Emanuel E. Schwartz

The mechanism of action of AET. IV. The distribution and the chemical forms of 2-mercaptoethylguanidine and bis(2-guanidoethyl) disulfide in protected mice.

The distribution and chemical nature of the protective agent in the various tissues of 8- to 10-week-old C57BL/6J male mice given a protective dose of MEG-S/sup 35/ and GEDS/sup 35/ were studied. Results were obtained at 20 minutes after an intraperitoneal (i.p.) injection of 140 and 280 mg of MEG per kilogram and at 20, 60, and 120 min after an i.p, injection of 140 mg of GED per kilogram. Protein-bound S/sup 35/, GED, taurocyamine, guanidoethanesulfinic acid, MEG, and sulfate were identified in the serum, tissues, and excreta. Several unknown compounds were also observed. Concentrations of protein-bound S/ sup 35/ and GED decreased at 120 minutes after GED administration and correlated best with protection of the mice. All products increased in the tissues at the higher dose of MEG. Some differences in the concentrations of products were noted on comparison of MEG with GED-treated animals. The relation of the results to the mechanisms of action of MEG and GED is discussed. (auth)

The protection of mice against radiation by 2-mercaptoethylguanidine and its disulfide.

Some sulfhydryl compounds lose their ability to protect against ionizing radiation when they are administered in the oxidized state. Oxidized glutathione (1, 2) and cystine (3), the oxidized form of cysteine, are inactive as protectors, whereas cystamine (4-7), the oxidized form of cysteamine, is highly effective in reducing the injurious effects of radiation. Gordy and Miyagawa (8) have suggested that cystamine is effective only on its reduction to cysteamine within the animal cell. 2-Mercaptoethylguanidine (MEG) is formed by transguanylation when S-(2aminoethyl)thiuronium bromide hydrobromide (AET) is dissolved in aqueous buffered solutions at neutral pH (9). Hence, MEG rather than AET has usually been the substance administered in previously reported protective studies. MEG is readily oxidized in mildly alkaline solutions to bis(2-guanidoethyl) disulfide (GED), and solutions of MEG are therefore frequently contaminated with the disulfide. In their survey of related compounds with protective activity, Shapira et al. (10) observed that GED, as well as MEG, protected mice against radiation. The present study was undertaken to investigate, in greater detail, the relationship between the state of oxidation of this agent prior to administration, and its therapeutic efficiency.

Large-volume continuous-flow electrophoresis of serum proteins with glass microbeads

Abstract A continuous-flow electrophoresis apparatus utilizing siliconized Pyrex glass microbeads has been described. The apparatus has been used to separate and collect large quantities of serum proteins in a relatively short period of time. Evidence is presented to indicate that there is little or no loss of biological activity in the collected fractions.

Radiation-induced changes in the gastrointestinal function of mice and their prevention by chemical means.

Death of rodents during the first week after whole-body or abdominal exposure to 1 to 10,000 r is due mainly to small-bowel injury (1, 2). Among the events which precede death are the mitotic arrest of the crypt cells (1, 3), impairment of DNA synthesis (4, 5), intestinal weight loss (6, 7), alterations in gastrointestinal motility (8), and water and electrolyte imbalance (9, 10). These effects can be prevented, in part, by the administration of certain sulfhydryl compounds shortly before irradiation (11–15). Studies of the effect of radiation on the normal functions of the gastrointestinal tract, such as digestion and absorption, may provide further insight into the mechanism of injury and death from this cause. Morehouse and Searcy (16) observed that supralethal doses of radiation retard the absorption of dioleylpalmitin in rats. Carbohydrate absorption has also been found to be reduced after whole-body x-ray exposure (17, 18). The purpose of the present investigation was to evaluate the effect of diffe...

Pulmonary hemorrhage in renal disease: Goodpasture's syndrome and other causes.

Pulmonary hemorrhage is generally due to neoplasm, tuberculosis, necrotizing pneumonia, or bronchiectasis. If these are not found, kidney diseases, including anti-glomerular basement membrane antibody-induced bleeding (Goodpastures syndrome), should be considered. Hemoptysis in renal disease is more often due to azotemic hypervolemia than immune reaction. Typically linear immunofluorescent patterns along the glomerular and pulmonary alveolar basement membranes must be demonstrated to confirm the diagnosis of Goodpastures syndrome.

Pulmonary parenchymal damage complicating intravenous alimentation

Summary A pulmonary lesion representing a cavitating infarct resulted from the inadvertent administration of hypertonic intravenous alimentation solution into the left pulmonary artery. Insistence upon the exact localization of the catheter tip prior to the start of the infusion should be mandatory in the management of parenteral nutrition

The Mechanism of Action of AET: V. The Distribution and the Chemical Forms of 2-Mercaptoethylguanidine and Bis(2-Guanidoethyl) Disulfide Given Orally in Protective Doses to Mice

The distribution and chemical forms of 2-mercaptoethylguanidine (MEG) and bis(2-guanidoethyl) disulfide (GED) in the various tissues or 8- to 10-week- old C57Bl male mice 30 min after an oral radiation protective dose of 400 mg of MEG-S35 and GED-S35/kg were studied. At 30 min after oral administration of MEG or GED, a significant amount of protective agent remained in the gastrointestinal tract. This accounts for some of the differences in LD50(30) values for equal doses of protective agent by oral and intraperitoneal routes. MEG was absorbed from the intestines more rapidly than GED, and protective forms appeared in the tissues in higher concentration after MEG administration. This explains the better protection provided by oral MEG as compared with oral GED at 30 min. The difference in absorption rates of MEG and GED may be useful in controlling the speed of onset and duration of protection by these agents in mice.

Combined Irradiation and Chemotherapy in Ovarian Carcinoma

Despite recent advances in radiotherapy, ovarian carcinoma which has spread beyond the pelvis has an extremely poor prognosis (1, 2). The difficulty in treating such cases can be partially ascribed to the limitation upon radiation dose imposed by the tolerance of normal abdominal organs. Various chemotherapeutic agents have also been administered in these cases, among which triethylene-thiophos-phoramide (ThioTEPA) appears to be one of the most effective (3, 4). In the hope of improving upon results thus far achieved, a program has been formulated based upon the concomitant use of ThioTEPA and irradiation. When abdominal involvement is found, ThioTEPA (0.4–0.5 mg./kg.) is introduced directly into the peritoneal cavity. This is done either at laparotomy or via an indwelling polyethylene tube within several days of surgery. Irradiation (cobalt 60) and intravenous ThioTEPA are started two to three weeks later on the same day. Five milligrams of the drug is given intravenously each day of irradiation until an...

STUDIES CONCERNING THE NATURE OF THE PROTEIN-BOUND PROTECTIVE AGENT IN THE TISSUES OF MICE GIVEN BIS (2-GUANIDOETHYL DISULFIDE (GED).

The presence of disulfide and thiolester bonds between the protective agent and tissue protein in protected animals was determined qualitatively and quantitatively. Tissue homogenates were dialyzed against water and then against cysteine, taking the additional amount of radioactivity removed from the protein, as a measure of mixed disuifide bonding of /sup 35/S-labeled bis(2-guanidoethyl) disulfide (GED). Thiolester bonds were measured by dialyzing tissue homogenates against water and then against hydroxylamine, taking the additional amount of radioactivity removed from the protein as a measure of thiolester-binding of /sup 35/S-labeled GED. Results of the work indicate that the protective agent is bound to the protein by a thiolester bond as well as by a mixed disulfide bond. (H.M.G.)

Chemical protection against radiation in tumorbearing mice.

Sulfur-35-labeled AET, both in its reduced and oxidized forms; namely, 2- mercaptoethylguanidine (MEG) and bis(2-guanidoethyl) disulfide (GED), was injected into adult mice that had previously received a subcutaneous inoculum of isologous mammary adenocarcinoma. Animals were sacrificed within 20 min or 2 hr later; various organs and tumors were assayed for radioactivity; and the different metabolites present were separated, identified, and quantitated by paper chromatography. Brain, subcutaneous mammary tumors, and testes were found to have the lowest concentrations of AET sulfur; while kidney, small intestines, and liver had the highest. The most prominent difference between mice carrying mammary tumors and normal mice is seen in the kidney where approximately twice the normal concentration is found in tumor bearers. Survival studies after whole- body irradiation revealed a proiongation of survival with ME0 and GED in tumorbearing mice as well as in normal mice. GED recipients survived longer than MEG recipients. The extent of x-ray dose reduction in locally growing mammary tumors in MEG and GED recipients was also determined. (H.M.G.)