RESUMEN
MTRX1011A is a humanized anti-CD4 antibody with an amino acid substitution (N434H) to improve its binding to the neonatal Fc receptor (FcRn). Pharmacokinetic/pharmacodynamic (PK/PD) data in baboons suggest that the increased binding to FcRn reduces the nonspecific elimination rate (K(el)) of MTRX1011A by ~50% but does not affect its PK-PD relationship. The human PK/PD data of MTRX1011A from a phase I study in patients with rheumatoid arthritis (RA) were compared with those previously reported for TRX1, its predecessor antibody, using population PK-PD modeling. The results suggest a comparable PK-PD relationship and no significant difference between the K(el) values of the two antibodies. However, the results may have been confounded by the differences in the clinical populations in which the two antibodies were studied and the presence of preexisting immunoglobulin M (IgM) antibodies in the RA sera that recognize N434H in MTRX1011A. This study highlights the challenges in translating from animal studies to human application the effects of FcRn-directed mutations on the PK of monoclonal antibodies.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/farmacocinética , Artritis Reumatoide/tratamiento farmacológico , Antígenos CD4/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Receptores Fc/metabolismo , Animales , Humanos , Modelos Biológicos , Papio , Investigación Biomédica TraslacionalRESUMEN
A computer-guided laser probe has been developed for the application of ultrashort-pulsed lasers in neurosurgery. It is part of a novel operation concept for the treatment of deep-seated brain tumours. The system combines the positioning accuracy of stereotactic or neuronavigated instruments with the precise and therefore gentle characteristics of surgical lasers. The probe has an outer diameter of 5.5 mm and is directly inserted into the target volume. By a synchronized movement of three coaxial tubes, which guide the embedded optics, the laser radiation is focused at any time onto the current tissue surface. Since every single laser pulse has only a small effective volume of about 8 x 10(5) microm3, the application of a large number of succeeding pulses can be adapted to required geometries. Tissue fragments are removed from the growing operation cavity by continuous irrigation and suction through the laser probe. Blood vessels are detected by a confocal laser-scanning microscope, which is integrated into the probe, and can be closed by an additional coagulating laser. In this paper, the design and technical properties of the laser probe as well as its use in ablation and coagulation experiments are presented. A description of the overall operation system is given.
Asunto(s)
Neoplasias Encefálicas/radioterapia , Terapia por Láser/métodos , Radioterapia Asistida por Computador/instrumentación , Radioterapia Asistida por Computador/métodos , Animales , Bovinos , Microscopía Electrónica de Rastreo , PorcinosRESUMEN
One method of rate responsive pacing utilizes an analog of minute ventilation as the input to the rate control algorithm. A measure of the intravenous impedance along the pacing catheter is a convenient means of determining minute ventilation. Design of the impedance converter requires a knowledge of the range of DC and AC impedance signals. During normal and deep breathing, 116 AC measurements were taken from 34 Electrophysiology (EP) patients and 31 DC measurements were taken from 13 EP patients. The patient data produced skewed distributions with a normal AC mean of 0.45 +/- 0.40 ohms p-p, a deep AC mean of 2.0 +/- 1.6 ohms and a DC mean of 44 +/- 13 ohms. An eight variable static model was derived from prior work. Five of the physiological variables were chosen from established clinical ranges, one geometrical variable was chosen from prior work and two were selected by matching the statistics of a Monte Carlo analysis of the model with the statistics of the patient data. The blood resistivity was obtained from prior work. A simulation of 1000 measurements produced a normal breathing range of 0 to 2.24 ohms, a deep breathing range of 0 to 9.6 ohms and a DC range of 19 to 100 ohms.