Administration Of Perchlorate Research Articles

Maternal Hypothyroidism Decreases Progesterone Receptor Expression in the Cortical Subplate of Foetal Rat Brain

Steroid hormones exert profound effects on the development of brain areas controlling complex cognitive function in adulthood. One class, progestins, may contribute by acting on the progestin receptor (PR), which is transiently expressed in a critical layer of developing cortex: the subplate. PR expression in the subplate coincides with the establishment of ongoing cortical connectivity and may play an important organisational role. Identification of the factor(s) that regulate the precise timing of PR expression within subplate may help elucidate the function of PR. Thyroid hormone may interact with hormone response elements within the PR gene. The present study examined the effects of maternal hypothyroidism on levels of PR immunoreactivity (PR-IR) within the foetal subplate. Pregnant rats were made hypothyroid by the administration of methimazole and potassium perchlorate in drinking water. Maternal hypothyroidism significantly decreased PR-IR within the foetal subplate. Using the incorporation of 5-bromo-2'-deoxyuridine (BrDU) during subplate cell neurogenesis (embryonic day 13.5) to determine subplate cell survival in hypothyroid animals, we found that decreases in PR-IR cannot be attributed to significant subplate cell loss but are more likely the result of altered PR expression. Gestational thyroxine replacement to hypothyroid dams prevented the decrease in PR-IR within the subplate. These results identify thyroid hormone as a potential factor in the regulation of PR expression in the developing brain. These results are consistent with the idea that endocrine cross-talk between progesterone and thyroid hormone may be one mechanism by which maternal hypothyroidism alters normal cortical development.

Iodide treatment acutely increases pendrin (SLC26A4) mRNA expression in the rat thyroid and the PCCl3 thyroid cell line by transcriptional mechanisms

Iodine is a critical element involved in thyroid hormone synthesis. Its efflux into the follicular lumen is thought to occur, in part, through pendrin at the apical membrane of thyrocytes. This study attempted to investigate whether iodide administration affects SLC26A4 mRNA expression in rat thyroid and in PCCl3 cells. Rats and cells were treated or not with NaI from 30min up to 48h. One group was concomitantly treated with sodium perchlorate. SLC26A4 mRNA expression was also investigated in PCCl3 cells treated with actinomycin D prior to NaI treatment. Iodide administration significantly increased SLC26A4 mRNA content in both models. The simultaneous administration of NaI and perchlorate, as well as the treatment of PCCl3 cells with actinomycin D prevented this effect, indicating that intracellular iodide is essential for this event, which appears to be triggered by transcriptional mechanisms. These data show that intracellular iodide rapidly upregulates SLC26A4 mRNA expression.

Thyroid status of female rhesus monkeys and preliminary information on impact of perchlorate administration

Thyroid status was assessed in adult female rhesus monkey breeders at the California National Primate Research Center at the beginning of the breeding season. The 95% confidence intervals for thyrotropin (TSH), thyroxine (T(4)) and triiodothyronine (T(3)) (n = 66-80) were similar to those previously reported in smaller samples of macaque monkeys. Based on human criteria, 10 of 80 monkeys (12%) were hypothyroid (TSH > 2.0 µIU/mL). Because hypothyroxinaemia can be a risk factor in pregnancy, T(4) status was compared with past breeding history, breeding outcome for that season and general health records in a subset of 42 breeders. Age, weight and parity did not differ between monkeys in the lowest T(4) quartile as compared with those in the upper three quartiles. However, T(4) concentrations were significantly associated with the number of missed menstrual cycles during the previous breeding season. In additional work, three healthy lactating rhesus monkeys were given three different doses of environmental contaminant and thyroid iodine uptake inhibitor, ammonium perchlorate (0.006, 0.34, 12.8 mg/kg/day, respectively) in food for two weeks. Thyroid status variables (TSH, T(4), T(3), thyroid radioactive iodine uptake) were then measured. In the monkey receiving the highest perchlorate dose, iodine uptake was suppressed relative to baseline. The study shows the availability of tools to study thyroid status in rhesus monkeys, the variability of thyroid status in the breeder colony and the potential ability of environmental factors to influence thyroid status.

Significance of Oral Administration of Sodium Perchlorate in Planning Liver-Directed Radioembolization

(99m)Tc-macroaggregated albumin ((99m)Tc-MAA) scanning precedes radioembolization of the liver to detect extrahepatic shunting to the lung or gastrointestinal tract. Despite strict preventive measures in the production of (99m)Tc-MAA and in scanning protocols, the images frequently show a gastric concentration of free (99m)Tc-pertechnetate, hindering accurate evaluation of the gastroduodenal region. Our aim was to evaluate whether oral administration of sodium perchlorate (NaClO(4)) before (99m)Tc-MAA scanning will improve its accuracy by blocking free (99m)Tc-pertechnetate gastric uptake. In 144 patients, 171 diagnostic hepatic angiograms combined with a (99m)Tc-MAA scan were performed; 86 angiograms were performed after oral administration of NaClO(4), and 85 were performed without this premedication. Clinical follow-up, esophagogastroduodenoscopy, and angiography served as reference standards. (99m)Tc-MAA studies showed tracer uptake in the gastric region of 25 patients who did not receive NaClO(4). The uptake was interpreted as a free (99m)Tc-pertechnetate concentration in 21 studies and as a (99m)Tc-MAA accumulation in 4 studies. In 5 patients with a free (99m)Tc-pertechnetate concentration, aberrant vessels were detected in angiographic reexamination, and 3 patients developed gastrointestinal ulcer. In 7 studies, gastric findings viewed pretherapeutically as free (99m)Tc-pertechnetate were retrospectively classified as equivocal. Of the patients receiving NaClO(4), 2 showed gastric accumulation of (99m)Tc-MAA but no equivocal or free (99m)Tc-pertechnetate. Oral administration of NaClO(4) increased the negative predictive value and accuracy of the test concerning the detection of gastric perfusion from 68% and 69%, respectively, to 93% and 94%, respectively. Oral administration of NaClO(4) before the test angiogram with (99m)Tc-MAA resulted in effective avoidance of free (99m)Tc-pertechnetate concentration and, consequently, of equivocal findings in the gastroduodenal region. This technique increased test accuracy and reporter confidence, saved time in reviewing the angiograms, and can improve treatment planning and reduce therapeutic side effects.

A method for the analysis of six thyroid hormones in thyroid gland by liquid chromatography–tandem mass spectrometry

Perchlorate can competitively inhibit iodide uptake by the thyroid gland (TG) via the sodium/iodide symporter, consequently reducing the production of thyroid hormones (THs). Until recently, the effects of perchlorate on TH homeostasis are being examined through measurement of serum levels of TH, by immunoassay (IA)-based methods. IA methods are fast, but for TH analysis, they are compromised by the lack of adequate specificity. Therefore, selective and sensitive methods for the analysis of THs in TG are needed, for assessment of the effects of perchlorate on TH homeostasis. In this study, we developed a method for the analysis of six THs: l-thyroxine (T 4), 3,3′,5-triiodo- l-thyronine (T 3), 3,3′,5′-triiodo- l-thyronine (rT 3), 3,5-diiodo- l-thyronine (3,5-T 2), 3,3′-diiodo- l-thyronine (3,3′-T 2), and 3-iodo- l-thyronine (3-T 1) in TG, using liquid chromatography (LC)–tandem mass spectrometry (MS/MS). TGs used in this study were from rats that had been placed on either iodide-deficient diet or iodide-sufficient diet, and that had either been provided with perchlorate in drinking water (10 mg/kg/day) or control water. TGs were extracted by pronase digestion and then analyzed by LC–MS/MS. The instrumental calibration range for each TH ranged from 1 to 200 ng/ml and showed a high linearity ( r > 0.99). The method quantification limits (LOQs) were determined to be 0.25 ng/mg TG for 3-T 1; 0.33 ng/mg TG for 3,3′- and 3,5-T 2; and 0.52 ng/mg TG for rT 3, T 3, and T 4. Rats were placed on an iodide-deficient or -sufficient diet for 2.5 months, and for the last 2 weeks of that period were provided either perchlorate (10 mg/kg/day) in drinking water or control water. Iodide deficiency and perchlorate administration both reduced TG stores of rT 3, T 3, and T 4. In iodide-deficient rats, perchlorate exacerbated the reduction in levels of THs in TG. With the advances in analytical methodology, the use of LC–MS/MS for measurement of hormone levels in TG will allow more comprehensive evaluations of the hypothalamic-pituitary–thyroid axis.

Modifying effects of prepubertal exposure to potassium perchlorate and tetrabromobisphenol A on susceptibility to N-bis(2-hydroxypropyl)nitrosamine- and 7,12-dimethylbenz( a)anthracene-induced carcinogenesis in rats

Early life exposure to certain kinds of chemicals is of concern because of a possible increase in cancer risk, but relevant data are limited. In the present experiment, modifying effects of prepubertal administration of potassium perchlorate (KClO 4) and tetrabromobisphenol A (TBBPA) on susceptibility to multi-organ carcinogenesis were evaluated. F344 dam rats were administered 0% (control), 0.01%, 0.1% or 1% TBBPA in diet or 0.01% KClO 4 in drinking water after parturition. Their weaned offspring in each group were treated for 2 weeks in the same manner. From 6 weeks of age, all offspring were treated with N-bis(2-hydroxypropyl)nitrosamine in drinking water for 4 weeks. In addition the females at 7 weeks of age were gavaged once with 7,12-dimethylbenz( a)anthracene. At weeks 39 and 47 of age, the males and females, respectively, were euthanized and the liver, kidney, lung, esophagus, thyroid, urinary bladder, testis, epididymis, ovary and mammary gland were histopathologically examined. The incidences of thyroid follicular adenomas in 1% TBBPA females ( p < 0.05) and of transitional cell papillomas in the urinary bladder of 0.01%, 0.1% and 1% TBBPA females were increased ( p < 0.05) as compared to the controls. These results indicate that prepubertal exposure to TBBPA raises susceptibility to thyroid and urinary bladder tumorigenesis in rats. Although causes of the effect on thyroid carcinogenesis might be direct and/or indirect hormonal actions, further studies are needed for confirmation.

Clinical Studies of Exposure to Perchlorate in the United States

Perchlorate is a competitive inhibitor of the sodium/iodine symporter, decreasing the active transport of iodine into the thyroid. It was used as an antithyroid drug in the treatment of hyperthyroidism in the 1950s and 1960s but was discontinued because of the occasional occurrence of aplastic anemia. More recently, lower doses of perchlorate have been used successfully in the treatment of iodine-induced hyperthyroidism. There has been concern that naturally occurring perchlorate and industrial contamination of water supplies with perchlorate might pose a health hazard by inducing or aggravating underlying thyroid dysfunction. In a series of studies in normal volunteers, administration of perchlorate from 2 weeks to 6 months and in perchlorate production workers exposed intermittently to high levels of perchlorate for years, no abnormalities of circulating thyroid hormones, thyroid-stimulating hormone, thyroglobulin, or ultrasound evaluation of thyroid structure were observed even though the thyroid (123)I uptake was decreased in some studies. Further studies of the effects of perchlorate on thyroid function in normal volunteers will now be difficult to carry out due to the adverse publicity that perchlorate and the studies on its effect have received.

Standardization of the perchlorate discharge assay for thyroid toxicity testing in rats

The perchlorate discharge assay (PDA) is potentially of high diagnostic value to distinguish between direct and indirect thyroid toxicity mechanisms, provided that standard treatment times are established and positive controls yield reproducible results. Therefore the PDA was evaluated after 2 and/or 4 weeks of treatment with positive control compounds in rats. Phenobarbital, Aroclor 1254 and β-naphthoflavone (indirect toxic mechanism) enhanced thyroidal radioiodide accumulation, and the administration of potassium perchlorate had no effect on thyroid: blood 125I ratio. Phenobarbital caused follicular cell hypertrophy and hyperplasia in the thyroid and centrilobular hypertrophy in the liver, without effects on serum triiodotyronine (T 3), thyroxine (T 4) levels. Thyroid-stimulating hormone (TSH) levels were moderately increased. Propylthiouracil (direct toxic mechanism) caused severe thyroid follicular cell hypertrophy and hyperplasia, reduced serum T 3 and T 4 levels and increased serum TSH levels, and reduced thyroidal radioiodide accumulation; perchlorate administration significantly reduced thyroid: blood 125I ratio, demonstrating an iodide organification block. Potassium iodide (direct toxic mechanism) virtually blocked thyroidal radioiodide accumulation, without significant effects on serum T 3, T 4, and TSH levels and a microscopic correlate for higher thyroid weights. Thus, positive controls yielded reproducible results and we conclude that both the 2- and 4-week PDA is suitable to distinguish between direct and indirect thyroid toxicity mechanisms.

Determination of Perchlorate in Biological Samples by Capillary Electrophoresis

A rapid capillary electrophoresis method was developed to detect perchlorate in tissues of male rats after the administration of perchlorate. Supernatants of ethanol-precipitated rat fluids were evaporated to dryness, and silver acetate solution was added. Precipitated silver chlorides were separated by centrifugation and supernatants were injected into a capillary electrophoresis system coupled with UV detection. The separation and quantification of perchlorate was achieved using Agilent inorganic anion buffer as the carrier electrolyte, electrokinetic injection and indirect detection at 200 nm. The lower detection limits for perchlorate in fluids and tissues of rats were 0.01 μg/ml and 0.25 mg/kg, respectively. Perchlorate in biological samples was determined for the first time by capillary electrophoresis already described.

Effects of Six Months of Daily Low-Dose Perchlorate Exposure on Thyroid Function in Healthy Volunteers

Perchlorate has been detected in U.S. drinking water supplies at levels ranging from 4 to 200 microg/liter as well as in agricultural products. Perchlorate is known to be a competitive inhibitor of iodine uptake by the thyroid through the sodium-iodide symporter. The objective of the study was to determine whether prolonged exposure (6 months) to low levels of perchlorate would perturb thyroid function. This was a prospective, double-blinded, randomized trial. The study population consisted of 13 healthy volunteers. INTERVENTIONs included placebo vs. 0.5 mg or 3.0 mg potassium perchlorate daily. Serum thyroid function tests, 24-h radioactive iodine uptake, serum thyroglobulin (Tg), urinary iodine and perchlorate, and serum perchlorate were measured. Mean urinary perchlorate value during ingestion of 0.5 mg perchlorate daily was 332.7 +/- 66.1 microg per 24 h or 248.5 +/- 64.5 microg/g creatinine and mean values for the four subjects who received 3 mg perchlorate daily were 2079.5 +/- 430.0 microg per 24 h or 1941.7 +/- 138.5 microg/g creatinine. There was no significant change in the thyroid (123)I uptakes during perchlorate administration. There were no significant changes in serum T(3), free T(4) index, TSH, or Tg concentrations during the exposure period, compared to baseline or postexposure values. Urine iodine values for the 3-mg perchlorate group were higher, but not significantly so, at baseline than during perchlorate exposure. We observed that a 6-month exposure to perchlorate at doses up to 3 mg/d had no effect on thyroid function, including inhibition of thyroid iodide uptake as well as serum levels of thyroid hormones, TSH, and Tg.

Sensitive high-performance liquid chromatography method for the determination of low levels of perchlorate in biological samples

A rapid and sensitive high-performance liquid chromatography (HPLC) method was developed to detect perchlorate in tissues of male and female rats, both pregnant and lactating (including milk) after administration of perchlorate. Supernatants of ethanol precipitated rat fluids and tissues were evaporated to dryness under nitrogen and reconstituted in deionized water. Reconstituted samples were injected into HPLC system coupled with conductivity detection. Isocratic separation of perchlorate was achieved using an anion-exchange column with sodium hydroxide as mobile phase and a conductivity detector. In this method, perchlorate showed a linear response range from 5 to 100 ng/ml. The lower detection limits for perchlorate in fluids and tissues of rats were 3–6 ng/ml and 0.007–0.7 mg/kg, respectively. The described method has the unique advantage over the existing methods of determining low traces of perchlorate in different biological matrices without complex sample preparation.

Abstract

Purpose. Irradiation of the arterial wall with beta particles has been shown to be effective in inhibiting neointimal hyperplasia following percutaneous transluminal coronary angioplasty (PTCA). In this study, we describe the use of 188W/188Re generators to obtain 188Re (half-life 16.9 h, maximal beta energy of 2.12 MeV) as a new candidate radioisotope for endovascular irradiation. We have evaluated two [188Re]-compounds as candidates for use as solution-based radiation sources that would allow conventional liquid-filled balloon inflation for delivery of radiation to the vessel wall. While balloon rupture at nominal inflation pressures is a very rare event, (<1 per 10,000 at high pressure), radioisotope release could potentially result in significant dose to radiation-sensitive organs. We have thus evaluated the biodistribution, dosimetry, and kinetics of excretion in rats of two 188Re-labeled compounds that are proposed for intravascular therapy.Materials and Methods. Rhenium-188 was obtained as [188Re]-sodium perrhenate by saline elution of an alumina-based 188W/188Re generator system (>500 mCi). High specific volume solutions of the [188Re]-sodium perrhenate (>50 mCi/ml) were obtained by postelution concentration of the generator bolus by passage through a tandem silver cation/anion column system. Rhenium-188-labeled benzoylthioacetyltriglycine (MAG3) was prepared by stannous ion reduction of [188Re]-perrhenate in the presence of the benzyl-MAG3 substrate, and was characterized as a single radioactive component. Rhenium-188-perrhenate and [188Re]-MAG3 were administered to separate groups of Fischer rats, which were sacrificed at various times and the tissue distribution of 188Re determined in the major organs. Excretory products were also collected daily from separate groups of rats for each agent over 7 days. The effects of perchlorate and iodide preblocking and postdisplacement of thyroid uptake of [188Re]-perrhenate were also evaluated.Results. Organ uptake values were modest for both agents [<0.25 % injected dose(ID)/gram of tissue at 6 h] for all organs evaluated except for the thyroid, with the intestines and intestinal contents showing the highest uptake values (0.72–1.97 %ID/gram). Whereas thyroid uptake of 188Re after injection of [188Re]-MAG3 was low (0.16 %ID/gram), uptake after injection of [188Re]-perrhenate was higher and could be blocked by pretreatment with perchlorate (intravenous [IV]) or displaced by perchlorate posttreatment. Also, oral or IV iodide pre- or postadministration could also significantly block or displace thyroid uptake of [188Re]-perrhenate. Both [188Re] agents were excreted primarily via the urinary bladder. The excretion half-life of [188Re]-perrhenate was about 7 h; in contrast, the [188Re]-MAG3 complex showed 50% excretion in less than 2 h. The large intestines received the most significant adsorbed dose, with values of 2.0 cGy/mCi for [188Re]-perrhenate and 4.6 × 10−3 cGy/mCi for [188Re]-MAG3.Conclusions. Rhenium-188-MAG3 shows more rapid urinary bladder excretion in rats than perrhenate and both agents show low organ uptake. Thyroid uptake of free [188Re]-perrhenate can be blocked or displaced with oral perchlorate administration. For the projected use of [188Re]-MAG3 for balloon inflation required for irradiation of the arterial wall, calculated organ dose values are within acceptable limits in the unlikely event of low pressure balloon rupture. Rhenium-188-MAG3 in solution is thus a new candidate for balloon dilation providing uniform endovascular irradiation following PTCA for restenosis therapy. Published by Elsevier Science Inc.

Abstract

Purpose. Irradiation of the arterial wall with beta particles has been shown to be effective in inhibiting neointimal hyperplasia following percutaneous transluminal coronary angioplasty (PTCA). In this study, we describe the use of 188W/188Re generators to obtain 188Re (half-life 16.9 h, maximal beta energy of 2.12 MeV) as a new candidate radioisotope for endovascular irradiation. We have evaluated two [188Re]-compounds as candidates for use as solution-based radiation sources that would allow conventional liquid-filled balloon inflation for delivery of radiation to the vessel wall. While balloon rupture at nominal inflation pressures is a very rare event, (<1 per 10,000 at high pressure), radioisotope release could potentially result in significant dose to radiation-sensitive organs. We have thus evaluated the biodistribution, dosimetry, and kinetics of excretion in rats of two 188Re-labeled compounds that are proposed for intravascular therapy.Materials and Methods. Rhenium-188 was obtained as [188Re]-sodium perrhenate by saline elution of an alumina-based 188W/188Re generator system (>500 mCi). High specific volume solutions of the [188Re]-sodium perrhenate (>50 mCi/ml) were obtained by postelution concentration of the generator bolus by passage through a tandem silver cation/anion column system. Rhenium-188-labeled benzoylthioacetyltriglycine (MAG3) was prepared by stannous ion reduction of [188Re]-perrhenate in the presence of the benzyl-MAG3 substrate, and was characterized as a single radioactive component. Rhenium-188-perrhenate and [188Re]-MAG3 were administered to separate groups of Fischer rats, which were sacrificed at various times and the tissue distribution of 188Re determined in the major organs. Excretory products were also collected daily from separate groups of rats for each agent over 7 days. The effects of perchlorate and iodide preblocking and postdisplacement of thyroid uptake of [188Re]-perrhenate were also evaluated.Results. Organ uptake values were modest for both agents [<0.25 % injected dose(ID)/gram of tissue at 6 h] for all organs evaluated except for the thyroid, with the intestines and intestinal contents showing the highest uptake values (0.72–1.97 %ID/gram). Whereas thyroid uptake of 188Re after injection of [188Re]-MAG3 was low (0.16 %ID/gram), uptake after injection of [188Re]-perrhenate was higher and could be blocked by pretreatment with perchlorate (intravenous [IV]) or displaced by perchlorate posttreatment. Also, oral or IV iodide pre- or postadministration could also significantly block or displace thyroid uptake of [188Re]-perrhenate. Both [188Re] agents were excreted primarily via the urinary bladder. The excretion half-life of [188Re]-perrhenate was about 7 h; in contrast, the [188Re]-MAG3 complex showed 50% excretion in less than 2 h. The large intestines received the most significant adsorbed dose, with values of 2.0 cGy/mCi for [188Re]-perrhenate and 4.6 × 10−3 cGy/mCi for [188Re]-MAG3.Conclusions. Rhenium-188-MAG3 shows more rapid urinary bladder excretion in rats than perrhenate and both agents show low organ uptake. Thyroid uptake of free [188Re]-perrhenate can be blocked or displaced with oral perchlorate administration. For the projected use of [188Re]-MAG3 for balloon inflation required for irradiation of the arterial wall, calculated organ dose values are within acceptable limits in the unlikely event of low pressure balloon rupture. Rhenium-188-MAG3 in solution is thus a new candidate for balloon dilation providing uniform endovascular irradiation following PTCA for restenosis therapy. Published by Elsevier Science Inc.

Abstract

Purpose. Irradiation of the arterial wall with beta particles has been shown to be effective in inhibiting neointimal hyperplasia following percutaneous transluminal coronary angioplasty (PTCA). In this study, we describe the use of 188W/188Re generators to obtain 188Re (half-life 16.9 h, maximal beta energy of 2.12 MeV) as a new candidate radioisotope for endovascular irradiation. We have evaluated two [188Re]-compounds as candidates for use as solution-based radiation sources that would allow conventional liquid-filled balloon inflation for delivery of radiation to the vessel wall. While balloon rupture at nominal inflation pressures is a very rare event, (<1 per 10,000 at high pressure), radioisotope release could potentially result in significant dose to radiation-sensitive organs. We have thus evaluated the biodistribution, dosimetry, and kinetics of excretion in rats of two 188Re-labeled compounds that are proposed for intravascular therapy.Materials and Methods. Rhenium-188 was obtained as [188Re]-sodium perrhenate by saline elution of an alumina-based 188W/188Re generator system (>500 mCi). High specific volume solutions of the [188Re]-sodium perrhenate (>50 mCi/ml) were obtained by postelution concentration of the generator bolus by passage through a tandem silver cation/anion column system. Rhenium-188-labeled benzoylthioacetyltriglycine (MAG3) was prepared by stannous ion reduction of [188Re]-perrhenate in the presence of the benzyl-MAG3 substrate, and was characterized as a single radioactive component. Rhenium-188-perrhenate and [188Re]-MAG3 were administered to separate groups of Fischer rats, which were sacrificed at various times and the tissue distribution of 188Re determined in the major organs. Excretory products were also collected daily from separate groups of rats for each agent over 7 days. The effects of perchlorate and iodide preblocking and postdisplacement of thyroid uptake of [188Re]-perrhenate were also evaluated.Results. Organ uptake values were modest for both agents [<0.25 % injected dose(ID)/gram of tissue at 6 h] for all organs evaluated except for the thyroid, with the intestines and intestinal contents showing the highest uptake values (0.72–1.97 %ID/gram). Whereas thyroid uptake of 188Re after injection of [188Re]-MAG3 was low (0.16 %ID/gram), uptake after injection of [188Re]-perrhenate was higher and could be blocked by pretreatment with perchlorate (intravenous [IV]) or displaced by perchlorate posttreatment. Also, oral or IV iodide pre- or postadministration could also significantly block or displace thyroid uptake of [188Re]-perrhenate. Both [188Re] agents were excreted primarily via the urinary bladder. The excretion half-life of [188Re]-perrhenate was about 7 h; in contrast, the [188Re]-MAG3 complex showed 50% excretion in less than 2 h. The large intestines received the most significant adsorbed dose, with values of 2.0 cGy/mCi for [188Re]-perrhenate and 4.6 × 10−3 cGy/mCi for [188Re]-MAG3.Conclusions. Rhenium-188-MAG3 shows more rapid urinary bladder excretion in rats than perrhenate and both agents show low organ uptake. Thyroid uptake of free [188Re]-perrhenate can be blocked or displaced with oral perchlorate administration. For the projected use of [188Re]-MAG3 for balloon inflation required for irradiation of the arterial wall, calculated organ dose values are within acceptable limits in the unlikely event of low pressure balloon rupture. Rhenium-188-MAG3 in solution is thus a new candidate for balloon dilation providing uniform endovascular irradiation following PTCA for restenosis therapy. Published by Elsevier Science Inc.

Abstract

Purpose. Irradiation of the arterial wall with beta particles has been shown to be effective in inhibiting neointimal hyperplasia following percutaneous transluminal coronary angioplasty (PTCA). In this study, we describe the use of 188W/188Re generators to obtain 188Re (half-life 16.9 h, maximal beta energy of 2.12 MeV) as a new candidate radioisotope for endovascular irradiation. We have evaluated two [188Re]-compounds as candidates for use as solution-based radiation sources that would allow conventional liquid-filled balloon inflation for delivery of radiation to the vessel wall. While balloon rupture at nominal inflation pressures is a very rare event, (<1 per 10,000 at high pressure), radioisotope release could potentially result in significant dose to radiation-sensitive organs. We have thus evaluated the biodistribution, dosimetry, and kinetics of excretion in rats of two 188Re-labeled compounds that are proposed for intravascular therapy.Materials and Methods. Rhenium-188 was obtained as [188Re]-sodium perrhenate by saline elution of an alumina-based 188W/188Re generator system (>500 mCi). High specific volume solutions of the [188Re]-sodium perrhenate (>50 mCi/ml) were obtained by postelution concentration of the generator bolus by passage through a tandem silver cation/anion column system. Rhenium-188-labeled benzoylthioacetyltriglycine (MAG3) was prepared by stannous ion reduction of [188Re]-perrhenate in the presence of the benzyl-MAG3 substrate, and was characterized as a single radioactive component. Rhenium-188-perrhenate and [188Re]-MAG3 were administered to separate groups of Fischer rats, which were sacrificed at various times and the tissue distribution of 188Re determined in the major organs. Excretory products were also collected daily from separate groups of rats for each agent over 7 days. The effects of perchlorate and iodide preblocking and postdisplacement of thyroid uptake of [188Re]-perrhenate were also evaluated.Results. Organ uptake values were modest for both agents [<0.25 % injected dose(ID)/gram of tissue at 6 h] for all organs evaluated except for the thyroid, with the intestines and intestinal contents showing the highest uptake values (0.72–1.97 %ID/gram). Whereas thyroid uptake of 188Re after injection of [188Re]-MAG3 was low (0.16 %ID/gram), uptake after injection of [188Re]-perrhenate was higher and could be blocked by pretreatment with perchlorate (intravenous [IV]) or displaced by perchlorate posttreatment. Also, oral or IV iodide pre- or postadministration could also significantly block or displace thyroid uptake of [188Re]-perrhenate. Both [188Re] agents were excreted primarily via the urinary bladder. The excretion half-life of [188Re]-perrhenate was about 7 h; in contrast, the [188Re]-MAG3 complex showed 50% excretion in less than 2 h. The large intestines received the most significant adsorbed dose, with values of 2.0 cGy/mCi for [188Re]-perrhenate and 4.6 × 10−3 cGy/mCi for [188Re]-MAG3.Conclusions. Rhenium-188-MAG3 shows more rapid urinary bladder excretion in rats than perrhenate and both agents show low organ uptake. Thyroid uptake of free [188Re]-perrhenate can be blocked or displaced with oral perchlorate administration. For the projected use of [188Re]-MAG3 for balloon inflation required for irradiation of the arterial wall, calculated organ dose values are within acceptable limits in the unlikely event of low pressure balloon rupture. Rhenium-188-MAG3 in solution is thus a new candidate for balloon dilation providing uniform endovascular irradiation following PTCA for restenosis therapy. Published by Elsevier Science Inc.

Abstract

Purpose. Irradiation of the arterial wall with beta particles has been shown to be effective in inhibiting neointimal hyperplasia following percutaneous transluminal coronary angioplasty (PTCA). In this study, we describe the use of 188W/188Re generators to obtain 188Re (half-life 16.9 h, maximal beta energy of 2.12 MeV) as a new candidate radioisotope for endovascular irradiation. We have evaluated two [188Re]-compounds as candidates for use as solution-based radiation sources that would allow conventional liquid-filled balloon inflation for delivery of radiation to the vessel wall. While balloon rupture at nominal inflation pressures is a very rare event, (<1 per 10,000 at high pressure), radioisotope release could potentially result in significant dose to radiation-sensitive organs. We have thus evaluated the biodistribution, dosimetry, and kinetics of excretion in rats of two 188Re-labeled compounds that are proposed for intravascular therapy.Materials and Methods. Rhenium-188 was obtained as [188Re]-sodium perrhenate by saline elution of an alumina-based 188W/188Re generator system (>500 mCi). High specific volume solutions of the [188Re]-sodium perrhenate (>50 mCi/ml) were obtained by postelution concentration of the generator bolus by passage through a tandem silver cation/anion column system. Rhenium-188-labeled benzoylthioacetyltriglycine (MAG3) was prepared by stannous ion reduction of [188Re]-perrhenate in the presence of the benzyl-MAG3 substrate, and was characterized as a single radioactive component. Rhenium-188-perrhenate and [188Re]-MAG3 were administered to separate groups of Fischer rats, which were sacrificed at various times and the tissue distribution of 188Re determined in the major organs. Excretory products were also collected daily from separate groups of rats for each agent over 7 days. The effects of perchlorate and iodide preblocking and postdisplacement of thyroid uptake of [188Re]-perrhenate were also evaluated.Results. Organ uptake values were modest for both agents [<0.25 % injected dose(ID)/gram of tissue at 6 h] for all organs evaluated except for the thyroid, with the intestines and intestinal contents showing the highest uptake values (0.72–1.97 %ID/gram). Whereas thyroid uptake of 188Re after injection of [188Re]-MAG3 was low (0.16 %ID/gram), uptake after injection of [188Re]-perrhenate was higher and could be blocked by pretreatment with perchlorate (intravenous [IV]) or displaced by perchlorate posttreatment. Also, oral or IV iodide pre- or postadministration could also significantly block or displace thyroid uptake of [188Re]-perrhenate. Both [188Re] agents were excreted primarily via the urinary bladder. The excretion half-life of [188Re]-perrhenate was about 7 h; in contrast, the [188Re]-MAG3 complex showed 50% excretion in less than 2 h. The large intestines received the most significant adsorbed dose, with values of 2.0 cGy/mCi for [188Re]-perrhenate and 4.6 × 10−3 cGy/mCi for [188Re]-MAG3.Conclusions. Rhenium-188-MAG3 shows more rapid urinary bladder excretion in rats than perrhenate and both agents show low organ uptake. Thyroid uptake of free [188Re]-perrhenate can be blocked or displaced with oral perchlorate administration. For the projected use of [188Re]-MAG3 for balloon inflation required for irradiation of the arterial wall, calculated organ dose values are within acceptable limits in the unlikely event of low pressure balloon rupture. Rhenium-188-MAG3 in solution is thus a new candidate for balloon dilation providing uniform endovascular irradiation following PTCA for restenosis therapy. Published by Elsevier Science Inc.

Abstract

Purpose. Irradiation of the arterial wall with beta particles has been shown to be effective in inhibiting neointimal hyperplasia following percutaneous transluminal coronary angioplasty (PTCA). In this study, we describe the use of 188W/188Re generators to obtain 188Re (half-life 16.9 h, maximal beta energy of 2.12 MeV) as a new candidate radioisotope for endovascular irradiation. We have evaluated two [188Re]-compounds as candidates for use as solution-based radiation sources that would allow conventional liquid-filled balloon inflation for delivery of radiation to the vessel wall. While balloon rupture at nominal inflation pressures is a very rare event, (<1 per 10,000 at high pressure), radioisotope release could potentially result in significant dose to radiation-sensitive organs. We have thus evaluated the biodistribution, dosimetry, and kinetics of excretion in rats of two 188Re-labeled compounds that are proposed for intravascular therapy.Materials and Methods. Rhenium-188 was obtained as [188Re]-sodium perrhenate by saline elution of an alumina-based 188W/188Re generator system (>500 mCi). High specific volume solutions of the [188Re]-sodium perrhenate (>50 mCi/ml) were obtained by postelution concentration of the generator bolus by passage through a tandem silver cation/anion column system. Rhenium-188-labeled benzoylthioacetyltriglycine (MAG3) was prepared by stannous ion reduction of [188Re]-perrhenate in the presence of the benzyl-MAG3 substrate, and was characterized as a single radioactive component. Rhenium-188-perrhenate and [188Re]-MAG3 were administered to separate groups of Fischer rats, which were sacrificed at various times and the tissue distribution of 188Re determined in the major organs. Excretory products were also collected daily from separate groups of rats for each agent over 7 days. The effects of perchlorate and iodide preblocking and postdisplacement of thyroid uptake of [188Re]-perrhenate were also evaluated.Results. Organ uptake values were modest for both agents [<0.25 % injected dose(ID)/gram of tissue at 6 h] for all organs evaluated except for the thyroid, with the intestines and intestinal contents showing the highest uptake values (0.72–1.97 %ID/gram). Whereas thyroid uptake of 188Re after injection of [188Re]-MAG3 was low (0.16 %ID/gram), uptake after injection of [188Re]-perrhenate was higher and could be blocked by pretreatment with perchlorate (intravenous [IV]) or displaced by perchlorate posttreatment. Also, oral or IV iodide pre- or postadministration could also significantly block or displace thyroid uptake of [188Re]-perrhenate. Both [188Re] agents were excreted primarily via the urinary bladder. The excretion half-life of [188Re]-perrhenate was about 7 h; in contrast, the [188Re]-MAG3 complex showed 50% excretion in less than 2 h. The large intestines received the most significant adsorbed dose, with values of 2.0 cGy/mCi for [188Re]-perrhenate and 4.6 × 10−3 cGy/mCi for [188Re]-MAG3.Conclusions. Rhenium-188-MAG3 shows more rapid urinary bladder excretion in rats than perrhenate and both agents show low organ uptake. Thyroid uptake of free [188Re]-perrhenate can be blocked or displaced with oral perchlorate administration. For the projected use of [188Re]-MAG3 for balloon inflation required for irradiation of the arterial wall, calculated organ dose values are within acceptable limits in the unlikely event of low pressure balloon rupture. Rhenium-188-MAG3 in solution is thus a new candidate for balloon dilation providing uniform endovascular irradiation following PTCA for restenosis therapy. Published by Elsevier Science Inc.

Clinical role of 99mTcO4/MIBI scan, ultrasound and intra-operative gamma probe in the performance of unilateral and minimally invasive surgery in primary hyperparathyroidism

The main purposes of this study were: (a) to investigate the efficacy of an imaging protocol based on the combination of (99m)TcO4/MIBI scintigraphy and neck ultrasound (US) in selecting patients with primary hyperparathyroidism (HPT) for unilateral neck exploration, and (b) to help define the role of the intraoperative MIBI gamma probe (IMGP) technique in the performance of minimally invasive radio-guided surgery (MIRS). One hundred and forty-three consecutive patients with primary HPT were enrolled in the study. We used a modified (99m)TcO4/MIBI scintigraphic procedure which included the oral administration of potassium perchlorate to cause rapid (99m)TcO4 washout from the thyroid tissue, thereby permitting the acquisition of high-quality early MIBI images. A single-photon emission tomography (SPET) acquisition was also obtained in 21 patients, of whom seven had an enlarged parathyroid gland (EPG) in the mediastinum at planar scintigraphy and 14 had discordant scan/US findings for the presence of a cervical EPG. Neck US was performed in the same session as scintigraphy using a small-parts, high-resolution 10-MHz transducer. All patients were then operated on by the same surgical team. Quick PTH assay (QPTH) was used to measure PTH intraoperatively to confirm successful parathyroidectomy. In patients with scan/US evidence of a solitary EPG and with a normal thyroid gland, limited, unilateral neck surgery or, more recently, MIRS was planned (n=91). In patients with scan/US evidence of multiglandular disease (MGD) (n=21) or concomitant nodular goitre (n=24) or in patients with a negative scan/US evaluation (n=7), extensive bilateral neck exploration was planned (n=52). In 87 of the 91 patients (95.6%) in whom preoperative imaging indicated the presence of a solitary EPG and a normal thyroid gland, a single parathyroid adenoma was found at surgery, and these patients were treated by unilateral neck exploration or MIRS. In the remaining four patients of this group, conversion to bilateral neck exploration was required because parathyroid carcinoma (n=3) or MGD (n=1) was diagnosed at operation. In some cases SPET was helpful in better localising the EPG. In particular, in 5 of the 21 patients evaluated, SPET localised an EPG deep in the neck or mediastinum and at surgery a parathyroid adenoma was found in the paratracheal or para-oesophageal space. In 43 of the 46 patients (93.5%) who were candidates for MIRS, the IMGP technique allowed parathyroidectomy to be performed through a small, 2- to 2.5-cm skin incision with a short duration of intervention (mean 34min). We conclude that: (a) The integrated scan/US imaging protocol that we used appears to be accurate in selecting patients with primary HPT for unilateral neck exploration. (b) In our series the most prevalent cause of bilateral neck exploration was the co-existence of a nodular goitre; thus accurate preoperative evaluation of the thyroid gland by dual-tracer scintigraphy and US imaging is strongly recommended in all patients with HPT. (c) SPET can provide the surgeon with useful information when an EPG is located deep in the neck or mediastinum. (d) IMGP appears to be a useful intraoperative device in HPT patients with solitary parathyroid adenomas and a normal thyroid gland, since it permits minimally invasive and time-saving surgery.

The various effects of amiodarone on thyroid function.

Amiodarone, a benzofuranic-derivative iodine-rich drug used mostly for tachyarrhythmias, often causes changes in the peripheral metabolism of thyroid hormones mainly due to the inhibition of 5'-deiodinase activity: an increase in serum thyroxine and reverse triiodothyronine, and a decrease in serum triiodothyronine concentrations. Overt thyroid dysfunction, either amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH), occurring in 14% to 18% of patients receiving long-term treatment, may develop both in apparently normal thyroid glands and in glands with preexisting abnormalities. AIH is mainly due to the failure to escape from the acute Wolff-Chaikoff effect, and, in patients with thyroid autoimmune phenomena, to concomitant Hashimoto's thyroiditis. AIT is due to excess iodine-induced thyroid hormone synthesis (type I AIT) or to amiodarone-related destructive thyroiditis (type II AIT), although mixed forms often occur. Treatment of AIH consists of levothyroxine replacement therapy while continuing amiodarone therapy; alternatively, amiodarone can be discontinued, if possible, and the natural course toward euthyroidism can be accelerated by a short trial of potassium perchlorate. In type I AIT, the simultaneous administration of thionamides and potassium perchlorate is the treatment of choice, while in type II AIT steroids are the most useful therapeutic option. Mixed forms are best treated with a combination of thionamides, potassium perchlorate, and glucocorticoids. The low thyroidal 131I uptake usually makes radioiodine therapy not feasible, while thyroidectomy is a valid alternative in cases resistant to medical therapy.

The effects of amiodarone on the thyroid.

Amiodarone is a benzofuranic-derivative iodine-rich drug widely used for the treatment of tachyarrhythmias and, to a lesser extent, of ischemic heart disease. It often causes changes in thyroid function tests (typically an increase in serum T(4) and rT(3), and a decrease in serum T(3), concentrations), mainly related to the inhibition of 5'-deiodinase activity, resulting in a decrease in the generation of T(3) from T(4) and a decrease in the clearance of rT(3). In 14-18% of amiodarone-treated patients, there is overt thyroid dysfunction, either amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH). Both AIT and AIH may develop either in apparently normal thyroid glands or in glands with preexisting, clinically silent abnormalities. Preexisting Hashimoto's thyroiditis is a definite risk factor for the occurrence of AIH. The pathogenesis of iodine-induced AIH is related to a failure to escape from the acute Wolff-Chaikoff effect due to defects in thyroid hormonogenesis, and, in patients with positive thyroid autoantibody tests, to concomitant Hashimoto's thyroiditis. AIT is primarily related to excess iodine-induced thyroid hormone synthesis in an abnormal thyroid gland (type I AIT) or to amiodarone-related destructive thyroiditis (type II AIT), but mixed forms frequently exist. Treatment of AIH consists of L-T(4) replacement while continuing amiodarone therapy; alternatively, if feasible, amiodarone can be discontinued, especially in the absence of thyroid abnormalities, and the natural course toward euthyroidism can be accelerated by a short course of potassium perchlorate treatment. In type I AIT the main medical treatment consists of the simultaneous administration of thionamides and potassium perchlorate, while in type II AIT, glucocorticoids are the most useful therapeutic option. Mixed forms are best treated with a combination of thionamides, potassium perchlorate, and glucocorticoids. Radioiodine therapy is usually not feasible due to the low thyroidal radioiodine uptake, while thyroidectomy can be performed in cases resistant to medical therapy, with a slightly increased surgical risk.