RESUMEN
A forensic method for the retrospective determination of preparation methods used for illicit ricin toxin production was developed. The method was based on a complex set of biomarkers, including carbohydrates, fatty acids, seed storage proteins, in combination with data on ricin and Ricinus communis agglutinin. The analyses were performed on samples prepared from four castor bean plant (R. communis) cultivars by four different sample preparation methods (PM1-PM4) ranging from simple disintegration of the castor beans to multi-step preparation methods including different protein precipitation methods. Comprehensive analytical data was collected by use of a range of analytical methods and robust orthogonal partial least squares-discriminant analysis- models (OPLS-DA) were constructed based on the calibration set. By the use of a decision tree and two OPLS-DA models, the sample preparation methods of test set samples were determined. The model statistics of the two models were good and a 100% rate of correct predictions of the test set was achieved.
Asunto(s)
Ricina/análisis , Ricinus/química , Biomarcadores/análisis , Análisis Discriminante , Toxicología Forense , Humanos , Análisis de los Mínimos Cuadrados , Ricina/efectos adversosRESUMEN
Ricinus cmmunis L. (Castor oil plant) is an important medicinal plant belonging to family Euphorbiaceae. Its phytochemistry, biological and pharmacological activities, and ethnomedicinal uses have been reviewed in the present study. The reported chemical constituents showed the presence of flavonoids, phenolic compounds, fatty acids, amino acids, terpenoids, phytosterol etc. The compounds have been reported to exhibit anticonceptive, antidiabetic, antifertility, anti-inflammatory, antimicrobial, antioxidant, hepatoprotective, insecticidal and wound-healing activities. They also showed free radical scavenging and Hg scavenging activities, and repellent properties. Various parts of R. communis have been widely used in traditional medicine such as abdominal disorders, arthritis, backache, muscle aches, bilharziasis, chronic backache and sciatica, chronic headache, constipation, expulsion of placenta, gallbladder pain, period pain, menstrual cramps, rheumatism, sleeplessness, and insomnia. Castor oil plant has also revealed toxic effects due to the presence of ricin (protein) and ricinine (alkaloid). Comparatively, ricin is more toxic. But still there is need of more research to be conducted with reference to its medicinal importance (particularly exploring of medicinal recipes) and active compounds responsible for various activities.
Asunto(s)
Aceite de Ricino/uso terapéutico , Medicina Tradicional , Extractos Vegetales/uso terapéutico , Ricinus , Alcaloides/efectos adversos , Alcaloides/aislamiento & purificación , Animales , Aceite de Ricino/efectos adversos , Aceite de Ricino/aislamiento & purificación , Humanos , Seguridad del Paciente , Extractos Vegetales/efectos adversos , Extractos Vegetales/aislamiento & purificación , Piridonas/efectos adversos , Piridonas/aislamiento & purificación , Ricina/efectos adversos , Ricina/aislamiento & purificación , Ricinus/efectos adversos , Ricinus/química , Medición de RiesgoRESUMEN
BACKGROUND: Ricin is a protein toxin derived from the castor bean plant Ricinus communis. Several cases secondary to its consumption have been published and, more recently, its use as a potential bioterrorism agent has also been reported. Oral absorption of ricin is highly erratic, leading to a wide spectrum of symptoms. In addition, conventional urine drug screening tests will not be able to detect this compound, posing a diagnostic challenge. CASE REPORT: A male teenager intended to die by ingesting 200 castor beans after mixing and blending them with juice. Eight hours later, he presented with weakness, light-headedness, nausea, and vomiting and sought medical treatment. The patient was admitted and treated conservatively. An immune-based standard urine toxicology drug screen panel was reported as negative. A comprehensive untargeted urine drug screen test showed the presence of ricinine, a surrogate marker of ricin intoxication. He was transferred to the psychiatric service 3 days after admission. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case highlights the importance of knowing the peculiar pharmacokinetic properties of ricin after oral ingestion of castor beans and toxin release through mastication. Emergency physicians should be aware that oral absorption of ricin is dependent on several factors, such type and size of seeds and the geographic harvesting region, making it extremely difficult to estimate its lethality based solely on the number of ingested beans. Finally, comprehensive untargeted urine drug screening testing is highly valuable as a diagnostic tool in this context.
Asunto(s)
Ingestión de Alimentos/psicología , Ricina/química , Ricinus communis/envenenamiento , Adolescente , Antídotos/uso terapéutico , Ricinus communis/química , Carbón Orgánico/uso terapéutico , Depresión/complicaciones , Depresión/psicología , Mareo/etiología , Servicio de Urgencia en Hospital/organización & administración , Lavado Gástrico/métodos , Humanos , Masculino , Debilidad Muscular/etiología , Náusea/etiología , Intoxicación , Ricina/efectos adversos , Ricina/envenenamiento , Suicidio , Vómitos/etiologíaRESUMEN
Exposure of the lungs to airborne toxicants from different sources in the environment may lead to acute and chronic pulmonary or even systemic inflammation. Cigarette smoke is the leading cause of chronic obstructive pulmonary disease, although wood smoke in urban areas of underdeveloped countries is now recognized as a leading cause of respiratory disease. Mycotoxins from fungal spores pose an occupational risk for respiratory illness and also present a health hazard to those living in damp buildings. Microscopic airborne particulates of asbestos and silica (from building materials) and those of heavy metals (from paint) are additional sources of indoor air pollution that contributes to respiratory illness and is known to cause respiratory illness in experimental animals. Ricin in aerosolized form is a potential bioweapon that is extremely toxic yet relatively easy to produce. Although the aforementioned agents belong to different classes of toxic chemicals, their pathogenicity is similar. They induce the recruitment and activation of macrophages, activation of mitogen-activated protein kinases, inhibition of protein synthesis, and production of interleukin-1 beta. Targeting either macrophages (using nanoparticles) or the production of interleukin-1 beta (using inhibitors against protein kinases, NOD-like receptor protein-3, or P2X7) may potentially be employed to treat these types of lung inflammation without affecting the natural immune response to bacterial infections.
Asunto(s)
Microbiología del Aire , Contaminantes Ambientales/efectos adversos , Exposición por Inhalación/efectos adversos , Pulmón , Micotoxinas/efectos adversos , Neumonía , Ricina/efectos adversos , Humo/efectos adversos , Fumar/efectos adversos , Animales , Interacciones Huésped-Patógeno , Humanos , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/microbiología , Pulmón/virología , Neumonía/inducido químicamente , Neumonía/inmunología , Neumonía/microbiología , Neumonía/virología , Medición de Riesgo , Factores de Riesgo , Transducción de Señal/efectos de los fármacosRESUMEN
Ricin, a large, water soluble toxic glycoprotein, is distributed majorly in the kernels of castor beans (the seeds of Ricinus communis L.) and has been used in traditional Chinese medicine (TCM) or other folk remedies throughout the world. The toxicity of crude ricin (CR) from castor bean kernels was investigated for the first time using an NMR-based metabolomic approach complemented with histopathological inspection and clinical chemistry. The chronic administration of CR could cause kidney and lung impairment, spleen and thymus dysfunction and diminished nutrient intake in rats. An orthogonal signal correction partial least-squares discriminant analysis (OSC-PLSDA) of metabolomic profiles of rat biofluids highlighted a number of metabolic disturbances induced by CR. Long-term CR treatment produced perturbations on energy metabolism, nitrogen metabolism, amino acid metabolism and kynurenine pathway, and evoked oxidative stress. These findings could explain well the CR induced nephrotoxicity and pulmonary toxicity, and provided several potential biomarkers for diagnostics of these toxicities. Such a (1)H NMR based metabolomics approach showed its ability to give a systematic and holistic view of the response of an organism to drugs and is suitable for dynamic studies on the toxicological effects of TCM.
Asunto(s)
Ricina/efectos adversos , Ricinus communis/efectos adversos , Semillas/efectos adversos , Aminoácidos/metabolismo , Animales , Biomarcadores/metabolismo , Metabolismo Energético/efectos de los fármacos , Quinurenina/metabolismo , Análisis de los Mínimos Cuadrados , Imagen por Resonancia Magnética/métodos , Masculino , Medicina Tradicional China/efectos adversos , Metabolómica/métodos , Nitrógeno/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Novel agents are needed for patients with refractory and relapsed acute lymphoblastic leukaemia (ALL). Combotox is a 1:1 mixture of two immunotoxins (ITs), prepared by coupling deglycosylated ricin A chain (dgRTA) to monoclonal antibodies directed against CD22 (RFB4-dgRTA) and CD19 (HD37-dgRTA). Pre-clinical data demonstrated that Combotox was effective in killing both pre-B-ALL cell lines and cells from patients with pre-B ALL. A clinical study of paediatric patients in which 3 of 17 patients with ALL experienced complete remission, supported the preclinical work and motivated this study. This study was a Phase I, dose-escalation trial using Combotox in adults with refractory or relapsed B-lineage-ALL. A cycle consisted of three doses, with one dose given every other day. Dose levels were 3, 5, 6, 7 and 8 mg/m(2) per dose. Seventeen patients, aged 19-72 years, were enrolled in this multi-institution study. The maximum tolerated dose was 7 mg/m(2) /dose (21 mg/m(2) /cycle) and vascular leak syndrome was the dose-limiting toxicity. Two patients developed reversible grade 3 elevations in liver function tests. One patient achieved partial remission and proceeded to allogeneic stem cell transplantation. All patients with peripheral blasts experienced decreased blast counts following the administration of Combotox. Thus, Combotox can be safely administered to adults with refractory leukaemia.
Asunto(s)
Antineoplásicos/administración & dosificación , Inmunotoxinas/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Ricina/administración & dosificación , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Antígenos CD19/inmunología , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inmunotoxinas/efectos adversos , Inmunotoxinas/uso terapéutico , Masculino , Persona de Mediana Edad , Recurrencia , Ricina/efectos adversos , Ricina/uso terapéutico , Lectina 2 Similar a Ig de Unión al Ácido Siálico/inmunología , Resultado del Tratamiento , Adulto JovenRESUMEN
Anti-B4-blocked ricin (anti-B4-bR) is a potent immunotoxin directed against the CD19 antigen. Previous phase I and II studies suggested a possible role for anti-B4-bR as consolidation after high-dose chemotherapy and autologous stem cell transplant. Cancer and Leukemia Group B (CALGB) 9254 is a phase III study which randomized 157 patients with B-cell lymphoma in complete remission following autologous transplant to treatment with anti-B4-bR or observation. With a median follow-up time for patients of 5.8 years, the median event-free survival for protocol treatment and observation are 2.1 and 2.9 years, respectively (p = 0.275). The median overall survival for treatment and observation are 6.1 years and not reached, respectively (p = 0.063). Therefore, no differences were found in event-free survival and overall survival between protocol treatment and observation, although there was a trend toward improved survival with observation. These data fail to support a role for anti-B4-bR as consolidative therapy after bone marrow transplant in patients with B-cell lymphoma.
Asunto(s)
Adyuvantes Inmunológicos/uso terapéutico , Trasplante de Médula Ósea , Inmunoconjugados/uso terapéutico , Linfoma de Células B/terapia , Ricina/uso terapéutico , Trasplante Autólogo , Adyuvantes Inmunológicos/efectos adversos , Adyuvantes Inmunológicos/farmacocinética , Adolescente , Adulto , Anciano , Quimioterapia Adyuvante , Femenino , Humanos , Inmunoconjugados/efectos adversos , Inmunoconjugados/farmacocinética , Linfoma de Células B/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Ricina/efectos adversos , Ricina/farmacocinética , Análisis de Supervivencia , Acondicionamiento Pretrasplante , Resultado del Tratamiento , Adulto JovenRESUMEN
A growing body of evidence suggests that ribosome-inactivating proteins (RIPs) remove adenine moieties not only from rRNA, but also from DNA--an effect leading to DNA damage in cultured cells. We herein report that two distinct RIPs of bacterial (shiga toxin 1, Stx1) and plant (ricin) origin, inhibit the repair of the DNA lesions generated by hydrogen peroxide in cultured human cells. This effect is unrelated either to inhibition of protein synthesis or to depletion of cellular antioxidant defenses and is likely to derive from direct interactions with cellular DNA repair machinery. Therefore, the genotoxicity of these toxins on mammalian cells seems to be a complex phenomenon resulting from the balance between direct (DNA damaging activity), indirect (DNA repair inhibition) effects and the eventual presence of other DNA damaging species. In particular, with regard to Stx1, it could be hypothesized that Stx-producing bacteria increase the risk of transformation of surrounding, inflamed tissues in the course of human infections.
Asunto(s)
Reparación del ADN/efectos de los fármacos , Reparación del ADN/genética , ADN/metabolismo , Peróxido de Hidrógeno/farmacología , Ricina/efectos adversos , Toxina Shiga I/efectos adversos , Apoptosis/efectos de los fármacos , Catalasa/metabolismo , Núcleo Celular/efectos de los fármacos , Células Cultivadas , ADN/genética , Daño del ADN , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Glutatión Peroxidasa/metabolismo , Humanos , Oxidantes/farmacología , Biosíntesis de Proteínas/efectos de los fármacosRESUMEN
BACKGROUND: Prostate-specific membrane antigen (PSMA) is a transmembrane protein that is largely restricted to prostatic epithelial cells in humans and is strongly upregulated on prostatic carcinoma cells. It is also expressed on the endothelium of tumor vasculature in humans, but not on the vasculature of normal tissues. Expression of low levels of PSMA has also been found on non-vascular cells in several normal tissues, most prominently on the brain and kidney in humans. PSMA is an excellent candidate for targeting prostate cancer or targeting tumor vasculature of various solid tumors. The high potential clinical benefit of these agents has prompted the search for an animal model in which to assess the efficacy and safety of anti-PSMA monoclonal antibody (mAb)-based therapies. METHODS: A rat monoclonal antibody, E6 that recognizes both mouse and human PSMA was generated using conventional hybridoma techniques. The antibody was characterized by enzyme-linked immunosorbent assay (ELISA), Western blot, and immunohistochemistry. An immunotoxin composed of E6, antibody and deglycosylated ricin A-chain (dgA) was prepared chemically. The anti-tumor effects of the immunotoxin were determined in vitro and in mice bearing subcutaneous LnCaP human prostate tumors, which express PSMA on the tumor cell surface. RESULTS: E6 recognizes the extracellular domain of both human and mouse PSMA in ELISA, immunoblot and by immunohistochemistry. E6 strongly stained the vascular endothelium of tumors from humans but not from mice. E6 stained proximal tubules in mouse and human kidneys, and neurons in the mouse and human hippocampus but, unlike the human, did not detectably stain epithelial cells in mouse prostate or small intestine. An E6-dgA immunoconjugate strongly inhibited the growth of LnCaP tumor xenografts without causing apparent toxicity to the mice. Histological observation indicated that the anti-tumor effects were mediated through direct cytotoxic effects on the tumor cells. CONCLUSIONS: We have generated and characterized a rat mAb (E6) that reacts specifically with both human and mouse PSMA and have demonstrated that an immunotoxin constructed from E6 is safe and effective against human prostatic carcinoma cells growing subcutaneously in nude mice.
Asunto(s)
Antígenos de Superficie/inmunología , Glutamato Carboxipeptidasa II/inmunología , Inmunotoxinas/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Ricina/farmacología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Línea Celular Tumoral , Pruebas Inmunológicas de Citotoxicidad , Endotelio Vascular/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Inmunohistoquímica , Inmunotoxinas/efectos adversos , Masculino , Ratones , Ratones Desnudos , Neoplasias de la Próstata/inmunología , Ratas , Ratas Endogámicas Lew , Proteínas Recombinantes , Ricina/administración & dosificación , Ricina/efectos adversos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Immunotoxins (ITs) consist of cell binding ligands coupled to toxins or their subunits. Hodgkin's lymphoma (HL) is an excellent target for ITs since lymphocyte activation markers such as CD25 and CD30 are expressed in large numbers. The ITs RFT5.dgA (anti CD25) and Ki-4.dgA (anti CD30) were constructed by linking the monoclonal antibodies RFT5 and Ki-4 to deglycosylated ricin A-chain (dgA). Both ITs showed potent specific activity against HL cells in vitro and in vivo in animal models, and were subsequently evaluated in phase I/II clinical trials in humans. PATIENTS AND METHODS: In two separate trials, the ITs were administered i.v. four times every other day over 4 h. The objectives of the phase I trials included the determination of the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, antitumor activity and immune response against the IT. RESULTS: Twenty-seven patients with refractory HL were included in the phase I/II study of RFT5.dgA and 17 patients were included in the phase I study of Ki-4.dgA. The MTD of RFT5.dgA was 15 mg/m(2), whereas that of Ki-4.dgA was 5 mg/m(2). DLTs were related to vascular leak syndrome, consisting of edema, tachycardia, dyspnea, weakness and myalgia. Measurement of serum levels of RFT5.dgA demonstrated a C(max) of 0.2-9.7 micro g/ml with a half-life (t()) varying from 4 to 10.5 h. Peak serum concentration of Ki-4.dgA ranged from 0.23 to 1.7 micro g/ml. In both trials approximately 60% of patients developed human anti-mouse and/or anti-dgA antibodies. Seventeen of 18 patients treated at the MTD of RFT5.dgA were evaluable for clinical response. Responses included two partial remissions (PR), one minor response (MR) and five stable diseases (SD). Fifteen of 17 patients treated with Ki-4.dgA were evaluable for clinical response. Responses included one PR, one MR and two SD. CONCLUSIONS: RFT5.dgA and Ki-4.dgA showed moderate efficacy in heavily pretreated refractory patients with HL. Ki-4.dgA was less well tolerated than RFT5.dgA. This might be due, at least in part, to the formation of Ki-4.dgA/sCD30 complexes.
Asunto(s)
Enfermedad de Hodgkin/tratamiento farmacológico , Inmunotoxinas/uso terapéutico , Ricina/uso terapéutico , Adulto , Antígenos/sangre , Citocinas/sangre , Citotoxicidad Inmunológica/efectos de los fármacos , Femenino , Citometría de Flujo , Enfermedad de Hodgkin/inmunología , Enfermedad de Hodgkin/patología , Humanos , Inmunotoxinas/efectos adversos , Inmunotoxinas/farmacocinética , Células Asesinas Naturales/inmunología , Masculino , Persona de Mediana Edad , Ricina/efectos adversos , Ricina/farmacocinéticaAsunto(s)
Bioterrorismo , Carbunco/diagnóstico , Botulismo/diagnóstico , Brucelosis/diagnóstico , Diagnóstico Diferencial , Encefalitis/diagnóstico , Fiebres Hemorrágicas Virales/diagnóstico , Humanos , Peste/diagnóstico , Ricina/efectos adversos , Viruela/diagnóstico , Infecciones Estafilocócicas/diagnóstico , Síndrome , Tularemia/diagnósticoRESUMEN
Ki-4.dgA is an anti-CD30 immunotoxin (IT) constructed by coupling the monoclonal antibody Ki-4 via a sterically hindered disulfide linker to deglycosylated ricin A-chain. This IT was efficacious in vitro and in SCID mice with disseminated human Hodgkin's lymphoma. Accordingly, a Phase I trial in patients (pts) with Hodgkin's lymphoma was designed. The objectives of this Phase I trial were to determine the maximum tolerated dose, the dose-limiting toxicities, pharmacokinetics, and antitumor activity. Seventeen pts with relapsed CD30+ lymphoma were treated with escalating doses (5, 7.5, or 10 mg/m(2)/cycle) of the IT as four bolus infusions on days 1, 3, 5, and 7 for one to three cycles. All of the pts had progressive disease and were heavily pretreated. Nine had primary progressive disease and 14 had advanced disease with massive tumor burdens. The mean age was 35 years (24-52 years). Peak serum concentrations of the intact IT varied from 0.23 to 1.1 microg/ml. Side effects and dose-limiting toxicities were related to vascular leak syndrome, i.e., decreases in serum albumin, edema, weight gain, hypotension, tachycardia, myalgia, and weakness. The maximum tolerated dose was 5 mg/m(2). Seven of 17 (40%) pts made human antiricin antibodies (> or =1.0 microg/ml), and 1 pt developed human antimouse antibodies (> or =1.0 microg/ml). Clinical response in the 15 evaluable pts included 1 partial remission, 1 minor response, and 2 stable diseases. In conclusion, the IT was less well tolerated than other ITs of this type. This might be because of the low number of CD30+ peripheral blood mononuclear cells, and in part because of binding of the IT to soluble CD30 antigen and the resulting circulation of IT/sCD30 complexes.
Asunto(s)
Enfermedad de Hodgkin/terapia , Inmunotoxinas/administración & dosificación , Linfoma no Hodgkin/terapia , Ricina/administración & dosificación , Adulto , Trasplante de Médula Ósea , Femenino , Citometría de Flujo , Enfermedad de Hodgkin/inmunología , Enfermedad de Hodgkin/patología , Humanos , Inmunotoxinas/efectos adversos , Inmunotoxinas/farmacocinética , Antígeno Ki-1/inmunología , Linfoma no Hodgkin/inmunología , Linfoma no Hodgkin/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Estadificación de Neoplasias , Ricina/efectos adversos , Ricina/farmacocinética , Resultado del TratamientoRESUMEN
Allergen cross-reactions among three strongly sensitizing Euphorbiaceae species, i.e., the rubber tree (Hevea brasiliensis), castor bean (Ricinus communis), and the Mediterranean weed Mercurialis annua were studied in Finnish patients (n = 25) allergic to natural rubber latex (NRL), but with no known exposure to castor bean or M. annua, and French patients allergic to castor bean (n = 26) or to M. annua (n = 9), but not to NRL. In immunoglobulin E (IgE)-immunoblotting, 28% of NRL-allergic patient sera recognized castor bean seed and 48% reacted to castor bean pollen proteins. Likewise, 35% of the NRL-allergic patient sera bound to M. annua pollen allergens. Nineteen percent of castor bean-allergic patients showed IgE to NRL and 8% to M. annua proteins. Sera from patients allergic to M. annua reacted in 44% to NRL, in 56% to castor bean seed, and in 78% to castor bean pollen proteins. In immunoblotting, castor bean seed extract inhibited the binding of NRL-reactive IgE to 20 kDa, 30 kDa of NRL, and 55 kDa of proteins; NRL extract, in turn, inhibited the binding of castor bean-reactive IgE to 14, 21-22, 29, and 32-34 kDa of castor bean proteins. In ELISA inhibition, NRL extract inhibited 33% of the binding of M. annua--reactive IgE of pooled sera to M. annua pollen. In conclusion, allergen cross-reactivity in vitro was observed among three botanically related Euphorbiaceae members, H. brasiliensis, R. communis, and M. annua, but the molecular specificity of the observed cross-reactions as well as their clinical significance remains to be elucidated. Allergen cross-reactivity should be taken into account in diagnostic work.
Asunto(s)
Alérgenos/farmacología , Euphorbiaceae/efectos adversos , Hevea/efectos adversos , Hipersensibilidad al Látex/etiología , Hipersensibilidad al Látex/inmunología , Proteínas de Plantas/efectos adversos , Proteínas de Plantas/farmacología , Polen/efectos adversos , Ricina/efectos adversos , Ricina/farmacología , Semillas/efectos adversos , Adolescente , Adulto , Anciano , Alérgenos/inmunología , Niño , Euphorbiaceae/inmunología , Femenino , Finlandia , Hevea/inmunología , Humanos , Técnicas In Vitro , Masculino , Persona de Mediana Edad , Proteínas de Plantas/inmunología , Polen/inmunología , Ricina/inmunología , Semillas/inmunologíaRESUMEN
Since October 3, 2001, the Centers for Disease Control and Prevention and other organizations have been investigating potential bioterrorist-related anthrax cases. The pediatrician may be faced with complex issues related to diagnosis and treatment of illnesses caused by intentionally released biological agents. The agents that pose a major potential bioterrorist threat are reviewed by the clinical syndromes they produce: acute respiratory distress with fever, influenza-like illnesses, acute rash with fever, neurologic syndromes, and blistering syndromes. Specific and detailed diagnostic, treatment, and prophylaxis information is provided for anthrax, plague, tularemia, smallpox, botulism, viral hemorrhagic fevers, and other diseases. In cases of suspected bioterrorism, the pediatrician must be able to obtain diagnostic and treatment information efficiently and expeditiously. The system controlling the interaction between public and nonpublic health laboratories in suspected cases of bioterrorism is described. Finally, information regarding emergency contacts and links to educational resources is provided.
Asunto(s)
Bioterrorismo/clasificación , Bioterrorismo/prevención & control , Carbunco/complicaciones , Carbunco/diagnóstico , Infecciones Bacterianas/complicaciones , Infecciones Bacterianas/diagnóstico , Infecciones Bacterianas/terapia , Botulismo/diagnóstico , Niño , Diagnóstico Diferencial , Exantema/etiología , Fiebre/etiología , Humanos , Micotoxicosis/diagnóstico , Micotoxicosis/terapia , Peste/complicaciones , Peste/diagnóstico , Enfermedades Respiratorias/etiología , Ricina/efectos adversos , Viruela/complicaciones , Viruela/diagnóstico , Estados Unidos , Virosis/complicaciones , Virosis/diagnóstico , Virosis/terapiaRESUMEN
A retrospective analysis of 102 patients with relapsed, non-Hodgkin's lymphoma treated with two different ricin A chain-containing immunotoxins (ITs) in five Phase I clinical trials indicates that the dose-limiting toxicity, vascular leak syndrome, was more frequent and more severe in patients who had undergone prior radiotherapy (RT). Excluding patients with prior RT from the calculations of the maximum tolerated dose indicates that the maximum tolerated doses of these ITs had not been reached in any trial and are clearly higher than reported previously. Excluding patients with prior RT from future clinical trials may increase the dose of ITs that can be given in the absence of severe vascular leak syndrome.
Asunto(s)
Síndrome de Fuga Capilar/inducido químicamente , Inmunotoxinas/efectos adversos , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/radioterapia , Ricina/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Ensayos Clínicos como Asunto , Femenino , Humanos , Inmunotoxinas/metabolismo , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estudios Retrospectivos , Ricina/metabolismoAsunto(s)
Síndrome de Fuga Capilar/inducido químicamente , Permeabilidad Capilar/efectos de los fármacos , Permeabilidad de la Membrana Celular/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Inmunotoxinas/efectos adversos , Ricina/efectos adversos , Animales , Transporte Biológico/efectos de los fármacos , Técnicas de Cultivo de Célula/instrumentación , Línea Celular/efectos de los fármacos , Línea Celular/metabolismo , Citocalasina D/farmacología , Diseño de Equipo , Humanos , Inmunotoxinas/farmacología , Inmunotoxinas/toxicidad , Ratas , Reología/instrumentación , Ricina/farmacología , Ricina/toxicidad , Venas Umbilicales/citologíaRESUMEN
Monoclonal antibodies, specific for antigens expressed on lymphoid malignancies, which have been conjugated to toxins such as ricin, hold promise in the therapy of childhood leukemia and lymphoma. Anti-B4-blocked ricin (anti-B4-bR) is such an agent, and a phase I study of this agent was conducted in children with relapsed or refractory B-lineage leukemia and lymphoma. Anti-B4-bR was given as two 7-day continuous infusions separated by 7 days. Twenty patients were enrolled and 19 received the drug. Two dosage levels (30 and 40 microg/kg per day) were evaluated. Forty micrograms per kilogram per day was the maximally tolerated dose. Dose-limiting toxicity was capillary leak syndrome. Grade 3 reversible elevation in transaminases was also encountered. Human antimouse antibodies or human antiricin antibodies were detected in five patients. No complete remissions or partial remissions were seen.
Asunto(s)
Antineoplásicos/uso terapéutico , Linfoma de Burkitt/tratamiento farmacológico , Inmunoconjugados/uso terapéutico , Linfoma de Células B/tratamiento farmacológico , Ricina/uso terapéutico , Adolescente , Adulto , Antineoplásicos/efectos adversos , Antineoplásicos/inmunología , Linfoma de Burkitt/inmunología , Linfoma de Burkitt/mortalidad , Niño , Preescolar , Femenino , Humanos , Inmunoconjugados/efectos adversos , Inmunoconjugados/inmunología , Lactante , Linfoma de Células B/inmunología , Linfoma de Células B/mortalidad , Masculino , Ricina/efectos adversos , Ricina/inmunologíaRESUMEN
This study used an 8-day continuous infusion regimen of a 1:1 mixture of two immunotoxins (ITs) prepared from deglycosylated ricin A chain (dgA) conjugated to monoclonal antibodies directed against CD22 (RFB4-dgA) and CD19 (HD37-dgA; Combotox) in a Phase I trial involving 22 patients with refractory B cell lymphoma to determine the maximum tolerated dose, clinical pharmacology, and toxicity profile and to characterize any clinical responses. Adult patients received a continuous infusion of Combotox at 10, 20, or 30 mg/m2/192 h. No intrapatient dose escalation was permitted. Patients with > or =50 circulating tumor cells (CTCs)/mm3 in peripheral blood tolerated all doses without major toxicity. The maximum level of serum IT (Cmax) achieved in this group was 345 ng/ml of RFB4-dgA and 660 ng/ml of HD37-dgA (1005 ng/ml of Combotox). In contrast, patients without CTCs (<50/mm3) had unpredictable clinical courses that included two deaths probably related to the IT. Additionally, patients exhibited a significant potential for association between mortality and a history of either autologous bone marrow or peripheral blood stem cell transplants (P2 = 0.003) and between mortality and a history of radiation therapy (P2 = 0.036). In patients with CTCs, prior therapies appeared to have little impact on toxicity. Subsequent evaluation of the ITs revealed biochemical heterogeneity between two lots of HD37-dgA. In addition, HD37-dgA thawed at the study site tended to contain significant particulates, which were not apparent in matched controls stored at the originating site. This suggests that a tendency to aggregate may have resulted from shipping, storage, and handling of the IT that occurred prior to preparation for administration. It is not clear to what extent, if any, the aggregation of HD37-dgA IT was related to the encountered clinical toxicities; however, the potential to aggregate does suggest one possible basis for problems in our clinical experience with HD37-dgA and leads us to the conclusion that non-aggregate-forming formulations for these ITs should be pursued prior to future clinical trials.
Asunto(s)
Anticuerpos Monoclonales/farmacocinética , Antígenos CD19/inmunología , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos B/inmunología , Moléculas de Adhesión Celular , Inmunotoxinas/farmacocinética , Lectinas , Linfoma de Células B/terapia , Adulto , Anciano , Anticuerpos/sangre , Anticuerpos/efectos de los fármacos , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Área Bajo la Curva , Permeabilidad Capilar/efectos de los fármacos , Cromatografía Líquida de Alta Presión/métodos , Diarrea/inducido químicamente , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Quimioterapia Combinada , Fatiga/inducido químicamente , Femenino , Fiebre/inducido químicamente , Humanos , Inmunotoxinas/efectos adversos , Inmunotoxinas/uso terapéutico , Infusiones Intravenosas , Linfoma de Células B/inmunología , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Células Neoplásicas Circulantes/efectos de los fármacos , Células Neoplásicas Circulantes/patología , Ricina/efectos adversos , Ricina/inmunología , Ricina/uso terapéutico , Lectina 2 Similar a Ig de Unión al Ácido Siálico , Resultado del TratamientoRESUMEN
This Phase II trial was undertaken to determine the safety, toxicity, and potential efficacy of the B-cell restricted immunotoxin anti-B4-blocked ricin (Anti-B4-bR) when administered as adjuvant therapy to patients in complete remission (CR) after autologous bone marrow transplantation (ABMT) for B-cell non-Hodgkin's lymphoma (NHL). Forty-nine patients with B-cell NHL in CR 46-202 days (median, 112 days) post-ABMT received Anti-B4-bR at a dose of 30 microg/kg lean body weight/day for 7 days by continuous i.v. infusion. Patients were eligible for up to two additional courses of therapy at 14-day intervals. A total of 83 courses of Anti-B4-bR were administered, with 31 patients receiving two or more courses of therapy. The mean serum level on day 7 of the first course was 0.77+/-0.41 nM. Reversible toxicities included hepatic transaminase elevations, thrombocytopenia, myalgias, fatigue, nausea, hypoalbuminemia, and dyspnea. Human antimouse antibody (HAMA) and/or human antiricin antibody (HARA) responses occurred in 23 patients at a median of 22 days from the initiation of Anti-B4-bR therapy (range, 11-100 days). The 4-year disease-free survival and overall survival are estimated at 56 and 72%, respectively. Twenty-six patients remain in CR after a median follow-up of 54.5 months. This study demonstrates that Anti-B4-bR can be administered safely to patients as adjuvant therapy early after ABMT for B-cell NHL. The toxicities are tolerable and reversible. Although the early estimate of disease-free survival was very encouraging in this single-armed trial, the 4-year follow-up data demonstrate continued relapse.
Asunto(s)
Trasplante de Médula Ósea , Inmunotoxinas/uso terapéutico , Linfoma de Células B/terapia , Ricina/uso terapéutico , Adulto , Anticuerpos Heterófilos/sangre , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Quimioterapia Adyuvante , Terapia Combinada , Esquema de Medicación , Femenino , Humanos , Inmunotoxinas/inmunología , Infusiones Intravenosas , Linfoma de Células B/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Ricina/efectos adversos , Ricina/inmunologíaRESUMEN
PURPOSE: To assess the safety and effectiveness of an immunotoxin, MDX-RA, designed to inhibit posterior capsule opacification (PCO). SETTING: Eleven private practices in the United States. METHODS: This study comprised 63 eyes of 63 patients having extracapsular cataract extraction by phacoemulsification; these patients were enrolled in a Phase I/II clinical investigation of the immunotoxin MDX-RA. At the close of surgery, 21 patients were treated with placebo, 23 patients with 50 units of the immunotoxin, and 19 patients with 175 units of the immunotoxin as an aqueous solution. The patients were monitored for 24 months after primary cataract surgery using external eye and slitlamp examinations, visual acuity assessment, ophthalmoscopy, pachymetry, tonometry, endothelial cell counts, and lens capsule photography. Posterior capsule opacification, recorded on lens capsule photographs, was graded independently by a committee of 3 cataract surgeons. The incidence of neodymium:YAG (Nd:YAG) capsulotomy was projected from the opacification results. RESULTS: The immunotoxin, at the 50 unit dose, was well tolerated and effective in inhibiting PCO. At the 175 unit dose, there was a trend toward increased postoperative inflammation that was transient with no residua. From 6 to 24 months postoperatively, the 50 unit dose significantly inhibited PCO compared with the placebo (P < .05). This significant reduction in PCO translated into a significantly lower projected need for Nd:YAG capsulotomy in the 50 unit than the placebo group (P < .004). About 60% in the placebo group and 4% in the 50 unit group were projected to need an Nd:YAG capsulotomy by 3 years postoperatively. CONCLUSION: The immunotoxin was well tolerated and was effective in reducing PCO for up to 24 months after cataract surgery. Although these preliminary results are encouraging, a larger study is underway to determine whether the reduction in PCO by the immunotoxin decreases the need for Nd:YAG capsulotomy.