RESUMEN
Monoclonal antibody 791T/36, recognizing a Mr 72,000 antigen on the surface of colon carcinoma cells, has been used to construct an immunotoxin by conjugating to it the ribosomal inhibitor protein, ricin toxin A chain. The antibody 791T/36 has been shown to bind to membranes of freshly disaggregated tumor cells from human colon tumors, and to localize in tumors in vivo. Subacute toxicology testing in rats receiving immunotoxin i.v. showed, at highest doses, weight loss, decreased serum albumin, and hepatocyte vacuolization without elevation in liver function tests. A Phase I dose escalation study was carried out in which 17 patients with metastatic colorectal cancer were treated with doses of immunotoxin ranging from 0.02 to 0.2 mg/kg/day in 1-h i.v. infusions for a 5-day course. Side-effects included a composite of signs and symptoms thought to be generic to ricin A chain immunotoxins, including decreased serum albumin, mild fever, and flu-like symptoms, all being reversible. Two additional findings, reversible proteinuria and mental status changes, were also noted which may be characteristic of this immunotoxin. By 10-20 days after therapy, most patients developed IgM and IgG antibodies against both the ricin toxin A chain and the immunoglobulin portion of the immunotoxin, which were asymptomatic. A strong anticombining site antibody response was seen. Biological activity manifest as mixed tumor regression was seen in five patients.
Asunto(s)
Anticuerpos Monoclonales/efectos adversos , Neoplasias del Colon/terapia , Inmunotoxinas/efectos adversos , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/secundario , Ricina/efectos adversos , Adulto , Anciano , Animales , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/toxicidad , Formación de Anticuerpos , Antígeno Carcinoembrionario/análisis , Neoplasias del Colon/inmunología , Evaluación de Medicamentos , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunoglobulina G/análisis , Inmunoglobulina M/análisis , Inmunotoxinas/uso terapéutico , Inmunotoxinas/toxicidad , Dosificación Letal Mediana , Pruebas de Función Hepática , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/terapia , Masculino , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Metástasis de la Neoplasia , Ratas , Ratas Endogámicas , Ricina/uso terapéutico , Ricina/toxicidad , Albúmina Sérica/análisisRESUMEN
Monoclonal antibody 791 (XMMCO-791) recognizes a colorectal tumour-associated antigen. Antibody 791-ricin A chain immunotoxin (XMMCO-791-RTA) inhibits growth of human tumour xenografts and it is therefore being evaluated for the treatment of colorectal cancer. One of the problems with therapy with mouse monoclonal antibodies is they stimulate humoral responses in patients. However antigens linked to ricin are cytotoxic for B cells and therefore XMMCO-791-RTA may not be immunogenic. The humoral antibody response to murine monoclonal antibody XMMCO-791 (IgG2b) conjugated to the plant toxin, ricin A chain (RTA), was measured in colorectal cancer patients in a phase I clinical trial. All patients produced strong responses to the XMMCO-791 immunoglobulin and to RTA. The predominant response to the antibody was against the idiotypic determinant although anti-subclass and anti-mouse antibodies were also detected. A component of the anti-idiotypic immunoglobulin response in the colorectal cancer patients was directed against the combining site of XMMCO-791. These antibodies inhibited in-vitro binding of XMMCO-791 to target 791 cells and so may be inhibitors of repeated immunotoxin therapy. Immunotoxins do not abrogate the immune response to mouse immunoglobulin in vivo but instead are highly immunogenic.
Asunto(s)
Neoplasias Colorrectales/inmunología , Inmunotoxinas/inmunología , Ricina/inmunología , Adulto , Anciano , Animales , Anticuerpos Antiidiotipos/biosíntesis , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Neoplasias Colorrectales/terapia , Evaluación de Medicamentos , Humanos , Inmunoglobulina G/biosíntesis , Inmunoglobulina M/biosíntesis , Inmunotoxinas/uso terapéutico , Persona de Mediana EdadRESUMEN
PURPOSE: An increased risk of malignancies, including Kaposi's sarcoma and non-Hodgkin's lymphoma, is found in patients infected with the human immunodeficiency virus type 1 (HIV-1). Treatment of such patients may be complicated by their underlying immunodeficiency, especially when aggressive regimens are used. Clinical presentation and treatment outcomes were assessed in 31 patients with non-Hodgkin's lymphoma who had or were at risk for infection with HIV-1 at a single community institution. PATIENTS AND METHODS: Lymphomas presented in advanced stages and involved extranodal sites. Twenty-six patients received therapy (two radiation, one surgery), and a total of 23 patients received chemotherapy. RESULTS: A 52 percent response rate was seen with the use of chemotherapy. A history of opportunistic infections, or Kaposi's sarcoma, or both impacted negatively on the ability to achieve a complete response. Sixty-four percent of the 11 patients who received an intensive chemotherapeutic regimen, MACOP-B (methotrexate, Adriamycin, cyclophosphamide, vincristine, prednisone, bleomycin) had complete remissions. Overall median survival for 23 patients who received chemotherapy was seven months. Patients achieving complete responses had a median survival of 20 months. CONCLUSION: Our results support intensive chemotherapy for patients with lymphoma and HIV-1 infection.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/complicaciones , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma no Hodgkin/tratamiento farmacológico , Adulto , Anciano , Terapia Combinada , Humanos , Linfoma no Hodgkin/etiología , Linfoma no Hodgkin/terapia , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Inducción de Remisión , Estudios Retrospectivos , Factores de RiesgoRESUMEN
To reduce the risk of thromboembolic complications in prosthetic blood pumps, we have developed a new segmented polyurethane elastomer. This material is unique because its mechanical properties for long-term durability and surface properties for biocompatibility have been separated and developed in two distinct materials. Improved thromboresistance is then obtained by a 1% concentration of a new polymeric surface-modifying additive blended with the base polyurethane before fabrication of the blood pump. To evaluate this material in vivo, we performed 10 implants, in calves, of the Pierce-Donachy prosthetic ventricle with blood-pumping sacs and cannulas fabricated from the new surface-modifying additive copolymer blend (Thoratec's BPS-215M). In four control implants the blood sacs and cannulas were fabricated from Ethicon's Biomer segmented polyurethane, which is the present clinical standard for most artificial hearts and circulatory support devices. The blood pumps were connected from the apex of the left ventricle to the descending aorta in male Holstein calves weighing 82 to 108 kg and were driven pneumatically in the full-to-empty mode with flows averaging 5 to 6 L/min. Each calf was medicated with aspirin and dipyridamole throughout the study period and was electively put to death after 4 weeks for evaluation of explanted blood sacs and for examination of the kidneys for infarction. All 10 explanted blood sacs made with the surface-modifying additive copolymer blend were shiny and completely free of thrombus. Three of the four explanted Biomer blood sacs showed visible red thrombus, and all four showed small areas of white thrombus. The average surface area of the Biomer blood sacs covered with thrombus was 45 +/- 32 mm2. Use of a semiquantitative scale to assess renal infarction demonstrated that nine of 10 animals with a surface-modifying additive copolymer blend blood sac had infarction less severe than the mean infarct score of the animals with a Biomer sac. The surface-modifying additive copolymer blend has excellent mechanical and physical properties necessary for use in artificial heart blood pumps. From these experiments, we conclude that the surface-modified polyurethane blend is superior to Biomer polyurethane in blood compatibility and in freedom from thromboembolic risk. This material is now approved by the Food and Drug Administration for investigational device exemption studies in the Pierce-Donachy prosthetic ventricle.
Asunto(s)
Corazón Artificial , Poliuretanos/uso terapéutico , Tromboembolia/prevención & control , Animales , Bovinos , Hemodinámica , Infarto/patología , Riñón/irrigación sanguínea , Riñón/patología , Masculino , Ensayo de Materiales , Recuento de Plaquetas , Relación Estructura-Actividad , Propiedades de Superficie , Tromboembolia/patología , Factores de TiempoRESUMEN
Two patients developed hemolytic anemia while taking cimetidine. Neither patient was taking other drugs known to cause hemolytic anemia. In both, the hemolytic anemia resolved after the drug was stopped. In one patient, the direct antiglobulin (Coombs') test was strongly positive when the hemolytic anemia was recognized and became only weakly positive as the hemolysis subsided. However, serologic studies for antidrug antibodies yielded negative results in both patients; readministration of cimetidine for 55 days in patient 1 and for more than 24 months in patient 2 did not cause recurrence of hemolysis. We conclude that we cannot incriminate cimetidine as the cause of the hemolytic anemia in either of our patients. These findings emphasize that a temporal association of drug administration and hemolytic anemia is not proof of a cause-effect relationship and that reports of drug-related adverse hematologic effects must be interpreted with caution.
Asunto(s)
Anemia Hemolítica/inducido químicamente , Cimetidina/efectos adversos , Adulto , Anciano , Anemia Hemolítica/inmunología , Cimetidina/administración & dosificación , Cimetidina/inmunología , Diagnóstico Diferencial , Femenino , Humanos , MasculinoRESUMEN
A 32-year-old white woman with a history of 2 episodes of abruptio placentae was found to have congenital hypofibrinogenemia. She had no bleeding difficulties except when pregnant. The patient's sisters and her mother also had reduced fibrinogen levels. Results of fibrinogen measurement by clotting assays and immunologic studies were similar. Immunoelectrophoresis, molecular weight of fibrinogen chains, cross-linking by factor XIII, carbohydrate staining, and sialic acid quantitation were all normal, suggesting the diagnosis of hypofibrinogenemia rather than dysfibrinogenemia. Fibrinolysis did not account for the reduced fibrinogen level. This case demonstrates that congenital low fibrinogen levels may be associated with placental abruption and that an abnormal fibrinogen molecule is not necessary.
Asunto(s)
Desprendimiento Prematuro de la Placenta/etiología , Afibrinogenemia/congénito , Adulto , Afibrinogenemia/diagnóstico , Afibrinogenemia/genética , Pruebas de Coagulación Sanguínea , Femenino , Fibrinógeno/análisis , Humanos , Embarazo , RecurrenciaRESUMEN
The purpose of this investigation was to analyze the thromboembolic and/or major bleeding complications of 124 consecutive but nonrandomized patients who had only mitral valve replacement with the Hancock porcine xenograft between September, 1974 and June, 1979. These patients were treated either with or without anticoagulants. Four basic study groups were created: Group 1, warfarin; Group 2, aspirin; Group 3, no anticoagulants; and Group 4, warfarin and aspirin. Group 5 combined Groups 1 and 4 (warfarin and warfarin plus aspirin) and Group 6 combined Groups 2 and 3 (aspirin and no anticoagulants). The cardiac rhythm, history of embolism, and intraoperative findings of a thrombus in the left atrium were examined as risk factors for later thromboembolism . Follow-up time was 3.03 years (range 2.0 to 4.2 years). The embolic rate was not significantly different in any group (n = NS). In Groups 5 and 6 the embolic rate was 2.97 and 3.25 embolisms per 100 patient-years, respectively. Warfarin therapy resulted in significant major bleeding episodes, including two deaths (p less than 0.05). The number of patients with a history of a previous embolism, the finding of an intraoperative left atrial thrombus, or abnormal cardiac rhythm was insufficient to test embolic risk in the four treatment groups. We conclude that long-term warfarin therapy increases the risk of bleeding complications but may not significantly influence the incidence of thromboembolism arising from the Hancock porcine xenograft mitral valve. Other and larger studies are needed to confirm this last point.
Asunto(s)
Bioprótesis , Prótesis Valvulares Cardíacas , Warfarina/administración & dosificación , Adulto , Anciano , Aspirina/administración & dosificación , Hemorragia Cerebral/epidemiología , Hemorragia Cerebral/etiología , Femenino , Hemorragia Gastrointestinal/epidemiología , Hemorragia Gastrointestinal/etiología , Humanos , Masculino , Persona de Mediana Edad , Válvula Mitral/cirugía , Complicaciones Posoperatorias , Riesgo , Tromboembolia/epidemiología , Tromboembolia/etiologíaRESUMEN
Two cases of acute aortic thrombosis, a previously unreported complication of antithrombin III deficiency, are reported. Both patients had abnormally low antithrombin III levels, which improved to normal levels with warfarin ;sodium therapy. The possibility of antithrombin III deficiency should be considered in young patients with acute arterial thrombosis.
Asunto(s)
Deficiencia de Antitrombina III , Enfermedades de la Aorta/etiología , Trombosis/etiología , Enfermedad Aguda , Adulto , Antitrombina III/análisis , Aorta Abdominal , Femenino , Humanos , Infarto/etiología , Claudicación Intermitente/etiología , Riñón/irrigación sanguínea , Masculino , Trombosis/tratamiento farmacológico , Warfarina/farmacologíaAsunto(s)
Síndrome de Dificultad Respiratoria/etiología , Sepsis/complicaciones , Animales , Bacterias/aislamiento & purificación , Trastornos de la Coagulación Sanguínea/etiología , Humanos , Respiración con Presión Positiva , Síndrome de Dificultad Respiratoria/complicaciones , Síndrome de Dificultad Respiratoria/mortalidad , Síndrome de Dificultad Respiratoria/terapia , Sepsis/microbiología , Coloración y EtiquetadoAsunto(s)
Coagulación Sanguínea/efectos de los fármacos , Dronabinol/farmacología , Administración Oral , Tiempo de Sangría , Plaquetas/efectos de los fármacos , Factor V/metabolismo , Factor VIII/metabolismo , Humanos , Masculino , Adhesividad Plaquetaria/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacosRESUMEN
On two separate occasions, a 26-year-old white woman bled from arterial puncture wounds while receiving heparin for thromboembolic disease. Bleeding time was prolonged after heparin administration at the time that she was ill and bled, and when she was re-challenged 2 years later. Heparin may produce bleeding as a result of a qualitative platelet dysfunction.
Asunto(s)
Trastornos de las Plaquetas Sanguíneas/complicaciones , Hemorragia/etiología , Heparina/uso terapéutico , Tromboembolia/tratamiento farmacológico , Adulto , Tiempo de Sangría , Plaquetas/efectos de los fármacos , Femenino , Heparina/farmacología , HumanosRESUMEN
Calves given LVADs have been studied to determine changes in platelet turnover induced by the device and modified by time and anticoagulants. Passivation with time occurs but is surprisingly incomplete even one month later and despite coumadin, aspirin and dipyridamole. Without these drugs, enhanced platelet turnover and local thrombus formation on the device is exaggerated. Sequential platelet turnover studies may be useful to quantitate, monitor and/or predict thromboembolic events.
Asunto(s)
Circulación Asistida/instrumentación , Plaquetas/fisiología , Fibrinolíticos/farmacología , Tromboembolia/etiología , Animales , Plaquetas/citología , Bovinos , Supervivencia Celular , Ventrículos Cardíacos , Indio , Cinética , Agregación Plaquetaria/efectos de los fármacos , RadioisótoposRESUMEN
An in vitro system for the assessment of blood compatibility of artificial surfaces is described. Anticoagulated human whole blood was pumped through columns of beads and then analyzed for evidence of platelet retention and the release of platelet constitutents. Platelets were retained on the columns by adhesion to the beads and by aggregation. Experiments were conducted with PVAc, PC, PMA and PS beads to provide data on the reproducibility of the system and the effects of anticoagulants and RBC concentration on platelet adhesion and release. The system is versatile, inexpensive, reproducibile, and also suitable for studies of the effects of pharmacologic agents and other aspects of platelet-artificial surface interaction.
Asunto(s)
Sangre , Modelos Biológicos , Anticoagulantes/farmacología , Recuento de Células Sanguíneas , Plaquetas , Hemólisis , Humanos , Técnicas In Vitro , Métodos , Microscopía Electrónica de Rastreo , Adhesividad PlaquetariaAsunto(s)
Circulación Extracorporea , Oxigenadores de Membrana , Insuficiencia Respiratoria/terapia , Enfermedad Aguda , Circulación Extracorporea/efectos adversos , Circulación Extracorporea/métodos , Humanos , Oxigenadores de Membrana/efectos adversos , Oxigenadores de Membrana/métodos , Pronóstico , Capacidad de Difusión PulmonarRESUMEN
Acute respiratory failure is an often-fatal syndrome of multiple etiologies in which altered factor VIII may be a marker of endothelial disease. 12 women with overwhelming viral pneumonia were studied with serial factor VIII antigen, procoagulant activity, and von Willebrand's factor assays. Antigen levels were elevated (range: 86--1644%) out of proportion to procoagulant activity (range: 35--521% by a one-stage assay), and factor VIII antigen to activity ratios were as high as 16:1. Von Willebrand's factor was normal but correlated best with procoagulant activity. All patients had abnormal antigen patterns on crossed immunoelectrophoresis, with increases in protein of both fast and slow mobility. These changes in factor VIII correlated with the patient's clinical courses.
Asunto(s)
Factor VIII , Insuficiencia Respiratoria/sangre , Enfermedad Aguda , Adulto , Antígenos , Coagulación Sanguínea , Factor VIII/inmunología , Femenino , Humanos , Inmunoelectroforesis Bidimensional , Persona de Mediana Edad , Factor de von Willebrand/inmunologíaAsunto(s)
Plaquetas/efectos de los fármacos , Hemostasis/efectos de los fármacos , Somatostatina/farmacología , Adenosina Difosfato/farmacología , Animales , Recuento de Células Sanguíneas , Plaquetas/fisiología , Diabetes Mellitus/fisiopatología , Epinefrina/farmacología , Humanos , Agregación Plaquetaria/efectos de los fármacosAsunto(s)
Plaquetas/efectos de los fármacos , Trastornos Cerebrovasculares/tratamiento farmacológico , Fibrinolíticos/uso terapéutico , Plaquetas/fisiología , Femenino , Humanos , Embolia y Trombosis Intracraneal/sangre , Ataque Isquémico Transitorio/sangre , Ataque Isquémico Transitorio/tratamiento farmacológico , Masculino , Adhesividad Plaquetaria/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacos , Sulfinpirazona/uso terapéutico , Tromboxanos/fisiologíaRESUMEN
Case histories of 140 patients who had mitral valve replacement with the Hancock xenograft were reviewed according to the incidence of thromboembolic complications. There were 16 patients with preoperative and/or postoperative low-output syndrome (Group A.) Eight of these patients died, and six had autopsies which showed major thrombi on the heterograft valve. In 126 long-term survivors (followed 1 to 33 months) nine thromboembolic events occurred (thromboembolic incidence 5.3 percent per patient-year). All patients with emboli were in atrial fibrillation. Additional predisposing factors included a history of systemic emboli and the presence of atrial clots at the time of surgery. The majority (7/9) of emboli occurred during the first 3 postoperative months. Two emboli occurred immediately following the operation (before oral anticoagulation therapy could have been begun). Five occurred in patients who were not on anticoagulation (Group B) and two occurred under warfarin treatment (Group C). There was no thromboembolic event in patients taking aspirin (Group D). It is concluded that hemodynamically stable patients have a decreased risk of thromboembolism and do not require anticoagulation. Patients with atrial fibrillation have an increased thromboembolic risk and should be on a regimen of warfarin for 3 months postoperatively and then on aspirin therapy.