The development of copper-67-labeled porphyrin-antibody conjugates.
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Biomedical subjects
Publications and source records attributed to J C Roberts.
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We analyzed patients who died on chronic dialysis because they stopped the treatment, although there was no technical dialysis complication or new medical complication. These patients preferred death to the stress of dialysis. This occurred in 26/1766 (1.5%) patients, and was responsible for 26/704 (4%) of all deaths. We compared these 26 patients to 40 competent patients who discontinued treatment when a medical complication arose. The patients were similar in most respects (age, sex, diagnosis, duration of dialysis, living situation, and type of dialysis) and had the same number of medical complications when starting dialysis. However, the patients who stopped dialysis were more often on home dialysis, 8/24 vs. 3/40 of the other patients (p less than 0.05). Overall, stopping was three times more common in home than in center patients (3.0% vs. 1.1%) (p less than 0.02). Relatives responding to a written interview felt that nurses and social workers but not physicians had been helpful in the difficult time surrounding the patient's decision and death. This study indicates that particularly home dialysis patients are at a high risk of discontinuing dialysis because of the stress of the dialysis procedure. A realistic introduction to and realization of their dialysis problems, better training and better psychological support, particularly from physicians, are necessary to eradicate this avoidable cause of death in chronic dialysis patients.
Methods were developed to label antibodies with copper-67, a potentially useful medical radioisotope, using the porphyrin chelating agent N-benzyl-5,10,15,20-tetrakis(4-carboxyphenyl) porphine. The porphyrin was activated for coupling using either (1) 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide HCl and N-hydroxysuccinimide or (2) 1,1'-carbonyldiimidazole. The coupling reactions were optimized as a function of activation time, coupling time, coupling pH, and reagent concentrations to achieve maximum coupling to IgG monomer. Sodium dodecylsulfate polyacrylamide gel electrophoresis was used to determine coupling yields. After purification by gel filtration, the antibody-porphyrin conjugates were labeled with copper-67 in aqueous solution. The coupling protocols were used to label antibodies from several species, demonstrating the general utility of these methods. Characterization of the conjugates indicated that the porphyrin label was attached randomly to the IgG molecule. Antigen binding capacities after conjugation were unaltered or slightly lowered as determined by a competitive ELISA.
A series of beta-mono- and beta,beta-disubstituted cysteines were evaluated in rats as sequestering agents for metabolically generated acetaldehyde (AcH) during the oxidation of ethanol in vivo and compared against D-(-)-penicillamine. Both threo- (5) and erythro-beta-phenyl-DL-cysteine (6) reduced ethanol-derived blood AcH by ca. 40% and 60%, respectively, whereas the corresponding beta-methyl-DL-cysteines (3 and 4) and the alpha-substituted alpha-methyl-DL-cysteine (8) had no effect. beta,beta-Tetramethylene-DL-cysteine (7), however, was as effective as D-(-)-penicillamine in sequestering AcH in vivo, reducing blood AcH after ethanol to 20% of maximal values. Thus, bulky beta-substitution or, better, beta,beta-disubstitution on cysteine is required for such activity. 14C-Labeled 2(RS),5,5-trimethylthiazolidine-4(S)-carboxylic acid (1) prepared by the condensation of D-(-)-penicillamine with [1,2-14C]acetaldehyde was found to be relatively stable in vivo, giving rise to less than 6% 14CO2 excretion in the expired air and the recovery of 65.5% of the administered dose in the urine as unchanged 1.
Eight prodrugs of L-cysteine (1a-h) were synthesized by the condensation of the sulfhydryl amino acid with naturally occurring aldose monosaccharides containing three, five, and six carbon atoms. The resulting 2-(polyhydroxyalkyl)thiazolidine-4(R)-carboxylic acids (TCAs) are capable of releasing L-cysteine and the sugars by nonenzymatic ring opening and hydrolysis. Thus, when added to rat hepatocyte preparations in vitro, these TCAs (1.0 mM) raised cellular glutathione (GSH) levels 1.2-2.1-fold relative to controls. On the basis of this finding, the cysteine prodrugs were tested as protective agents against acetaminophen-induced hepatotoxicity in a mouse model. The TCA derived from D-ribose and L-cysteine (RibCys, 1d) showed the greatest therapeutic promise of the series, with a 100% (12/12) survival profile compared to 17% without treatment. However, the degree of stimulation of GSH production in rat hepatocytes by these prodrugs did not correlate with the extent of protection afforded in mice, suggesting that pharmacokinetic parameters must supervene in vivo. To evaluate the effect of increased lipid solubility, we prepared prodrugs 2a-c by using peracetylated aldehydic sugars in the condensation reaction. These compounds, however, displayed acute toxicity to mice, possibly due to liberation of the acetylated sugars themselves. Nevertheless, the efficacy of the unacetylated TCAs, and RibCys (1d) in particular, suggests that the prodrug approach for the delivery of L-cysteine to the liver represents a viable means of augmenting existing detoxication mechanisms in protecting cells against xenobiotic substances that are bioactivated to toxic, reactive metabolites.
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As a consequence of rapidly increasing and complex ethical dilemmas in medicine, health care institutions are responding by forming biomedical ethics committees. In this article, the authors review the origins, functions, and potential drawbacks of these committees and also make suggestions on starting these committees.
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Reduction in maternal mortality, infant mortality, and infant morbidity have been successively the goals of perinatal medicine. The fourth is to reduce bonding failure. In July 1978 a preventive service was started in the John Radcliffe Maternity Hospital. A twice-weekly round is made. Midwives refer families who cause them concern. In the first year the referral rate ws 20.5 per 1000 liveborn babies. The referred sample differed from the hospital population in terms of maternal psychiatric history, marital state and babies' admission to special care. The main reasons for referral were: doubt about parenting ability (27%), psychiatric history (15%), disturbed behaviour in hospital (14%), and diffuse social and medical problems (17%). Long-term care was needed for only 14% of families. At their first birthdays, six babies were placed away from their natural parents; the sample had had a slightly higher than expected admission rate to hospital; the distribution of weights did not differ from the expected; doctors and health visitors were still concerned about one-quarter of the families. Seven cases of screening failure were found among those not referred to our service, but only one was seriously abused. No child referred in the first year has been seriously neglected or abused.
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This paper investigates the relationship between Trail Making scores and observer rated aggressive behaviour of 33 patients in a therapeutic community. Significant correlations (.34 to .59) were found between Trail Making scores and aggressive outbursts.
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The wear of cental amalgam was studied by single- and double-pass sliding and by a silicon carbide abrasion test. A dispersed amalgam showed significantly better resistance to two-body abrasion than the spherical amalgams tested. The wear amalgam was determined by resistance to penetration and by a ductile mode of surface failure over the load range studied. Differences in the wear of amalgam and restorative resins and composites are discussed.
1. Adult Mongolian gerbils (Meriones unguiculatus) were acclimated to 5 +/- 1, 24 +/- 1 and 34 +/- 1 degrees C for 6-8 weeks. 2. Body weights of temperature acclimated gerbils did not differ significantly from controls. Organ wt/body wt ratios of liver, kidney and heart increased in cold-acclimated and decreased in heat-acclimated gerbils. Adrenal wt/body wt ratio increased in the cold and was unchanged in the heat. Relative weights of brain, spleen, lungs, brown fat and ovaries + uterus did not change with temperature acclimation. 3. Cold acclimation produced significant increases in specific and total activity of brown fat alpha GPO and liver SO and AAO and in total activity of kidney SO; a significant decrease in liver mitochondrial ADP/O ratio with succinate as substrate; and no change in brown fat SO or liver alpha KGO. 4. Heat acclimation produced significant decreases in specific and total activity of liver and kidney SO, and in total activity of brown fat SO and alpha GPO, and liver AAO and alpha KGO. 5. The combined biochemical and organ wt changes seen in temperature-acclimated gerbils suggest that this species is capable of altering its metabolic thermogenic potential in response to a wide range of ambient temperatures.
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