RESUMEN
Overcoming therapeutic resistance in glioblastoma (GBM) is an essential strategy for improving cancer therapy. However, cancer cells possess various evasion mechanisms, such as metabolic reprogramming, which promote cell survival and limit therapy. The diverse metabolic fuel sources that are produced by autophagy provide tumors with metabolic plasticity and are known to induce drug or radioresistance in GBM. This study determined that autophagy, a common representative cell homeostasis mechanism, was upregulated upon treatment of GBM cells with ionizing radiation (IR). Nuclear receptor binding factor 2 (NRBF2)-a positive regulator of the autophagy initiation step-was found to be upregulated in a GBM orthotopic xenograft mouse model. Furthermore, ATP production and the oxygen consumption rate (OCR) increased upon activation of NRBF2-mediated autophagy. It was also discovered that changes in metabolic state were induced by alterations in metabolite levels caused by autophagy, thereby causing radioresistance. In addition, we found that lidoflazine-a vasodilator agent discovered through drug repositioning-significantly suppressed IR-induced migration, invasion, and proliferation by inhibiting NRBF2, resulting in a reduction in autophagic flux in both in vitro models and in vivo orthotopic xenograft mouse models. In summary, we propose that the upregulation of NRBF2 levels reprograms the metabolic state of GBM cells by activating autophagy, thus establishing NRBF2 as a potential therapeutic target for regulating radioresistance of GBM during radiotherapy.
Asunto(s)
Proteínas Relacionadas con la Autofagia , Autofagia , Neoplasias Encefálicas , Glioblastoma , Tolerancia a Radiación , Transactivadores , Animales , Humanos , Ratones , Proteínas Relacionadas con la Autofagia/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/radioterapia , Línea Celular Tumoral , Supervivencia Celular , Modelos Animales de Enfermedad , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Glioblastoma/radioterapia , Transactivadores/metabolismo , Lidoflazina/uso terapéuticoRESUMEN
UNLABELLED: We explored the hypothesis that brain damage after cardiac arrest caused by ventricular fibrillation (VF) needs different therapies than that after asphyxiation, which has been studied less thoroughly. In 67 healthy mongrel dogs of both sexes cardiac arrest (at normothermia) by ventricular fibrillation (no blood flow lasting 10 min) or asphyxiation (no blood flow lasting 7 min) was reversed by normothermic external cardiopulmonary resuscitation, followed by intermittent positive-pressure ventilation for 20 h, and intensive care to 96 h. To ameliorate ischemic brain damage, the calcium entry blocker lidoflazine or a solution of free radical scavengers (mannitol and L-methionine in dextran 40) plus magnesium sulphate, was given intravenously immediately upon restoration of spontaneous circulation. Outcome was evaluated as functional deficit, brain creatine kinase (CK) leakage into the cerebrospinal fluid (CSF) and brain morphologic changes. Lidoflazine seemed to improve cerebral outcome after VF but not after asphyxiation. Free radical scavengers plus magnesium sulphate seemed to improve cerebral outcome after asphyxiation, but not after VF. After VF, scattered ischemic neuronal changes in multiple brain regions dominated, and total brain histopathologic damage scores correlated with final neurologic deficit scores at 96 h (r = 0.66) and with peak CK levels in CSF (r = 0.81). After asphyxiation, in addition to the same ischemic neuronal changes, microinfarcts occurred, and there was no correlation between total brain histopathologic damage scores and neurologic deficit scores or CK levels in CSF. CONCLUSIONS: Different mechanisms of cardiac arrest, which cause different morphologic patterns of brain damage, may need different cerebral resuscitation treatments.
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Asfixia/complicaciones , Isquemia Encefálica/prevención & control , Reanimación Cardiopulmonar/métodos , Paro Cardíaco/etiología , Fibrilación Ventricular/complicaciones , Animales , Isquemia Encefálica/etiología , Bloqueadores de los Canales de Calcio/uso terapéutico , Perros , Femenino , Depuradores de Radicales Libres/uso terapéutico , Paro Cardíaco/terapia , Lidoflazina/uso terapéutico , Sulfato de Magnesio/uso terapéutico , Masculino , Respiración con Presión PositivaRESUMEN
The purpose of this research utilization article is to familiarize cardiovascular nurses with the Brain Resuscitation Clinical Trials (BRCTs) I and II and discuss the application of these trials to nursing practice. The BRCTs are a series of studies that examine the effects of selected interventions on neurologic outcome after cardiac arrest.
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Lesiones Encefálicas/prevención & control , Reanimación Cardiopulmonar , Paro Cardíaco/complicaciones , Bloqueadores de los Canales de Calcio/uso terapéutico , Reanimación Cardiopulmonar/enfermería , Paro Cardíaco/mortalidad , Paro Cardíaco/enfermería , Paro Cardíaco/terapia , Humanos , Hipnóticos y Sedantes/uso terapéutico , Lidoflazina/uso terapéutico , Tiopental/uso terapéutico , Índices de Gravedad del Trauma , Vasodilatadores/uso terapéuticoRESUMEN
BACKGROUND: Factors determining the outcome of operative correction of valvular abnormalities combined with coronary artery bypass grafting are still incompletely defined. METHODS: Determinants of early and late (more than 90 days) deaths and event-free survival were studied for combined valve operations and coronary artery bypass grafting in 741 patients using multivariate analysis. RESULTS: Ninety-day survival probability was 89% (95% confidence interval, 87% to 92%). Preoperative risk factors for early death were age, female sex, renal failure, New York Heart Association class IV or V, and mitral insufficiency. The operative risk factor was the duration of aortic cross-clamping. Five- and 10-year survival probabilities were 74% (95% confidence interval, 71% to 78%) and 43% (95% confidence interval, 36% to 50%), respectively. Preoperative risk factors for late death were age, preoperative renal failure, New York Heart Association class IV or V, vessel disease, and nonsinus rhythm. Five- and 10-year event-free survival probabilities were 57% (95% confidence interval, 53% to 61%) and 23% (95% confidence interval, 17% to 28%), respectively. Preoperative risk factors for non-event-free survival were age, female sex, reduced left ventricular function, mitral regurgitation, and pacemaker rhythm. CONCLUSION: The demographic factors of age and female sex; the comorbid condition of renal failure; the cardiac conditions of advanced New York Heart Association class, left ventricular function, mitral regurgitation, vessel disease, and cardiac rhythm; and the operative condition of ischemia time are the most important predictors of clinical outcome after combined valve operations and coronary artery bypass grafting.
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Puente de Arteria Coronaria , Enfermedad Coronaria/cirugía , Enfermedades de las Válvulas Cardíacas/cirugía , Prótesis Valvulares Cardíacas , Factores de Edad , Anciano , Válvula Aórtica/cirugía , Puente de Arteria Coronaria/mortalidad , Enfermedad Coronaria/complicaciones , Enfermedad Coronaria/mortalidad , Femenino , Enfermedades de las Válvulas Cardíacas/complicaciones , Enfermedades de las Válvulas Cardíacas/mortalidad , Mortalidad Hospitalaria , Humanos , Fallo Renal Crónico/complicaciones , Lidoflazina/uso terapéutico , Masculino , Persona de Mediana Edad , Válvula Mitral/cirugía , Análisis Multivariante , Premedicación , Modelos de Riesgos Proporcionales , Factores de Riesgo , Factores Sexuales , Análisis de Supervivencia , Resultado del Tratamiento , Válvula Tricúspide/cirugía , Vasodilatadores/uso terapéuticoAsunto(s)
Puente de Arteria Coronaria , Enfermedad Coronaria/fisiopatología , Vasos Coronarios/fisiopatología , Isquemia Miocárdica/fisiopatología , Adenosina/agonistas , Adenosina/fisiología , Aorta/fisiología , Aorta/fisiopatología , Vasos Coronarios/fisiología , Humanos , Lidoflazina/uso terapéutico , Contracción Miocárdica , Necrosis , Vasodilatadores/uso terapéuticoRESUMEN
OBJECTIVE: To assess survival after cardiac arrest and to determine whether age is an independent determinant of late mortality or poor neurologic outcome. DESIGN: Analyses using results of Brain Resuscitation Clinical Trial I (1979 to 1984) and Brain Resuscitation Clinical Trial II (1984 to 1989), two randomized, double-blind studies of outcome following cardiac arrest. SETTING: A multicenter study in 12 acute care hospitals in nine countries (Brain Resuscitation Clinical Trial I), and 24 hospitals in eight countries (Brain Resuscitation Clinical Trial II). PATIENTS: A total of 774 patients who were initially comatose after successful resuscitation from cardiac arrest. The analyses include both in- and out-of-hospital cardiac arrests. RESULTS: The 6-month mortality rate for the entire group was 81%. Mortality rate was 94% for the oldest group (> 80 yrs) compared with 68% for the youngest group (< or = 45 yrs) (p < .01). Other independent predictors of mortality were history of diabetes mellitus, inhospital arrests, arrest time of > 5 mins, history of congestive heart failure, a noncardiac cause of arrest, and cardiopulmonary resuscitation time of > 20 mins. Of the 774 patients, 27% recovered good neurologic function. There was no statistically significant difference in neurologic recovery rates by age. Multivariate analysis showed that independent predictors of good neurologic recovery were: no history of diabetes mellitus, a cardiac cause of arrest, short arrest time, and short cardiopulmonary resuscitation time. CONCLUSION: Increasing age was a factor in postresuscitation mortality, but was not an independent predictor of poor neurologic outcome.
Asunto(s)
Reanimación Cardiopulmonar , Coma/terapia , Paro Cardíaco/terapia , Factores de Edad , Anciano , Anciano de 80 o más Años , Reanimación Cardiopulmonar/mortalidad , Coma/etiología , Coma/mortalidad , Método Doble Ciego , Femenino , Escala de Coma de Glasgow , Paro Cardíaco/complicaciones , Paro Cardíaco/mortalidad , Humanos , Lidoflazina/uso terapéutico , Masculino , Persona de Mediana Edad , Examen Neurológico , Pronóstico , Factores de Riesgo , Tiopental/uso terapéuticoRESUMEN
Expensive clinical trials have become the gold standard for evaluating the efficacy of promising new therapeutic agents. Full exploration of the collected data is routine to maximize the yield of the information available. However, potential methodologic flaws in these extensive analyses may not be appreciated by investigators or readers. One such problem with subgroup analyses is discussed, using hypothetical examples and data from a recently completed clinical trial of brain resuscitation as illustrations.
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Ensayos Clínicos como Asunto , Interpretación Estadística de Datos , Enfermedades Cardiovasculares/tratamiento farmacológico , Humanos , Lidoflazina/uso terapéutico , Modelos Estadísticos , Ensayos Clínicos Controlados Aleatorios como Asunto , ResucitaciónRESUMEN
The effects of pretreatment with the nucleoside transport inhibitor lidoflazine on repeated ischemia-reperfusion injury induced by normothermic intermittent aortic crossclamping were studied in canine hearts. Eighteen mongrel dogs were allocated to three groups: placebo (n = 6), lidoflazine (1 mg/kg) (n = 6), and lidoflazine (1 mg/kg) plus the adenosine receptor blocker aminophylline (7 mg/kg) (n = 6). Pretreatment was performed intravenously during 15 minutes before extracorporeal circulation. All hearts were subjected to four intervals of 15 minutes of global ischemia each followed by 10 minutes of reperfusion. After weaning from extracorporeal circulation, functional recovery was followed for 1 hour. In the lidoflazine group, myocardial adenosine content (0.25 +/- 0.06 mumol/gm dry weight) was 3.5 times higher than that in the control group (0.07 +/- 0.03 mumol/gm dry weight; p < 0.05) at the end of the last aortic crossclamping. The release of adenosine from the myocardium during each reperfusion period was significantly higher than that in the control group (p < 0.05). Myocardial extraction of lactate was normalized at every reperfusion interval in the lidoflazine group but not in the control group (p < 0.05). In the lidoflazine group functional recovery was significantly better than that in the control group. Positive rate of rise of pressure, negative rate of rise of pressure, and cardiac output recovered to, respectively, 150% +/- 19%, 82% +/- 8%, and 131% +/- 15% in the lidoflazine group versus, respectively, 37% +/- 9%, 23% +/- 7%, and 29% +/- 8% in the control group (p < 0.001) at 1 hour after extracorporeal circulation. When the adenosine receptor blocker aminophylline was administered in association with lidoflazine, protection dropped significantly: positive and negative rate of rise of pressure and cardiac output were, respectively, 58% +/- 8%, 46% +/- 9%, and 67% +/- 16% at 1 hour after extracorporeal circulation (p < 0.05 versus lidoflazine alone). These results suggest that the cardioprotective effects of lidoflazine are at least in part mediated by adenosine receptor stimulation via nucleoside transport inhibition-induced accumulation of endogenous adenosine in the myocardium.
Asunto(s)
Adenosina/metabolismo , Aminofilina/farmacología , Lidoflazina/farmacología , Daño por Reperfusión Miocárdica/metabolismo , Miocardio/metabolismo , Adenosina/análisis , Animales , Aorta , Transporte Biológico/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Puente Cardiopulmonar , Constricción , Circulación Coronaria/efectos de los fármacos , Perros , Femenino , Inosina/análisis , Lidoflazina/uso terapéutico , Masculino , Isquemia Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/fisiopatología , Daño por Reperfusión Miocárdica/prevención & control , Miocardio/química , Premedicación , Receptores Purinérgicos/efectos de los fármacosRESUMEN
The Brain Resuscitation Clinical Trial (BRCT) II was a double-masked, randomized, controlled clinical study of cardiopulmonary-cerebral resuscitation (CPCR) designed to test therapy for the amelioration of brain damage after cardiac arrest. Lidoflazine, a calcium entry blocker, was chosen for investigation because of its beneficial effects on postischemic encephalopathy in animals, its minimal cardiovascular depressant effects, and its protective actions in myocardial ischemia in patients. Twenty-four hospitals in eight countries participated. Over 4 years, 520 patients were recruited, of whom 4 were subsequently lost to follow-up. Patients' age averaged 63 years and 62% were men. Cardiac arrest occurred prior to hospitalization in 63%. All patients received basic and advanced life support until circulation was restored, and then standardized extracerebral organ support. After restoration of spontaneous circulation with normal blood pressure, patients who failed to awaken were randomly assigned to receive IV administration of either lidoflazine or placebo. In each patient, outcome was evaluated by cerebral performance during a 6-month follow-up period. Periodic safety monitoring was carried out to assure that no excess of mortality or complications occurred in the lidoflazine-treated group compared with the placebo-treated group.
Asunto(s)
Coma/tratamiento farmacológico , Paro Cardíaco/complicaciones , Lidoflazina/uso terapéutico , Estudios Multicéntricos como Asunto/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Daño Encefálico Crónico/prevención & control , Reanimación Cardiopulmonar , Método Doble Ciego , Humanos , Placebos , Resultado del TratamientoRESUMEN
BACKGROUND: Abnormalities of cellular calcium homeostasis have been implicated in the pathophysiology of postischemic encephalopathy. Calcium-entry-blocking drugs inhibit the influx of calcium into cells and have been shown to mitigate postischemic encephalopathy in animal models. METHODS: Five hundred twenty patients with cardiac arrest who remained comatose after the restoration of spontaneous circulation were randomly assigned to receive three doses of lidoflazine, an experimental calcium-entry blocker, or a placebo and were followed for six months. Four patients were lost to follow-up. Treated patients received an intravenous loading dose (1 mg per kilogram of body weight) of lidoflazine and two subsequent doses (0.25 mg per kilogram) 8 and 16 hours after resuscitation. The investigators were blinded to treatment assignment. RESULTS: There was no statistically significant difference between the lidoflazine group (n = 259) and the placebo group (n = 257) in the proportion of patients who died during the six-month follow-up (82 vs. 83 percent), who survived with good cerebral recovery (15 vs. 13 percent), or who survived with severe neurologic deficit (1.2 vs. 1.9 percent). Analysis of the best level of recovery achieved at any time during follow-up also did not show a difference between the treatment groups: 24 percent of those given lidoflazine and 23 percent of those given placebo recovered good cerebral function (normal or only moderately disabled cerebral performance) at some time. CONCLUSIONS: The administration of lidoflazine after cardiac arrest was not found to be beneficial. Our data do not support the routine use of this calcium-entry-blocking drug in comatose survivors of cardiac arrest.
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Bloqueadores de los Canales de Calcio/uso terapéutico , Coma/tratamiento farmacológico , Paro Cardíaco/complicaciones , Lidoflazina/uso terapéutico , Daño Encefálico Crónico/prevención & control , Coma/fisiopatología , Evaluación de Medicamentos , Femenino , Estudios de Seguimiento , Humanos , Lidoflazina/administración & dosificación , Masculino , Persona de Mediana Edad , ResucitaciónRESUMEN
Risk monitoring for the Brain Resuscitation Clinical Trial II, a multicenter, placebo-controlled trial to evaluate the efficacy of the calcium-entry blocker lidoflazine in the amelioration of brain damage in comatose cardiac-arrest survivors, posed unexpected challenges. Concern arose when monitoring of adverse reactions showed an excess of dangerous cardiac arrhythmias, including rearrest, in the lidoflazine group. To ascertain the cause of this problem and determine whether it was ethical for the trial to continue, an in-depth review of data was conducted, outside experts were consulted, and additional data were collected. These efforts suggested possible causes for the problem. Existing drug administration protocols for blood pressure control were reinforced, resulting in lower subsequent arrhythmia rates. Thus, through an efficient monitoring system, an important problem was uncovered and resolved, allowing the trial to be completed without major changes.
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Arritmias Cardíacas/inducido químicamente , Lesiones Encefálicas/tratamiento farmacológico , Protocolos Clínicos/normas , Ensayos Clínicos como Asunto/normas , Paro Cardíaco/complicaciones , Lidoflazina/efectos adversos , Garantía de la Calidad de Atención de Salud/organización & administración , Medición de Riesgo , Arritmias Cardíacas/epidemiología , Arritmias Cardíacas/mortalidad , Encefalopatías , Lesiones Encefálicas/etiología , Lesiones Encefálicas/mortalidad , Toma de Decisiones en la Organización , Ética Médica , Humanos , Lidoflazina/farmacología , Lidoflazina/uso terapéutico , Comité de Profesionales/organización & administración , Proyectos de Investigación/normas , Resucitación/métodos , Resucitación/normasRESUMEN
Lidoflazine, a piperazine derivative calcium antagonist, was investigated as therapy in 22 patients with microvascular angina (chest pain, angiographically normal coronary arteries and left ventricle, microvascular constrictor response to pacing after ergonovine administration and limited coronary flow response to dipyridamole). Eighteen of 22 patients reported symptom benefit while taking lidoflazine 360 mg daily. Compared to baseline exercise treadmill testing, lidoflazine resulted in significant improvement in exercise duration (812 +/- 337 vs 628 +/- 357 seconds, p less than 0.01) and time to onset of chest pain (530 +/- 343 vs 348 +/- 246 seconds, p less than 0.01). The 5 patients with ischemic ST-segment changes during baseline testing demonstrated an almost 4-minute delay in ST-segment depression (3 patients) or no ST-segment depression (2 patients) while taking lidoflazine. Repeat invasive study of coronary flow in 11 patients taking lidoflazine demonstrated significantly greater coronary vasodilation at rest, during pacing, during pacing after ergonovine and after dipyridamole administration (all p less than 0.03), compared to the initial drug-free study. During the randomized, placebo-controlled phase of the study with 7-week treatment periods, 9 of 11 patients who completed this phase of the study preferred lidoflazine and all demonstrated improved exercise capacity with lidoflazine compared to placebo. However, 3 patients developed malignant ventricular arrhythmias, and 1 died while taking lidoflazine, resulting in termination of the study. Limited coronary vasodilator response in microvascular angina has a reversible vasoconstrictor component and may be due to elevated systolic calcium levels. Despite the hemodynamic, symptom and exercise benefit, lidoflazine may be unsafe for clinical use because of its propensity to cause potentially fatal ventricular arrhythmias.
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Angina de Pecho/tratamiento farmacológico , Lidoflazina/uso terapéutico , Piperazinas/uso terapéutico , Adulto , Anciano , Angina de Pecho/diagnóstico por imagen , Angina de Pecho/fisiopatología , Angiografía Coronaria , Circulación Coronaria/efectos de los fármacos , Método Doble Ciego , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Lidoflazina/efectos adversos , Masculino , Microcirculación/fisiopatología , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
In order to compare the efficacy of oral lidoflazine (240 mg/die) and oral quinidine (1200 mg/die) in re-establishing sinus rhythm, we studied 115 patients (mean age 63.8 years; range 32-91) with atrial fibrillation of recent onset (less than 3 months). Patients with cardiac failure, acute myocardial infarction, severe intraventricular conduction disturbances, kaliemia less than 3.8 mEq/L or digoxinemia greater than 2 ng/ml were not included. Patients were randomly given one of the 2 drugs, until conversion to sinus rhythm was achieved, severe side effects occurred or for a maximum therapy of 5 days. No significant differences were present between the 2 groups in terms of age, male/female ratio, duration of atrial fibrillation, presence of an enlarged left atrium, presence of organic heart disease (or arterial hypertension) or digitalis therapy. Sinus rhythm resumption was obtained in 41/58 (71%) patients treated with quinidine and in 47/57 (82%) patients treated with lidoflazine (p = ns). In successful cases, the mean treatment time was 79 +/- 33 (SD) hours for quinidine and 66 +/- 36 hours for lidoflazine (p = ns). Both drugs showed the same efficacy in 3 subgroups of patients in whom the arrhythmia had different duration (less than 24 hours; between 24 hours and 3 days; more than 3 days). Treatment was stopped in 5 patients receiving quinidine (gastrointestinal side effects) and in 3 patients receiving lidoflazine (frequent premature ventricular beats in 2 and polymorphic ventricular tachycardia of the "torsade de pointes" type in 1).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Fibrilación Atrial/tratamiento farmacológico , Lidoflazina/uso terapéutico , Piperazinas/uso terapéutico , Quinidina/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Fibrilación Atrial/fisiopatología , Evaluación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
The effect of the combination of two drugs, i.e. lidoflazine (a calcium antagonist), and deferoxamine (an iron chelator) was evaluated following 15 min global brain ischaemia (GBI) and reperfusion in dogs in a randomized blind study. GBI was produced by complete cardiac arrest of 15 min duration. Histopathological analysis performed on in situ fixed brains 40 h post-resuscitation revealed diffuse microhaemorrhages in the control group. These were noted rarely in the treatment group, the mean value of foci of microhaemorrhages/20 low power fields (LPF) being 5.2 in the treatment group versus 28 in the control group (p less than 0.001). Diffuse coagulative necrosis of neurons (ischaemic cell change) in the cerebral cortex, especially lamina 3, hippocampus, striatum, brain stem and cerebellum was present in all cases. Quantitation of the degree of cellular damage obtained by counting the number of anoxic neurons (in consistent regions of the brain) with the use of an image analysis system, revealed no significant difference between the 2 groups. The mean percentages of the ischaemic neurons in the control group in the various areas studied were: parietal cortex, 22.25; hippocampus, 50.37 and cerebellum (Purkinje cells), 66.75; and in the treatment group 25.3, 55.04 and 70.6 respectively. Thus, the lidoflazine-deferoxamine regimen significantly reduced the incidence of microhaemorrhages in the brain, but it did not have any protective effect against anoxic neuronal injury 40 h post-ischaemia in this experimental model of GBI of 15 min duration.
Asunto(s)
Bloqueadores de los Canales de Calcio/uso terapéutico , Deferoxamina/uso terapéutico , Hierro/metabolismo , Ataque Isquémico Transitorio/tratamiento farmacológico , Lidoflazina/uso terapéutico , Piperazinas/uso terapéutico , Animales , Perros , Quimioterapia Combinada , Ataque Isquémico Transitorio/metabolismo , Ataque Isquémico Transitorio/patologíaRESUMEN
To determine the efficacy of calcium channel blockers in preserving neurologic function after central nervous system ischemia, we studied three such agents in two animal models. We treated rabbits after inducing ischemia in the brain with intra-arterial microspheres and in the spinal cord using a removable aortic occluding device. We found no benefit, in terms of neurologic functional outcome, from lidoflazine, nimodipine, or nicardipine. All three agents elevated regional blood flow in the spinal cord. We conclude that calcium antagonists are not likely to prove beneficial if used alone in the treatment of focal central nervous system ischemia.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Bloqueadores de los Canales de Calcio/uso terapéutico , Sistema Nervioso/efectos de los fármacos , Animales , Isquemia Encefálica/fisiopatología , Lidoflazina/uso terapéutico , Sistema Nervioso/fisiopatología , Nicardipino/uso terapéutico , Nimodipina/uso terapéutico , ConejosRESUMEN
The purpose of this study was to determine whether ketanserin protects the globally ischemic canine heart and whether such protection, if present, is independent of that provided by hypothermia or calcium channel blockade with lidoflazine. Forty mongrel dogs, anesthetized with halothane, were divided into eight groups of five and subjected to one hour of global myocardial ischemia during hypothermic (30 degrees C; groups 1 to 4) or normothermic (37 degrees C; groups 5 to 8) cardiopulmonary bypass (CPB). Dogs in groups 1 and 5 served as controls with respect to prebypass myocardial protective therapy, and received only placebo (a normal saline bolus) prior to CPB. Before bypass, dogs in groups 2 and 6 received lidoflazine, 1.25 mg/kg intravenously (IV); those in groups 3 and 7 received ketanserin, 5 mg IV bolus, followed by a continuous infusion at 33 microg/min during bypass. Animals in groups 4 and 8 were given both lidoflazine and ketanserin according to the dosing schedules above. No type of pharmacologic or mechanical cardiovascular support was provided after termination of CPB. Postbypass hemodynamic performance and survival of the unsupported animal were assumed to reflect the degree of myocardial protection during CPB. One minute after bypass, mean arterial pressure and cardiac output were decreased in all groups. Cardiac output was lower in groups 5 to 8 (normothermic CPB) than in groups 1 to 4 (hypothermic CPB). After CPB, left ventricular filling pressures were elevated in all groups kept normothermic and in group 3 (hypothermic CPB plus ketanserin). By 15 minutes after CPB, there were no survivors in groups 5, 7, and 8. Sixty percent of animals in group 6 (normothermic CPB plus lidoflazine) survived to the end of the study. Relative odds of survival were increased 110-fold by hypothermia and sevenfold by lidoflazine. Conversely, treatment with ketanserin was associated with an increased likelihood of nonsurvival. It is concluded that, at the doses studied, ketanserin does not protect the canine myocardium against ischemic injury and may exert a detrimental effect when combined with calcium channel blockade in this setting.