Study of the influence of peroral zincacin on the removing of ingested Americium

Effect of different cincacine doses was studied in rats ingesting americium citrate during 2 weeks. As a result new data showing the possibility and efficacy of per oral cincacine administration at americium intake into digestive tract have been obtained. Dose dependence of cincacine efficacy has been stated for per oral 241Am intake. Preparation administration at a dose of 25 mumol/kg reduces amount of 241Am in skeleton, liver and kidney by 93, 90 and 33%, respectively and is optimum for radionuclide removal from the body and for the prevention of its deposition in organs. Digestive system organs and kidney structure at cincacine administration at a dose of 150 and 300 mumol/kg) to the rats ingesting 241Am have been studied.     

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.     

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.     

Effect of external gamma radiation on shortening the life expectancy and rates of the formation of absorbed doses from incorporated 239Pu in dogs

External gamma irradiation of dogs with doses of 103.2 and 51.6 mC/kg combined with the effect of inhaled plutonium-239 accelerates the formation of absorbed doses in secondary organs of the radionuclide deposition by 41.7 and 2.4 times, respectively, whereas the dose of 25.8 mC/kg is ineffective. As estimated by the rate of 239Pu accumulation and by the life span shortening, the minimum effective and the maximum ineffective doses are 104.8 and 80.5 cGy and 89.2 and 79.2 cGy, respectively.     

Effects of neurohypophyseal hormones on food-reinforced classical conditioning in the rat

The effects of different doses of lysine vasopressin (LVP) and oxytocin (OXT) were studied on the six-day acquisition or extinction of a food-reinforced classical conditioning reflex (conditional stimulus: light) when intraperitoneal (ip.) injections were carried out 20 min prior to the behavioural sessions. The highest (600 mU/kg) dose of LVP inhibited acquisition, and all LVP doses tested (150, 300 and 600 mU/kg) facilitated the extinction of conditioned behaviour. These same mU doses of OXT did not significantly affect the food-reinforced conditioning, although a consequent tendency towards increased performance (the opposite action to vasopressin) was observed. When 2.5 or 25 micrograms/kg doses of desglycinamide-arginine-vasopressin (DGAVP), a 500 micrograms/kg dose of prolyl-leucyl-glycinamide (PLG) or a 1200 mU/kg dose of OXT was injected during the extinction sessions, 2.5 micrograms/kg DGAVP and 1200 mU/kg OXT significantly facilitated extinction; the other treatments were without effect. LVP in a dose of 300 or 600 mU/kg and OXT in a dose of 300, 600 or 1200 mU/kg did not influence the food intake of 22 h food-deprived rats in a nonconditional situation. The present results indicate that the effects of LVP and OXT on memory display reinforcement-dependent characteristics, and are thus indirect or non-specific in nature.     

In vivo dose response relationship between physostigmine and cholinesterase activity in RBC and tissues of rats

Dose response of physostigmine (Phy) was studied in rat using various doses (25-500 micrograms/kg i.m.). Rats were sacrificed 15 min after Phy administration. Blood and tissues were analyzed for ChE activity by radiometric method and Phy concentration by HPLC method. A comparison of ChE values in different tissues of rats indicated that ChE activity was highest in brain (7.11 mumol/min/g) and least in diaphragm (0.67 mumol/min/g). The enzyme activity was eleven times more in brain as compared to diaphragm. Phy produced a dose-dependent inhibition of ChE in RBC (18-42%), brain (23-35%) and diaphragm (25-35%) from 50 to 200 micrograms/kg, then ChE inhibition was plateaued from 200 to 500 micrograms/kg in these tissues. A dose related ChE inhibition was seen in heart (16-50%) and thigh muscle (8-53%) from 50 to 500 micrograms/kg. Phy concentration increased linearly from 50 to 400 micrograms/kg in plasma, brain, heart and thigh muscle. These results indicate that ChE inhibition is linear up to 200 micrograms/kg in RBC, 150 micrograms/kg in brain and 300 micrograms/kg in heart. This linearity is not consistent in other tissues.     

Controlled Administration of Penicillamine Reduces Radiation Exposure in Critical Organs during 64Cu-ATSM Internal Radiotherapy: A Novel Strategy for Liver Protection

Purpose

⁶⁴Cu-diacetyl-bis (N ⁴-methylthiosemicarbazone) (⁶⁴Cu-ATSM) is a promising theranostic agent that targets hypoxic regions in tumors related to malignant characteristics. Its diagnostic usefulness has been recognized in clinical studies. Internal radiotherapy (IRT) with ⁶⁴Cu-ATSM is reportedly effective in preclinical studies; however, for clinical applications, improvements to reduce radiation exposure in non-target organs, particularly the liver, are required. We developed a strategy to reduce radiation doses to critical organs while preserving tumor radiation doses by controlled administration of copper chelator penicillamine during ⁶⁴Cu-ATSM IRT.

Methods

Biodistribution was evaluated in HT-29 tumor-bearing mice injected with ⁶⁴Cu-ATSM (185 kBq) with or without oral penicillamine administration. The appropriate injection interval between ⁶⁴Cu-ATSM and penicillamine was determined. Then, the optimal penicillamine administration schedule was selected from single (100, 300, and 500 mg/kg) and fractionated doses (100 mg/kg×3 at 1- or 2-h intervals from 1 h after ⁶⁴Cu-ATSM injection). PET imaging was performed to confirm the effect of penicillamine with a therapeutic ⁶⁴Cu-ATSM dose (37 MBq). Dosimetry analysis was performed to estimate human absorbed doses.

Results

Penicillamine reduced ⁶⁴Cu accumulation in the liver and small intestine. Tumor uptake was not affected by penicillamine administration at 1 h after ⁶⁴Cu-ATSM injection, when radioactivity was almost cleared from the blood and tumor uptake had plateaued. Of the single doses, 300 mg/kg was most effective. Fractionated administration at 2-h intervals further decreased liver accumulation at later time points. PET indicated that penicillamine acts similarly with the therapeutic ⁶⁴Cu-ATSM dose. Dosimetry demonstrated that appropriately scheduled penicillamine administration reduced radiation doses to critical organs (liver, ovaries, and red marrow) below tolerance levels. Laxatives reduced radiation doses to the large intestine.

Conclusions

We developed a novel strategy to reduce radiation exposure in critical organs during ⁶⁴Cu-ATSM IRT, thus promoting its clinical applications. This method could be beneficial for other ⁶⁴Cu-labeled compounds.     

Effect of age on the efficacy of Zn-diethylenetriaminepentaacetic acid therapy for removal of Am and Pu from beagles

Decorporation of intravenously injected monomeric 241Am and 237+239Pu by the administration of 30 mumole Zn-diethylenetriaminepentaacetic acid (DTPA)/kg each day beginning 2 weeks after radionuclide injection was compared in beagles entered into the experiment when 3 months (juveniles). 1.9 years (young adults), or 10 years (mature adults) old and studied for about 5 months. DTPA therapy was most effective in the juvenile dogs and least effective in the mature adults. Retention of 241Am in the liver decreased from a pretreatment value for adults of about 50% of the injected activity to about 10% in the mature adults and less than 1% in the young adults at 140 days of treatment, while the liver retention of juveniles decreased from pretreatment values of about 16% to undetectable levels by 28 days of treatment. Plutonium retention in the liver decreased from adult pretreatment levels of about 30% of the injected activity (corrected for radioactive decay) to near 10% in the mature adults and 6% in the young adults at 140 days of treatment, while juvenile liver retention decreased from pretreatment values near 15% to undetectable levels by 56 days of treatment. Nonliver Am retention (mainly skeleton) decreased in mature adults from pretreatment values of about 45% of the injected activity to near 25%, in young adults from 35 to 20%, and in juveniles from roughly 70 to 9% by 140 days of DTPA administration. Nonliver Pu retention decreased from pretreatment values of about 50% of the injected activity (corrected for radioactive decay) for mature and young adults to about 30% by 140 days and from 75 to 16% in juveniles over the time period.     

Teratogenic effects of incorporated radionuclides

Experimental data on teratogenic effects induced by incorporated alpha, beta and gamma-emitters were analyzed. It was found that the radioactive substances as well as external irradiation induced teratogenic effects. Teratogenesis caused by incorporated radionuclides has some peculiarities compared to the effect caused by fetus exposure to external radiation. These peculiarities are related to the fact of the limited penetration of incorporated radionuclides via placenta barrier so the radiation fetal doses are accumulated within long period of time and radiation dose rates are relatively low. The exposure to incorporated radionuclides does not induce severe developmental defects. Most frequent developmental defects of fetus include its death, general retardation of the development and growth. In such case the earlier pregnancy term was affected by radionuclide the more severe fetal damages occur in fetus because of the gradual increase of absorbed dose even in case of single intake of radionuclide. RBEs of radionuclides if compared to that for external gamma radiation are evaluated as follows: 2-4 (tritium oxide), 20 (241Am), 50 (238Pu) and 3-5 (131I in thyroid).     

Protective effect of hesperidin on nicotine induced toxicity in rats

Nicotine administration (2.5 mg/kg of body weight, sc, 5 days a week for 22 weeks) enhanced lipid peroxidative indices (thiobarbituric acid reactive substances and hydroperoxides) accompanied by a significant increase in the marker enzymes alanine transaminase, aspartate transaminase, alkaline phosphatase and lactate dehydrogenase and elevated levels of cholesterol, triglycerides, phospholipids and free fatty acids in Wistar rats. There was a significant protection by hesperidin administration at different doses (25, 50, 75, 100 and 150 mg/kg body weight) in nicotine-treated rats. However, the effect of hesperidin was more significant at 25mg/kg dose. The results suggest that hesperidin exerts the protective effects by modulating the extent of lipid peroxidation. The results are supported by histopathological observations of lung, liver and kidney.     

Experimental investigations of 211Am accumulation by macrophytes of the Yenisei River

Experiments were carried out in which 241Am was added to water samples containing macrophytes of the Yenisei River, and the radionuclide absorption rates and concentration factors were determined for the plants. It has been shown that the water moss (Fontinalis antipyretica) has a higher capacity to accumulate 241Am than the Canadian pondweed (Elodea canadensis) does. The laboratory experiments revealed that the capacity of dead biomass of the Canadian pondweed to accumulate 241Am is twice higher than that of living biomass. In contrast, no significant increase in 241Am accumulation by dead biomass of the water moss has been recorded. The transuranic element 241Am was firmly fixed by the plant biomass and was not released into water in the course of long-duration experiments.     

Osteosarcoma risk after simultaneous incorporation of the long-lived radionuclide 227Ac and the short-lived radionuclide 227Th

The effect of injection of 1.85 kBq/kg of the long-lived radionuclide 227Ac on the induction of osteosarcomas in female NMRI mice by different dose levels (18.5, 74, and 185 kBq/kg) of the short-lived radionuclide 227Th was investigated. The highest absolute osteosarcoma incidence was observed with the highest doses of 227Th. Addition of 227Ac resulted in an additional osteosarcoma incidence only at the lowest dose of 227Th and did not affect the osteosarcoma incidence resulting from higher doses of 227Th. The longest times to tumor appearance were observed with 227Ac alone. The latent period in two different age groups (4 weeks and 10-12 weeks) appeared to be similar following injection with combined doses of 227Th and 227Ac but different after injection of each radionuclide alone.     

Removal of monomeric 239Pu from bones and liver by liposome-encapsulated pentacin

Dependence of monomeric 239Pu removal from the liver and skeleton by liposome-encapsulated pentacine on dose and concentration of encapsulated chelate was studied in rats. It has been shown that the liposome-encapsulated pentacine (LP) removed 1.5-2.5 times as much 239Pu as free chelate (FP). Dose-effect dependences were logarithmic. The distinction between LP and FP in 239Pu removal from the liver was maximum when chelate had been used in a dose of 50 mumol/kg, with the dose effect upon injection in a large number of liposomes (200 mumol of lipids/kg) being 1.8 times as high as upon injection in smaller number of liposomes (50 mumol/kg). LP doses varying from 100 to 400 mumol/kg, there were no differences between two types of LP; with a LP dose of 400 mumol/kg its action is a bit stronger than that of the chelate. The distinction between LP and FP in 239Pu removal from the skeleton is the greatest with chelate doses exceeding 100 mumol/kg. The use of liposomes in combination with concentrated chelate solution is more effective. Possible interpretation of the features revealed are discussed.     

90Sr, 137Cs, 238Pu, 239+240Pu,and 241Am radionuclides in macrophytes within the Krasnensky flood plain: species specificity of concentration and distribution in phytocenosis components

The analysis of the content of radionuclides 90Sr, 137Cs, 238Pu, 239 + 240Pu and 241Am in water vegetation of flood plain reservoirs has allowed studing features of radionuclide accumulation by various species of macrophytes and revealing bioindicators of radionuclide contamination. Thus species-specificity of radionuclide accumulation can essentially change the contribution of different species to a percentage ratio of the radionuclide content in phytomass of reservoirs in comparison with fund of higher aquatic plants.     

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.     

Development of nanostructured phosphorite: Study of the safety of application

A nanostructured mineral food supplement with a particle size of 60.0–120.0 nm was manufactured from phosphorite by ultrasonic dispersion. It was found that intragastric administration of nanostructures phosphorite to mice is relatively safe: clinical signs of intoxication appeared after a single administration of the preparation only at a dose of 90 mg/kg; a dose of 150 mg/kg caused death of 8% of mice, in which injuries of organs of the gastrointestinal tract were observed. When the preparation was administered subcutaneously, intramuscularly, or intraperitoneally, small phosphorite conglomerates and inflammation of the surrounding tissues and organs were observed at the injection site. Death of 25% of animals was observed in the group of mice which received intraperitoneal injections of nanophosphorite at a dose of 200 mg/kg.     

Suppression of food intake by a complement C3a agonist [Trp5]-oryzatensin(5-9)

[Trp5]-oryzatensin(5-9) (WPLPR), an agonist peptide for complement C3a receptor, has been designed based on the C-terminal region of ileum-contracting peptide oryzatensin derived from rice protein. We previously reported that WPLPR has anti-analgesic and anti-amnesic activities after central or oral administration. In this study, we found a novel function of WPLPR on food intake. WPLPR suppressed food intake after intracerebroventricular or intraperitoneal (i.p.) administration at a dose of 3-30 nmol/mouse or 30-300 mg/kg, respectively, in fasted mice. Orally administered WPLPR at a dose of 300 mg/kg also decreased food intake. WPLPR decreased gastric emptying after i.p. injection at a dose of 300 mg/kg. The anorexigenic activity of WPLPR was blocked by cyclooxygenase inhibitor or antagonist for prostaglandin (PG) E receptor EP4 subtype. These results suggest that WPLPR decreases food intake through PGE2 production followed by EP4 receptor activation.     

Effects of low dose versus conventional dose thiazide diuretic on insulin action in essential hypertension.

OBJECTIVE--To see whether low dose thiazide diuretics given to patients with essential hypertension might avoid the adverse metabolic consequences seen with conventional doses. DESIGN--Double blind randomised crossover study of two 12 week treatment periods with either low dose (1.25 mg) or conventional dose (5.0 mg) bendrofluazide given after a six week placebo run in period. SETTING--Outpatient clinics serving the greater Belfast area. SUBJECTS--16 white non-diabetic patients (9 male) under 65 with essential hypertension recruited from general practices within the greater Belfast area. MAIN OUTCOME MEASURES--Systolic and diastolic blood pressure and peripheral and hepatic insulin action. RESULTS--One man failed to complete the study. There were no differences between doses in their effects on systolic and diastolic blood pressure. Bendrofluazide 1.25 mg had substantially less effect on serum potassium concentration than the 5.0 mg dose. There were no intertreatment differences in fasting glucose, insulin, cholesterol, and triglyceride concentrations. Bendrofluazide 5.0 mg significantly increased postabsorptive endogenous glucose production compared with baseline (mean 10.9 (SD 1.2) v 10.0 (0.8) mumol/kg/min), whereas bendrofluazide 1.25 mg did not. Postabsorptive endogenous glucose production was significantly higher with bendrofluazide 5.0 mg compared with 1.25 mg (10.9 (1.2) v 9.9 (0.8) mumol/kg/min) but was suppressed to a similar extent after insulin (bendrofluazide 5.0 mg 2.8 (1.5) mumol/kg/min v bendrofluazide 1.25 mg 2.2 (1.5) mumol/kg/min). Exogenous glucose infusion rates required to maintain euglycaemia were not significantly different between doses and were similar to baseline. CONCLUSIONS--Bendrofluazide 1.25 mg is as effective as conventional doses but has less adverse metabolic effect. In contrast with conventional doses, low dose bendrofluazide has no effect on hepatic insulin action. There is no difference between low and conventional doses of bendrofluazide in their effect on peripheral insulin sensitivity.     

The dose rate dependence of the relative biological effectiveness of 241Am versus 226Ra gamma rays

The survival of Chinese hamster cells exposed to 59.5 keV 241Am gamma rays was compared with that obtained after exposure to 226Ra gamma rays. The Fricke dosimeter in conjunction with the calculational techniques of transition-zone dosimetry was employed to determine the dose rates to the cells at the petri dish/growth medium interface. The dose rates to the cells ranged from 11 to 133 cGy/h. In all cases, cell survival versus dose was best described by a simple exponential function of dose. For both radiations, graphs of D0 versus dose rate show complex but similar patterns of peaks and valleys. As the curve for 241Am is displaced toward lower dose rates compared with that for 226Ra, the relative biological effectiveness of 241Am vs 226Ra varies considerably with dose rate, ranging from 1.7 at 20 cGy/h to 1.1 at 40 cGy/h to 1.6 at 50 cGy/h. This phenomenon may be due to the LET-dependent accumulation of cells at the G2 + M interface in the cell cycle. The mean unrestricted track-average LET of 241Am (3.7 keV/microns) is 12 times higher than that for 226Ra (0.31 keV/microns) but only one-fifth that of carbon ions (18 keV/microns) for which G2 + M pile-up is observed. Application of the in vitro data derived from this study to the clinical situation, where the dose rate decreases rapidly with distance from the source, suggests that, dose for dose, 241Am will produce results little different from those obtained with 226Ra.     

Atenolol,methyldopa, and chlorthalidone in moderate hypertension.

Combined treatment with low doses of different drugs is widely used for moderate hypertension. The effects of atenolol and methyldopa at two dose levels and in combination at the lower doses were studied in patients with moderate hypertension on continuous treatment with moderate hypertension on continuous treatment with chlorthalidone. The mean reduction in standing blood pressures obtained with atenolol 150 and 300 mg/day was about 27/17 mm Hg and with methyldopa 750 and 1500 mg/day about 28/14 mm Hg. Combined treatment with atenolol 150 mg/day and methyldopa 750 mg/day for four weeks resulted in a reduction of 38/25 mm Hg. No difference was observed between the two doses of methyldopa. The lower dose of atenolol was better than the lower dose of methyldopa in reducing lying and standing diastolic blood pressures. These findings show that in patients on continuous treatment with chlorthalidone the addition of atenolol alone or methyldopa alone or of atenolol and methyldopa in combination is effective in the treatment of moderate hypertension.