Amiodarone compared with iodine exhibits a potent and persistent inhibitory effect on TSH-stimulated cAMP production in vitro: a possible mechanism to explain amiodarone-induced hypothyroidism.
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Amiodarone (AMD) is a powerful anti-arrhythmic drug used for the treatment of a wide variety of cardiac arrhythmias and its most striking feature is its high iodine content. Thyroid dysfunction is a limiting side-effect of the drug and both AMD-induced hypothyroidism (AIH) and AMD-induced thyrotoxicosis (AIT) are reported. To examine the hypothesis that altered bioavailability of iodine is a contributing event in the pathogenesis of AIH, we compared the effects of AMD and inorganic iodine in vitro on events involved in the process of thyroid autoregulation. FRTL-5 cells and JP26 CHO cells (transfected with the human TSH receptor) were exposed to AMD or NaI in the presence of TSH, and cAMP production was measured as an indicator of cellular function. Forskolin and cholera toxin were also used to determine the possible target sites of AMD and iodide. Our results indicated that there was a difference between the effects of AMD versus those of physiological doses of iodide. The inhibitory effects of AMD occurred at lower concentrations of iodide than those seen in the NaI-treated cells. The effects of AMD were irreversible indicating a possible persistence of the Wolff-Chaikoff effect due to a constant high intracellular iodide level. The inhibitory effects of AMD (also seen at supraphysiological doses of iodide) were partially overcome by forskolin but not by cholera toxin indicating an effect on TSH receptor interactions with the other signal transduction elements such as G proteins and adenylate cyclase. The persistence of the Wolff-Chaikoff effect through loss of autoregulation may be a mechanism of the observed hypothyroidism in some patients taking AMD. The combined effects of the constant release of iodide together with the drug toxicity may be the mechanism for the observed effects. (+info)
Evaluation of three gamma detectors for intraoperative detection of tumors using 111In-labeled radiopharmaceuticals.
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Attempts to detect tumors with intraoperative scintillation using tumor-binding radiopharmaceuticals have intensified recently. In some cases previously unknown lesions were found, but in most cases no additional lesions were detected. In this study the physical characteristics of three detector systems and their ability to detect tumors through accumulation of an 111In-labeled radiopharmaceutical were investigated. The first was a sodium iodide (NaI[TI]) detector; the second, a cesium iodide (CsI[TI]) detector; and the third, a cadmium telluride (CdTe) detector. METHODS: A body phantom and tumor phantoms (diameter 5-20 mm) made of water, agarose gel or epoxy with a density and attenuation coefficient similar to those of soft tissue were used to simulate a clinical situation. The activity concentration in the body phantom was based on reported values of 111In-octreotide in normal tissue in humans. The 111In activity concentration in the tumor phantoms varied from 3 to 80 times the 111In activity concentration in the body phantom. Data were processed to determine tumor detection levels. RESULTS: The NaI(TI) detector showed the lowest values for full width at half maximum because this detector had the best collimation, leading to a high ratio between counts from tumor and counts from background, i.e., small tumors could be detected. Because of high efficiency, the CsI(TI) detector sometimes required a somewhat shorter acquisition time to produce a statistically significant difference between tumor phantom and background. For deep-lying tumors the NaI(TI) detector was superior, whereas the CdTe detector was best suited for superficial tumors with a high activity concentration in the underlying tissue. CONCLUSION: At a maximum acquisition time of 30 s, almost all superficial tumors with a diameter of 10 mm or larger were detected if the ratio between the 111In concentration in the tumor and the 111In concentration in the background exceeded 3. However, in clinical situations, biologic variations in the uptake of 111In-octreotide in tumors and in normal tissue makes difficult the determination of a distinct detection level. For such clinical conditions, the NaI(TI) detector is the best choice because it has good resolution despite a lower efficiency. Documentation of detector characteristics is important so that clinicians can make an adequate device in relation to tumor location and receptor expression. (+info)
Hypothyroidism in transgenic mice expressing IFN-gamma in the thyroid.
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IFN-gamma has been implicated with contradictory results in the pathogenetic process of autoimmune (Hashimoto's) thyroiditis, the most common cause of hypothyroidism in adults. To test whether the local production of IFN-gamma can lead to thyroid dysfunction, we have generated transgenic mice that express constitutively IFN-gamma in the thyroid follicular cells. This expression resulted in severe hypothyroidism, with growth retardation and disruption of the thyroid architecture. The hypothyroidism derived from a profound inhibition of the expression of the sodium iodide symporter gene. Taken together, these results indicate a direct role of IFN-gamma in the thyroid dysfunction that occurs in autoimmune thyroiditis. (+info)
Volatility of radiopharmacy-prepared sodium iodide-131 capsules.
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OBJECTIVE: The aims of this study were to quantify the extent of volatilization from 131I-NaI therapeutic capsules prepared in a centralized radiopharmacy and to quantify the amount of volatile 131I released from a dispensing vial containing a compounded 131I-NaI therapy capsule. METHODS: Therapy capsules were prepared by injecting 131I oral solution into capsules containing anhydrous dibasic sodium phosphate. Volatilized activity was obtained by filtering air drawn across samples that were placed open on the bottom of a sample holder cup. Volatile 131I was captured by filtering it through 3 triethylenediamine-impregnated carbon cartridge filters, arranged in series. To quantify the amount of volatile 131I released from a dispensing vial during a simulated patient administration, a vial containing a compounded 131I therapy capsule was opened inside a collapsible plastic bag and all the air was drawn across TEDA-impregnated carbon cartridge filters. RESULTS: The 370-MBq (10-mCi) 131I capsules from the first part of the experiment released an average of 0.035% (SD 0.031%) of the capsule activity on the first day, 0.012% (SD 0.002%) on the second day, and 0.012% (SD < 0.001%) for days 3 through 5. The 37-MBq (1-mCi) 131I capsules released an average of 0.058% (SD 0.025%) on the first day, 0.029% (SD 0.009%) on the second day, and 0.020% (SD 0.004%) on the third day. The activity released from the vial during a simulated patient administration was 0.00093% of the 131I capsule activity. CONCLUSION: The amount of 131I, which volatilized daily from the exposed therapy capsules, was a small percentage of the capsule activity. The volatile 131I that would be released during a patient administration was much less than the activity that volatilized from the exposed therapy capsules. (+info)
Endothelium modulates anion channel-dependent aortic contractions to iodide.
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Anion currents contribute to vascular smooth muscle (VSM) membrane potential. The substitution of extracellular chloride (Cl) with iodide (I) or bromide (Br) initially inhibited and then potentiated isometric contractile responses of rat aortic rings to norepinephrine. Anion substitution alone produced a small relaxation, which occurred despite a lack of active tone and minimal subsequent contraction of endothelium-intact rings (4.2 +/- 1.2% of the response to 90 mM KCl). Endothelium-denuded rings underwent a similar initial relaxation but then contracted vigorously (I > Br). Responses to 130 mM I (93.7 +/- 1.9% of 90 mM KCl) were inhibited by nifedipine (10(-6) M), niflumic acid (10(-5) M), tamoxifen (10(-5) M), DIDS (10(-4) M), and HCO(-)(3)-free buffer (HEPES 10 mM) but not by bumetanide (10(-5) M). Intact rings treated with N(omega)-nitro-L-arginine (10(-4) M) responded weakly to I (15.5 +/- 2.1% of 90 mM KCl), whereas hemoglobin (10(-5) M), indomethacin (10(-6) M), 17-octadecynoic acid (10(-5) M), and 1H-[1,2, 4]oxadiazole[4,3-a]quinoxalin-1-one (10(-6) M) all failed to augment the response of intact rings to I. We hypothesize that VSM takes up I primarily via an anion exchanger. Subsequent I efflux through anion channels having a selectivity of I > Br > Cl produces depolarization. In endothelium-denuded or agonist-stimulated vessels, this current is sufficient to activate voltage-dependent calcium channels and cause contraction. Neither nitric oxide nor prostaglandins are the primary endothelial modulator of these anion channels. If they are regulated by an endothelium-dependent hyperpolarizing factor it is not a cytochrome P-450 metabolite. (+info)
Retinoic acid induces sodium/iodide symporter gene expression and radioiodide uptake in the MCF-7 breast cancer cell line.
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The sodium/iodide symporter (NIS) stimulates iodide uptake in normal lactating breast, but is not known to be active in nonlactating breast or breast cancer. We studied NIS gene regulation and iodide uptake in MCF-7 cells, an estrogen receptor (ER)-positive human breast cancer cell line. All-trans retinoic acid (tRA) treatment stimulated iodide uptake in a time- and dose-dependent fashion up to approximately 9.4-fold above baseline. Stimulation with selective retinoid compounds indicated that the induction of iodide uptake was mediated by retinoic acid receptor. Treatment with tRA markedly stimulated NIS mRNA and immunoreactive protein ( approximately 68 kDa). tRA stimulated NIS gene transcription approximately 4-fold, as shown by nuclear run-on assay. No induction of iodide uptake was observed with RA treatment of an ER-negative human breast cancer cell line, MDA-MB 231, or a normal human breast cell line, MCF-12A. The iodide efflux rate of tRA-treated MCF-7 cells was slow (t(1/2) = 24 min), compared with that in FRTL-5 thyroid cells (t(1/2) = 3.9 min), favoring iodide retention in MCF-7 cells. An in vitro clonogenic assay demonstrated selective cytotoxicity with (131)I after tRA stimulation of MCF-7 cells. tRA up-regulates NIS gene expression and iodide uptake in an ER-positive breast cancer cell line. Stimulation of radioiodide uptake after systemic retinoid treatment may be useful for diagnosis and treatment of some differentiated breast cancers. (+info)
Expression of sodium iodide symporter in metastatic and follicular human thyroid tissues.
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Active iodide uptake across the basal membrane mediated by human sodium iodide symporter (hNIS) has been shown to be a process coupled with the flow of sodium. There is still controversy as to the amount of hNIS expression present in different kinds of human thyroid cancer tissues. In this study, we present a 58-year-old women with follicular thyroid carcinoma with vertebra and skull metastases. 201Tl and 5 mCi 131I scans clearly demonstrated the metastatic lesions in the brain of this patient. Thyroid and metastatic tissues were then obtained for this study, which is aimed at comparing the iodide trapping ability in vivo and in vitro of hNIS, and then comparing their expression in both thyroid tissue and metastatic tissues. Polyclonal antibodies to hNIS and competitive RT PCR were used to analyze the symporter protein and mRNA expressed in follicular human thyroid and metastatic tissues. Positive staining of the symporter protein was performed in the follicular thyroid carcinomas, otherwise, the metastatic tissues could not have demonstrated the protein in the staining. Follicular thyroid carcinoma tissues from thyroid were revealed around 5 pg hNIS expressed in follicular thyroid carcinoma tissues from the thyroid. Otherwise, there was almost an absence of hNIS expression in the metastatic tissue. These discrepancies of the expression in hNIS in vivo and in vitro studies need further investigation. (+info)
Comparative roles of free fatty acids with reactive nitrogen intermediates and reactive oxygen intermediates in expression of the anti-microbial activity of macrophages against Mycobacterium tuberculosis.
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We assessed the role of free fatty acids (FFA) in the expression of the activity of macrophages against Mycobacterium tuberculosis in relation to the roles of two major anti-microbial effectors, reactive nitrogen intermediates (RNI) and reactive oxygen intermediates (ROI). Intracellular growth of M. tuberculosis residing inside macrophages was accelerated by treatments of macrophages with either quinacrine (phospholipase A2 (PLA2) inhibitor), arachidonyl trifuloromethylketone (type IV cytosolic PLA2 inhibitor), NG-monomethyl-L-arginine (nitric oxide synthase inhibitor), and superoxide dismutase plus catalase (ROI scavengers). In addition, M. tuberculosis-infected macrophages produced and/or secreted these effectors sequentially in the order ROI (0-3 h), FFA (0-48 h), and RNI (3 to at least 72 h). Notably, membranous FFA (arachidonic acid) of macrophages translocated to M. tuberculosis residing in the phagosomes of macrophages in phagocytic ability- and PLA2-dependent fashions during cultivation after M. tuberculosis infection. FFA, RNI and H2O2-mediated halogenation system (H2O2-halogenation system) displayed strong activity against M. tuberculosis in cell-free systems, while ROI alone exerted no such effects. Combinations of 'FFA + RNI' and 'RNI + H2O2-halogenation system' exhibited synergistic and additive effects against M. tuberculosis, respectively, while 'FFA + H2O2-halogenation system' had an antagonistic effect. Moreover, a sequential attack of FFA followed by RNI exerted synergistic activity against M. tuberculosis. Since M. tuberculosis-infected macrophages showed simultaneous production of RNI with FFA secretion for relatively long periods (approx. 45 h) and prolonged RNI production was seen thereafter, RNI in combination with FFA appear to play critical roles in the manifestation of the activity of macrophages against M. tuberculosis. (+info)