Reduction of renal uptake of monoclonal antibody fragments by amino acid infusion

The renal uptake of radiolabeled antibody fragments and peptides presents a problem in radioimmunodetection and therapy, compromising lesion sensitivity, especially with intracellularly-retained isotopes. Previously, we showed that cationic amino acids and their derivatives are capable of significantly reducing kidney uptake in animals. We report our initial clinical results of successful renal uptake reduction in five patients who underwent cancer radioimmunodetection with 99mTc-anti-CEA Fab' fragments. METHODS: The patients were infused with two liters of a commercially-available nutritive amino acid solution (containing approximately 2.25 g/liter lysine-glutamate and 2.50 g/liter arginine), whereas 75 control patients received the same volume of saline (quantification of organ and tumor kinetics from conjugate whole-body views by ROI technique). RESULTS: The renal uptake in the amino acid group was significantly lower (p<0.05) than in the control group (11.1 +/- 2.0% injected dose versus 17.7 +/- 7.0% injected dose at 24 hr postinjection), whereas the uptake of all other organs remained unaffected. Gel filtration chromatography of the urine taken from amino-acid-treated patients showed that a significantly higher amount of excreted activity was bound to intact Fab' (53% of excreted activity) in contrast to only less than 10% in the control group. CONCLUSION: The renal uptake of monoclonal antibody fragments in patients can be reduced significantly by amino acid infusion, even at considerably lower doses than those that were safe and effective in animals. As was found in animals, the mechanism seems to rely on an inhibition of the re-absorption of tubularly-filtered proteins by the proximal tubule cells. These results encourage further clinical trials to lower the renal uptake experienced in radioimmunodetection, as well as in therapeutic trials with antibody fragments and peptides.     

Adsorption of chitin derivatives onto liposomes: optimization of adsorption conditions

A 2(4) factorial design is used to optimize the adsorption conditions of the hydrophilic anionic polyelectrolytes. Carboxymethylchitin (CMC) and Carboxymethyl/Glycolchitin (CO) onto liposomes at physiological ionic strength (I) and pH using phosphate buffered saline (PBS, I = 154 mM, pH = 7.4). Positive ([+]) or high surface affinity liposomes (DSPC:CHOL:DMTAP, 5:4:1), and Neutral ([N]) or low surface affinity liposomes (DSPC:CHOL, 1:1) were used as adsorption surfaces. Results of the calculations of the main effects indicate that polymer molecular weight (mwt), Surface Affinity (S), Number of Adsorption Shots (Sh), Temperature (T), and the combinations mwt x S, mwt x Sh are the most important process parameters. Results of a study conducted at T = 37 degrees C show that no loss occurs from the positive surface at the highest particle concentration, Np = 4.043 x 10(11). Finally, the extent of polymer-induced particle aggregation is decreased when the diameter of the uncoated liposomes is doubled from 0.22 to 0.45 micron. These results are as expected, given the stiffness and the dimensions of the macromolecules.     

CT combined with arterial portography. A sensitive method for evaluation of liver tumors

During the period 1994-95, 22 patients were examined with CT during arterial portography for evaluation of hepatic tumours. The majority, 20 patients, had metastases from colon cancer. All patients were candidates for liver resection. In the series of patients described here, this process detected additional lesions in four more of the patients than found with any other imaging techniques. This supports that CT during arterial portography is the most sensitive method for detecting small malignant hepatic tumours, and for localizing them in relation to liver segments and major vascular structures. Optimal results are obtained in the absence of diffuse parenchymal disease and portal hypertension. Non-tumourous perfusion defects limit the accuracy of this technique, but such defects have characteristic locations and appearance. In difficult cases the technique should be correlated with ultrasonography and MR.     

Obese gene expression: reduction by fasting and stimulation by insulin and glucose in lean mice, and persistent elevation in acquired (diet-induced) and genetic (yellow agouti) obesity

Mutations in the obese (ob) gene lead to obesity. This gene has been recently cloned, but the factors regulating its expression have not been elucidated. To address the regulation of the ob gene with regard to body weight and nutritional factors, Northern blot analysis was used to assess ob mRNA in adipose tissue from mice [lean, obese due to diet, or genetically (yellow agouti) obese] under different nutritional conditions. ob mRNA was elevated in both forms of obesity, compared to lean controls, correlated with elevations in plasma insulin and body weight, but not plasma glucose. In lean C57BL/6J mice, but not in mice with diet-induced obesity, ob mRNA decreased after a 48-hr fast. Similarly, in lean C57BL/6J controls, but not in obese yellow mice, i.p. glucose injection significantly increased ob mRNA. For up to 30 min after glucose injection, ob mRNA in lean mice significantly correlated with plasma glucose, but not with plasma insulin. In a separate study with only lean mice, ob mRNA was inhibited >90% by fasting, and elevated approximately 2-fold 30 min after i.p. injection of either glucose or insulin. These results suggest that in lean animals glucose and insulin enhance ob gene expression. In contrast to our results in lean mice, in obese animals ob mRNA is elevated and relatively insensitive to nutritional state, possibly due to chronic exposure to elevated plasma insulin and/or glucose.     

The role of dermabrasion and chemical peels in the treatment of patients with xeroderma pigmentosum

We describe our experience with two patients with xeroderma pigmentosum who underwent periodic trichloroacetic acid chemical peels. One also received a full-face dermabrasion. The effect of chemical peeling was more transient than dermabrasion but was associated with less morbidity. Both chemical peeling and dermabrasion provided a prophylactic effect against the development of skin malignancies; the latter had a more pronounced effect.     

Spatial and temporal features of recurrent facilitation among motoneurons innervating synergistic muscles of the cat

1. The temporal features and strength of recurrent facilitatory potentials were examined in pairs of lumbosacral motoneurons that were separated by a known distance and were identified by antidromic stimulation of muscle nerves. One motoneuron was stimulated by injecting depolarizing current pulses, and responses were recorded in the second motoneuron. The distance between motoneurons in pairs was also measured to assess the spatial distribution in strength of recurrent facilitation in motor pools. All motoneurons in these pairs innervated muscles that act as hip or ankle extensors. 2. Recurrent facilitatory potentials were found frequently among motoneurons innervating the hindlimb extensor muscles examined. Several categories of recurrent facilitatory responses were identified. One category was composed of facilitation responses that followed an inhibition response. A second category was composed of facilitation responses that were not preceded by a significant inhibition and consisted of a monophasic response. There was a considerable range of latencies in this category. 3. Responses in which recurrent facilitatory potentials were preceded by recurrent inhibitory postsynaptic potentials (RIPSPs) among close motoneuron pairs demonstrated an inverse correlation between the durations of the facilitatory and the inhibitory phases. In addition, the duration of inhibition responses without facilitation was longer on average, than the duration of inhibitory responses that were followed by facilitation. It was suggested that recurrent facilitation may restrict the time course of RIPSPs. 4. In contrast to the topographic distribution of RIPSPs described in the previous report, amplitudes of monophasic facilitations were directly correlated with the distance separating motoneurons in pairs, rather than inversely correlated as was the case for RIPSP amplitudes.(ABSTRACT TRUNCATED AT 250 WORDS)