RESUMEN
OBJECTIVES: Development of a simple and accurate technique for detecting active inflammation in the joints and other tissues of patients with inflammatory disorders is an unmet need in rheumatic diseases. This study is a preliminary assessment of the safety and usage of a radiopharmaceutical, FolateScan (Technetium-99m EC20; 99mTc-EC20), for detecting disease activity in patients with rheumatoid arthritis. METHODS: EC20 is a folate-targeted diagnostic radiopharmaceutical which binds to the folate receptor and is preferentially taken up by activated macrophages. In this open-label, cross-sectional study, a total of 40 patients with RA (26 with one or more swollen joints, 14 with clinically quiescent joint disease; 0/66 joint count) as well as 6 patients with osteoarthritis, 12 patients with other inflammatory conditions and 5 healthy subjects received 0.1 mg of EC20 labeled with 20-25mCi of technetium-99m. Disease activity was scored in each joint and other target tissues by a radiologist blinded to the clinical assessment, and results were compared to the rheumatologist's physical examination, which served as the test standard. RESULTS: The 40 patients (78% female) with RA had a mean age of 56.9 years. Assessment of uptake of 99mTc-EC20 in joints of patients with RA based on image analysis was compared to the clinical examination. FolateScan detected more actively involved joints in 27 patients (68%) than joints recorded as "swollen", and more actively involved joints in 25 patients (63%) than joints recorded as "painful and/or swollen". The number of swollen joints by clinical exam was correlated with ESR (r=0.43; p=0.006) and C-rp (r=0.35; p=0.03). The number of actively involved joints by FolateScan was also correlated with ESR (r=0.47; p=0.002) and C-rp (r=0.36; p=0.02). Joint uptake was also seen in patients with osteoarthritis. CONCLUSION: FolateScan is a potentially useful tool for detection of disease activity in patients with RA and may be more sensitive than the physical examination.
Asunto(s)
Artritis Reumatoide/diagnóstico por imagen , Ácido Fólico/análogos & derivados , Oligopéptidos , Radiofármacos , Índice de Severidad de la Enfermedad , Pertecnetato de Sodio Tc 99m , Adulto , Anciano , Artritis Reumatoide/patología , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteoartritis/diagnóstico por imagen , Osteoartritis/patología , Valor Predictivo de las Pruebas , CintigrafíaRESUMEN
A sensitive and selective reversed-phase LC-ESI-MS method to quantitate perifosine in human plasma was developed and validated. Sample preparation utilized simple acetonitrile precipitation without an evaporation step. With a Develosil UG-30 column (10 x 4 mm I.D.), perifosine and the internal standard hexadecylphosphocholine were baseline separated at retention times of 2.2 and 1.1 min, respectively. The mobile phase consisted of eluent A, 95% 9 mM ammonium formate (pH 8) in acetonitrile-eluent B, 95% acetonitrile in 9 mM ammonium formate (pH 8) (A-B, 40:60, v/v), and the flow-rate was 0.5 ml/min. The detection utilized selected ion monitoring in the positive-mode at m/z 462.4 and 408.4 for the protonated molecular ions of perifosine and the internal standard, respectively. The lower limit of quantitation of perifosine was 4 ng/ml in human plasma, and good linearity was observed in the 4-2,000 ng/ml range fitted by linear regression with 1/x weight. The total LC-MS run time was 5 min. The validated LC-MS assay was applied to measure perifosine plasma concentrations from patients enrolled on a phase I clinical trial for pharmacokinetic/pharmacodynamic analyses.
Asunto(s)
Antineoplásicos/sangre , Cromatografía Líquida de Alta Presión/métodos , Fosforilcolina/sangre , Espectrometría de Masa por Ionización de Electrospray/métodos , Antineoplásicos/farmacocinética , Humanos , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacocinética , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
PURPOSE: To define the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of the novel protein kinase inhibitor, UCN-01 (7-hydroxystaurosporine), administered as a 72-hour continuous intravenous infusion (CIV). PATIENTS AND METHODS: Forty-seven patients with refractory neoplasms received UCN-01 during this phase I trial. Total, free plasma, and salivary concentrations were determined; the latter were used to address the influence of plasma protein binding on peripheral tissue distribution. The phosphorylation state of the protein kinase C (PKC) substrate alpha-adducin and the abrogation of DNA damage checkpoint also were assessed. RESULTS: The recommended phase II dose of UCN-01 as a 72-hour CIV is 42.5 mg/m(2)/d for 3 days. Avid plasma protein binding of UCN-01, as measured during the trial, dictated a change in dose escalation and administration schedules. Therefore, nine patients received drug on the initial 2-week schedule, and 38 received drug on the recommended 4-week schedule. DLTs at 53 mg/m(2)/d for 3 days included hyperglycemia with resultant metabolic acidosis, pulmonary dysfunction, nausea, vomiting, and hypotension. Pharmacokinetic determinations at the recommended dose of 42.5 mg/m(2)/d for 3 days included mean total plasma concentration of 36.4 microM (terminal elimination half-life range, 447 to 1176 hours), steady-state volume of distribution of 9.3 to 14.2 L, and clearances of 0.005 to 0.033 L/h. The mean total salivary concentration was 111 nmol/L of UCN-01. One partial response was observed in a patient with melanoma, and one protracted period ( > 2.5 years) of disease stability was observed in a patient with alk-positive anaplastic large-cell lymphoma. Preliminary evidence suggests UCN-01 modulation of both PKC substrate phosphorylation and the DNA damage-related G(2) checkpoint. CONCLUSION: UCN-01 can be administered safely as an initial 72-hour CIV with subsequent monthly doses administered as 36-hour infusions.
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Alcaloides/efectos adversos , Antineoplásicos/efectos adversos , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Alcaloides/administración & dosificación , Alcaloides/farmacocinética , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Daño del ADN , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Resistencia a Antineoplásicos , Femenino , Humanos , Hiperglucemia/inducido químicamente , Hipotensión/inducido químicamente , Infusiones Intravenosas , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Masculino , Melanoma/tratamiento farmacológico , Persona de Mediana Edad , Náusea/inducido químicamente , Neoplasias/patología , Neoplasias Cutáneas/tratamiento farmacológico , Estaurosporina/análogos & derivados , Vómitos/inducido químicamenteRESUMEN
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/metabolismoRESUMEN
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
The mechanical properties of sickle erythrocyte membranes were evaluated in the ektacytometer. When ghosts from the total red blood cell population were examined, the rigidity of the resealed ghosts and their rate of fragmentation by shear stress (t1/2) were normal. However, fractionation on Stractan density gradients revealed that sickle cells were heterogenous in their membrane mechanical properties. The ghosts from dense cell fractions exhibited both increased rigidity and decreased stability. Presumably, these altered mechanical properties are a reflection of the well-documented biochemical damage found in irreversibly sickle cell membranes. Nevertheless, neither of the alterations in mechanical properties are likely to be significant elements in the hemolysis of sickle cell anemia. Earlier studies of abnormal erythrocytes suggest that increases in membrane rigidity per se do not increase hemolysis, and they are, therefore, unlikely to do so in this case. The stability of membranes from the dense cell fractions was reduced to about two thirds of the control value. Comparison with the results of studies of red blood cell membranes with genetically defective or deficient spectrin suggests that a reduction in t 1/2 of 50% is not associated with significant increases in the rate of hemolysis. Although altered ghost stability and flexibility can be demonstrated in dense sickle cells, these changes in membrane mechanical properties are not likely to be significant factors in the hemolytic process.