of action associated with endothelial vasorelaxant compounds, voltage-gated Ca2+ channels (LTCCs), and inositol triphosphate receptors were examined in isolated rat aortic rings. Also, an in silico approach was used to predict the activity of the two test compounds. RESULTS: Experimental results revealed that both chloroquine and cinchonine significantly decrease phenylephrine-induced smooth muscle contractions, although to a different extent. Evaluated mechanisms of action indicate that endothelium is not involved in the vasorelaxant action of the two tested alkaloids. On the other hand, voltage-gated Ca2+ channels were found to be the dominant way of action associated with the vasorelaxant action of chloroquine and cinchonine. Finally, IP3R is found to have only a small impact on the observed activity of the tested compounds. CONCLUSION: Molecular docking studies predicted that chloroquine possesses a significant activity toward a suitable model of LTCCs, while cinchonine does not. The results of the present study point to the fact that great caution should be paid while administering chloroquine to vulnerable patients, especially those with cardiovascular disorders (Tab. 3, Fig. 3, Ref. 28).
Assuntos
Canais de Cálcio , Cloroquina , Simulação de Acoplamento Molecular , Músculo Liso Vascular , Animais , Cloroquina/farmacologia , Ratos , Músculo Liso Vascular/efeitos dos fármacos , Canais de Cálcio/efeitos dos fármacos , Canais de Cálcio/metabolismo , Vasodilatadores/farmacologia , Tono Muscular/efeitos dos fármacos , Masculino , Ratos Wistar , Simulação por Computador , Fenilefrina/farmacologiaRESUMO
Introducción: El p-clorofenol alcanforado es un derivado clorofenólico de uso común como medicación intraconducto en Endodoncia. Son escasos los reportes científicos sobre sus efectos en la musculatura lisa vascular arterial y la regulación del flujo sanguíneo local. Objetivo: Determinar el efecto del p-clorofenol alcanforado sobre la dinámica contráctil del músculo liso vascular arterial en el tiempo. Método: Se realizó una investigación experimental preclínica utilizando 14 anillos de aorta obtenidos de ratas Wistar. Los anillos se colocaron en baño de órganos y se preactivaron con noradrenalina, registrándose luego la tensión desarrollada por el músculo liso vascular tras la adición de p-clorofenol alcanforado durante diferentes intervalos de tiempo. Resultados: El 51,4 porciento de la musculatura lisa vascular se relajó por la acción del p-clorofenol alcanforado. El mayor descenso del tono vascular se produjo entre el tercer y quinto minuto de añadido el medicamento. Las pruebas de Wilcoxon de los rangos con signos evidenciaron diferencias significativas entre la tensión base inicial y la registrada en los diferentes intervalos de tiempo estudiados. Conclusiones: el p-clorofenol alcanforado, induce in vitro, relajación del músculo liso arterial a través de un acoplamiento excitación-contracción de tipo farmacomecánico, la cual se incrementa en función del tiempo(AU).
Introduction: Camphorated p-chlorophenol is a chlorophenolic derivative commonly used as an intra-oral medication in endodontics. Scientific reports on its effects in arterial vascular smooth muscle and local blood flow regulation are scarce. Objective: To determine the effect of camphorated p-chlorophenol on the contractile dynamics of arterial vascular smooth muscle. Method: An experimental and preclinical research was conducted with the use of 14 aortic rings of Wistar rats. The rings were placed in an organ bath and preactivated with noradrenaline, and the tension developed by the vascular smooth muscle at different time intervals was recorded after induction of camphorated p-chlorophenol. Results: Most of the vascular smooth muscle (51.4 percent) relaxed with the use of camphorated p-chlorophenol. The greatest decrease in vascular tone occurred between the third and fifth minute after use the drug. Wilcoxon rank tests showed significant differences between tension observed at baseline and those recorded at the different time intervals studied. Conclusions: Camphorated p-chlorophenol, induces in vitro, relax the arterial smooth muscle through a pharmacomechanical excitation-contraction link, which increases according to the time(AU).
Introdução: O cânfora-clorofenol é um derivado clorofenólico comumente utilizado como medicamento intracanal em Endodontia. Relatórios científicos sobre seus efeitos no músculo liso vascular arterial e na regulação do fluxo sanguíneo local são escassos. Objetivo: Determinar o efeito da cânfora-clorofenol na dinâmica contrátil do músculo liso vascular arterial ao longo do tempo. Método: Foi realizada investigação experimental pré-clínica com 14 anéis aórticos obtidos de ratos Wistar. Os anéis foram colocados em banho de órgãos e pré-ativados com norepinefrina, em seguida, a tensão desenvolvida pela musculatura lisa vascular foi registrada após a adição de cânfora-clorofenol em diferentes intervalos de tempo. Resultados: 51,4 porcento dos músculos lisos vasculares estavam relaxados pela ação do cânfora-clorofenol. A maior diminuição do tônus vascular ocorreu entre o terceiro e o quinto minuto após a adição do medicamento. Os testes de Wilcoxon das faixas com sinais mostraram diferenças significativas entre a tensão base inicial e a registrada nos diferentes intervalos de tempo estudados. Conclusões: O cânfora-clorofenol induz, in vitro, relaxamento da musculatura lisa arterial por meio de um acoplamento excitação-contração do tipo farmacomecânico, que aumenta em função do tempo(AU).
Assuntos
Animais , Ratos , Clorofenóis/administração & dosagem , Músculo Liso Vascular/efeitos dos fármacos , Tono Muscular/efeitos dos fármacos , Ratos Wistar , AlemanhaRESUMO
PURPOSE: To study racemic bupivacaine, non-racemic bupivacaine and ropivacaine on myocardial contractility. METHODS: Isolated Wistar papillary muscles were submitted to 50 and 100 mM racemic bupivacaine (B50 and B100), non-racemic bupivacaine (NR50 and NR100) and ropivacaine (R50 and R100) intoxication. Isometric contraction data were obtained in basal condition (0.2 Hz), after increasing the frequency of stimulation to 1.0 Hz and after 5, 10 and 15 min of local anesthetic intoxication. Data were analyzed as relative changes of variation. RESULTS: Developed tension was higher with R100 than B100 at D1 (4.3 ± 41.1 vs -57.9 ± 48.1). Resting tension was altered with B50 (-10.6 ± 23.8 vs -4.7 ± 5.0) and R50 (-14.0 ± 20.5 vs -0.5 ± 7.1) between D1 and D3. Maximum rate of tension development was lower with B100 (-56.6 ± 38.0) than R50 (-6.3 ± 37.9) and R100 (-1.9 ± 37.2) in D1. B50, B100 and NR100 modified the maximum rate of tension decline from D1 through D2. Time to peak tension was changed with NR50 between D1 and D2. CONCLUSIONS: Racemic bupivacaine depressed myocardial contractile force more than non-racemic bupivacaine and ropivacaine. Non-racemic and racemic bupivacaine caused myocardial relaxation impairment more than ropivacaine. .
Assuntos
Animais , Masculino , Amidas/farmacologia , Anestésicos Locais/farmacologia , Bupivacaína/farmacologia , Contração Miocárdica/efeitos dos fármacos , Bupivacaína/química , Depressão Química , Tono Muscular/efeitos dos fármacos , Tono Muscular/fisiologia , Contração Miocárdica/fisiologia , Músculos Papilares/efeitos dos fármacos , Músculos Papilares/fisiologia , Ratos Wistar , Valores de Referência , Estereoisomerismo , Fatores de TempoRESUMO
BACKGROUND: Ruta graveolens L. (R. graveolens) is a medicinal plant employed in non-traditional medicines that has various therapeutic properties, including anthelmintic, and vasodilatory actions, among others. We evaluated the trachea-relaxant effects of hydroalcoholic extract of R. graveolens against potassium chloride (KCl)- and carbachol-induced contraction of rat tracheal rings in an isolated organ bath. RESULTS: The results showed that the airway smooth muscle contraction induced by the depolarizing agent (KCl) and cholinergic agonist (carbachol) was markedly reduced by R. graveolens in a concentration-dependent manner, with maximum values of 109 ± 7.9 % and 118 ± 2.6 %, respectively (changes in tension expressed as positive percentages of change in proportion to maximum contraction), at the concentration of 45 µg/mL (half-maximal inhibitory concentration IC50: 35.5 µg/mL and 27.8 µg/mL for KCl- and carbachol-induced contraction, respectively). Additionally, the presence of R. graveolens produced rightward parallel displacement of carbachol dose-response curves and reduced over 35 % of the maximum smooth muscle contraction. CONCLUSIONS: The hydroalcoholic extract of R. graveolens exhibited relaxant activity on rat tracheal rings. The results suggest that the trachea-relaxant effect is mediated by a non-competitive antagonistic mechanism. More detailed studies are needed to identify the target of the inhibition, and to determine more precisely the pharmacological mechanisms involved in the observed biological effects.
Assuntos
Animais , Ratos , Parassimpatolíticos/farmacologia , Traqueia/efeitos dos fármacos , Extratos Vegetais/farmacologia , Ruta/química , Músculo Liso/efeitos dos fármacos , Fármacos Neuromusculares Despolarizantes/farmacologia , Cloreto de Potássio/farmacologia , Furocumarinas/análise , Quercetina/análise , Rutina/análise , Traqueia/cirurgia , Técnicas In Vitro , Carbacol/farmacologia , Extratos Vegetais/química , Cromatografia Líquida , Ratos Sprague-Dawley , Colinérgicos/farmacologia , Concentração Inibidora 50 , Componentes Aéreos da Planta/química , Contração Muscular/efeitos dos fármacos , Tono Muscular/efeitos dos fármacosRESUMO
We evaluated the safety and effectiveness of botulinum toxin A (BoNT/A) in the treatment of spasticity in 20 children with spastic diplegic cerebral palsy (CP). All the patients received injections in the gastrocnemius and soleus, and 15 received injections in the adductors. The total dose varied from 70 to 140 U (99.75±16.26 U), or 7.45±2.06 U/kg per patient. The treatment improved the patients' walking and gait pattern significantly. There was also a significant alteration in the heel-ground distance and increased motion of the ankle joint. These structural changes in the feet were sustained until the end of the follow-up, although the same was not observed for the functional parameters. Three patients complained of weakness in the lower limbs. In conclusion, BoNT/A is safe and effective when used in a single session of injections and produces a sustained structural modification of the lower limbs. However, functional changes are temporary and are only observed during the peak effect of the drug.
Para avaliação da segurança e eficácia do tratamento com toxina botulínica A (TB-A) na espasticidade na paralisia cerebral (PC), foram selecionadas 20 crianças com a forma diplegia espástica. Todos os pacientes receberam injeções nos gastrocnêmios e sóleos, 15 receberam doses nos adutores da coxa. A dose total variou de 70 a 140 Us (99,75±16,26 U), 7,45±2,06 U/Kg por paciente. O tratamento com a TB-A melhorou significativamente a deambulação e o padrão de marcha. Houve também significativa alteração da distância tornozelo-solo e aumento da amplitude de movimento da articulação do tornozelo. Essas mudanças estruturais dos pés se mantiveram até o final do acompanhamento. O mesmo não foi observado com parâmetros funcionais. Três pacientes apresentaram fraqueza em membros inferiores. Conclui-se que a TB-A, em uma única aplicação, é segura e eficaz. Há modificação sustentada da estrutura motora dos membros inferiores, porém mudanças funcionais são temporárias, durante o pico de ação do medicamento.
Assuntos
Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Toxinas Botulínicas Tipo A/administração & dosagem , Paralisia Cerebral/tratamento farmacológico , Fármacos Neuromusculares/administração & dosagem , Paralisia Cerebral/complicações , Seguimentos , Marcha/efeitos dos fármacos , Extremidade Inferior/fisiopatologia , Espasticidade Muscular/tratamento farmacológico , Tono Muscular/efeitos dos fármacos , Estatísticas não Paramétricas , Resultado do TratamentoRESUMO
The primary clinical symptom of Paralytic Shellfish Poisoning is acute paralytic illness produced by paralyzing toxins. Paralytic shellfish poison is formed by a mixture of phycotoxins and their toxicity is due to its reversible binding to a receptor site on the voltage-gated sodium channel on excitable cells, thus blocking neuronal transmission. We studied the effect of the gonyautoxin 2/3 epimers by local infiltration in the anal internal sphincter of healthy voluntary adults in order to reduce anal tone. The toxin was injected after prior clinical evaluation, anoscopy and anorectal manometry. Post injection clinical examination, electromyography and anorectal manometry were performed. Resting and voluntary contraction pressures were measured and the anorectal inhibitory and anocortical reflexes were tested by manometry. Blood and urine samples were obtained from each participant, and hemogram, basic metabolic panel, and urinalysis were done both before and one week after the injection. This study shows, for the first time, that gonyautoxin 2/3 reduces the anal tone by relaxing the anal sphincters in 100 % of the participants. Manometric recordings showed a significant decrease in anal maximal voluntary contraction pressure after the toxin injection, dropping to 55.2 ± 6.2 % and 47.0 ± 6.8 % (Mean Value ± Std.Dev.) of the baseline values at 2 minutes and at 24 hours respectively after the injection. Post-injection electromyography showed that activity of the muscle was abolished. We conclude that local administration of gonyautoxin 2/3 to the anal sphincter produces immediate relaxation and a statistically significant decrease in the anal tone (p <0.001)..
Assuntos
Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Canal Anal/efeitos dos fármacos , Relaxantes Musculares Centrais/farmacologia , Relaxamento Muscular/efeitos dos fármacos , Tono Muscular/efeitos dos fármacos , Saxitoxina/farmacologia , Eletromiografia , Injeções Intramusculares , ManometriaRESUMO
The underlying mechanisms of acetycholine-induced intestinal relaxation in the lizard Liolaemus tenuis tenuis are still unknows. By using a classical model of intestinal recording of isometric contraction and relaxation in conjunction with specific pharmacological tools, this article studies the possible influence of EDRF/NO and nicotinic ganglionar receptors on the Ach-induced relaxation in an effort to elucidate the probable mechanisms involved in ACh effect. It was observed that the relaxation of the lizard intestine elicited by ACh (10(-7) - 4 x 10(-4) M) was not affected by hexametonium (5 x 10(4) M) or tetrodotoxin (10(-6) M). Nicotine (10(-7) to 10(-4) M) induced relaxation was significantly antagonized by hexametonium; however, it was not influenced by tetrodotoxin. These results allow us to discard a neuronal pathway in cholinergic-induced relaxation, suggesting a more direct cholinergic effect on the smooth muscle, perhaps mediated by an unknown substance released by some specialized tissue. N-nitro-L-arginine, used to block NO-synthase and NO production, induced no changes in ACh-induced relaxation. Methylene blue, a soluble guanylate cyclase inhibitor, induced no changes in ACh-induced relaxation. These results allow us to dicard a probable role of EDRF/nitric oxide in the ACh-induced relaxation of lizard small intestine, providing evidence that this mechanism could be different from reported on other species.
Assuntos
Animais , Masculino , Feminino , Agonistas Colinérgicos/farmacologia , Esôfago/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Tono Muscular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Hexametônio/farmacologia , Lagartos , Azul de Metileno/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/farmacologia , Óxido Nítrico Sintase , Nitroarginina/farmacologia , Tetrodotoxina/farmacologiaRESUMO
Se presenta una serie de 7 pacientes con SIDA en quienes se diagnosticó poliradiculomielopatía causada por Citomegalovirus (CMV-PRAM), con el objetivo de evaluar la eficacia del tratamiento con ganciclovir, foscarnet, o la combinación de ambos agentes. Se realizaron evaluaciones clínicas y neurológicas al momento de presentación y durante el tratamiento para el CMV. La fuerza muscular fue establecida de acuerdo a la escala del Medical Research Council (MRC). Se clasificó la respuesta al tratamiento de acuerdo al grado de mejoría en la fuerza muscular. En 6 de los 7 pacientes se observó una mejoría en la fuerza muscular con tratamiento anti-CMV alcanzando grado 4, o una mejoría de por lo menos 3 grados de acuerdo a la escala MRC. El paciente restante tuvo una respuesta intermedia. CMV-PRAM puede ser tratada con ganciclovir o la combinación de ganciclovir y foscarnet con buenos resultados.
Assuntos
Adulto , Feminino , Humanos , Infecções Oportunistas Relacionadas com a AIDS/complicações , Antivirais/uso terapêutico , Infecções por Citomegalovirus/complicações , Foscarnet/uso terapêutico , Ganciclovir/uso terapêutico , Polirradiculopatia/tratamento farmacológico , Polirradiculopatia/microbiologia , Doenças da Medula Espinal/tratamento farmacológico , Doenças da Medula Espinal/microbiologia , Antivirais , Ensaios Clínicos como Assunto , Infecções por Citomegalovirus/tratamento farmacológico , Quimioterapia Combinada , Eletromiografia , Foscarnet , Ganciclovir , Tono Muscular/efeitos dos fármacos , Resultado do Tratamento , Retenção Urinária/tratamento farmacológico , Retenção Urinária/microbiologiaRESUMO
Human skinned muscle fibers were used to investigate the effects of bovine serum albumin (BSA) on the tension/pCa relationship and on the functional properties of the Ca2+- release channel of the sarcoplasmic reticulum (SR). In both fast-and slow-type fibers, identified by their tension response to pSr 5.0, BSA (0.7-15 muM) had no effect on the Ca2+ affinity of the contractile proteins and elicited no tension per se in Ca2+-loaded fibers. In contrast, BSA (>1.0 muM) potentiated the caffeine induced tension in Ca2+-loaded fibers, this effect being more intense in slow-type fibers. Thus, BSA reduced the threshold caffeine concentration required for eliciting detectable tension, and increased the amplitude, the rate of rise and the area under the curve of caffeine-induced tension BSA also potentiated the tension elicited in Ca2+-loaded fibers by low-Mg2+ solutions containing 1.0 mM free ATP. These results suggest that BSA modulates the response of the human skeletal muscle SR Ca2+-release channel to activators such as caffeine and ATP.