RESUMEN
PURPOSE: Preclinical studies have demonstrated that the adenovirus type 5 E1A gene is associated with antitumor activities by transcriptional repression of HER-2/neu and induction of apoptosis. Indeed, E1A gene therapy is known to induce regression of HER-2/neu-overexpressing breast and ovarian cancers in nude mice. Therefore, we evaluated the feasibility of intracavitary injection of E1A gene complexed with DC-Chol cationic liposome (DCC-E1A) in patients with both HER-2/neu-overexpressing and low HER-2/neu-expressing breast and ovarian cancers in a phase I clinical trial. PATIENTS AND METHODS: An E1A gene complexed with DCC-E1A cationic liposome was injected once a week into the thoracic or peritoneal cavity of 18 patients with advanced cancer of the breast (n = 6) or ovary (n = 12). RESULTS: E1A gene expression in tumor cells was detected by immunohistochemical staining and reverse transcriptase-polymerase chain reaction. This E1A gene expression was accompanied by HER-2/neu downregulation, increased apoptosis, and reduced proliferation. The most common treatment-related toxicities were fever, nausea, vomiting, and/or discomfort at the injection sites. CONCLUSION: These results argue for the feasibility of intracavitary DCC-E1A administration, provide a clear proof of preclinical concept, and warrant phase II trials to determine the antitumor activity of the E1A gene.
Asunto(s)
Proteínas E1A de Adenovirus/genética , Neoplasias de la Mama/terapia , Transferencia de Gen Horizontal , Terapia Genética , Neoplasias Ováricas/terapia , Adulto , Anciano , Apoptosis , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Colesterol/análogos & derivados , Citocinas/metabolismo , Femenino , Expresión Génica , Genes erbB-2 , Humanos , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Inyecciones , Antígeno Ki-67 , Liposomas , Persona de Mediana Edad , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Cavidad Peritoneal , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tórax , Células Tumorales CultivadasRESUMEN
PURPOSE: Indirect evidence suggests a decrease in organ perfusion as a result of nitric oxide (NO) inhibition in endotoxic shock. Cardiac and regional hemodynamic responses to N-methyl-L-arginine (L-NMA), a nonspecific inhibitor of constitutive and inducible nitric oxide synthase (NOS), were assessed in nine conscious dogs subjected to endotoxin. MATERIALS AND METHODS: Lipopolysaccharide (LPS) was titrated to a maximum of 200 microg/kg, IV, over 45 minutes. L-NMA was given in a dose of 20 mg/kg, IV. Hemodynamic parameters were recorded for 6 hours following L-NMA administration. RESULTS: LPS induced significant decreases in mean arterial blood pressure (MAP), cardiac output (CO), first derivative of left ventricular pressure (dP/dt), coronary blood flow, carotid blood flow, mesenteric blood flow, renal blood flow, and a significant hepatic vasodilation. L-NMA fully reversed the effects of LPS on MAP, heart rate, dP/dt, coronary and carotid blood flow, and reversed mesenteric blood flow and hepatic blood flow at 1 and 3 hours, respectively. L-NMA partially overcame the LPS-induced decrease in renal blood flow at 30 minutes and 1 hour. Except for mesenteric and carotid circulation, L-NMA did not change regional vascular resistance. CONCLUSIONS: It is likely that constitutive NOS is implicated in immediate cardiac, carotid, mesenteric, and renal vascular changes, whereas inducible NOS accounted for delayed responses in hepatic and coronary circulation.
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Vasos Coronarios/efectos de los fármacos , Inhibidores Enzimáticos/uso terapéutico , Choque Séptico/tratamiento farmacológico , omega-N-Metilarginina/uso terapéutico , Animales , Modelos Animales de Enfermedad , Perros , Inhibidores Enzimáticos/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Flujo Sanguíneo Regional/efectos de los fármacos , Choque Séptico/enzimología , Choque Séptico/fisiopatología , Resistencia Vascular/efectos de los fármacos , omega-N-Metilarginina/farmacologíaRESUMEN
PURPOSE: The clinical utility of high-dose intravenous recombinant interleukin (IL)-2 therapy is limited by severe toxicity including hypotension, fever, chills, pulmonary edema, and oliguria Hypotension has been previously shown to result from excessive vascular relaxation due to overproduction of the endogenous vasodilator nitric oxide. Nitric oxide production can be decreased by administration of the competitive enzyme inhibitor NG-monomethyl-L-arginine (NMA). A clinical trial to investigate the dose-dependent effects of NMA on blood pressure was undertaken in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: Patients with metastatic renal cell carcinoma receiving a 5-day continuous infusion of IL-2 (18 million IU/m2/d) who developed hypotension were treated with increasing doses of NMA, ranging from 3 to 36 mg/kg. RESULTS: Twenty-three patients received a total of 61 courses of IL-2; 18 of these patients developed hypotension and received NMA. Antihypotensive activity was observed at all dose levels, and the duration of the effect varied directly with the dose of NMA. At the higher dose levels tested (12 to 36 mg/kg), increased pulmonary vascular resistance and decreased cardiac output were observed. Patients experiencing a significant decrease in cardiac output received dobutamine (2.5 to 10 microg/kg/min). Pulmonary capillary wedge pressure was unaffected by administration of NMA. One patient treated at 24 mg/kg (bolus) experienced a major motor seizure, but no neurologic disorders were observed in other patients treated with NMA doses of 24 to 36 mg/kg. No other adverse events involving hepatic, renal, or hematologic systems were attributed to NMA. Three patients received NMA by an initial bolus followed by a continuous infusion. Similar antihypotensive effects were noted, and these patients were able to complete a full 5-day course of IL-2. CONCLUSION: The antihypotensive effects of NMA appear to be optimal at a dose of 24 mg/kg, with maintenance doses of 8 mg/kg every 4 to 6 hours. At this dose level, blood pressure was restored, and IL-2-associated vasodilatation was fully reversed. Coincident with the reversal of hypotension, the state of high cardiac output was also reversed by NMA administration. These results suggest that NMA may be effective for alleviating the hypotensive effects of high-dose IL-2 therapy in cancer patients.
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Carcinoma de Células Renales/terapia , Hipotensión/prevención & control , Interleucina-2/efectos adversos , Neoplasias Renales/terapia , omega-N-Metilarginina/uso terapéutico , Adulto , Relación Dosis-Respuesta a Droga , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Células Asesinas Activadas por Linfocinas/inmunología , Masculino , Persona de Mediana Edad , Nitratos/metabolismo , omega-N-Metilarginina/efectos adversos , omega-N-Metilarginina/farmacocinéticaAsunto(s)
Arginina/farmacología , Óxido Nítrico/biosíntesis , Choque Séptico/metabolismo , Animales , Bacteriemia/metabolismo , Bacteriemia/fisiopatología , Modelos Animales de Enfermedad , Endotelio Vascular/metabolismo , Humanos , Neuronas/metabolismo , Óxido Nítrico Sintasa/efectos de los fármacos , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo II , Ovinos , Choque Séptico/fisiopatología , Regulación hacia Arriba , Vasodilatación/efectos de los fármacosRESUMEN
Nitric oxide is an uncharged free radical that mediates a range of physiologic processes in the vasculature. As a principal determinant of vascular tone, the overproduction of nitric oxide has been implicated in the pathogenesis of sepsis- and cytokine-induced hypotension. The enzyme that produces nitric oxide, nitric oxide synthase, exists in three isoforms. One of the three isoforms, inducible nitric oxide synthase, is expressed in many cell types only after stimulation by cytokines and/or endotoxin. Compared to the constitutive nitric oxide synthase enzymes, the inducible enzyme generates larger quantities of nitric oxide for longer periods. Expression of the inducible isoform in vitro requires stimulation by a mixture of cytokines including interferon-gamma, tumor necrosis factor-alpha, and interleukin-1 beta. These proinflammatory cytokines are known mediators of sepsis and are also produced in the serum of cancer patients during interleukin-2 therapy, thereby leading to excessive production of nitric oxide. Interleukin-2 therapy is associated with a spectrum of cardiovascular toxicities and hemodynamic alterations that are indistinguishable from those seen in septic shock. Many of these hemodynamic effects have been linked to the overproduction of nitric oxide via a cytokine-inducible nitric oxide pathway. In this regard, inhibition of nitric oxide synthesis represents a novel approach to limit the cardiovascular toxicity associated with interleukin-2 therapy and to improve its therapeutic index. Clinical trials to evaluate the efficacy of nitric oxide synthase inhibitors in reversing the hypotension associated with IL-2 therapy are now underway.
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Hipotensión/inducido químicamente , Óxido Nítrico/fisiología , Animales , Inducción Enzimática , Humanos , Óxido Nítrico Sintasa/biosíntesis , Óxido Nítrico Sintasa de Tipo IIRESUMEN
Extreme arterial vasoconstriction (vasospasm) is a common problem encountered in microvascular surgery. An ideal pharmacologic tool able to counteract ischemia during microsurgery should be easy to apply and exert its action both locally and distally in the microcirculation of the flap. We have compared in vitro and in vivo vascular properties of nicardipine, papaverine, and lidocaine in the rabbit carotid artery. In vitro, rings from the rabbit carotid artery (n = 7) were bathed in Krebs-Ringers solution and stretched progressively to an optimal tension of 3.7 to 4.2 g. The specimens were contracted with norepinephrine (1 microM), and a cumulative dose response curve was established. In vivo, microvascular anastomoses were performed bilaterally in the rabbit carotid artery in 35 animals using 9-0 nylon suture and standard microsurgical techniques. During and after the anastomoses, nicardipine (0.1, 0.01 mg topical, or 0.1 mg/hour IV), papaverine (30 mg/cc topical), and lidocaine (2% with and without epinephrine) were applied (blinded) at the anastomotic site in five rabbits each. Heparinized sodium chloride was used as topical irrigation for control and to clean the anastomosis. Blood flow changes were monitored continuously with the transonic Doppler for 30 minutes after the procedure. The systemic blood pressure was also monitored in a group of pilot experiments. A documented decrease in blood flow was noted in all animals after the microvascular anastomosis. Nicardipine and papaverine evoked a concentration-dependent relaxation to precontracted rings to norepinephrine. Nicardipine was greater than papaverine in inducing relaxation. Lidocaine demonstrated a biphasic response with low concentrations potentiating contraction. Systemic nicardipine and papaverine significantly increased the blood flow in the rabbit carotid artery. Topical application of nicardipine and lidocaine did not significantly alter the blood flow; however, the application of nicardipine demonstrates a trend toward increased flow. Lidocaine with epinephrine significantly decreased the blood flow. No drug was found to alter the blood pressure of the animals. Our results demonstrate that nicardipine and papaverine seem to be pharmacologic tools able to increase the blood flow in anastomotic arteries. In contrast, the use of 2% lidocaine as a spasmolytic agent should be re-evaluated, since this substance may act as a partial agonist.
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Arterias Carótidas/efectos de los fármacos , Lidocaína/farmacología , Nicardipino/farmacología , Papaverina/farmacología , Vasodilatadores/farmacología , Administración Tópica , Anastomosis Quirúrgica , Animales , Presión Sanguínea/efectos de los fármacos , Arterias Carótidas/cirugía , Relación Dosis-Respuesta a Droga , Estudios de Seguimiento , Isquemia/tratamiento farmacológico , Soluciones Isotónicas , Lidocaína/administración & dosificación , Lidocaína/agonistas , Lidocaína/uso terapéutico , Microcirculación/efectos de los fármacos , Microcirugia , Monitoreo Fisiológico , Nicardipino/administración & dosificación , Nicardipino/uso terapéutico , Norepinefrina/farmacología , Papaverina/administración & dosificación , Papaverina/uso terapéutico , Conejos , Flujo Sanguíneo Regional/efectos de los fármacos , Método Simple Ciego , Colgajos Quirúrgicos/irrigación sanguínea , Ultrasonografía Doppler , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/farmacología , Vasodilatadores/administración & dosificación , Vasodilatadores/uso terapéuticoRESUMEN
Shock can be defined as the failure of the circulatory system to provide necessary cellular nutrients, including oxygen, and to remove metabolic wastes. Although it is now recognized that more than 100 different forms of shock exist, this recognition is more a reflection of the widespread use of the term to describe a variety of disease states. For the purpose of this monograph, we concentrate on various forms of cardiovascular shock, in particular, shock that may be linked to inappropriate vasodilation from overproduction of the endogenous vasodilator, nitric oxide. Some forms of shock have been extensively studied, and convincing evidence exists for the role of nitric oxide. Other disease states have been less well characterized in terms of their association with excess nitric oxide production. Available evidence of a role for nitric oxide is discussed in the hope of stimulating the interest of investigators to explore these areas more thoroughly.
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Óxido Nítrico/biosíntesis , Choque Cardiogénico/metabolismo , Vasodilatación/fisiología , Anafilaxia/fisiopatología , Animales , GMP Cíclico/metabolismo , Citocinas/metabolismo , Depresión Química , Endotelio/metabolismo , Inhibidores Enzimáticos/metabolismo , Corazón/fisiopatología , Humanos , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Óxido Nítrico/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Consumo de Oxígeno , Choque Cardiogénico/fisiopatología , Choque Cardiogénico/terapia , Choque Séptico/fisiopatología , Toxinas Biológicas/metabolismoRESUMEN
Septic shock is a physiological derangement of the cardiovascular system characterized by pathological vasodilation. Recent studies have established a role for nitric oxide, previously known as endothelium-derived relaxing factor, in the vascular dysfunction of sepsis. This finding suggests that inhibition of nitric oxide synthase (NOS), the enzyme responsible for nitric oxide production, could be a target for therapeutic intervention. Animal studies have provided conflicting results, demonstrating both beneficial and detrimental effects. We provide here an overview of the preclinical studies of NOS inhibitors and an update of the clinical studies. The low toxicity and marked antihypotensive activity of NOS inhibitors in humans highlight some of the drawbacks of certain animal models and provide important insights into the experimental study of septic shock.
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Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Óxido Nítrico Sintasa/antagonistas & inhibidores , Choque Séptico/tratamiento farmacológico , Animales , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Perros , Quimioterapia Combinada , Depuradores de Radicales Libres/farmacología , Depuradores de Radicales Libres/uso terapéutico , Humanos , Ratones , NG-Nitroarginina Metil Éster/farmacología , NG-Nitroarginina Metil Éster/uso terapéutico , Óxido Nítrico/metabolismo , Conejos , Ratas , Roedores , Choque Séptico/metabolismoRESUMEN
1. Incubation of rato aortic rings with tetrahydrobiopterin synthesis inhibitors (NAS or DAHP) significantly decreased contractions to phenylephrine. These two compounds significantly potentiated the vascular hyporeactivity induced by endotoxin. Inhibitors of nitric oxide synthesis (NLA or MLA) restored the contractile responses to this alpha 1-agonist in NAS- or DAHP-treated control rings and abolished the NAS- or DAHP-induced increased hyporeactivity to PE in endotoxin-treated aortic rings. These observations suggest that treatment of isolated blood vessels with BH4 synthesis inhibitors induces the production of NO.synthesis, resulting in turn in a vascular hyporeactivity to PE potentiated in endotoxin-treated preparations.
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Oxidorreductasas de Alcohol/antagonistas & inhibidores , Aorta/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , GTP Ciclohidrolasa/antagonistas & inhibidores , Hipoxantinas/farmacología , Músculo Liso Vascular/efectos de los fármacos , Óxido Nítrico/biosíntesis , Serotonina/análogos & derivados , Agonistas alfa-Adrenérgicos/farmacología , Animales , Aorta/enzimología , Relación Dosis-Respuesta a Droga , Técnicas In Vitro , Lipopolisacáridos , Masculino , Músculo Liso Vascular/enzimología , Fenilefrina/farmacología , Ratas , Ratas Wistar , Serotonina/farmacología , VasoconstricciónRESUMEN
We have examined whether specific protein tyrosine kinase (PTK) inhibitors (genistein, tyrphostin, or geldanamycin) prevent nitric oxide (NO.) production in rat smooth muscle cells (SMC), in murine brain endothelial cells (MBE), and in isolated rat aortas treated with endotoxin (LPS) and/or cytokines. Tyrphostin failed to inhibit either the release of nitrite in both endothelial and smooth muscle cells or vascular hyporeactivity in rat aorta, caused by immunostimulants. Genistein decreased nitrite production in MBE only at high concentration but had no effect on nitrite production in SMC and on the hypocontractility in aortic rings. In contrast, low concentrations of geldanamycin abolished the release of nitrite in MBE and in SMC treated with endotoxin and/or cytokines. Geldanamycin inhibited also the hypocontractility to phenylephrine in aortic rings treated with LPS or interleukin-1. This inhibitor failed to inhibit the release of nitrite and the vascular hyporeactivity once nitric oxide synthase (NOS) was induced by immunostimulants whereas methyl-L-arginine, an inhibitor of NOS, had significant effects. These data suggest that LPS- and cytokines-induced NO. production initiate a common signaling pathway involving a PTK that is inhibited by geldanamycin but not or slightly by tyrphostin or genistein at a point that precedes the induction of NOS.
Asunto(s)
Aorta/enzimología , Músculo Liso/enzimología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Quinonas/farmacología , Animales , Aorta/efectos de los fármacos , Benzoquinonas , Encéfalo/citología , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Células Cultivadas , Citocinas/farmacología , Endotelio/efectos de los fármacos , Endotelio/enzimología , Endotelio/metabolismo , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/enzimología , Inhibidores Enzimáticos/farmacología , Genisteína , Interleucina-1/farmacología , Isoflavonas/farmacología , Lactamas Macrocíclicas , Lipopolisacáridos/farmacología , Masculino , Ratones , Músculo Liso/citología , Músculo Liso/efectos de los fármacos , Nitritos/metabolismo , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Ratas , Ratas Wistar , Resistencia Vascular/efectos de los fármacosRESUMEN
It is now just 10 years since it was first appreciated that NO is endogenously synthesized in mammals. In this period, two constitutive and one inducible isoform of NOS have been isolated, sequenced, and characterized with respect to their protein chemistry and catalytic mechanism. A wide variety of NOS inhibitors, most targeted to the arginine binding site in the oxygenase domain, have been synthesized and used to elucidate the physiological and pathophysiological roles of NO. It is now clear that NO is involved in signal transduction (e.g., in neurotransmission and blood pressure homeostasis), and that these roles are mediated by low concentrations of NO synthesized by nNOS or eNOS. The NO receptor is the heme cofactor of soluble isoform of guanylyl cyclase. Higher amounts of NO, typically but not always synthesized by iNOS, are often cytotoxic. At a minimum, high concentrations of NO derange the signal transduction pathways normally served by nNOS or eNOS. In addition, NO or its nitrosative products (RSNO, N2O3, or ONOO-) inhibit or damage cellular constituents, interfering with DNA synthesis, energy metabolism, and the structural integrity of the cell. Such cytotoxicity can be beneficial to the host if pathogens or tumor cells are destroyed, but is detrimental to the host if it results in inappropriate inflammation, hypotension, or immunosuppression. Therapeutic utility of NOS inhibitors has been demonstrated in sepsis and cytokine-induced hypotension; additional applications are being identified in a treatment of inflammatory and autoimmune disorders.
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Diseño de Fármacos , Inhibidores Enzimáticos/uso terapéutico , Hipotensión/tratamiento farmacológico , Inmunoterapia/efectos adversos , Interleucina-2/uso terapéutico , Neoplasias/terapia , Óxido Nítrico Sintasa/antagonistas & inhibidores , Animales , Arginina/análogos & derivados , Arginina/metabolismo , Arginina/farmacología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Perros , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Hipotensión/etiología , Interleucina-2/farmacología , Neoplasias/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/metabolismo , omega-N-Metilarginina/farmacologíaRESUMEN
This meeting showed how the surge of research in the field of NO biology has led to novel therapeutic approaches in multiple clinical disciplines. Some approaches have already advanced towards clinical applications. Continued research efforts will undoubtedly lead to new applications.
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Óxido Nítrico/metabolismo , Animales , Arteriosclerosis/tratamiento farmacológico , Arteriosclerosis/fisiopatología , Ensayos Clínicos Fase I como Asunto , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Inflamación/fisiopatología , Óxido Nítrico/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Choque Séptico/tratamiento farmacológico , Choque Séptico/fisiopatología , omega-N-Metilarginina/farmacología , omega-N-Metilarginina/uso terapéuticoRESUMEN
BACKGROUND: In vitro, halothane appears to affect the role played by nitric oxide in the regulation of vascular tone and cardiac function. In vivo, the results of the interactions between halothane and the nitric oxide pathway remain controversial. The authors investigated the effects of halothane on the cardiac and regional hemodynamic properties of N-methyl-L-arginine (NMA), a specific nitric oxide synthase inhibitor, in dogs. METHODS: Twenty-five dogs were chronically instrumented. Aortic pressure, the first derivative of left ventricular pressure, cardiac output, heart rate, and carotid, coronary, mesenteric, hepatic, portal and renal blood flows were continuously recorded. N-methyl-L-arginine was infused intravenously at 20 mg/kg over 1 min in awake dogs (n = 11) and in 1.2% halothane-anesthetized dogs (n = 10). As a control group, the remaining four dogs were studied awake and during 1.2% halothane for 2 h in the absence of NMA. RESULTS: In awake dogs, NMA produced a sustained pressor response (34%) and systemic vasoconstriction (40%) associated with a decrease in cardiac output (16%). Regional circulation changes included an immediate and transient increase in carotid (43%) and coronary (237%) blood flows and a subsequent decrease in carotid blood flow (25%). Hepatic and mesenteric blood flows also decreased, by 43% and 16%, respectively. Except for the coronary circulation, regional vascular resistance increased significantly. Halothane did not affect the pressor response to NMA but did blunt the cardiac output changes. Consequently, the systemic vasoconstriction after nitric oxide synthase inhibition was of shorter duration and of lesser magnitude during halothane anesthesia. Halothane also blunted the carotid, mesenteric, and renal vasoconstriction induced by NMA. Finally, in 1.2% halothane-anesthetized dogs, NMA induced a coronary vasoconstriction. CONCLUSIONS: Halothane minimally interferes with the systemic and regional hemodynamic consequences of nitric oxide synthase blockade. The nature and magnitude of the interaction depend on the territory in which they occur.
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Anestésicos por Inhalación/farmacología , Arginina/análogos & derivados , Inhibidores Enzimáticos/farmacología , Halotano/farmacología , Hemodinámica/efectos de los fármacos , Óxido Nítrico Sintasa/antagonistas & inhibidores , Animales , Arginina/farmacología , Perros , Femenino , Masculino , Óxido Nítrico Sintasa/metabolismo , omega-N-MetilargininaAsunto(s)
Infecciones por Bacterias Gramnegativas/inmunología , Óxido Nítrico Sintasa/genética , Óxido Nítrico/inmunología , Choque Séptico/inmunología , Animales , Humanos , Hipotensión/microbiología , Lipopolisacáridos/toxicidad , Ratones , Ratones Noqueados , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/inmunologíaAsunto(s)
Aminoácidos/farmacología , Arginina/análogos & derivados , Arginina/farmacología , Inhibidores Enzimáticos/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Aminoácidos/toxicidad , Animales , Arginina/toxicidad , Citrulina/análogos & derivados , Citrulina/farmacología , Citrulina/toxicidad , Inhibidores Enzimáticos/toxicidad , Isoenzimas/antagonistas & inhibidores , Cinética , Macrófagos/efectos de los fármacos , NG-Nitroarginina Metil Éster/farmacología , NG-Nitroarginina Metil Éster/toxicidad , Nitroarginina/farmacología , Nitroarginina/toxicidad , Roedores , Relación Estructura-Actividad , Tiourea/análogos & derivados , Tiourea/farmacología , Tiourea/toxicidad , omega-N-Metilarginina/farmacología , omega-N-Metilarginina/toxicidadRESUMEN
We studied the action of nitric oxide synthase (NOS) inhibition on changes in regional blood flow during a continuous infusion of live bacteria. Eighteen ewes were chronically instrumented. After a 7-day recovery period, an infusion of 10(6) colony-forming units/min Pseudomonas aeruginosa was begun. At 24 h, cardiac output increased significantly above baseline in all groups (5.9 +/- 0.4 vs. 8.2 +/- 0.6 l.min 1.m-2), systemic vascular resistance decreased (1,362 +/- 120 vs. 821 +/- 145 dyn.g.cm-5.m-2), and cerebral, cephalic mesenteric, and hindlimb blood flows increased. The animals were then equally and randomly assigned to a bolus of a NOS inhibitor, either 25 mg/kg N omega-nitro-L-arginine methyl ester (L-NAME) or 20 mg/kg N omega-monomethyl-L-arginine (L-NMMA), followed by a continuous infusion of 7 mg.kg-1.min-1 L-NMMA or saline. After NOS inhibition, cardiac index decreased [5.6 +/- 0.1 (L-NAME) and 5.5 +/- 0.4 l.min-1.m-2 (L-NMMA)] and remained significantly decreased for 12 h. 1-NAME decreased carotid and mesenteric blood flows to 64% of the preseptic baseline, and they remained below baseline for 20 h. L-NMMA decreased blood flows only to preseptic baseline values. NOS inhibitors may affect blood flows independently of their hemodynamic effects.
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Bacteriemia/fisiopatología , Circulación Sanguínea , Óxido Nítrico/antagonistas & inhibidores , Animales , Circulación Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Femenino , Hemodinámica/efectos de los fármacos , NG-Nitroarginina Metil Éster/farmacología , Infecciones por Pseudomonas/fisiopatología , Flujo Sanguíneo Regional/efectos de los fármacos , Ovinos , Resistencia Vascular/efectos de los fármacos , omega-N-Metilarginina/farmacologíaRESUMEN
PURPOSE: Hematopoietic growth factors have been shown to ameliorate the side effects of chemotherapy. Here we assess the ability of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to increase the dose-intensity and reduce the side effects of escalated methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy. PATIENTS AND METHODS: A prospective randomized trial to compare escalated MVAC versus escalated MVAC with rhGM-CSF was conducted. All patients were treated at The University of Texas M.D. Anderson Cancer Center (UTMDACC) and had a metastatic or unresectable urothelial tumor. Forty-eight patients were randomized (25 to MVAC with rhGM-CSF and 23 to escalated MVAC alone). The clinical characteristics of the study populations were similar (ie, degree of tumor dissemination and performance status). RESULTS: The dose-intensity in the two arms of the study did not differ significantly. No difference in the frequency of bacteriologically documented infections occurred between the two study arms. CONCLUSION: The use of the hematopoietic growth factor rhGM-CSF did not result in an increased dose-intensity of escalated MVAC. The inability to increase the dose-intensity of MVAC further was a result of nonhematologic side effects of the chemotherapy. Escalation of treatment delivered at its median-tolerated dose is unlikely to result in additional therapeutic benefit for patients with common solid tumors. Future development of therapy may require the development of new agents or concepts, rather than modification of existing therapies.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Neoplasias Urológicas/tratamiento farmacológico , Adulto , Anciano , Agranulocitosis/inducido químicamente , Agranulocitosis/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Infecciones Bacterianas/prevención & control , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Estudios de Factibilidad , Femenino , Fiebre/prevención & control , Humanos , Masculino , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Estudios Prospectivos , Proteínas Recombinantes/uso terapéutico , Tasa de Supervivencia , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias Urológicas/mortalidad , Vinblastina/administración & dosificación , Vinblastina/efectos adversosRESUMEN
1. New potent inhibitors of nitric oxide synthase (NOS) may be useful in the treatment of septic shock, a disorder characterized by a vascular hyporeactivity to catecholamines caused by an overproduction of nitric oxide (NO-). We examined the effects of L-thiocitrulline (L-TC) and S-methyl-L-thiocitrulline (L-SMTC), novel NOS inhibitors, on the constitutive and inducible NOS in rat aorta and compared those effects with inhibition due to NG-methyl-L-arginine (L-NMA). 2. Phenylephrine evoked similar concentration-contraction curves in the control rings and in the rings treated with these different NOS inhibitors (10 microM), whereas 100 microM of L-NMA, L-TC or L-SMTC increased significantly, and to a similar extent, contractions evoked by phenylephrine in aortic rings with endothelium without significantly affecting the maximal responses. 3. Relaxations evoked by acetylcholine, adenosine triphosphate, or calcium ionophore were significantly inhibited in a dose-dependent manner by L-NMA, L-SMTC, or L-TC (10-100 microM). The potencies of these inhibitors in reducing the relaxations of these vasodilators were not significantly different. 4. In endotoxin-treated preparations with endothelium, the three L-arginine analogues (10 microM) significantly potentiated contractile responses to phenylephrine (pEC50: 6.73 +/- 0.12 and 7.3 +/- 0.12, 7.34 +/- 0.13, or 7.22 +/- 0.14; in the absence and the presence of L-NMA, L-TC, or L-SMTC respectively) and increased maximal contractions from 1.53 +/- 0.15 g to 1.95 +/- 0.13 g, 2.08 +/- 0.12 g, and 2.03 +/- 0.13 g with L-NMA, L-TC, and L-SMTC respectively. A higher concentration of these NOS inhibitors (100 microM)further increased contractions evoked by this alpha1-agonist without further enhancing the maximal contractions; however, contractions evoked by 10 nM phenylephrine were significantly greater in the presence of L-SMTC or L-TC than in the presence of L-NMA (100 microM) (L-NMA: 0.4 +/- 0.11 g; L-TC:0.78 +/- 0.14 g and L-SMTC: 0.82+/-0.17 g). The effects of these inhibitors on NO- synthesis induced by endotoxin were significantly reversed by addition of L-arginine (1 mM) but not by L-citrulline (1 mM). InLPS-treated rings with endothelium, all three NOS inhibitors (100 microM) shifted the concentration contraction curves evoked by phenylephrine significantly to the left (pEC5o: 7.19 +/- 0.03 and 7.79 +/- 0.08,8.01 +/- 0.07, or 8.02 +_ 0.07, in the absence and the presence of L-NMA, L-TC, or L-SMTC, respectively)and increased significantly maximal contractions from 2.05 +/- 0.05 g to 2.38 +/- 0.14 g, 2.5 +/- 0.12 g, and 2.4 +_ 0.21 g with L-NMA, L-TC, and L-SMTC, respectively. L-TC and L-SMTC were significantly more potent than L-NMA in potentiating contractions evoked by 10 nM and 30 nM phenylephrine.5. L-TC and L-SMTC produced dose-dependent increases in tone in LPS-treated aortic rings with and without endothelium. In LPS-treated rings with endothelium, L-NMA induced contractions but in preparations without endothelium low concentrations of L-NMA induced small contractions while high concentrations of this inhibitor evoked relaxations. In both preparations L-TC and L-SMTC were significantly more potent than L-NMA in increasing vascular tone.6. These results suggest that L-SMTC, L-TC and L-NMA were equipotent on basal and agonist stimulated NO- synthesis produced by the constitutive isoform of NOS, whereas the two new L-arginine analogues were more potent than L-NMA in inhibiting the production of NO- induced by endotoxin in rat aorta.
Asunto(s)
Aorta Torácica/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Músculo Liso Vascular/efectos de los fármacos , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico/antagonistas & inhibidores , Acetilcolina/farmacología , Adenosina Difosfato/farmacología , Análisis de Varianza , Animales , Aorta Torácica/enzimología , Arginina/análogos & derivados , Arginina/farmacología , Calcimicina/farmacología , Citrulina/análogos & derivados , Citrulina/farmacología , Relación Dosis-Respuesta a Droga , Inducción Enzimática/efectos de los fármacos , Ionóforos/farmacología , Masculino , Contracción Muscular/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Óxido Nítrico Sintasa/antagonistas & inhibidores , Fenilefrina/farmacología , Ratas , Ratas Wistar , Tiourea/análogos & derivados , Tiourea/farmacología , Vasoconstrictores/farmacología , omega-N-MetilargininaRESUMEN
OBJECTIVE: To evaluate the role of NG-methyl-L-arginine as a modulator of the hyperdynamic shock induced by the administration of interleukin-2 (IL-2). DESIGN: A prospective, pilot clinical study. SETTING: Intensive care unit of a tertiary care center. PATIENTS: Three sequential patients with metastatic renal cell carcinoma who developed hypotension during their first course of treatment with high-dose IL-2 (18 x 10(6) IU/m2/day by continuous infusion for 5 days). INTERVENTIONS: Upon developing hypotension during their subsequent therapy with IL-2, patients were administered 12 mg/kg of NG-methyl-L-arginine. Thereafter, a dose of 4 mg/kg was given every 4 hrs, as needed, to maintain the systolic blood pressure above 100 mm Hg. MEASUREMENTS AND MAIN RESULTS: Invasive hemodynamic monitoring was instituted before the initiation of treatment with IL-2. Differences noted before, and 15 mins after, the administration of NG-methyl-L-arginine were analyzed using the paired t-test. NG-methyl-L-arginine (12 mg/kg) induced a significant antihypotensive effect (mean blood pressure increased from 87 +/- 4 to 121 +/- 7 mm Hg), accompanied by an increase of the systemic vascular resistance (549 +/- 51 to 860 +/- 167 dyne.sec/cm5) and pulmonary vascular resistance (81 +/- 16 to 117 +/- 29 dyne.sec/cm5). A decrease in the cardiac index was also documented (4.5 +/- 0.5 to 3.6 +/- 0.3 L/min/m2). No significant changes in pulmonary artery occlusion and central venous pressures were observed. Maintenance doses of 4 mg/kg of NG-methyl-L-arginine induced similar hemodynamic results, although the duration of the antihypotensive effect of NG-methyl-L-arginine decreased with sequential doses. CONCLUSIONS: The hemodynamic effects induced by IL-2 administration are reversed by NG-methyl-L-arginine, a nitric oxide synthesis inhibitor. These results provide evidence for the biological activity of NG-methyl-L-arginine when administered alone to hypotensive patients. While no adverse effects were observed in this preliminary study, issues of toxicity and effectiveness need to be defined further in formal clinical trials. NG-methyl-L-arginine may play a therapeutic role in the modulation of the extreme vasodilation induced by cytokine administration or in septic shock.