RESUMEN
BACKGROUND: Dulanermin (rhApo2L/TRAIL) induces apoptosis by binding to death receptors DR4 and DR5, leading to caspase activation and subsequent cell death. A Phase1a trial evaluated the safety and tolerability of dulanermin in patients with advanced tumours. One aim was to develop and validate pharmacodynamic biomarkers to monitor dulanermin activity in patient serum. METHODS: We optimised assays to measure the cell-death markers caspase 3/7, cytokeratin 18 and genomic DNA in serum. Mice bearing Colo205 xenografts were treated with dulanermin and sera were collected and assayed for apoptotic markers. Upon validating these assays, we monitored apoptotic markers in patients who received dulanermin. RESULTS: We detected transient increases in apoptotic markers in mouse sera 8-24 h after dulanermin treatment. This increase was dose-dependent and correlated with active caspase 3 detected by IHC in Colo205 tumours. A statistically significant increase in serum caspase 3/7 was detected in cohorts of colorectal and sarcoma patients 24 h after receiving dulanermin dosed above 4 mg kg(-1). CONCLUSION: Owing to limited responses in the Phase 1a study, the changes in circulating cell-death markers were not evaluable. Future studies with dulanermin are needed to determine the utility of these assays with respect to providing evidence of activity or predicting overall response.
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Biomarcadores de Tumor/sangre , Neoplasias/tratamiento farmacológico , Ligando Inductor de Apoptosis Relacionado con TNF/uso terapéutico , Animales , Apoptosis , Secuencia de Bases , Cartilla de ADN , Humanos , Inmunohistoquímica , Ratones , Neoplasias/metabolismo , Neoplasias/patología , Proteínas Recombinantes/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The pivotal phase II and III Herceptin trials proved the efficacy and safety of second- or third-line single-agent Herceptin and first-line Herceptin in combination with chemotherapy, respectively. In the current trial, 114 patients were randomized to one of two dose groups of first-line Herceptin monotherapy: standard dose of 4 mg/ kg initial dose followed by 2 mg/kg intravenous (i.v.) weekly; or high dose of 8 mg/kg initial dose followed by 4 mg/kg i.v. weekly. The regimen was generally well tolerated. A similar incidence of adverse events was demonstrated in the two dose groups with the possible exception of acute infusion-related events such as fever and chills as well as rash and dyspnea, which appear to be more prevalent in the higher dose group. The overall response rate was 26% and response rates were similar between the two dose groups (24% for the standard Herceptin dose group and 28% for the high Herceptin dose group). Subgroup analysis determined a higher response rate in IHC 3+ patients (35%) and FISH-positive patients (41%). When women with stable disease for > or =6 months were included with responders, the clinical benefit rate in IHC 3+ patients was 47%. Median survival was 24.4 months, which is comparable with the survival rate seen in the pivotal phase III combination trial (25 months). Therefore, single-agent Herceptin is an important new option for the first-line treatment of HER2-positive metastatic breast cancer patients.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/química , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Terapia Combinada , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Fiebre/inducido químicamente , Cardiopatías/inducido químicamente , Humanos , Metástasis de la Neoplasia , Proteínas de Neoplasias/análisis , Dolor/virología , Cuidados Paliativos , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptor ErbB-2/análisis , Receptores de Estrógenos/análisis , Seguridad , Terapia Recuperativa , Análisis de Supervivencia , Trastuzumab , Resultado del TratamientoRESUMEN
Following confirmation of the appropriate dosage, safety and potential efficacy of Herceptin(R) (trastuzumab) in small-scale phase I and II trials involving patients with refractory disease, a large trial was conducted in 222 patients with breast cancer who had relapsed after one or two chemotherapy regimens for their metastatic disease. The results showed a positive and durable overall response rate (15% according to a response evaluation committee (REC) assessment) using trastuzumab monotherapy (initial dose 4 mg/kg intravenously (i.v.) followed by 2 mg/kg i.v. weekly). In another recently completed phase II trial, 113 patients were randomised to two dose levels (initial dose of 4 mg/kg i.v. dose followed by 2 mg/kg i.v. weekly, or initial dose of 8 mg/kg followed by 4 mg/kg i.v. weekly) of single-agent trastuzumab as first-line therapy for metastatic disease. The preliminary overall response rate was 23% based on investigator assessment, and tolerability was excellent as in previous trials; efficacy was similar in both dose groups, but the side-effects tended to be more frequent in the higher dose group. The preferred dosage is therefore the same as that currently recommended, i.e. an initial dose of 4 mg/kg i.v. followed by 2 mg/kg weekly i.v. until disease progression.
RESUMEN
PURPOSE: Tumor angiogenesis mediated by vascular endothelial growth factor (VEGF) is inhibited by the recombinant humanized (rhu) monoclonal antibody (MAb) rhuMAbVEGF, which has synergy with chemotherapy in animal models. The present study was designed to assess the safety and pharmacokinetics of weekly intravenous (IV) rhuMAbVEGF with one of three standard chemotherapy regimens. PATIENTS AND METHODS: Twelve adult patients were enrolled four on each combination. rhuMAbVEGF, 3 mg/kg IV, was administered weekly for 8 weeks with (1) doxorubicin 50 mg/m(2) every 4 weeks; (2) carboplatin at area under the curve of 6 plus paclitaxel 175 mg/m(2) every 4 weeks; and (3) fluorouracil (5-FU) 500 mg/m(2) with leucovorin 20 mg/m(2) weekly, weeks 1 to 6 every 8 weeks. RESULTS: The median number of rhuMAbVEGF doses delivered was eight (range, four to eight doses). Grade 3 toxicities were diarrhea (one 5-FU patient), thrombocytopenia (two patients on carboplatin plus paclitaxel), and leukopenia (one patient on carboplatin plus paclitaxel). These toxicities were likely attributable to the chemotherapy component of the regimen. The mean (+/- SD) peak serum level of rhuMAbVEGF was 167 +/- 46 microg/mL, and the mean terminal half-life was 13 days. Total (free plus bound) serum VEGF levels increased from 51 +/- 39 pg/mL (day 0) to 211 +/- 112 (day 49) pg/mL. Three responding patients continued treatment with rhuMAbVEGF and chemotherapy, receiving the equivalent of 36, 20, and 40 total rhuMAbVEGF doses with no cumulative or late toxicities. CONCLUSION: rhuMAbVEGF can be safely combined with chemotherapy at doses associated with VEGF blockade and without apparent synergistic toxicity. Its contribution to the treatment of advanced solid tumors should be evaluated in randomized treatment trials.
Asunto(s)
Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Factores de Crecimiento Endotelial/inmunología , Linfocinas/inmunología , Neoplasias/terapia , Adulto , Anciano , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Terapia Combinada , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Esquema de Medicación , Interacciones Farmacológicas , Factores de Crecimiento Endotelial/antagonistas & inhibidores , Factores de Crecimiento Endotelial/sangre , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Infusiones Intravenosas , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Linfocinas/antagonistas & inhibidores , Linfocinas/sangre , Masculino , Persona de Mediana Edad , Neoplasias/irrigación sanguínea , Neoplasias/tratamiento farmacológico , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
Following confirmation of the appropriate dosage, safety and potential efficacy of Herceptin(trastuzumab) in small-scale phase I and II trials involving patients with refractory disease, a large trial was conducted in 222 patients with breast cancer who had relapsed after one or two chemotherapy regimens for their metastatic disease. The results showed a positive and durable overall response rate (15% according to a response evaluation committee (REC) assessment) using trastuzumab monotherapy (initial dose 4 mg/kg intravenously (i.v.) followed by 2 mg/kg i.v. weekly). In another recently completed phase II trial, 113 patients were randomised to two dose levels (initial dose of 4 mg/kg i.v. dose followed by 2 mg/kg i.v. weekly, or initial dose of 8 mg/kg followed by 4 mg/kg i.v. weekly) of single-agent trastuzumab as first-line therapy for metastatic disease. The preliminary overall response rate was 23% based on investigator assessment, and tolerability was excellent as in previous trials; efficacy was similar in both dose groups, but the side-effects tended to be more frequent in the higher dose group. The preferred dosage is therefore the same as that currently recommended, i.e. an initial dose of 4 mg/kg i.v. followed by 2 mg/kg weekly i.v. until disease progression.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados , Femenino , Humanos , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Trastuzumab , Resultado del TratamientoRESUMEN
Sibrafiban is a double prodrug that is converted to the inactive single prodrug and to the active GP IIb/IIIa antagonist after oral administration. This clinical investigation evaluated whether coadministration of oral aspirin or intravenous heparin would alter the pharmacokinetics or pharmacodynamics of oral sibrafiban. Twenty-four adult subjects received two of the following four combinations: sibrafiban alone, sibrafiban with ASA, sibrafiban with heparin, and sibrafiban with ASA and heparin, separated by a 2-week washout period. Concentration profiles of active drug in citrate and EDTA plasma were unchanged with coadministration of ASA or heparin. No pharmacodynamic interaction was seen with coadministration of heparin. Inhibition of platelet aggregation increased 4% to 55%, and Ivy bleeding time increased 58% to 87% with coadministration of sibrafiban and ASA. The combined pharmacodynamic effect of sibrafiban and ASA may indicate a potentially greater therapeutic effect but an increased risk of bleeding when these drugs are used in combination.
Asunto(s)
Anticoagulantes/farmacología , Aspirina/farmacología , Heparina/farmacología , Oximas/farmacocinética , Piperidinas/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacología , Profármacos/farmacocinética , Adenosina Difosfato/farmacología , Administración Oral , Adulto , Anticoagulantes/farmacocinética , Área Bajo la Curva , Aspirina/farmacocinética , Tiempo de Sangría , Estudios Cruzados , Interacciones Farmacológicas , Femenino , Heparina/farmacocinética , Humanos , Masculino , Persona de Mediana Edad , Oximas/sangre , Tiempo de Tromboplastina Parcial , Fragmentos de Péptidos/farmacología , Piperidinas/sangre , Agregación Plaquetaria/efectos de los fármacos , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Tiempo de Protrombina , Receptores de Trombina/químicaRESUMEN
BACKGROUND: Exposure to indoor fungus growth and tobacco smoke has been epidemiologically linked to unexplained pulmonary hemorrhage in infants. OBJECTIVE: To describe the 40-day-old male infant who had been exposed to fungi for a discrete 2-week period followed by acute exposure to environmental tobacco smoke prior to development of a life-threatening pulmonary hemorrhage. PATIENT AND METHODS: History and clinical evaluation of the infant immediately followed the pulmonary hemorrhage. Air and surface sampling for isolation and identification of fungal growth in the dwelling where the infant resided before the acute hemorrhage was accomplished when the homeowner returned from vacation 4 months after the clinical event. RESULTS: Two fungi associated with mycotoxin production were cultured from surface samples collected in the residence: Penicillium (possibly Penicillium purpurogenum) and a Trichoderma species. Stachybotrys atra was not isolated from air or surface samples. Environmental tobacco smoke exposure occurred over a discrete several-hour period prior to onset of the acute pulmonary hemorrhage. CONCLUSIONS: Avoidance of unnecessary exposure of infants to fungus growth in water-damaged environments or exposure to tobacco smoke is prudent. Further investigation into the toxic effects of indoor fungi as causes of infantile pulmonary hemorrhage is warranted.
Asunto(s)
Contaminación del Aire Interior/efectos adversos , Hemorragia/etiología , Enfermedades Pulmonares/etiología , Micotoxinas/efectos adversos , Penicillium , Contaminación por Humo de Tabaco/efectos adversos , Trichoderma , Humanos , Lactante , Masculino , Factores de RiesgoRESUMEN
Sibrafiban is a double prodrug that is converted to the inactive single prodrug and to the active IIb/IIIa antagonist following oral administration. Pharmacokinetics (PK) and pharmacodynamics (PD) of oral sibrafiban and its metabolites were evaluated in patients postacute coronary syndrome receiving once- or twice-daily sibrafiban for up to 28 days at several dose levels. Mean peak concentrations of sibrafiban were < 5 ng/mL. Peak single prodrug concentrations occurred 1.7 +/- 1.0 (mean +/- SD) hours after sibrafiban dosing. Total apparent plasma clearance of the single prodrug was 40 +/- 15 L/h, and the elimination half-life was 2.3 +/- 0.8 hours. Mean values of the steady-state pharmacokinetics for total concentrations of the active drug over all doses were: time to peak plasma concentration, 5.0 +/- 1.7 hours; apparent clearance, 13.9 +/- 3.9 L/h; and half-life, 11.0 +/- 2.8 hours. Once-daily dosing resulted in high peak-trough excursions in active drug concentrations: trough concentrations were 21% +/- 6% of peak. Twice-daily dosing resulted in an AUC for the active drug on Day 28 that was 168% +/- 36% of that on Day 1, and steady-state trough concentrations were 54% +/- 10% of peak with sustained inhibition of platelet aggregation. Dose-adjusted steady-state active drug concentrations increased with increasing age and with decreasing renal function and body weight.
Asunto(s)
Enfermedad Coronaria/tratamiento farmacológico , Oximas/farmacocinética , Piperidinas/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacocinética , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Profármacos/farmacocinética , Enfermedad Aguda , Administración Oral , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Amidinas/sangre , Amidinas/orina , Área Bajo la Curva , Peso Corporal , Enfermedad Coronaria/metabolismo , Método Doble Ciego , Femenino , Tasa de Filtración Glomerular , Compuestos Heterocíclicos/sangre , Compuestos Heterocíclicos/orina , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Oximas/sangre , Oximas/orina , Piperidinas/sangre , Piperidinas/orina , SíndromeRESUMEN
UNLABELLED: This study was designed to determine the magnitude and time course of platelet activation during therapy of acute coronary syndromes with an oral platelet antagonist. BACKGROUND: Platelet activation and aggregation are central to the pathogenesis of the acute coronary syndromes (ACS). However, few data are available on levels of platelet activation over time in patients with ACS, especially in the setting of chronic glycoprotein (GP) IIb/IIIa inhibition. METHODS: The Thrombolysis in Myocardial Infarction (TIMI) 12 trial was a phase II, double-blind trial evaluating the effects of sibrafiban, an oral, selective antagonist of the platelet glycoprotein IIb/IIIa receptor in patients stabilized after an ACS. A subset of 90 of the 329 patients in the study had measurement of platelet activation as assessed by the expression of platelet associated P-Selectin on days 0, 7 and 28. Platelet activation was measured in blood samples that were fixed either immediately (spontaneous activation) or after 5 minute incubation with 0, 1 microM or 5 microM ADP in order to assess platelet responsiveness to very low or moderate stimulation. RESULTS: At baseline there was a significant elevation of spontaneous platelet activation as compared to samples obtained from normal donors or from patients who did not have acute coronary syndromes (ACS patients 27.6+/-18.7%, Normal controls 8.5+/-4.4%, Patient controls 10.9+/-7.1%, p < 0.005 for both). In addition, there was a significant decrease in the levels of platelet activation with time during the 28 days of treatment with sibrafiban. Nevertheless, even on day 28, the TIMI-12 patients continued to show elevated platelet activation in comparison to the control groups (p < 0.05 for both). CONCLUSIONS: These results suggest that platelets remain activated long after clinical stabilization post ACS. Although platelet activation decreased after one month of oral GPIIb/IIIa inhibition, levels remained higher than normal, suggesting the need for long-term antiplatelet therapy following ACS.
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Angina Inestable/sangre , Infarto del Miocardio/sangre , Oximas/uso terapéutico , Piperidinas/uso terapéutico , Activación Plaquetaria/fisiología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Terapia Trombolítica , Administración Oral , Adulto , Anciano , Angina Inestable/tratamiento farmacológico , Plaquetas/metabolismo , Método Doble Ciego , Electrocardiografía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/tratamiento farmacológico , Oximas/administración & dosificación , Selectina-P/biosíntesis , Piperidinas/administración & dosificación , Activación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Resultado del TratamientoRESUMEN
OBJECTIVE: Prospective study of the efficacy of calf lung surfactant extract in pediatric respiratory failure. DESIGN: Multi-institutional, prospective, randomized, controlled, unblinded trial. SETTING: Eight pediatric intensive care units (ICU) of tertiary medical centers. PATIENTS: Forty-two children with acute hypoxemic respiratory failure characterized by diffuse, bilateral pulmonary infiltrates, need for ventilatory support, and an oxygenation index of >7. INTERVENTION: Instillation of intratracheal surfactant (80 mL/m2). MEASUREMENTS AND MAIN RESULTS: Ventilator parameters, arterial blood gases, and derived oxygenation and ventilation indices were recorded before and at intervals after surfactant administration. Complications and outcome measures, including mortality, duration of mechanical ventilation, and length of pediatric ICU and hospital stay, were also examined. Patients who received surfactant demonstrated rapid improvement in oxygenation and, on average, were extubated 4.2 days (32%) sooner and spent 5 fewer days (30%) in pediatric intensive care than control patients. There was no difference in mortality or overall hospital stay. Surfactant administration was associated with no serious adverse effects. CONCLUSIONS: Administration of calf lung surfactant extract, calfactant, appears to be safe and is associated with rapid improvement in oxygenation, earlier extubation, and decreased requirement for intensive care in children with acute hypoxemic respiratory failure. Further study is needed, however, before widespread use in pediatric respiratory failure can be recommended.
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Productos Biológicos , Cuidados Críticos , Surfactantes Pulmonares/uso terapéutico , Síndrome de Dificultad Respiratoria del Recién Nacido/tratamiento farmacológico , Insuficiencia Respiratoria/tratamiento farmacológico , Adolescente , Niño , Preescolar , Cuidados Críticos/métodos , Femenino , Humanos , Hipoxia/tratamiento farmacológico , Hipoxia/fisiopatología , Lactante , Recién Nacido , Masculino , Mid-Atlantic Region , Estudios Prospectivos , Respiración Artificial , Síndrome de Dificultad Respiratoria del Recién Nacido/fisiopatología , Insuficiencia Respiratoria/fisiopatología , Resultado del TratamientoRESUMEN
BACKGROUND: Inhibitors of the platelet glycoprotein IIb/IIIa receptor given intravenously have been shown to be effective in reducing ischemic complications after coronary angioplasty and in unstable angina, making this a promising new class of agents for the treatment and prevention of ischemic events in patients with acute coronary syndromes. Sibrafiban (Ro 48-3657) is an oral, peptidomimetic, selective antagonist of the glycoprotein IIb/IIIa receptor. METHODS AND RESULTS: The Thrombolysis in Myocardial Infarction (TIMI) 12 trial was a phase II, double-blind, dose-ranging trial designed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of sibrafiban in 329 patients after acute coronary syndromes. In the PK/PD cohort of TIMI 12, 106 patients were randomized to receive one of seven dosing regimens of sibrafiban, ranging from 5 mg daily to 10 mg twice daily for 28 days. In the safety cohort, 223 patients were randomized to one of four dose regimens of sibrafiban (ranging from 5 mg twice daily to 15 mg once daily) or aspirin for 28 days. High levels of platelet inhibition were achieved: mean peak values ranged from 47% to 97% inhibition of 20 micromol/L ADP-induced platelet aggregation on day 28 across the seven doses. Twice-daily dosing provided more sustained platelet inhibition (mean inhibition, 36% to 86% on day 28), whereas platelet inhibition returned to baseline levels by 24 hours with once-daily dosing. Major hemorrhage occurred in 1.5% of patients treated with sibrafiban and in 1.9% of patients treated with aspirin. Protocol-defined "minor" bleeding, usually mucocutaneous, occurred in 0% to 32% of patients in the various sibrafiban groups and in none of the patients treated with aspirin. Minor bleeding was related to total daily dose (P=.002), once- versus twice-daily dosing (P<.0001), renal function (P<.0001), and presentation with unstable angina (P<.01). CONCLUSIONS: The oral glycoprotein IIb/IIIa antagonist sibrafiban achieved effective, long-term platelet inhibition with a clear dose-response but at the expense of a relatively high incidence of minor bleeding. Oral IIb/IIIa inhibition deserves further study as a new treatment strategy in patients after acute coronary syndromes.
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Enfermedad Coronaria/tratamiento farmacológico , Oximas/administración & dosificación , Piperidinas/administración & dosificación , Inhibidores de Agregación Plaquetaria/administración & dosificación , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Enfermedad Aguda , Administración Oral , Anciano , Estudios de Cohortes , Enfermedad Coronaria/fisiopatología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Hemorragia/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , Oximas/efectos adversos , Oximas/uso terapéutico , Piperidinas/efectos adversos , Piperidinas/uso terapéutico , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/uso terapéutico , RecurrenciaRESUMEN
In the development of antisense therapeutics, there have been a number of hybridization-independent effects characterized for phosphorothioate oligodeoxynucleotides. One such effect is the transient prolongation of clotting times following intravenous infusion of high doses. In this study, inhibition of clotting times was characterized by determining the time course of both APTT and plasma oligonucleotide following intravenous infusion of ISIS 2302 in cynomolgus monkeys. Prolongation of APTT was also achieved by addition of ISIS 2302 to citrated blood from untreated monkeys, allowing the investigation of the mechanism of inhibition in vitro. Results from this study clearly indicate that the intrinsic pathway (APTT) was more sensitive to inhibition than the extrinsic pathway (PT). The prolongation of APTT was also shown to be transient and closely correlated with plasma oligonucleotide concentrations. The extent of APTT prolongation can be controlled by minimizing peak plasma oligonucleotide concentrations through lowering the dose or prolonging infusion duration. Direct addition of ISIS 2302 to blood produced quantitatively similar inhibition of clotting times. This effect was similar for a number of different phosphorothioate oligodeoxynucleotides, but oligonucleotides containing phosphodiester linkages and 2'-propoxy linkages were much less inhibitory. Additional in vitro studies indicated that the mechanism of inhibition was independent of that of heparin and possibly involved selective inhibition of the intrinsic pathway as well as the common clotting pathway. Investigation of selective clotting factors indicated that there was no direct inhibition of the enzymatic activity of factor Xa, XIa, or thrombin using chromogenic substrates. However, ISIS 2302 did produce a concentration-dependent increase in clotting time when fibrinogen was used as the substrate for thrombin.
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Coagulación Sanguínea/efectos de los fármacos , Oligodesoxirribonucleótidos Antisentido , Oligonucleótidos Antisentido/farmacología , Tionucleótidos/farmacología , Animales , Pruebas de Coagulación Sanguínea , Femenino , Humanos , Molécula 1 de Adhesión Intercelular/genética , Macaca fascicularis , Oligonucleótidos Fosforotioatos , ARN Mensajero/genéticaRESUMEN
Congenital hypoprothrombinemias are very rare, inherited disorders in which factor II (prothrombin) levels and/or activity are extremely low or absent. We report eight pregnancies in a patient with this disorder. Obstetric complications attributed to the coagulation disturbance included first-trimester bleeding in each pregnancy, miscarriage in four of the pregnancies, spontaneous maternal subarachnoid hemorrhage in one, and postpartum hemorrhage in one of four term pregnancies despite administration of clotting factor concentrate. The management of pregnancy in congenital hypoprothrombinemia, and issues of coagulation factor replacement, are discussed.
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Hipoprotrombinemias/congénito , Complicaciones Hematológicas del Embarazo/tratamiento farmacológico , Aborto Espontáneo/etiología , Adulto , Factores de Coagulación Sanguínea/uso terapéutico , Femenino , Humanos , Hipoprotrombinemias/tratamiento farmacológico , Tiempo de Tromboplastina Parcial , Hemorragia Posparto/etiología , Embarazo , Protrombina/análisis , Tiempo de Protrombina , Hemorragia Subaracnoidea/etiología , Hemorragia Uterina/etiologíaRESUMEN
Antiphospholipid antibodies, including anticardiolipin antibodies (ACA), are strongly associated with recurrent thrombosis in patients with the antiphospholipid syndrome (APS). To date, reports about the binding specificities of ACA and their role(s) in causing and/or sustaining thrombosis in APS are conflicting and controversial. The plasmas of patients with APS, usually containing a mixture of autoantibodies, vary in binding specificity for different phospholipids/cofactors and vary in in vitro lupus anticoagulant activity. Although in vivo assays that allow assessment of the pathogenic procoagulant activity of patient autoantibodies have recently been developed, the complex nature of the mixed species prevented determination of the particular species responsible for in vivo thrombosis. We have generated two human IgG monoclonal ACA from an APS patient with recurrent thrombosis. Both bound to cardiolipin in the presence of 10% bovine serum, but not in its absence, and both were reactive against phosphatidic acid, but were nonreactive against purified human beta-2 glycoprotein 1, DNA, heparan sulfate, or four other test antigens. Both monoclonal autoantibodies lacked lupus anticoagulant activity and did not inhibit prothrombinase activity. Remarkably, one of the monoclonal antibodies has thrombogenic properties when tested in an in vivo mouse model. This finding provides the first direct evidence that a particular antiphospholipid antibody specificity may contribute to in vivo thrombosis.
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Anticuerpos Anticardiolipina/inmunología , Síndrome Antifosfolípido/inmunología , Trombosis/inmunología , Adulto , Animales , Anticuerpos Monoclonales/inmunología , Especificidad de Anticuerpos , Cardiolipinas/inmunología , Femenino , Humanos , Ratones , Tromboplastina/antagonistas & inhibidores , Trombosis/etiologíaRESUMEN
Until recently, conversion of arginine to agmatine by arginine decarboxylase (ADC) was considered important only in plants and bacteria. In the following, we demonstrate ADC activity in the membrane-enriched fraction of brain, liver, and kidney cortex and medulla by radiochemical assay. Diamine oxidase, an enzyme shown here to metabolize agmatine, was localized by immunohistochemistry in kidney glomeruli and other nonrenal cells. Production of labeled agmatine, citrulline, and ornithine from [3H]arginine was demonstrated and endogenous agmatine levels (10(-6)M) in plasma ultrafiltrate and kidney were measured by HPLC. Microperfusion of agmatine into renal interstitium and into the urinary space of surface glomeruli of Wistar-Frömter rats produced reversible increases in nephron filtration rate (SNGFR) and absolute proximal reabsorption (APR). Renal denervation did not alter SNGFR effects but prevented APR changes. Yohimbine (an alpha 2 antagonist) microperfusion into the urinary space produced opposite effects to that of agmatine. Microperfusion of urinary space with BU-224 (microM), a synthetic imidazoline2 (I2) agonist, duplicated agmatine effects on SNGFR but not APR whereas an I1 agonist had no effect. Agmatine effects on SNGFR and APR are not only dissociable but appear to be mediated by different mechanisms. The production and degradation of this biologically active substance derived from arginine constitutes a novel endogenous regulatory system in the kidney.
Asunto(s)
Agmatina/metabolismo , Arginina/metabolismo , Riñón/metabolismo , Amina Oxidasa (conteniendo Cobre)/metabolismo , Animales , Carboxiliasas/metabolismo , Cromatografía Líquida de Alta Presión , Femenino , Tasa de Filtración Glomerular , Glomérulos Renales/enzimología , Mitocondrias/metabolismo , Ratas , Ratas WistarRESUMEN
We studied the rate of clearance of treatment doses of radiolabeled calf lung surfactant extract, which was instilled into the lungs of young adult rabbits exposed to air (control) or 100% oxygen for 64 h. More than 75% of the instilled surfactant remained lung-associated at all time points up to 24 h post-instillation in both groups; however, significantly more of the labeled phosphatidylcholine (PC) remained in the alveolar wash of oxygen-exposed rabbits (44 +/- 9% in 100% O2 versus 27 +/- 5% in controls at 6 h and 27 +/- 2% in 100% O2 versus 6 +/- 1% in control rabbits at 24 h, p < 0.05). Less of the labeled PC could be found in type II pneumocytes isolated from the oxygen exposed animals than in control animals, both at 6 h (24 +/- 2 cpm/10(6) cells in O2 versus 38 +/- 7 cpm/10(6) cells in control) and 24 h (42 +/- 5 cpm/10(6) cells in O2 versus 70 +/- 12 cpm/10(6) cells in control) post-instillation. Type II cells from animals exposed to 100% oxygen also demonstrated significantly lower PC synthesis rates than cells from lungs of control animals. Interestingly, clearance of exogenous surfactant in rabbits exposed to 100% oxygen for 48 h, an exposure that does not cause significant type II pneumocyte dysfunction, was not different from control. We concluded that injury to type II pneumocytes may result in decreased clearance of instilled surfactant from the alveolar space and may be important in determining dosing regimens for the use of surfactant therapy in adult respiratory distress syndrome.
Asunto(s)
Hiperoxia/metabolismo , Alveolos Pulmonares/metabolismo , Surfactantes Pulmonares/farmacocinética , Animales , Líquido del Lavado Bronquioalveolar/química , Bovinos , Masculino , Fosfatidilcolinas/análisis , Fosfatidilcolinas/farmacocinética , Alveolos Pulmonares/patología , Surfactantes Pulmonares/uso terapéutico , Conejos , Síndrome de Dificultad Respiratoria/terapiaRESUMEN
Diamine oxidase (histaminase), an enzyme that oxidatively deaminates putrescine and histamine, was purified from human placenta and from pig kidney. Both NH2-terminal sequences are highly homologous to the human kidney amiloride-binding protein, previously thought to be a component of the amiloride-sensitive Na+ channel. Monoclonal antibodies raised against the pig kidney amiloride-binding protein immunoprecipitate a polypeptide with the same M(r) (105,000) as that of pig kidney diamine oxidase. That polypeptide has both diamine oxidase activity and the capacity to bind [3H]phenamil, a tritiated amiloride derivative. Cells stably transfected with human kidney amiloride-binding protein cDNA express a high diamine oxidase activity. In transfected cells as well as with the purified enzyme, this activity was inhibited by amiloride and by some of its derivatives, such as phenamil and ethylpropylamiloride. Amiloride inhibition seems to be due to drug binding at the active site of the enzyme. These data indicate that human placental diamine oxidase is identical to the human kidney amiloride-binding protein and that amiloride analogues may have wider physiological effects besides those on epithelial ion transport.
Asunto(s)
Amilorida/análogos & derivados , Amilorida/farmacología , Amina Oxidasa (conteniendo Cobre)/metabolismo , Proteínas Portadoras/metabolismo , Riñón/enzimología , Placenta/enzimología , Amilorida/metabolismo , Amina Oxidasa (conteniendo Cobre)/antagonistas & inhibidores , Amina Oxidasa (conteniendo Cobre)/aislamiento & purificación , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales , Proteínas Portadoras/antagonistas & inhibidores , Proteínas Portadoras/aislamiento & purificación , Colon/metabolismo , ADN Complementario/metabolismo , Femenino , Humanos , Cinética , Datos de Secuencia Molecular , Peso Molecular , Embarazo , Homología de Secuencia de Aminoácido , Porcinos , TransfecciónRESUMEN
Perfluorocarbon-associated gas exchange (PAGE) has been proposed for the treatment of lung diseases characterized by high alveolar surface tension. Perflubron (perfluorooctyl bromide, LiquiVent, Alliance Pharmaceutical Corp.) is a high purity medical grade perfluorocarbon suitable for PAGE. We studied PAGE using perflubron in normal piglets and in animal models of pulmonary disease (meconium aspiration syndrome, oleic acid infusion and gastric acid aspiration as models of ARDS, and neonatal respiratory distress syndrome). All animals were studied under anesthesia. PAGE was instituted by intratracheal instillation of a volume of perflubron (generally 30 ml/kg) that approximates a normal functional residual capacity of the lung. Arterial blood gases were measured at 15 minute intervals. FiO2 during PAGE was 1.0. In normal piglets, PaO2 fell from 543 torr (during conventional gas breathing) to 363 torr (during PAGE). However, in models of lung disease, PAGE significantly enhanced PaO2.