Nuclear medicine patients do not have higher mutant frequencies after exposure to thallium-201

The HPRT-lymphocyte clonal assay has been used to detect mutants induced in vivo in humans. This method has previously detected a rise in mutant frequency among nuclear medicine patients following ex posure to technetium-99m, at a dose corresponding in theory to 5.1 mGy. In the present study, nuclear medicine patients were sampled before and after exposure to thallium-201, corresponding to a whole-body dose of 4.2 mGy. No rise in mutant frequency was found. We suggest that a difference in the effective dose received by the patients' lymphocytes accounts for the apparent contradiction with earlier results.     

In vitro irradiation of blood with 99mTc: evaluation of dose and chromosome aberrations in irradiated lymphocytes.

The use of ionizing radiation for diagnostic or therapeutic purposes in medicine represents the principal source of artificial radiation to humans. Calculation of radiation dose is essential to the analysis of risks (biological effects) and benefits in any application, including nuclear medicine. The dose assessment in many cases is not necessarily straightforward. Many radiopharmaceuticals are labelled with radionuclides that undergo not only gamma-emission but also emission of Auger and internal conversion electrons. A typical example is technetium-99m (99mTc), which is used in more than 80% of nuclear medicine applications. In this work, in vitro studies have been carried out to evaluate the dose delivered to lymphocytes by human serum albumin microspheres (HSAM) labelled with 99mTc. Experiments were performed in order to score unstable chromosomal aberrations induced by 99mTc-HSAM, using conventional cytogenetic techniques. Henceforth, the relationship between activities introduced into blood samples and induced chromosomal aberrations were evaluated. To assess the dose absorbed in lymphocytes, electron and photon transport was performed in a simple model representing the system used for irradiating the cells using the MCNP Monte Carlo code. In this report, analysis of dose-effect curve demonstrates a linear quadratic response for unstable chromosome aberrations.     

Technetium in biology and medicine

Although twenty-eigth radionuclides of technetium have been prepared, only technetium-99m, technetium-99 and technetium-95m have so far become important.Technetium-99, available in large amounts, is used in the study of the physical and chemical properties of the element, and offers the possibility of many industrial applications where its radioactivity does not create serious problems. With the increase in the use of nuclear power, however, more and more technetium-99 is being produced which is entering into the environment. This has resulted in increased interest in the biogeochemical behaviour of this radionuclide during recent years.The ideal physical properties, half-life of 6 hours and monochromatic gamma emission of 140 kev, and the versatile chemistry of technetium-99m have recently made it the radiotracer of choice for the external noninvasive imaging of almost all internal organs of the body. In the preparation of technetium- 99m radiopharmaceuticals and in the interpretation of their biological behaviour, the chemistry of technetium-99 has so far served as a guide. Similarly assumptions have been made that technetium-95m and technetium-99 have identical biogeochemical behaviour. We have shown that even the radioisomers, technetium-99m and technetium-99, have different chemical properties. These results suggest that in the study of the biological and environmental behaviour of technetium, a rigorous knowledge of the chemistry of each radionuclide is needed.     

The ingestion of a Nectandra membranacea extract changes the bioavailability of technetium-99m radiobiocomplex in rat organs

The radiobiocomplexes labeled with technetium-99m (Tc-99m) have been widely used in nuclear medicine in single photon emission computed tomography and in basic research. The aim of this study was to assess the influence of a Nectandra membranacea extract on the bioavailability of the sodium pertechnetate (Na(99m)TcO(4)) radiobiocomplex in rat organs. The animals were treated with a N. membranacea extract (30 mg/ ml), for 6 days. Na(99m)TcO(4) was injected, the organs were isolated and weighed, and the radioactivity was determined in each organ (%ATI/organ). The %ATI/organ was divided by the mass of each organ to calculate the %ATI/g. A significant increase of the %ATI/organ of Na(99m)TcO(4) was observed in muscle and thyroid as well as in the %ATI/g in the heart, kidney and thyroid. These findings could result from the interaction between components of the plant extract and the radiobiocomplex which may influence the uptake Na(99m)TcO(4) in rat organs. Therefore, precaution is suggested in the interpretation of nuclear medicine results in patients using this herb.     

Effect of Lipid Dose on the Redistribution and Blood Pool Clearance Kinetics of Peg-Modified Technetium-Labeled Lipid Vesicles

Abstract

The current literature reports that the circulation half-life of PEG-modified vesicles is independent of lipid dose over the range of β4-400 μmol/ kg. The results presented in this paper indicate that PEG-modified vesicles exhibit a dose-dependent circulation half-life at even lower lipid doses. At lipid doses of 2.13, 1.30, 0.50 and 0.16 μmol/kg, the half-life for the blood pool clearance of activity of technetium-99m encapsulated in PEG-coated vesicles was approximately 20, 16, 4, and 2 hr respectively. There was no statistically significant difference in clearance half-life for lipid doses of 2.13 and 1.30 μmol/kg (Kruskal-Wallis Anova, p>0.05). These results suggest that the dose-independent range may be extended down to approximately 1 (μmol/kg but that at lower doses, the circulation half-life is dependent on the lipid dose. These results are discussed in terms of the mechanism of clearance of activity from the circulation and the potential utility of PEG-modified technetium-99m labeled vesicles as blood pool imaging agents for nuclear medicine.     

Influence of antipyretic drugs on the labeling of blood elements with technetium-99m

Acetaminophen (AAP), acetylsalicylic acid (ASA) and dipyrone (DIP) are antipyretic and analgesics drugs that have wide use in health sciences. Some drugs can modify the labeling of blood elements with technetium-99m (99mTc). This work has evaluated the effect of AAP, ASA and DIP on the labeling of the blood elements with 99mTc. Blood was incubated with different concentrations of the drugs before the 99mTc-labeled process. Plasma (P), blood cells (BC), insoluble (IF-P, IF-BC) and soluble (SF-P, SF-BC) fractions were separated and percentage of radioactivity (%ATI) in each fraction was determined. Data have shown that the antipyretic drugs used in this study did not significantly modify the fixation of 99mTc on the blood elements when the experiments were carried out with the doses usually used in human beings. Although the experiments were carried out with rats, it is possible to suggest that AAP, ASA or DIP should not interfere with the procedures in nuclear medicine involving the labeling of blood elements with 99mTc.     

Sister chromatid exchanges in lymphocytes of nuclear medicine physicians

OBJECTIVE: The aim of this study was to assess whether occupational exposure to chronic, low doses of Iodine 131 (I-131) and Technetium 99m (Tc-99m) may lead to genotoxicity. Medical personnel occupied in nuclear medicine departments are occupationally exposed to low doses of I-131 and Tc-99m. The determination of the frequency of sister chromatid exchanges (SCEs) and of cells with a high frequency of SCEs (HFC) is considered to be a sensitive indicator for detecting genotoxic potential of mutagenic and carcinogenic agents. Therefore, we examined peripheral lymphocytes from nuclear medicine physicians for the presence of both SCE and HFC. METHODS: Sixteen exposed nuclear medicine physicians (non-smokers) were compared to 16 physicians (non-smokers) who had not been exposed to chemical or physical mutagens in their usual working environment at the same hospital. RESULTS: A statistically significant difference was found between SCE frequencies and HFC percentages measured in lymphocytes from the exposed and control groups. CONCLUSIONS: The present observation on the effect of chronic low doses of I-131 and Tc-99m indicates the possibility of genotoxic implications of this type of occupational exposure. Hence, the personnel who work in nuclear medicine departments should carefully apply the radiation protection procedures and should minimize, as low as possible, radiation exposure to avoid possible genotoxic effects.     

Psammocarcinome ovarien et médecine nucléaire

We report three cases of ovarian psammocarcinoma, which is a serous adenocarcinoma having psammoma calcifications. The FDG uptake in the psammomatous lesions is due to the tissular part of the lesion and the technetium-99m labelled agents uptake to its calcified part. Calcifications are detected on CT scans. Therefore, they are relatively simple to diagnose by nuclear medicine which is useful given relatively the better prognosis of the psammomatous ovarian serous carcinoma when compared to the serous one.     

Evaluation of the cytotoxic and mutagenic potentiality of technetium-99m in Escherichi coli.

Since technetium-99m (99mTc) was introduced in medical research it has become one of the most employed radionuclides in nuclear medicine. 99mTc is ideal for routine use on the labeling of different radiopharmaceuticals due to its favorable characteristics. However, some biological effects have been described. These effects may be related to internal conversion electron and/or Auger electron emissions from 99mTc decay that present high linear energy transfer and can generate reactive oxygen species (ROS) in the medium. We evaluated in Escherichia coli K12S and Salmonella typhimurium TA102, both proficient in DNA repair, contribution of those decay emissions on the cytotoxicity induced by 99mTc, both either by generating lesions on DNA or by inducing alterations at membrane. We also studied the genotoxic and/or mutagenic potentiality of 99mTc, in Salmonella typhimurium, using the Ames test. The results showed that: i/ 99mTc is cytotoxic to the Escherichia coli K12S strains; ii/ this effect is related to the electrons (Auger and internal conversion) emissions, and iii/ the 99mTc is not mutagenic and/or genotoxic, when measured by Ames test.     

Evaluation of the in vitro effect of a Lantana camara extract on the labeling of blood constituents of rats with technetium-99m

Blood constituents labeled with technetium-99m (99mTc) have been used in nuclear medicine procedures and drugs are capable to interfere on this labeling. Lantana camara (lantana) has medicinal properties and it has been used in folk medicine. The aim is to verify the effect of a lantana extract on the labeling of blood constituents with 99mTc. Blood of rats was incubated with extract, stannous chloride and 99mTc, as sodium pertechnetate. Plasma (P) and blood cells (BC) were isolated, also precipitated with trichloroacetic acid and soluble (SF) and insoluble fractions (IF) were separated. The % of radioactivity (%ATI) in these samples was calculated. Samples of labeled BC were washed and the %ATI maintained (%ATI-M) in the BC was determined. The results showed that lantana extract decreased significantly (p < 0.05) in the IF-P from 70.24 +/- 2.59 to 11.95 +/- 3.07. This effect was not observed in the BC and IF-BC. The BC-%ATI-M was significantly (p < 0.05) decreased in all concentrations tested when the BC was washed. This fact was not observed in the control. Substances present on the extract should have redoxi action decreasing the concentration of the stannous ion and this condition could justify the effect on the IF-P. The results about the BC-%ATI-M should indicate a possible effect on the transport of ions through the erythrocyte membrane.     

A propolis extract and the labeling of blood constituents with technetium-99m

Since ancient times propolis has been employed for many human purposes because to their favourable properties. Blood constituents labeled with technetium-99m (99mTc) have been used in nuclear medicine procedures. Some authors have reported that synthetic or natural drugs can interfere with the labeling of blood constituents with 99mTc. The aim of this work was to evaluate the action of a propolis extract on the labeling of blood elements with 99mTc. Samples of whole blood of male Wistar rats were incubated in sequence with an aqueous propolis extract at different concentrations, stannous chloride and 99mTc, as sodium pertechnetate. Blood samples were centrifuged to separate plasma and blood cells, soluble and insoluble fractions of plasma and blood cells were also separated after precipitation in trichloroacetic acid solution and centrifugation. The radioactivity was counted and the percentage of incorporated radioactivity (%ATI) for each fraction was calculated. The data obtained showed that the aqueous propolis extract used decreased significantly the %ATI in plasma proteins at higher concentration studied. Results suggest that at high concentration the constituents of this extract could alter the labeling of plasma proteins competing with same binding sites of the 99mTc on the plasma proteins or acting as antioxidant compounds.     

Adaptive response to H(2)O(2) protects against SnCl(2) damage: the OxyR system involvement

The stannous ion, mainly the stannous chloride (SnCl(2)) salt form, is widely used as a reducing agent to label radiotracers with technetium-99m ((99m)Tc). These radiotracers can be employed as radiopharmaceuticals in nuclear medicine procedures. In this case, there is no doubt about absorption of this complex, because it is intravenously administered in humans, although biological effects of these agents have not been fully understood. In this work we used a bacterial system to study the cytotoxic potential of stannous chloride. It is known that SnCl(2) induces lesions that could be mediated by reactive oxygen species (ROS). We, thus, investigated the existence of cross-adaptive response between hydrogen peroxide (H(2)O(2)) and SnCl(2) and the role of the OxyR system known to promote cellular protection against oxidative damages. Here we describe the results obtained with prior treatment of different Escherichia coli strains with sub-lethal doses of H(2)O(2), followed by incubation with SnCl(2). Our data show that H(2)O(2) is capable of inducing cross-adaptive response against the lethality promoted by SnCl(2), suggesting the OxyR system participation through catalase, alkyl hydroperoxide reductase and superoxide dismutase enzymes     

Comparison of relative renal functions calculated with 99mTc-DTPA and 99mTc-DMSA for kidney patients of wide age ranges

Renal scintigraphy is an imaging method that uses small amount of radioactive materials called radiotracers, a Gamma camera and a computer to evaluate kidney functions and its anatomy. The present work reports the comparison of the relative renal functions (RRF) calculated with technetium-99m dimercaptosuccinic acid (^99mTc‑DMSA) and technetium-99m diethylenetriaminepentaacetic acid (^99mTc‑DTPA) for kidney patients of ages between 5 months and 71 years. A total of 50 patients including 29 male and 21 female has been selected and studied for renography. The mean RRFs have been found to be 52.68 ± 23.63% and 47.32 ± 23.63% respectively for the left and right kidneys with ^99mTc-DMSA measurement. With ^99mTc-DTPA the values are 52.74 ± 23.54% and 47.26 ± 23.54% for the same. In bivariate correlation analysis, a significant positive correlation (r = 0.996, P < .001) has been found between the RRFs calculated with the two methods. Following the patients’ diagnosis, in ANOVA test, no difference has been found between the RRFs calculated for the left and right kidneys. In Bland-Altman plots, the mean difference between the two methods has been found to be 0.1 and the correlation limit lies between −4.3 and 4.2. According to the result obtained in the present work, both the ^99mTc-DMSA and ^99mTc-DTPA scanning methods provide almost the same RRF values. It is, therefore, always not necessary to calculate the RRFs with both the methods. This study suggests that ^99mTc-DMSA may be the primary choice for the evaluation of RRF, but if the glomerular filtration rate (GFR) and renogram curve are required, ^99mTc-DTPA can be the obvious selection.     

Biological consequences of irradiation by low doses of technetium 99m: ultrastructural studies, p53 protein expression and cytogenetic effects.

Few studies concerning the potential genetic effects of diagnostic radionuclides used in nuclear medicine have been reported. The aim of this study was to evaluate the biological and cytogenetic consequences of two technetium 99m-labelled radiopharmaceuticals. Ultrastructural modifications of pulmonary cells were first investigated after injection of 99mTc labelled microspheres in the rat. On the same irradiated cells, nuclear expression of p53 protein was assessed using immunohistochemistry. Despite very high previously calculated doses delivered to pulmonary cells, no morpholological cell damage and no significant increase of nuclear expression of the p53 were noted. There was no correlation between the calculated dose and the ultrastructural biological damage. Secondly, a specific in vitro curve, activity/number of unstable chromosomal aberrations, corresponding to physical characteristics of 99mTc, was established to verify the potentiality of 99mTc to induce such aberrations. In vivo, cytogenetic effects were assessed on blood samples of 5 patients with various arthrosic and periarthrosic diseases obtained after bone scintigraphy. Aberration frequencies of both in vitro and in vivo irradiated lymphocytes were determined using the classical Fluorescence Plus Giemsa technique. No cytogenetic effects appeared with the routinely 99mTc injected activities as predicted by the in vitro curve.     

Evaluation of the effect of mitomycin-C on the bioavailability of technetium-99m-labelled sodium pyrophosphate in mice.

We have reported that drugs alter the biodistribution of radiopharmaceuticals used in diagnostic imaging in nuclear medicine. Knowledge of such altered biodistribution is important in making diagnostic from scintigraphy. Mitomycin-C is used as component of many chemotherapeutic regimens to treat different tumors. The biological activities of mitomycin-C can be explained by its ability to inhibit deoxyribonucleic acid synthesis. Since patients on chemotherapeutic treatment can be submitted to nuclear medicine procedures, we studied the mitomycin-C effect on the bioavailability of the technetium-99m-labelled sodium pyrophosphate (9mTc-PYP) using an animal model. Mitomycin (0.45 mg) was administered by ocular plexus way Balb/c mice. One hour after the last dose, 99mTc-PYP (7.4 MBq) was administered and after 0.5 hr the animals (n = 15) were rapidly sacrificed. The organs were isolated, the radioactivity counted in a well counter and the percentage of radioactivity (%ATI) calculated. The results have shown that in the treated animals the %ATI has been decreased in spleen, thymus, heart and brain and increased in lung, liver and bone. The effect of this chemotherapeutic drug on the 99mTc-PYP biodistribution was statistically significant (Wilcoxon test, p < 0.05) and it could be explained by the metabolization or therapeutic action of mitomycin-C.     

Development of 99mTc radiolabeled A85380 derivatives targeting cerebral nicotinic acetylcholine receptor: Novel radiopharmaceutical ligand 99mTc-A-YN-IDA-C4

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels that have been implicated in higher brain functions. To elucidate the functional mechanisms underlying nAChRs and contribute significantly to development of drugs targeting neurological and neuropsychiatric diseases, non-invasive nuclear medical imaging can be used for evaluation. In addition, technetium-99m (^99mTc) is a versatile radionuclide used clinically as a tracer in single-photon emission computed tomography. Because A85380 is known as a potent α4β2-nAChR agonist, we prepared A85380 derivatives labeled with ^99mTc using a bifunctional chelate system. A computational scientific approach was used to design the probe efficiently. We used non-radioactive rhenium (Re) for a ^99mTc analog and found that one of the derivatives, Re-A-YN-IDA-C4, exhibited high binding affinity at α4β2-nAChR in both the docking simulation (?19.3 kcal/mol) and binding assay (Ki = 0.4 ± 0.04 nM). Further, ^99mTc-A-YN-IDA-C4 was synthesized using microwaves, and its properties were examined. Consequently, we found that ^99mTc-A-YN-IDA-C4, with a structure optimized by using computational chemistry techniques, maintained affinity and selectivity for nAChR in vitro and possessed efficient characteristics as a nuclear medicine molecular imaging probe, demonstrated usefulness of computational scientific approach for molecular improvement strategy.     

Effect of Thuya occidentalis on the labeling of red blood cells and plasma proteins with technetium-99m.

Thuya occidentalis is used in popular medicine in the treatment of condyloma and has antibacterial action. Red blood cells (RBC) labeled with technetium-99m (99mTc) are used for several evaluations in nuclear medicine. This labeling depends on a reducing agent, usually stannous ion. Any drug which alters the labeling of the tracer could be expected to modify the disposition of the radiopharmaceutical. We have evaluated the influence of T. occidentalis extract on the labeling of RBC and plasma proteins with 99mTc. Blood was withdrawn and incubated with T. occidentalis (0.25; 2.5; 20.5; and 34.1 percent v/v). Stannous chloride (1.2 micrograms/ml) was added and then 99mTc was added. Plasma (P) and blood cells (BC) were isolated, also precipitated with trichloroacetic acid and soluble (SF) and insoluble fractions (IF) separated. The analysis of the results shows that there is a decrease in radioactivity (from 97.64 to 75.89 percent) in BC with 34.1 percent of the drug. In the labeling process of RBC with 99mTc, the stannous and pertechnetate ions pass through the membrane, so we suggest that the T. occidentalis effect can be explained (i) by an inhibition of the transport of these ions, (ii) by damage in membrane, (iii) by competition with the cited ions for the same binding sites, or (iv) by possible generation of reactive oxygen species that could oxidize the stannous ion.     

Single isomer technetium-99m tamoxifen conjugates

To produce an imaging agent for breast cancer using a technetium-99m-labeled agent specific for estrogen receptors, an N(2)S(2) bifunctional chelator was conjugated to Z- and E-aminotamoxifens through an amide linker. These bioconjugates have been chelated with both technetium-99m and rhenium. For the Z-isomer, chelation with rhenium in the presence of sodium acetate yields a mixture of two isomers, anti and syn, in a 1:1 ratio and in the presence of hydroxide results in only the anti isomer. Both the Z- and E-tamoxifen conjugates have been chelated with technetium-99m at the tracer level yielding a single isomer product, which is assigned as anti based on chromatographic comparison to the rhenium complexes. Radiochemical yields were consistently greater than 80%, with Sep-Pak column purification yielding a final product with >99% radiochemical purity and no residual starting material. Both in vitro and in vivo biological evaluation of the tamoxifen chelates indicated very limited estrogen receptor binding.     

Assessment of the effect of Punica granatum (pomegranata) on the bioavailability of the radiopharmaceutical sodium pertechnetate (99mTc) in Wistar rats.

The many desirable characteristics of technetium-99m (99mTc) have stimulated the development of labeling techniques for different molecular and cellular structures. It is generally accepted that a variety of factors other than disease can alter the bioavailability of radiopharmaceuticals and one such factor is the drug therapy. The use of medicinal plants has increased in the last decades all over the world. Punica granatum (pomegranata) is used as food or as medication in folk medicine for antiviral, anthelmintic, antifungal, antibacterial and antimicrobial activity. We have studied in rats, the effect of the medicinal plant Punica granatum on the bioavailability of the radiopharmaceutical 99mTc-sodium pertechnetate (Na(99m)TcO4). The infusion of pomegranata was administered by intragastric via into Wistar rats during seven days. After that, the animals received by ocular plexus via, 0.1 ml of the Na(99m)TcO4 (3.7MBq) and the animals were rapidly sacrificed after 5, 20 and 40 min. The organs were isolated (brain, heart, thyroid, liver, lungs, kidneys, stomach, testis, intestines, pancreas, spleen, bladder, muscle and bone), the radioactivity determined in a well counter, the percentages of radioactivity (%ATI) in the organs were calculated and statistical analyses were performed by Wilcoxon test (p < 0.05). The results have shown a significant (p < 0.05) increase of the activity of the Na(99m)TcO4 in spleen, heart, stomach, liver, stout bowel, pancreas, lungs and testis at 5 min. Twenty minutes after the administration of the radiopharmaceutical, the analysis of the results reveals a significant (p < 0.05) increase of the %ATI in heart, stomach, femur, pancreas, lungs and kidneys. Forty minutes after the administration of the Na(99m)TcO4, the results show a significant (p < 0.05) increase in spleen, brain, heart, stomach, liver, stout bowel, muscle, femur, lungs, pancreas, kidneys and testis. These results can be justified by therapeutic effect of this extract and/or by generation of active metabolites capable to interfere with the biodistribution of the studied radiopharmaceutical.     

The hexachlorotechnetate reagent in the synthesis,characterization and biodistribution of two novel lipophilic complexes

The hexachlorotechnetate reagent has been used to synthesize lipophilic complexes of technetium-99m with polydentate ligands, using ligand exchange reactions and acetonitrile as an aprotic solvent. The complexes isolated were partially characterized by chromatographic (paper and HPLC) and electrophoretic methods. Preliminary data on biodistribution studies, carried out in rabbits, are also presented. This work documents that the hexachlorotechnetate reagent is a suitable intermediate for the rapid synthesis of new lipophilic complexes of technetium-99m.