RESUMEN
We had previously shown that microcystin-LR (MCLR) could induce lung and liver inflammation after acute exposure. The biological outcomes following prolonged exposure to MCLR, although more frequent, are still poorly understood. Thus, we aimed to verify whether repeated doses of MCLR could damage lung and liver and evaluate the dose-dependence of the results. Male Swiss mice received 10 intraperitoneal injections (i.p.) of distilled water (60 µL, CTRL) or different doses of MCLR (5 µg/kg, TOX5), 10 µg/kg (TOX10), 15 µg/kg (TOX15) and 20 µg/kg (TOX20) every other day. On the tenth injection respiratory mechanics (lung resistive and viscoelastic/inhomogeneous pressures, static elastance, and viscoelastic component of elastance) was measured. Lungs and liver were prepared for histology (morphometry and cellularity) and inflammatory mediators (KC and MIP-2) determination. All mechanical parameters and alveolar collapse were significantly higher in TOX5, 10, 15 and 20 than CTRL, but did not differ among them. Lung inflammatory cell content increased dose-dependently in all TOX groups in relation to CTRL, being TOX20 the largest. The production of KC was increased in lung and liver homogenates. MIP-2 increased in the liver of all TOX groups, but in lung homogenates it was significantly higher only in TOX20 group. All TOX mice livers showed steatosis, necrosis, inflammatory foci and a high degree of binucleated hepatocytes. In conclusion, sub-chronic exposure to MCLR damaged lung and liver in all doses, with a more important lung inflammation in TOX20 group.
Asunto(s)
Toxinas Bacterianas/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Hígado/efectos de los fármacos , Pulmón/efectos de los fármacos , Toxinas Marinas/toxicidad , Microcistinas/toxicidad , Neumonía/inducido químicamente , Animales , Toxinas Bacterianas/administración & dosificación , Toxinas Bacterianas/aislamiento & purificación , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/fisiopatología , Quimiocina CXCL2/agonistas , Quimiocina CXCL2/metabolismo , Quimiocinas/agonistas , Quimiocinas/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/aislamiento & purificación , Inhibidores Enzimáticos/toxicidad , Hepatitis/etiología , Inyecciones Intraperitoneales , Hígado/inmunología , Hígado/metabolismo , Hígado/patología , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Masculino , Toxinas Marinas/administración & dosificación , Toxinas Marinas/aislamiento & purificación , Ratones , Microcistinas/administración & dosificación , Microcistinas/aislamiento & purificación , Microcystis/química , Tamaño de los Órganos/efectos de los fármacos , Fosfoproteínas Fosfatasas/antagonistas & inhibidores , Neumonía/metabolismo , Neumonía/patología , Distribución Aleatoria , Pruebas de Toxicidad SubcrónicaRESUMEN
BACKGROUND: Gonyautoxin are phycotoxins, whose molecular mechanism of action is a reversible block of the voltage-gated sodium channels at axonal level, impeding nerve impulse propagation. OBJECTIVE: To evaluate clinical efficacy of gonyautoxin in the treatment of patients with chronic tensional-type headache. METHODS: Open trial from September 2004 to 2005 in Hospital Clínico Universidad de Chile. Twenty-seven patients with chronic tension-type headache were locally infiltrated with gonyautoxins (50 micrograms) in ten sites considered as pain trigger points in a fixed infiltration protocol. In each site, a volume of 200 microlitres was injected. EMG recording was performed before and immediately after infiltrations. Main outcome measures are where a significantly drop-off in acute headache pain score occurs and number of days without headache pain. RESULTS: No side effects were detected in the follow-up period. From base line of 2 weeks, 19 patients of 27 (70%) are the successfully responders to the treatment. They showed the remarkable immediate effect after infiltration demonstrated by trapezium EMG recording. Patients reported a fall in pain score 5 minutes post-injection from 5.0 +/- 2.8 to 1.6 +/- 1.6 (mean +/- SD). The responder showed an average of 8.1 +/- 9.9 weeks of headache pain-free, all of them without a second infiltration or use of any additional analgesic medication. DISCUSSION: The therapeutic properties of gonyautoxin local infiltration in chronic tension-type headache patients are shown to be safe and effective. This report describes a new therapy for chronic tension-type headache involving local infiltrations of gonyautoxins. The immediate headache pain relief effect shown only minutes after toxin infiltrations were the most remarkable feature of this protocol. This is the first gonyautoxins testing report in the treatment of chronic tension-type headache.
Asunto(s)
Saxitoxina/análogos & derivados , Cefalea de Tipo Tensional/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad Crónica , Electromiografía/efectos de los fármacos , Femenino , Humanos , Inyecciones Intramusculares/métodos , Masculino , Toxinas Marinas/administración & dosificación , Toxinas Marinas/efectos adversos , Persona de Mediana Edad , Dimensión del Dolor/efectos de los fármacos , Saxitoxina/administración & dosificación , Saxitoxina/efectos adversosRESUMEN
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).
Asunto(s)
Canal Anal/efectos de los fármacos , Toxinas Marinas/farmacología , Relajación Muscular , Tono Muscular/efectos de los fármacos , Saxitoxina/análogos & derivados , Saxitoxina/farmacología , Adulto , Canal Anal/fisiología , Electromiografía , Estudios de Seguimiento , Humanos , Inyecciones Intramusculares , Masculino , Manometría , Toxinas Marinas/administración & dosificación , Persona de Mediana Edad , Saxitoxina/administración & dosificaciónRESUMEN
Although the action of Gonyautoxins (GTXs) and Saxitoxin (STX) mechanisms is well known at the molecular level, there are still many unresolved questions associated with the intoxication syndrome in mammals. For example, how are these toxins absorbed in the digestive system? Where are they absorbed? What is the absorption rate? What is the maximal concentration in plasma (C(max)) and the time taken to reach this C(max) (T(max)) in the case of oral toxin administration? These questions are addressed in this paper, which describes an experimental design which allowed us to follow the toxicokinetics and toxicodynamics of GTX 2/3 epimers poisoning in vivo, when an oral dose of toxin was administered to an anaesthetized cat permanently coupled to an artificial ventilator. The GTX 2/3 epimers was orally administered with a dose of 70 microg/kg, then urine and blood samples were collected during a 5 h experimental period. The toxins were quantified using a post column derivatisation high performance liquid chromatography method. Procedure of extraction, clean up and detection of GTX 2/3 epimers are described. The arterial pressure of the cats was continuously monitored. The GTX 2/3 epimers oral dose was completely absorbed at intestinal level. This dose was sufficient to decrease arterial pressure and to produce death within the experimental time. However, with the intravenous (i.v.) administration of 2.5 microg/min kg of dobutamine, hemodynamic parameters were restored which allowed the animal to overcome the cardiovascular shock. The renal clearance of GTX 2/3 epimers measured in the cats was 4.6 ml/min kg, indicating that like STX, in cats with normal cardiovascular parameters and diuresis, the GTX 2/3 excretion mainly involves glomerular filtration. Oral doses of 35 microg/kg of GTX 2/3 epimers and plasma level of 36 ng/ml are lethal limits for cats. This is the first report that shows the effects of the GTX 2/3 epimers at different plasmatic levels and their relationship to their toxic effects when they are administered orally, resembling the intoxication illness in mammals.