Potency of peroral and parenteral administration of Zinc-DTPA for decorporation of 241Am from the gastrointestinal tract

An effect of cincacine at three doses (25, 150 and 300 mumol/kg) has been studied in rats receiving 241Am citrate intragastrically. The radionuclide was introduced every other day for 2 weeks. The total content was 925 kBq/kg. A cincacine administration leads to limitation of radionuclide accumulation in the major organs of deposition independent of the modes of intake. At gastrointestinal 241Am intake peroral cincacine administration is more effective in limiting this radionuclide accumulation in skeleton but less effective in reduction of its accumulation in liver compared to parenteral cincacine. No reliable dependence of cincacine efficacy on dosage has been revealed. A morphology study of organs has shown that cincacine ingestion at a dose of 150 mumol/kg for 4 weeks and at a dose of 300 mumol/kg for 2 weeks produces a toxic effect on the small intestine mucosa. 25 mumol/kg is the optimum dose and per os administration of higher doses is not expedient.     

Study of effectiveness of long-term per oral and parenteral cincacine administration at parenteral 241Am incorporation into the organism

Effect of long-term (during 4 weeks) cincacine administration following single parenteral 241Am intake has been studied on rats depending on method (per oral or parenteral), dosage and time of treatment initiation. Cincacine administration leads to limitation of radionuclide incorporation in the major organs of deposition for the both methods of introduction. At the parenteral 241Am intake in the organism parenteral cincacine administration was found to be more effective compared to per oral cincacine administration even in case of its dose increase by a factor of 6 and 12. At the parenteral introduction of the preparation, time of treatment beginning is more significant than at per oral administration.     

Absorption from the gastrointestinal tract of rats of biologically incorporated 241Am found in fish

In experiments on mongrel albino rats it was shown that the absorption of 241Am "biologically incorporated" in fish from the gastrointestinal tract amounted to 0.1% and exceeded by 4.5 times the intake of 241Am nitrate and by 6 times the absorption of 241Am administered in fish externally contaminated with americium 241.     

Chelation therapy of incorporated plutonium-238 and americium-241: comparison of LICAM(C), DTPA and DFOA in rats, hamsters and mice

The carboxylated catechoylamide 3,4,3-LICAM(C) was tested for removal of 238Pu and 241Am from small laboratory rodents. The effectiveness of treatment was compared with that of two ligand preparations approved for clinical use: calcium-trisodium diethylenetriaminepentaacetate (DTPA) and desferrioxamine (DFOA). With early treatment and at the dosage used clinically for the decorporation of actinides with DTPA (30 mumol/kg body weight) LICAM(C) was superior to DFOA but when compared with DTPA, the effect of LICAM(C) on 238Pu was greater only in bone; as little as 1 mumol LICAM(C)/kg was as effective as 30 mumol DTPA/kg. However, in all animals treated with LICAM(C) there was a large increase in the 238Pu content of the kidney. With 241Am the effect of DTPA was always superior to that of LICAM(C). The best overall results early (1 day) after injection of 238Pu and 241Am were achieved by a combination of a single injection of LICAM(C) and DTPA with subsequent continuous administration of DTPA in drinking water. LICAM(C) affected the retention of 238Pu even if given orally; the data suggested that about 3 per cent of ingested LICAM(C) was absorbed. When the beginning of treatment was delayed, LICAM(C) became equally effective or less effective than DTPA even as far as 238Pu retention in bone was concerned, but it still increased the accumulation of 238Pu in the kidneys.     

Combined prophylactic administration of riboxin and algisorbum at 239Pu intake into gastrointestinal tract of rats

The present study is devoted to the investigation of effectiveness of combined prophylactic administration of riboxin and algisorbum at 239Pu per oral intake and possible mechanisms of their interaction, and also to comparative estimation of effectiveness of combined administration of the preparations at per oral and intra peritoneal methods of riboxin introduction. The experiments have been carried out on white nonlinear rats. Riboxin (per oral and intra peritoneal) and algisorbum (per oral) have been introduced to the rats both separately and combined before per oral 239Pu introduction. Data obtained as a result of the investigation showed that combined riboxin and algisorbum introduction into gastrointestinal tract before 239PU intake lead to greater decrease in the plutonium content in the organs of deposition than single algisorbum administration. Intra peritoneal riboxin introduction reduced effectiveness of per oral algisorbum administration in plutonium binding in GI tract. Efficiency of combined riboxin and algisorbum administration in the reduction of 239Pu accumulation in organs depends on the method of riboxin introduction and develops only at per oral introduction.     

Experimental study of 241Am transfer from herbal food to organs and tissues of crucian carp

Freshwater fishes (Carassius auratus gibelio, crucian carp) were fed through catheter with homogenized biomass of submerged macrophytes labeled with transuranium element 241Am. The intensity of excretion of americium and its accumulation in organs and tissues of fishes were investigated. The highest release of americium (up to 70%) was recorded on the second day after feeding. 94-98% of americium were excreted during 3-4 days; however, americium was also recorded in the excrements after 11 days. Americium was registered in organs and tissues of fishes, including those tissues that had no direct contact with americium (bones and muscles). This implies assimilation of americium via digestive tract. The activity concentration of americium in bones (11 Bq/kg, fresh mass) was twice as high as that in muscles, heads and external tissues and organs (skin, scales and fins). The highest activity concentration of americium was registered in viscera (33 Bq/kg, 48% of the total activity in the body). Accumulation of americium in muscles enhances the probability of the further transfer of americium along a food chain.     

Stimulation of somatotropin secretion following peripheral administration of the tripeptide, syndyphalin 33 in sheep, pigs and rats

In the present study, a simple tripeptide alkylamine, syndyphalin 33 (SD33, Tyr-DMet (O)-Gly-methylphenethylamide) was shown to stimulate somatotropin (GH) secretion in sheep, hogs and rats following peripheral administration. Intravenous (i.v.) administration of SD33 at doses of 0.05, 0.1 and 0.2 mumol/kg stimulated a significant increase in circulating GH levels in sheep within 5 minutes post-injection. This response was not attenuated following repeated i.v. injections of SD33 (0.05 /mmol/kg) administered at 2 hour intervals. In addition, plasma GH levels were significantly stimulated following either subcutaneous (s.c.) or oral administration of SD33 in hogs and rats. Subcutaneous administration of SD33 at doses of 0.5, 1.0 and 2.0 mumol/kg stimulated a significant increase in plasma GH concentrations within 30 minutes of injection in both species. Oral administration of SD33 at 1.0, 10 or 100 mumol/kg in rats resulted in a significant elevation in plasma GH levels which peaked at 30 minutes post-gavage. In the pig, circulating GH levels were significantly increased within 30 minutes post-ingestion and remained elevated for at least 2 hours at the 2.0 mumol/kg dose level. The ability of naloxone to block SD33-stimulated GH secretion suggests that this peptide acts via mu opiate receptors.     

Proton relaxation enhancement in tissue due to ingested manganese chloride: time course and dose response in the rat

MnCl2, a potential NMR contrast agent, was force fed by cannula to 27 fasted rats in an attempt to establish the efficacy of this route of administration. The animals were sacrificed and the relaxation times (T1 and T2) of liver, spleen, kidney, heart, and skeletal muscle were determined in vitro. One group of rats was subject to a range of doses (8.3-333.3 mg/kg) and sacrificed at 90 minutes. Another group received a single large dose (500 mg/kg) with animals sacrificed at intervals from 15-225 minutes. The single large dose caused a rapid and prolonged reduction in liver T1 (-93% of normal) and to a lesser degree affected the other organs. The dose response data shows that liver T1 is also affected at significantly lower dosages than the other tissues tested. These results suggest the oral route as a possible alternative to IV Mn+2. Further studies with inorganic and organic manganese are indicated.     

Effect of gavaged chemical form of 241Am on its retention in mice

The retention of 241Am in mice 48 h after administration by gavage is reported here. The 241Am was given to mice in the form of either 241Am nitrate or 241Am citrate. The 241Am was also injected into rats in the same form. The homogenized livers of those rats were subsequently administered by gavage to another group of mice. The retention of 241Am citrate was 1.5 X 10(-2)% of the original dose and was the highest among the compounds examined. The retention of biologically incorporated 241Am into the liver as 241Am nitrate and as 241Am citrate was 2.4 X 10(-3) and 2.6 X 10(-3)%, respectively, and was similar to the retention of 241Am nitrate, which was 2.8 X 10(-3)%. The ratio of the retention in the carcass to that in the liver for the 241Am citrate was lower than that of the 241Am nitrate and the biologically incorporated 241Am. This difference indicates that the distribution of 241Am in the animal body depends on the chemical form administered. The retention of liver-incorporated 241Am as citrate after autolysis of the liver is similar to that of fresh liver-incorporated 241Am citrate.     

Toxic action of 2'-chloro-2,4-dinitro-5',6-di(trifluoromethyl) diphenylamine in the rat.

2'-Chloro-2,4-dinitro-5',6-di(trifluoromethyl)diphenylamine (CDTD) is a potent uncoupler of oxidative phosphorylation in isolated rat liver or brain mitochondria. The concentration of CDTD causing 50% uncoupling in vitro is dependent on the mitochdonrial protein concentration and is 2 nM at 0.9 mg protein/ml for rat liver mitochondria. Oxidative phosphorylation can be restored to CDTD uncoupled liver mitochondria by the addition of a 10 000-fold molar excess of bovine serum albumin to DCTD. Rats given a lethal dose (7.0 mumol/kg) of CDTD intrapertioneally show signs of toxicity typical of uncoupling agents. Mitochondria isolated from the livers of these rats show almost complete inhibition of ATP synthesis and mitochondria obtained from the livers of rats at various times after a single oral dose show maximal inhibition of ATP synthesis 4 h after dosing with complete recovery by about 24 h. A single oral administration of 58 mumol/kg or above, but not intraperitoneal injection, of CDTD into rats produced an increase in the water content of the brain and spinal cord. The additional fluid has been shown to contain Na+ ions. The increase in cerebral fluid is dose related, no effect being seen at 23 mumol/kg. This extra fluid is thought to be responsible for the hind limb weakness observed in these rats. These observations suggest that there are two facets to CDTD toxicity: early deaths (within 2 h), which appear to be due to uncoupling of oxidative phosphorylation, and delayed deaths, 2--3 days after dosing which are probably related to an increase in fluid in the brain and spinal cord.     

Organ and intracellular localization of short-chain acyl-CoA synthetases in rat and guinea-pig.

1. Homogenates of rat epididymal fat pad, heart, kidney, lactating mammary gland, liver, skeletal muscle and small intestinal mucosa have been partitioned into a particulate and supernatant fraction. With reliable marker enzymes for the mitochondrial matrix and the cytosol: propionyl-CoA carboxylase and pyruvate kinase, the distributions of the acyl-CoA synthetase activities measured at 1 and 10 mM C2, C3 and C4 over mitochondria and cytosol have been calculated. From these values an estimate was made of the K0.5 of the fatty acids. 2. A distinct fatty acid-activating enzyme was assumed to be present in one of the compartments when that fatty acid was activated with a K0.5 less than or equal to 1.5 mM in an amount of greater than 13% of the total cellular activity. Adipose tissue, gut, liver and mammary gland, all organs of a high lipogenetic capacity, contained a cytosolic acetyl-CoA synthetase. At 1 mM acetate 60, 31, 77 and 83% of the total cellular activities in these organs were cytosolic in nature, with activities of 0.021, 0.32, 0.37 and 1.16 mumol C2 activated per min per g wet weight, respectively. 3. Mitochondrial acetyl-CoA and butyryl-CoA synthetases were found in adipose tissue, gut, heart, kidney, mammary gland and muscle. They were absent in liver. Adipose tissue and liver contained a mitochondrial propionyl-CoA synthetase with activities at 1 mM C3 of 0.014 and 1.50 mumol C3 activated per min per g wet weight, respectively. 4. At 1 mM, C2 was activated with decreasing rates by kidney, heart, mammary gland and gut (7.6-1.0 mumol C2 activated per min per g wet weight). C3 (1 mM) activation was about equal (1.6-1.9 mumol C3 activated per min per g wet weight) in liver, kidney and heart. C4 (1 mM) was activated with decreasing rates by heart, liver, kidney and gut (4.0-0.5 mumol C4 activated per min per g wet weight) in the order given. 5. The influence of the isolation method and the diet on fatty acid activation in small intestinal mucosal scrapings have been studied. To demonstrate the existence of cytosolic acetyl-CoA synthetase in fed animals a pre-treatment of everted intestine by low amplitude vibration has been found essential. Also C16 activation was highly (95%) decreased in a non-pre-vibrated preparation. 24 h starvation lowered cytosolic C2 and total C16 activation by 90 and 80%, respectively. Refeeding of starved rats with a balanced fat-free diet, and not with sucrose only, gave the same cytosolic C2 and total C16 activation as normally fed rats. 6. In guienea-pig heart, kidney, liver and muscle about the same partitions have been found as in the respective rat organs. The acetate activation in liver was factor 6 lower. Acetate and butyrate activation in guinea-pig muscle was much higher (6 and 37 times, respectively).     

LY226936 Administered Orally and Centrally to Obese Zucker Rats Suppresses Food Intake and Body Weight Gain

LY226936, methylcarbamothoic acid-S-(4,5-dihydro-2-thiazolyl) ester, is a new compound that, when administered to obese Zucker rats, caused reduced food intake. LY226936 reduced the food consumption after a single oral dose of 50 and 100 mg/kg. On chronic oral administration to meal-fed obese (5 to 35 mg/kg. once daily) and to fed obese and lean (15 mg/kg. twice daily) Zucker rats, LY226936 reduced food intake and body weight gain for periods ranging from 40 to 48 days. The effect on both parameters was statistically significant. There is no evidence in our studies that tolerance to the actions of LY226936 developed. LY226936 decreased the consumption of both high carbohydrate and high fat diets. Food consumption of meal-fed obese Zucker rats was reduced significantly each time a single dose of 10 ugm LY226936 per rat was infused intracerebroventricularly. None of the receptors studied (mu and kappa opioid, CCK, serotonin, neuropeptide Y, galinin, N-methyl-D-aspartic acid) appeared to bind LY226936 and therefore, appear not to be involved in the depression of food intake by the obese Zucker rat.     

The effect of age on the distribution of 241Am in the rat body

In experiments with albino mongrel rats aged from 2 weeks to 1.5-2 years, the kinetics of 241Am distribution was studied after single intraperitoneal administration thereof. The content of 241Am in the skeleton was shown to decrease and in the liver to increase with age.     

Relative biological effectiveness of 241Am relative to 192Ir for continuous low-dose-rate irradiation of BA1112 rat sarcomas

Sealed sources of 241Am have been developed for intracavitary irradiation of gynecological cancers. Relative to conventional isotopes (that is, 226Ra, 137Cs, 192Ir), 241Am allows for better shielding of dose-limiting normal tissues in the patient. In addition, the long half-life of 241Am (432 years) makes it an attractive isotope both for clinical use and for long-term radiobiology studies. Using a previously developed in vivo applicator system, BA1112 sarcomas on WAG/Rij Y rats were irradiated using 241Am or 192Ir at three different dose rates. Following in vivo treatment of the sarcomas with graded doses of radiation, cell survival curves were determined using an in vitro colony formation assay. The slopes of the resulting cell survival curves were observed to increase significantly as the dose rate increased from 0.30 to 0.60 Gy/h, then to decrease slightly as the dose rate increased from 0.60 to 0.95 Gy/h. The relative biological effectiveness (RBE) of 241Am relative to 192Ir was observed to increase linearly with increasing dose rate; the RBEs were 0.96 +/- 0.009, 1.09 +/- 0.12, and 1.17 +/- 0.11 at dose rates of 0.30, 0.60, and 0.95 Gy/h, respectively.     

Response of tissue diamine oxidase activity to polyamine administration.

The administration to rats of putrescine (750 mumol/kg body wt.) caused in liver, kidney and heart an increase in putrescine at 1 h and in diamine oxidase (EC 1.4.3.6) activity within 3-6 h. An increase in spermidine was observed at 9 h in liver and at 6 h in kidney, whereas in heart there was no change. The increase in diamine oxidase activity by exogenous putrescine was prevented by the administration of actinomycin D and cycloheximide, suggesting that syntheses of mRNA and protein are involved. Equimolar doses of 1,3-diaminopropane, 1,5-diaminopentane and monoacetylputrescine stimulated, similarly to putrescine, hepatic, renal and cardiac diamine oxidase activity. After the injection of a non-toxic dose of spermidine (750 mumol/kg body wt.), the increase in diamine oxidase activity occurred at 9 h in all the tissues studied, when a substantial putrescine formation from spermidine occurred. sym-Norspermidine, which is unable to form putrescine, did not cause an increase in enzyme activity. The possibility that the tissue contents of putrescine might regulate diamine oxidase activity is discussed.     

Butyrobetaine is equal to L-carnitine in elevating L-carnitine levels in rats

This work shows that butyrobetaine administered to rats in a single dose can be highly effective in elevating L-carnitine levels in all tissues. This ability of butyrobetaine was compared to that of L-carnitine. In an experiment with tracer dose of the compounds, 12 h following administration of [3H]butyrobetaine plasma and tissues contained radioactivity exclusively in L-carnitine and in similar amounts as in the other group of animals receiving L-[3H]carnitine. This was observed both after intraperitoneal and oral administration of the compounds. In the loading experiments 100 mumol [3H]butyrobetaine was administered orally to one group and 100 mumol L-[3H]carnitine to the other group of animals and 12 h later it was found that butyrobetaine caused the same increments in L-carnitine as L-carnitine administration. The increments in the organs of the butyrobetaine-treated group (in decreasing order) were as follows: kidney, 1227 nmol/g vs. 652 nmol/g; liver, 469 nmol/g vs. 258 nmol/g; muscle, 1043 nmol/g vs. 881 nmol/g; plasma, 79.4 nmol/ml vs. 39.3 nmol/ml. Butyrobetaine (100 mumol) caused similar increments when it was administered intraperitoneally. Based on these results butyrobetaine can be considered as a potential agent for L-carnitine supplementation therapy.     

Absorption of 241Am in the gastrointestinal tract

In experiments with rats a study was made of a number of factors influencing the resorption of 241Am from the gastrointestinal tract (GIT). The resorption of 241Am from GIT was found to be 120-245 times more intensive in neonatal rats, during the first 21 days after birth (a milk diet), than in adult animals. A milk diet for adult rats produced a 5-fold increase in the resorption of 241Am from GIT. The additional administration of digestive enzymes, as a homogenate from pancreas and small intestine, produced a 7--9-fold increase in the rate of 241Am resorption from GIT.     

32P-postlabelling analysis of DNA adducts from Fischer-344 rats administered 2,4-diaminotoluene.

Using 32P-postlabelling and thin layer chromatography, DNA adduct formation by the potent animal carcinogen 2,4-diaminotoluene in Fischer-344 rats was investigated. DNA from four different organs, liver, mammary gland, kidney and lung, were examined for adducts following single administration of this compound. DNA binding was detected in all four organs, with each producing one major and two minor adduct spots on autoradiograms. The adducts induced were qualitatively identical among the different organs, but quantitative differences were observed. The two target organs of 2,4-diaminotoluene induced carcinogenesis, the liver and mammary gland produced higher adduct yields, with levels up to 30-times higher than those for the two non-target organs. Since the liver is the principal target for 2,4-diaminotoluene induced carcinogenesis, we further examined DNA adducts from this site for the effects of different doses and time points. DNA binding in liver was detected following doses as low as 4.1 mumol/kg. At the highest concentration examined (2046 mumol/kg), the level of the major adduct was 29.2 adducted nucleotides per 10(7) total nucleotides. The yields for the two minor adducts were approximately one-tenth that for the major adduct. Following a 410 mumol/kg dose, DNA adduct removal over time was examined. DNA adduct removal exhibited biphasic kinetics, with a rapid initial phase followed by a slower rate of elimination. Up to 60% of maximum adduct levels persisted after 2 weeks. DNA binding by 2,4-diaminotoluene was also compared to that by its weakly carcinogenic analog, 2,4-dinitrotoluene. The two compounds produced identical adduct patterns, suggesting that they share common metabolites and adducts. Adduct yields from 2,4-dinitrotoluene, however, were lower. The results of our studies suggest that the differences in carcinogenic potency between 2,4-diaminotoluene and 2,4-dinitrotoluene, as well as the organotropic effects of 2,4-diaminotoluene may be explained, in part, by quantitative differences in the extent of DNA adduct formation.     

The accumulation of 241Am by suspended matter of the Yenisei River

Laboratory experiments were performed to determine parameters of accumulation of 241Am by suspended particulate matter (seston) of the Yenisei River, with particles larger than 1 microm, and the diatoms A. formosa and D. vulgare. Concentration factors for seston were (2.8-4.1) x 10(5) and for diatoms--(1.5-4.2) x 10(4). As phytoplankton's contribution to the seston mass is rather small (< 10%), we assume that suspended matter contains other particles similar in size to the Yenisei River phytoplankton, which make larger contribution to 241Am concentration of seston than the studied algae. No energy-dependent accumulation of americium by algae was detected in the experiments. Addition of dissolved organics and hydrogen carbonates led to a lower uptake of 241Am from the Yenisei water by seston.     

Effects of juice from Morinda citrifolia (Noni) on gastric emptying in male rats

The effects of juice from Morinda citrifolia (noni) on gastric emptying, gastrointestinal transit, and plasma level of cholecystokinin (CCK) in rats were studied. Male rats were given noni by gavage at levels of 0.25, 1, or 4 ml/kg once per day for one or 7 days. The rats in the control group were given water, while the rats in the experimental group were fasted overnight before measurement of gastrointestinal motility. Gastrointestinal motility was assessed in rats 15 min after intragastric instillation of a test meal containing charcoal (10%) and Na251CrO4 (0.5 microCi/ml). Gastric emptying was determined by measuring the amount of radiolabeled chromium contained in the small intestine as a percentage of the initial amount received. Then, gastrointestinal transit was evaluated by calculating the geometric center of distribution of the radiolabeled marker. Finally, blood samples were collected for measurement of CCK by radioimmunoassay. The administration of noni at 0.25 ml/kg, but not at 1 ml/kg and 4 ml/kg, for 1 day significantly inhibited gastric emptying. In contrast, gastric emptying was significantly inhibited by oral noni (0.25, 1, or 4 ml/kg) for 7 days. Intraperitoneal injection of lorglumide (5 or 10 mg/kg), a selective CCK1 receptor antagonist, effectively attenuated the noni-induced inhibition of gastric emptying. The intestinal transit and body weight, food intake, water intake, urine volume as well as feces weight were not altered by the administration of noni either acutely or chronically, but the administration of oral noni (1 ml/kg) for 7 days increased the level of plasma CCK in male rats. These results suggest that oral noni inhibits gastric emptying in male rats via a mechanism involving stimulation of CCK secretion and CCK1 receptor activation.