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1.
Intensive Care Med ; 24(7): 709-15, 1998 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-9722042

RESUMEN

OBJECTIVE: Oleic acid (OA) can produce a lung injury similar to the adult respiratory distress syndrome (ARDS). Elastase and superoxides are thought to have an effect in ARDS. However, the effect that elastase and superoxide have in OA lung injury is unclear. To examine their involvement in OA lung injury, we tested the effects of methoxysuccinyl-alanyl-alanyl-prolyl-valyl chloromethyl ketone (MAAPVCK), an elastase inhibitor, and N-acetyl-L-cysteine (NAC), an active oxygen scavenger, on the increase in pulmonary vascular permeability caused by OA. We also examined whether OA stimulated elastase and/or superoxide release from polymorphonuclear leukocytes (PMNs). DESIGN: Prospective trial. SETTING: University laboratory. INTERVENTIONS: (1) Guinea pigs were anesthetized. MAAPVCK (2.5 mg/ kg) or NAC (150 mg/kg) was infused over OA (15 microl/kg) injection. Evans blue was used to measure vascular permeability. (2) PMNs were isolated from the blood of guinea pigs and rats. Elastase release was measured with MeO-Suc-Ala-Ala-Pro-Val-7-amino-4-methylcoumarin. Superoxide production was measured by the ferricytochrome c reduction method. MEASUREMENTS AND RESULTS: OA caused pulmonary hemorrhage and an increase in vascular permeability. MAAPVCK and NAC significantly attenuated the increase in vascular permeability in distal bronchus and trachea, respectively. OA induced superoxide production from PMNs in guinea pigs, but elastase release from PMNs was not detected. CONCLUSIONS: These results suggest that elastase and superoxide are involved in OA lung injury.


Asunto(s)
Acetilcisteína/farmacología , Clorometilcetonas de Aminoácidos/farmacología , Permeabilidad Capilar/efectos de los fármacos , Modelos Animales de Enfermedad , Depuradores de Radicales Libres/farmacología , Neutrófilos/inmunología , Ácido Oléico , Circulación Pulmonar/efectos de los fármacos , Síndrome de Dificultad Respiratoria/inducido químicamente , Síndrome de Dificultad Respiratoria/inmunología , Inhibidores de Serina Proteinasa/farmacología , Animales , Evaluación Preclínica de Medicamentos , Femenino , Cobayas , Elastasa de Leucocito/efectos de los fármacos , Elastasa de Leucocito/inmunología , Masculino , Estudios Prospectivos , Ratas , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Superóxidos/inmunología
2.
Intensive Care Med ; 21(12): 1003-8, 1995 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-8750125

RESUMEN

OBJECTIVE: Activation of fibrinolysis is implicated in the development of vascular injury in certain lung injuries. It has yet to be reported that activation of plasmin is involved in extravasation caused by oleic acid (OA). We examined whether or not plasmin is involved in pulmonary extravasation by OA. DESIGN: Prospective trial. SETTING: University laboratory. SUBJECTS: A total of 78 guinea pigs (498.9 +/- 10.6 g). INTERVENTIONS: Evans blue (EB) was administered to anesthetized guinea pigs. Subsequently four protocols were followed: (1) After 1 min, 60 micro l/kg of OA was injected. Perfusion was performed 30, 60 or 90 min after OA injection to wash out intravascular EB. (2) After 1 min, 15, 30 or 60 micro l/kg of OA was injected. (3) Tranexamic acid (TA) (2 g/kg) or saline was administered 30 min before OA (15 micro l/kg) injection. (4) Diphenhydramine hydrochloride (2.9 mg/kg) or saline was administered 7 min before OA (15 micro l/kg) injection. MEASUREMENT AND RESULTS: Except in protocol 1, the chest cavity was opened 90 min after OA injection. Perfusion was then performed. Airway was separated into four parts from trachea to distal bronchus. EB was extracted from the tissues and measured. OA caused an extravasation throughout airways in a time- and dose-dependent manner. Extravasation was more conspicuous in peripheral tissues. TA significantly attenuated extravasation, while diphenhydramine hydrochloride did not. CONCLUSIONS: It is suggested that plasmin, but not histamine, is involved in extravasation by OA. Inhibition of plasmin can be an effective strategy for treatment of this kind of lung injury.


Asunto(s)
Permeabilidad Capilar/efectos de los fármacos , Ácidos Oléicos/farmacología , Circulación Pulmonar/efectos de los fármacos , Edema Pulmonar/inducido químicamente , Síndrome de Dificultad Respiratoria/sangre , Ácido Tranexámico/farmacología , Análisis de Varianza , Animales , Difenhidramina/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Fibrinolisina/efectos de los fármacos , Fibrinólisis/efectos de los fármacos , Cobayas , Ácido Oléico , Presión Parcial , Estudios Prospectivos , Estadísticas no Paramétricas
4.
Crit Care Med ; 23(2): 357-64, 1995 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-7867360

RESUMEN

OBJECTIVES: a) To determine whether pentoxifylline has a preventive effect on the decrease in PaO2 that is caused by oleic acid, and whether pentoxifylline facilitates normalization of PaO2 from the decreased state. b) To examine whether pentoxifylline can attenuate an increase in pulmonary vascular permeability that is induced by oleic acid. DESIGN: Prospective trial. SETTING: University laboratory. SUBJECTS: a) A total of 48 guinea pigs (700 to 1100 g) for blood gas analysis. b) A total of 28 guinea pigs (390 to 670 g) for measurement of pulmonary vascular permeability. INTERVENTIONS: a) For blood gas analysis, the guinea pigs were mechanically ventilated. Oleic acid (15 microL/kg) was injected into the guinea pigs to decrease PaO2. Pentoxifylline (5 or 20 mg/kg) was administered 40 or 3 mins before oleic acid injection or 13 mins after oleic acid injection. b) For measurement of pulmonary vascular permeability, the guinea pigs were anesthetized with pentobarbital and catheterized via the external jugular vein for drug administration. Pentoxifylline (20 mg/kg) plus Evans blue (30 mg/kg) or theophylline (20 mg/kg) plus Evans blue (30 mg/kg) were administered at 40- and 1-min intervals before oleic acid (15 microL/kg) injection, respectively. Perfusion with saline was performed through the aorta 90 mins after the oleic acid injection. The airways were removed and separated into the trachea, the main bronchus, the proximal bronchus, and the distal bronchus. Evans blue was extracted from the airways with formamide for 18 hrs and measured. MEASUREMENTS AND MAIN RESULTS: a) We measured PaO2, PaCO2, and pH, and recorded airway pressure and systemic blood pressure at 15, 10, and 5 mins before oleic acid injection and at 6, 10, 15, 35, 55, and 75 mins after oleic acid injection. Compared with the control groups, a decrease in PaO2 by oleic acid was significantly prevented when pentoxifylline (5 or 20 mg/kg) was administered 40 mins before oleic acid injection. However, a decrease in PaO2 by oleic acid was not significantly reduced when pentoxifylline was administered 3 mins before oleic acid injection. Pentoxifylline administered 13 mins after oleic acid injection did not affect the recovering course of PaO2 significantly. b) An increase in pulmonary vascular permeability by oleic acid was significantly attenuated by both pentoxifylline and theophylline. The effect of theophylline was significantly stronger than the effect of pentoxifylline in the main bronchi. The effect of theophylline was not significantly different from the effect of pentoxifylline in other areas. CONCLUSION: Pentoxifylline is a noteworthy drug that could be a candidate as a therapy to help prevent hypoxemia in lung injuries that share a common mechanism with oleic acid-induced lung injury.


Asunto(s)
Oxígeno/sangre , Pentoxifilina/farmacología , Síndrome de Dificultad Respiratoria/sangre , Resistencia de las Vías Respiratorias , Animales , Presión Sanguínea , Permeabilidad Capilar/efectos de los fármacos , Dióxido de Carbono/sangre , Cobayas , Concentración de Iones de Hidrógeno , Hipoxia/prevención & control , Ácido Oléico , Ácidos Oléicos , Estudios Prospectivos , Circulación Pulmonar , Síndrome de Dificultad Respiratoria/inducido químicamente , Síndrome de Dificultad Respiratoria/fisiopatología , Teofilina/farmacología
5.
Nihon Yakurigaku Zasshi ; 103(1): 27-36, 1994 Jan.
Artículo en Japonés | MEDLINE | ID: mdl-8314181

RESUMEN

We constructed an oleic acid (OA)-induced PaO2 decrease model in guinea pigs. We then examined several basic conditions to establish the primary screening model to determine useful drugs for hypoxemia. Hartley strain guinea pigs were anesthetized with pentobarbital (25 mg/kg) and catheterized into the subclavian artery for blood sampling and for measuring blood pressure; they were also catheterized into the subclavian vein for drug administration. Then the animal was immobilized with pancuronium (0.1 mg/kg) and ventilated by a ventilator with room air. The following results were obtained: 1) there were no significant fluctuations of PaO2, PaCO2 and pH throughout the 11 sampling over a 2-hr period. Airway pressure and blood pressure also remained relatively constant. 2) Percentage of decrease in PaO2 by OA (15 microliters/kg) in the hyperventilated group was greater than that in the normally-ventilated group. 3) Increasing doses of 10, 15, 30 and 60 microliters/kg of OA resulted in dose-dependently lower values of PaO2. 4) Tranexamic acid (2 g/kg, i.p.) significantly prevented the decrease in PaO2 at 10 and 15 min after OA (15 microliters/kg) injection. 5) Procaterol hydrochloride (0.1 microgram/kg, i.v.) failed to inhibit the decrease in PaO2 by OA (15 microliters/kg). These results suggest that by using a suitable ventilation and OA dose, this model could be used as a primary screening model of drugs for hypoxemia and that tranexamic acid might be an effective drug for hypoxemia caused by a mechanism by which OA decreases PaO2.


Asunto(s)
Hipoxia/tratamiento farmacológico , Procaterol/uso terapéutico , Ácido Tranexámico/uso terapéutico , Animales , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Cobayas , Hipoxia/inducido químicamente , Masculino , Ácido Oléico , Ácidos Oléicos , Presión Parcial
6.
Nihon Yakurigaku Zasshi ; 75(3): 291-307, 1979 Apr 20.
Artículo en Japonés | MEDLINE | ID: mdl-317064

RESUMEN

General pharmacological actions of M73101, a new non-steroidal analgesic anti-inflammatory drug were investigated in mice, rats, guinea pigs, rabbits, cats and dogs. Intravenous administration of M73101 produced a slight transient fall in blood pressure, an increase in heart rate and a respiratory stimulation, but no remarkable change in the electrocardiogram. The contraction induced by epinephrine in the isolated ear vessels of rabbits relaxed by M73101. In the isolated trachea of guinea pigs, M73101 relaxed the contraction induced by histamine. Furthermore, M73101 inhibited the bronchoconstriction by histamine but not by bradykinin in guinea pigs. These properties of M73101 on the tracheal smooth muscle were similar to those seen with aminopyrine but different from those seen with aspirin which inhibited only the contraction by bradykinin in vivo, suggesting that M73101 is a compound with properties similar to basic non-steroidal anti-inflammatory drugs. M73101 inhibited the intestinal propulsion in mice and also the gastrointestinal movement in rats and dogs. Moreover, M73101 showed a spasmolytic activity on the isolated ileum of guinea pigs, but such was not due to any specific antagonistic action on the chemical mediators. On the other hand, M73101 had no effect on the isolated uterus and vas deferens of rats. M73101, unlike aminopyrine and phenylbutazone, slightly increased urine volume and electrolytes excretion in rats, indicating that this compound probably does not produced edema. M73101 showed no significant pharmacological activities on the blood sugar level, blood coagulation, platelet aggregation, methemoglobin formation and local irritation.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Piridazinas/farmacología , Animales , Bilis/metabolismo , Velocidad del Flujo Sanguíneo , Presión Sanguínea/efectos de los fármacos , Gatos , Perros , Oído/irrigación sanguínea , Electrocardiografía , Femenino , Motilidad Gastrointestinal/efectos de los fármacos , Cobayas , Corazón/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Íleon/efectos de los fármacos , Técnicas In Vitro , Masculino , Ratones , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Membrana Nictitante/efectos de los fármacos , Conejos , Ratas , Respiración/efectos de los fármacos , Tráquea/efectos de los fármacos , Sistema Urogenital/efectos de los fármacos
8.
Nihon Yakurigaku Zasshi ; 75(2): 127-46, 1979 Mar.
Artículo en Japonés | MEDLINE | ID: mdl-395049

RESUMEN

The anti-inflammatory activity and the mode of action of M73101, a new non-steroid analgesic anti-inflammatory agent, were investigated in experimental animals and compared with those of reference drugs. M73101 inhibited the increase in vascular permeability induced by acetic acid and its activity was more potent than that of phenylbutazone. M73101 showed a marked inhibitory effect against rat paw edema induced by various phlogistic agents (carrageenin, dextran, histamine, serotonin and bradykinin) and the activities were equal to or more potent than those of aminopyrine, mepirizole and tiaramide HCl. M73101 also inhibited the edema induced by mustard, scalding and anti-rat rabbit serum in rats. In addition, the anti-edematous effect of M73101 on carrageenin-induced rat paw edema was not influenced by spinalectomy or adrenalectomy, indicating that the anti-inflammatory action of M73101 was not mediated by the central nervous system and the adrenals. Local and oral administration of M73101 inhibited significantly the leucocyte migration into the fluid of CMC pouch in rats and the activity was more potent than phenylbutazone, suggesting that the anti-inflammatory effect of M73101 was due to the direct action at the inflamed site. On the other hand, M73101 did not show any marked activities on the experimental chronic inflammatory models. From these results, it is suggested that M73101 may be useful for clinical application as a basic analgesic, anti-inflammatory drug with remarkable anti-inflammatory activity in acute and subacute cases. The mechanism of the anti-inflammatory action of M73101 probably involves inhibition of an increase in vascular permeability and leucocyte migration.


Asunto(s)
Antiinflamatorios , Edema/tratamiento farmacológico , Piridazinas/farmacología , Adrenalectomía , Animales , Artritis Experimental/tratamiento farmacológico , Temperatura Corporal/efectos de los fármacos , Permeabilidad Capilar/efectos de los fármacos , Carragenina , Edema/inducido químicamente , Femenino , Granuloma/tratamiento farmacológico , Cobayas , Factores Inhibidores de la Migración de Leucocitos , Masculino , Ratas , Médula Espinal/cirugía , Quemadura Solar/tratamiento farmacológico
9.
Nihon Yakurigaku Zasshi ; 74(7): 841-55, 1978 Oct.
Artículo en Japonés | MEDLINE | ID: mdl-744551

RESUMEN

The analgesic activity and the mode of action of M73101, a new analgesic anti-inflammatory agent, were investigated in mice and rats and compared to those of reference drugs. M73101 showed a marked analgesic activity against noxious stimuli induced by pressure (Haffner method and Randall-Selitto method), thermal (hot plate method), electric and chemical (acetic acid-stretching method and bradykinin-induced responses) stimulation, in a manner similar to those of basic anti-inflammatory drugs (BAD) such as aminopyrine, mepirizole, tiaramide HCl, and benzydamine HCl. The activities of M73101 were equal to and/or more potent than those of BAD, and more potent than those of acidic anti-inflammatory drugs. In addition, the analgesic activity of M73101 was not decreased by the pretreatment with levallorphan and showed no cross-tolerance to morphine in mice, indicating that the analgesic properties of M73101 differ from those of morphine. On the other hand, the analgesic activity of M73101 as well as BAD was decreased by repeated oral administration in mice, and the potency was weaker than mepirizole. Furthermore, the muscle relaxant effect of M73101 obtained by inclined screen test in mice was the weakest among the BAD, suggesting that analgesic activity of M73101 is not related to the muscle relaxant property. These results indicate that M73101 may be useful for clinical application as an anti-inflammatory drug possessing remarkable analgesic activity.


Asunto(s)
Analgésicos , Piridazinas/farmacología , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Tolerancia a Medicamentos , Inyecciones Intraperitoneales , Levalorfano/farmacología , Masculino , Ratones , Morfolinas/administración & dosificación , Morfolinas/farmacología , Relajantes Musculares Centrales , Piridazinas/administración & dosificación , Ratas
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