Long-term analgesic effect of a single dose of anti-NGF antibody on pain during motion without notable suppression of joint edema and lesion in a rat model of osteoarthritis.

OBJECTIVE: Osteoarthritis (OA) patients experience exaggerated pain during movements such as walking. Anti-nerve growth factor (NGF) antibodies have recently shown analgesic effects in OA patients. We examined the effect of a single dose of anti-NGF antibody on pain during motion, joint edema and lesion in a rat model of OA to determine whether the analgesic effect demonstrated in clinical studies can be translated to a preclinical model. METHODS: Sodium monoiodoacetate (MIA)-induced arthritic rats that develop a right-left gait imbalance when walking as an index of pain during motion. This imbalance was assessed using a gait analysis system called "CatWalk". Edema size and lesion score in the relevant knee joint were also measured. The effect of a single intravenous injection of an anti-NGF monoclonal antibody AS2886401-00 on these parameters was assessed. RESULTS: AS2886401-00 administered at 0.3 or 1 mg/kg on Day 3 post-MIA injection resulted in a statistically significant improvement in gait imbalance even on Day 35. When gait measurement was set on Week 3 post-MIA administration, administration of the antibody at a timing close to the gait measurement, i.e., 1 or 24 h prior to the measurement, was less effective. AS2886401-00 did not suppress either edema or lesion. CONCLUSIONS: A single dose of anti-NGF antibody exerts a long-lasting analgesic effect on pain during motion in a rat model of OA. This finding could be associated with the analgesic efficacies that anti-NGF antibodies have exhibited in clinical studies. It appears unlikely that analgesia is secondary to inhibition of joint edema and lesion.

Fetal circulatory responses to maternal blood loss.

We examined the fetal circulatory responses to maternal blood loss in pregnant women during the third trimester. Seven healthy women with placenta previa and singleton pregnancies underwent phlebotomies in an autologous donation program. Four hundred milliliters of blood was collected within 15 min at 34 and 35 weeks of gestation. Continuous electric recordings of fetal heart rate were performed during the first blood collection, and the maternal uterine artery (UtA), umbilical artery (UmA) and fetal middle cerebral artery (MCA) Doppler velocity waveforms were recorded before, immediately after and 24 h after the second collection in each patient. The average fetal heart rate, maternal UtA and UmA pulsatility indices did not change measurably during or after maternal blood collections. However, the average fetal MCA pulsatility index decreased significantly 24 h after maternal blood loss. The observation of a decrease in fetal MCA pulsatility index may indicate delayed fetal asphyxia following mild maternal hemorrhage.

Cloning and tyrosine phosphorylation of a novel invertebrate immunocyte protein containing immunoreceptor tyrosine-based activation motifs.

Immunoreceptor tyrosine-based activation motif (ITAM) plays an important role in signal transduction through mammalian T-cell and B-cell antigen receptors and Fc receptors. The ITAM has been found only in vertebrate immunocytes. Ascidians are intriguing invertebrates from the viewpoint of the evolution of immune systems because they are considered to be ancestors of the vertebrates. We have previously shown that the monoclonal antibody A74 inhibits cellular defense reactions of the ascidian. In the present studies, we found that the A74 antigen protein has two ITAMs and several motifs that are proposed to function in signal transduction. The A74 protein is tyrosine-phosphorylated and associated with other proteins in the initial stages of cellular defense reactions. The ITAMs of the A74 protein are tyrosine-phosphorylated by a c-Src kinase in vitro. The A74 protein provides a key to the understanding of the origin of vertebrate immune systems.