RESUMEN
The aim of this study was to compare safety and efficacy of bambuterol hydrochloride (10 mg) oral solution administered once daily in the evening with terbutaline sulphate (0.075 mg/kg body weight) oral solution administered three times daily in 2-5-year-old children with asthma. There were two treatment groups: (2/3) of the patients received bambuterol and (1/3) received terbutaline. The study was double-blind, randomized, and of a parallel group design, and it lasted for 3 months after a 2-week run-in period. The primary objective was to evaluate safety (adverse events, and changes in blood pressure, pulse rate, hematology, and clinical chemistry parameters). Plasma concentrations of terbutaline and/or bambuterol were also measured. Evaluation of efficacy (diary card data) was a secondary objective. A total of 155 patients (range, 2-6 years; 3 patients were 6 years old at randomization) were treated with the study drugs; 104 patients received bambuterol and 51 patients received terbutaline. Both treatments showed a good safety profile with respect to clinical and laboratory tests, and they were generally well tolerated. Reported adverse events were mild to moderate. There were no statistically significant differences between treatment groups in any of the efficacy variables (diary variables: peak expiratory flow (PEF), asthma symptoms, restlessness, other reported symptoms, use of inhaled bronchodilators, and nighttime awakenings). For morning PEF, the mean increase from run-in to treatment was 16.9 L/min in the terbutaline group and 23.3 L/min in the bambuterol group. For evening PEF, the mean increase was 20.2 L/min in the terbutaline group and 20.6 L/min in the bambuterol group. In conclusion, once-daily bambuterol is as safe and effective as terbutaline given three times daily. The study also confirmed that bambuterol has a 24-hr duration of action, and therefore its once daily administration, makes it a preferred bronchodilator agent. Pediatr Pulmonol. 2000:29:194-201.
Asunto(s)
Asma/tratamiento farmacológico , Broncodilatadores/uso terapéutico , Profármacos/uso terapéutico , Terbutalina/análogos & derivados , Terbutalina/uso terapéutico , Administración Oral , Asma/fisiopatología , Presión Sanguínea/efectos de los fármacos , Broncodilatadores/administración & dosificación , Broncodilatadores/efectos adversos , Broncodilatadores/sangre , Niño , Preescolar , Ritmo Circadiano , Método Doble Ciego , Esquema de Medicación , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Registros Médicos , Ápice del Flujo Espiratorio/efectos de los fármacos , Profármacos/administración & dosificación , Profármacos/efectos adversos , Profármacos/análisis , Agitación Psicomotora/fisiopatología , Seguridad , Sueño/fisiología , Terbutalina/administración & dosificación , Terbutalina/efectos adversos , Terbutalina/sangreRESUMEN
The effects of oxygen radicals, generated by the hypoxanthine-xanthine oxidase (XO) system, on pulmonary circulation and release of cysteinyl-containing leukotrienes (LTs) were studied in pigs after XO infusion into the right atrium. A 2.3-fold increase in pulmonary vascular resistance (PVR) (p < 0.05 vs. baseline) and a 2.1-fold increase in LT release (p < 0.05 vs. baseline) was observed. Pretreatment with indomethacin and allopurinol attenauted the vascular response (p < 0.01 and p < 0.05 vs. XO), and the LT release was inhibited by allopurinol and catalase (p < 0.01 and p < 0.02 vs. XO). We conclude that oxygen radicals stimulate lipoxygenase metabolism. This coincides with the observed increase in PVR, however, no causal relationship can be derived from the data presented.
Asunto(s)
Leucotrienos/metabolismo , Oxígeno/metabolismo , Circulación Pulmonar , Animales , Cisteína/metabolismo , Femenino , Radicales Libres , Hipoxantina , Hipoxantinas/sangre , Masculino , Óxido Nítrico/fisiología , Porcinos , Resistencia Vascular , Xantina Oxidasa/farmacologíaRESUMEN
Oxygen radicals produced by the hypoxanthine-xanthine oxidase (Hyp-XO) system potently constrict the pulmonary circulation of pigs. D-penicillamine (DPA) is thought to be a free radical scavenger. In the present work we have studied if DPA may influence the vasoactive action of Hyp-XO in pig lungs. Further, we have measured how this drug influences the output of cyclooxygenase and lipoxygenase products from the left atrium in pigs infused with XO into the pulmonary circulation. Twelve young pigs were divided into two groups. Group 1, the XO group, was infused 1 U/kg XO into right atrium. Group 2, the DPA group, was pretreated with DPA, 100 mg/kg intravenously before XO infusion as in group 1. Pulmonary artery pressure, left atrial pressure, pulmonary artery blood flow and systemic blood flow and pressure were recorded continuously. Plasma tromboxane B2 and prostaglandin (6-keto-PGF1 alpha) were determined with a radioimmunoassay method. Cysteinyl containing leukotrienes LTC4, LTD4, and LTE4, were measured together by RIA analyses of plasma samples, using a monoclonal antibody. There was a significant parallel decrease in paO2 and saO2 during the 130 minutes duration of the experiments in both groups without differences between the groups. Pulmonary vascular pressure and resistance increased sharply with a peak found after 25 minutes in the XO group. DPA attenuated the hemodynamic response. DPA inhibited the XO induced pulmonary blood pressure changes with 80% and inhibited the increase in pulmonary vascular resistance 68%. Plasma TXB2 increased two folds in the XO group reaching a maximum after 40 minutes, this effect was completely inhibited by DPA (92% inhibition). DPA also inhibited the XO induced increase in 6-keto-PGF1 alpha, however, not as efficient as with TXB2 (40% inhibition). Plasma cysteinyl leukotrienes increased after XO infusion reaching a peak at 20 minutes. DPA completely abolished this effect (100% inhibition). The study demonstrates that DPA attenuates or even abolishes the hemodynamic effects of XO on the pulmonary circulation in pigs. It seems that DPA inhibits the production of both lipoxygenase and cyclooxygenase products per se, and it is tempting to speculate that the observed DPA effect is caused by its action as an oxygen radical scavenger. It is further speculated that the vasoconstricting effect of XO is due to the fact that oxygen radicals may inactivate nitric oxide (NO), and that DPA stabilizes NO so it more efficiently possess its vasorelaxant activity. We conclude that DPA is an extremely potent inhibitor of XO induced pulmonary vascular effects. The mechanism of action is not fully understood, although its action as an oxygen radical scavenger may explain part of it.
Asunto(s)
Depuradores de Radicales Libres , Penicilamina/farmacología , Circulación Pulmonar/efectos de los fármacos , Especies Reactivas de Oxígeno/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Femenino , Lipooxigenasa/metabolismo , Masculino , Oxígeno/sangre , Prostaglandina-Endoperóxido Sintasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Porcinos , Tromboxano B2/metabolismo , Resistencia Vascular/efectos de los fármacos , Xantina Oxidasa/metabolismoRESUMEN
Reactive oxygen species have earlier been shown to induce vasoactive changes. In the present investigation we hypothesized that active oxygen intermediates would stimulate arachidonic acid metabolism and thereby influence the pulmonary circulation. Four groups of 8-week old pigs were studied after infusion of an oxygen radical generator. Haemodynamic changes were recorded, and thromboxane (TX)B2 (the stable metabolite of TXA2) and 6-keto-prostaglandin (PG)F1 alpha (the stable metabolite of prostacyclin, PGI2) measured by a radioimmunoassay technique after infusion of xanthine oxidase (XO) alone or in combination with pharmacological inhibitors. In the XO group pulmonary vascular resistance increased rapidly compared to baseline levels. Maximum resistance increase was 118.4 +/- 27.5%, 25 min after the XO infusion (p < 0.05 compared to baseline). The vasoconstriction was significantly attenuated after pretreatment with the cyclo-oxygenase inhibitor indomethacin. In this group the pulmonary resistance increase was 21.2 +/- 24.3% at 25 min (p < 0.01 vs. XO group). In a group given allopurinol (xanthine oxidase inhibitor), the resistance increased by 44.3 +/- 28.8% (p < 0.02 vs. XO group), and during catalase infusion (hydrogen peroxide scavenger), the increase was 52.9 +/- 24.2% (p < 0.01 vs. XO group). Along with the pulmonary vascular pressure augmentation, we measured 1.9 fold TXB2 and 2.2 fold 6-keto-PGF1 alpha concentration increases in the XO group. However, both TXB2 and 6-keto-PGF1 alpha formation was significantly inhibited by indomethacin (p < 0.01 respectively vs. XO group), allopurinol (p < 0.01 and p < 0.05 respectively vs. XO group) and catalase (p < 0.01 and p < 0.02 respectively vs. XO group).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Epoprostenol/biosíntesis , Pulmón/irrigación sanguínea , Especies Reactivas de Oxígeno/farmacología , Tromboxanos/biosíntesis , Vasoconstricción/efectos de los fármacos , Animales , Femenino , Radicales Libres , Masculino , Porcinos , Resistencia Vascular , Xantina Oxidasa/farmacologíaRESUMEN
The effects of infusion of the oxygen radical generating system, hypoxanthine-xanthine oxidase, on pulmonary hemodynamics and plasma proteolytic systems, as the plasma kallikrein-kinin and fibrinolytic systems, were studied in pigs by infusion of xanthine oxidase into the pulmonary circulation. A marked pulmonary vasoconstriction and increase in vasculature resistance with a maximum after 25 min was observed. The effects were attenuated by indomethacin, allopurinol and catalase. During the 130-min observation time there were no signs indicating activation of either the plasma kallikrein or the plasma fibrinolytic systems.
Asunto(s)
Circulación Pulmonar/fisiología , Especies Reactivas de Oxígeno/metabolismo , Vasoconstricción/fisiología , Alopurinol/farmacología , Animales , Catalasa/farmacología , Femenino , Fibrinólisis/fisiología , Radicales Libres , Hipoxantina , Hipoxantinas/farmacología , Indometacina/farmacología , Sistema Calicreína-Quinina/fisiología , Masculino , Circulación Pulmonar/efectos de los fármacos , Porcinos , Resistencia Vascular/efectos de los fármacos , Resistencia Vascular/fisiología , Vasoconstricción/efectos de los fármacos , Xantina Oxidasa/farmacologíaRESUMEN
Atrial natriuretic factor (ANF) is secreted from atrial myocytes in response to increased atrial wall stress caused by increased transmural pressure. This study investigates whether the presence of an intact pericardium restricts the ANF secretory response to an increment in left atrial pressure caused by acute aortic constriction in anaesthetized open-chest pigs. The rise in ANF plasma concentration secondary to constriction was higher when the pericardium had been surgically opened than when it was left intact. Furthermore, an opened pericardium led to a larger increase during constriction in left atrial diameter as measured by sonomicrometry. The results suggest that the intact pericardium restricts the cardiac release of ANF secondary to aortic constriction, probably by restricting left atrial dilatation.
Asunto(s)
Factor Natriurético Atrial/metabolismo , Corazón/fisiología , Pericardio/fisiología , Animales , Aorta Torácica/fisiología , Función Atrial , Factor Natriurético Atrial/sangre , Porcinos , Vasoconstricción/fisiologíaRESUMEN
Pulmonary hypertension is one of the major problems in the neonatal period. Free oxygen radicals play important role in the activation of pulmonary vasoconstriction. Since D-penicillamine has proved to be a strong antioxidant in newborns it was of interest to investigate the effect of the drug in the oxygen radical induced pulmonary hypertension. According to our animal experiments D-penicillamine inhibits the xanthine oxidase induced pulmonary hypertension in piglets. The same inhibitory effect was observed in the prostanoid metabolism. Could D-penicillamine be used in the treatment of pulmonary hypertension in the newborn?
Asunto(s)
Animales Recién Nacidos , Hipertensión Pulmonar/tratamiento farmacológico , Penicilamina/uso terapéutico , Animales , Evaluación Preclínica de Medicamentos , Radicales Libres/farmacología , Humanos , Hipertensión Pulmonar/inducido químicamente , Recién Nacido , Oxígeno , PorcinosRESUMEN
Reactive oxygen metabolites appear to modulate pulmonary vascular changes. To study the effects of free radical formation in vivo, we investigated five groups of young pigs by recording hemodynamic changes after xanthine oxidase infusion alone and after pretreatment with hypoxanthine or possible blocking agents. The pulmonary vascular pressure increased rapidly in the groups without inhibition reaching maximum levels 25 min after the start of the experiment. The pulmonary artery blood flow declined toward minimum values at the same time. Compared to baseline levels, the calculated vascular lung resistance increased by 300% when the pigs were pretreated with hypoxanthine, and by 150% when xanthine oxidase was given alone. These findings suggest enhanced pulmonary vasoconstriction as a result of high initial hypoxanthine levels probably capable of forming larger quantities of oxygen radicals. The vascular reaction was attenuated when the pigs were pretreated with indomethacin (cyclo-oxygenase inhibitor) or allopurinol (xanthine oxidase inhibitor). Furthermore, the presence of catalase (hydrogen peroxide scavenger) reduced the pulmonary vasoconstriction significantly. We observed less decline in arterial oxygen tension and oxygen saturation when the animals had been pretreated with inhibitory agents, compared to the blood gas changes found in the xanthine oxidase group. The systemic pressure recordings in the carotid artery remained at baseline levels in all groups. We conclude that oxygen radicals formed by the hypoxanthine-xanthine oxidase system produce severe pulmonary vascular constriction in young pigs.
Asunto(s)
Oxígeno/metabolismo , Circulación Pulmonar/fisiología , Vasoconstricción/fisiología , Alopurinol/farmacología , Animales , Catalasa/farmacología , Femenino , Radicales Libres , Hipoxantina , Hipoxantinas/metabolismo , Hipoxantinas/farmacología , Indometacina/farmacología , Masculino , Circulación Pulmonar/efectos de los fármacos , Porcinos , Vasoconstricción/efectos de los fármacos , Xantina Oxidasa/metabolismo , Xantina Oxidasa/farmacologíaRESUMEN
The concentrations of hypoxanthine, xanthine, and uric acid in plasma and cerebrospinal fluid (CSF), as well as the urinary output of hypoxanthine and xanthine, were measured in four groups of pigs (three groups with different degrees of hypoxemia and one control group). During hypoxemia with arterial O2 tension between 2.1 and 3.0 kPa [group 1, fractional inspired oxygen (FiO2) = 0.08], hypoxanthine increased in CSF from a mean basal value of 18.1 to 39.3 mumol/L at death (p less than 0.02), in plasma from 25.4 to 103.6 mumol/L (p less than 0.05), and in urine from 21.3 to 87.1 nmol/kg/min (p less than 0.02). Xanthine changed in a similar way: in CSF from 4.0 to 10.6 mumol/L (p less than 0.02), in plasma from 0.7 to 48.1 mumol/L (p less than 0.02), and in urine from 4.0 to 12.6 nmol/kg/min (p less than 0.05). Uric acid increased in CSF from 2.7 to 11.6 mumol/L (p less than 0.05), and in plasma from 15.4 to 125.0 mumol/L (p less than 0.02). During hypoxemia with arterial O2 tension between 3.0 and 4.0 kPa (group 2, FiO2 = 0.11), hypoxanthine increased in the CSF from 14.7 to 42.9 mumol/L (p less than 0.02). Plasma hypoxanthine increased from 20.3 to a maximum of 44.1 mumol/L (p less than 0.02), but decreased to initial values by the time of death. The urinary excretion of hypoxanthine increased from 13 to 54 nmol/kg/min (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Hipoxantinas/metabolismo , Hipoxia/metabolismo , Ácido Úrico/metabolismo , Xantinas/metabolismo , Animales , Femenino , Hipoxantina , Masculino , Oxígeno/sangre , Porcinos , XantinaRESUMEN
Oxygen radicals have vasoactive properties. The hypoxanthine-xanthine oxidase system generates oxygen radicals. This system relaxes isolated constricted ductus rings from fetal lambs and constricts the pulmonary circulation of adult pigs. Since catalase, and not superoxide dismutase, inhibits the effect of the hypoxanthine-xanthine oxidase system, we believe the effect is caused by the hydroxyl radical. The hydroxyl radical stimulates prostaglandin synthesis in the vessel wall and high concentrations of prostanoids can be measured after hypoxanthine-xanthine oxidase exposure. Indomethacin inhibits the vasoactive effects of the hypoxanthine-xanthine oxidase system. We believe the hypoxanthine-xanthine oxidase system plays an important role in regulating the normal circulation.