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Investigation of a novel modified fixed dose determination protocol for radioiodine treatment of feline hyperthyroidismWentworth-Morre, Wendy Ann 24 May 2017 (has links)
Background: Radioiodine is the treatment of choice for feline hyperthyroidism. The ideal method of dose determination of 131I remains controversial.
Objective: To compare a method of radioiodine dose determination that utilized thyroid scintigraphy with a standard fixed dose for treatment of feline hyperthyroidism.
Methods: Fifty-seven and 23 cats were in the novel and fixed dose groups, respectively. Cats with a percent dose uptake as determined using 99mTcO4- uptake on thyroid scintigraphy <5%, 5-10%, and >10% were designated to receive 3 mCi, 3.5 mCi, or 4.5 mCi of 131I, respectively, administered subcutaneously. Radioiodine dose was adjusted by thyroid size, determined by evaluating the thyroid:salivary size ratio (T:S) and categorized as <5, 5-10, and >10. If the thyroid size fell into a higher dosing category than percent uptake, the dose was increased accordingly. Cats in the fixed dose group received 4.5 mCi of 131I. Six months after treatment, cats were determined to be euthyroid, hypothyroid, or hyperthyroid based on serum T4 concentrations relative to an established reference interval. Univariate analysis using Chi-square was used to determine associations between treatment and outcome.
Results: There was no difference in outcome between the novel and fixed dose treatments. Euthyroidism, hypothyroidism, and hyperthyroidism developed in 61, 30, and 9% of cats in the fixed dose group, respectively compared to 58, 26, and 16% in the novel dose group.
Conclusions: A modified fixed dose method of radioiodine based upon thyroid size and percent dose uptake was ineffective in improving outcomes over a standard fixed dose method. / Master of Science
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Size dependent effects of gold nanoparticles in ISO-induced hyperthyroid ratsZhang, J., Xue, Y., Ni, Y., Ning, F., Shang, Lijun, Ma, A. 2018 July 1919 (has links)
Yes / In this study, we applied different sizes of gold nanoparticles (Au-NPs) to isoproterenol (ISO)-induced hyperthyroid heart disease rats (HHD rats). Single dose of 5, 40, 100 nm Au-NPs were injected intravenously. Cardiac safety tests were evaluated by cardiac marker enzymes in serum and cardiac accumulation of Au-NPs were measured by ICP-MS. Our results showed that size-dependent cardiac effects of Au-NPs in ISO-induced hyperthyroid rats. 5 nm Au-NPs had some cardiac protective effect but little accumulation in heart, probably due to smaller size Au-NPs can adapt to whole body easily in vivo. Histological analysis and TUNEL staining showed that Au-NPs can induce pathological alterations including cardiac fibrosis, apoptosis in control groups, however they can protect HHD groups from these harmful effects. Furthermore, transmission electron microscopy and western blotting employed on H9C2 cells showed that autophagy presented in Au-NPs treated cells and that Au-NPs can decrease LC3 II turning to LC3 I and decrease APG7 and caspase 12 in the process in HHD groups, while opposite effects on control groups were presented, which could be an adaptive inflammation reacts. As there are few animal studies about using nanoparticles in the treatment of heart disease, our in vivo and in vitro studies would provide valuable information before they can be considered for clinical use in general.
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Response to radioiodine in male hyperthyroid patients at Tygerberg HospitalOnimode, Yetunde Ajoke 03 1900 (has links)
Thesis (MSc (Medical Imaging and Clinical Oncology. Nuclear Medicine))--University of Stellenbosch, 2009. / ENGLISH ABSTRACT: Radioiodine therapy is reputed to yield poorer results in male patients than in females. We
retrospectively reviewed the records of 308 patients treated with radioiodine-131 (RAI) for Graves’
disease (n=266, 86.4%), toxic multinodular goitres (n=35, 11.4%) and toxic solitary nodules (n=7,
2.3%).
The mean age of the men was 44 ±13.6 years (range 14-77 years). Patients with GD were
predominantly in the younger age groups, while those with toxic nodular goitres were in the older
range. Two hundred and fifty-nine patients (84.1%) were treated with a single dose of RAI, while
49 (15.9%) required further doses. A second dose had to be administered to 38 patients, while 8
received 3 doses, 2 got 4 doses and 1 patient had 5 doses in all (these included a first dose received
prior to referral to our Thyroid Clinic). Cure was determined as euthyroidism or hypothyroidism at
the 3-month follow-up visit.
The average pre-treatment T4 value was 68.9 ± 31.8 pmol/L (range 5.7 – 155 pmol/L); while the
mean Tc-99m pertechnetate uptake value was 15.8 ± 10.9% (range 0.88 - 62.9).
Patients with GD presented with more severe hyperthyroidism than the other patients; mean free T4
of 71.9 ± 31.1 pmol/L compared to 51.4 ± 29.9 pmol/L for the TMG group of patients, and 39.6 ±
26.8 pmol/L for the TSN group (ANOVA p<0.0001, confirmed by the Kruskal-Wallis test). Patients
with TMG and TSN were treated with higher doses than patients with GD; mean first doses of
349.3 ± 88.5 MBq and 428.1 ± 28.6 MBq respectively, compared to a mean dose of 325.1 ± 69.3
MBq for patients with GD. Treatment with multiple doses of RAI correlated with higher values of
T4 and T3 at presentation (p<0.0001). However, none of the baseline variables of age, T4 and T3,
and first dose of RAI was significant predictors of free T4 outcome at 3 months. A consistently
higher dose was administered to the male patients, compared to female patients of similar age,
diagnosis and level of thyrotoxicosis (Tc-99m pertechnetate uptake). Despite this, male patients had
similar outcomes as the female patients 3 months after therapy.
Our findings lend weight to the theory that male patients are more difficult to treat than their female
counterparts, seeing that the former had similar outcomes despite the significantly higher doses of
RAI administered to the males. / AFRIKAANSE OPSOMMING: Radiojodium terapie lewer na bewering swakker resultate in mans as in vroulike pasiënte. Die
inligting van 308 pasiënte met Grave se siekte (n=266, 86.4%), toksiese multinodulêre tiroïed
(n=35, 11.4%) en enkel toksiese nodules (n=7, 2.3%) wat met radiojodium (I-131) behandel is, is
retrospektief nagegaan.
Die gemiddelde ouderdom van die mans was 44 ±13.6 jaar (reikwydte 14-77 jaar). Die meeste
pasiënte met Grave se siekte was in die jonger ouderdomsgroep, terwyl dié met toksiese
multinodulêre tiroïed, ouer was. Tweehonderd nege-en-vyftig pasiënte (84.1%) is met ‘n enkel
dosis radiojodium behandel, terwyl 49 (15.9%) meer as een dosis benodig het. ‘n Tweede dosis is
aan 38 pasiënte gegee, terwyl agt 3 dosisse, twee 4 dosisse en 1 pasiënt 5 dosisse in totaal ontvang
het (wat ‘n eerste dosis voor verwysing na die tiroïedkliniek, ingesluit het). Herstel is gedefinieer as
eutiroïdisme of hipotiroidisme tydens die drie maande opvolgbesoek.
Die gemiddelde T4-waarde voor behandeling was 68.9 ± 31.8 pmol/L (reikwydte 5.7–155 pmol/L);
terwyl die gemiddelde Tc-99m pertegnetaatopname 15.8 ± 10.9% (reikwydte 0.88–62.9) was.
Pasiënte met Grave se siekte het met erger hipertiroidisme as die ander pasiënte gepresenteer; met
‘n gemiddelde vry T4 van 71.9 ± 31.1 pmol/L vergeleke met 51.4 ± 29.9 pmol/L vir die toksiese
multinodulêre tiroïedgroep en 39.6 ± 26.8 pmol/L vir die enkel toksiese nodule groep (ANOVA
p<0.0001, bevestig met die Kruskal-Wallistoets). Pasiënte met toksiese multinodulêre tiroïed en
enkel toksiese nodule, is met hoër dosisse as dié met Grave se siekte behandel; met ‘n gemiddelde
eerste dosis van 349.3 ± 88.5 MBq en 428.1 ± 28.6 MBq onderskeidelik, vergeleke met ‘n
gemiddelde dosis van 325.1 ± 69.3 MBq vir pasiënte met Grave se siekte. Behandeling met meer as
een dosis radiojodium het gekorreleer met hoër T4- en T3- waardes by (p<0.0001). Geen van die
basislyn veranderlikes (ouderdom, T4 en T3, en die eerste dosis radiojodium) was egter ‘n
betekenisvolle voorspeller van die vry T4 uitkoms op 3 maande nie. Die dosis wat aan manlike
pasiënte toegedien is, was konstant hoër, vergeleke met die vroulike pasiënte van dieselfde
ouderdom, diagnose en vlak van tirotoksikose. (Tc-99m pertegnetaatopname). Ongeag hiervan, was
die uitkoms by manlike en vroulike pasiënte 3 maande na terapie dieselfde.
Ons bevindinge dra by tot die teorie dat manlike pasiënte moeiliker is om te behandel as hul
vroulike eweknieë, aangesien mans soortgelyke uitkomste gehad het ten spyte van betekenisvol
hoër dosisse radiojodium.
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Status of end organ damage in newly detected hypertension, hypertension in thyroid disorders and knowledge and awareness of hypertension among physicians and publicRamachandran, Meenakshi Sundaram January 2014 (has links)
Hypertension is associated with end organ damage (EOD). Since EOD is a risk factor for cardio- and cerebrovascular complications, it is a major requirement for these to be detected, prevented and treated. A total of 147 consecutive patients with newly-diagnosed essential hypertension and attending the outpatient clinic were included in this study based on a set of inclusion and exclusion criteria (patients with co-morbid illnesses were excluded from the investigation). Among them, 86% (70 male (M) and 56 female (F)) had one or more EODs, an observation which was very close to statistically significance (P=0.054). The presence of one or more EODs in newly-detected hypertension indicates widespread vascular damage which carries the high risk for cardio- and cerebrovascular morbidity and mortality. Although thyroid dysfunctions exert significant effects on blood pressure (BP), published literature available has revealed contradictory data. Objective of our study was to explore the inter-relationships between selected thyroid dysfunctional status (hyper and hypothyroid) and established biomarkers [thyroid stimulating hormone (TSH) and thyroxine (T4)]; and BP components [specifically Systolic BP (SBP), Diastolic BP (DBP), and Mean Arterial Pressure (MAP), and uniquely SBP:DBP ratio]. We followed rigid criteria in order to select adults with hyperthyroidism (n=71) and hypothyroidism (n=300), together with healthy age-matched controls (n =300), and applied a series of statistical analyses on the datasets acquired. We have observed thyroid dysfunctional status is associated with elevated BP, and increasing BP is positively-correlated with elevated serum thyroid biomarkers, hyper and hypothyroid disorders should be recognized and treated early in order to avoid critical hazards presented by high BP. Also, we have studied awareness among public and physicians in managing hypertension. Overall, the levels of knowledge and awareness among both groups are sub-optimal. Hence there is an urgent need for empowerment among both groups to enhance awareness and to bring effective standard of care.
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Biomimetic Studies On Anti-Thyroid Drugs And Thyroid Hormone SynthesisRoy, Gouriprasanna 05 1900 (has links)
Thyroxine (T4), the main secretory hormone of the thyroid gland, is produced on thyroglobulin by thyroid peroxidase (TPO)/hydrogen peroxide/iodide system. The synthesis of T4 by TPO involves two independent steps: iodination of tyrosine and phenolic coupling of the resulting iodotyrosine residues. The prohormone T4 is then converted to its biologically active form T3 by a selenocysteine-containing iodothyronine deiodinase (ID-I), which is present in highest amounts in liver, kidney, thyroid and pituitary. The 5'-deiodination catalyzed by ID-I is a ping-pong, bisubstrate reaction in which the selenol (or selenolate) group of the enzyme (E-SeH or E-Se-) first reacts with thyroxine (T4) to form a selenenyl iodide (E-SeI) intermediate. Subsequent reaction of the selenenyl iodide with an as yet unidentified intracellular cofactor completes the catalytic cycle and regenerates the selenol. Although the deiodination reactions are essential for the function of thyroid gland, the activation of thyroid stimulating hormone (TSH) receptor by auto-antibodies leads to an overproduction of thyroid hormones. In addition, these antibodies stimulate ID-I and probably other deiodinases to produce relatively more amount of T3.
Figure 1. Synthesis of thyroid hormones by heme-containing Thyroid Peroxidase(TPO)(Refer PDF File)
As these antibodies are not under pituitary feedback control system, there is no negative influence on the thyroid activity and, therefore, the uncontrolled production of thyroid hormones leads to a condition called “hyperthyroidism”. Under these conditions, the overproduction of T4 and T3 can be controlled by specific inhibitors, which either block the thyroid hormone biosynthesis or reduce the conversion of T4 to T3. A unique class of such inhibitors is the thiourea drugs, methimazole (1, MMI), 6-n-propyl-2-thiouracil (3, PTU), and 6-methyl-2-thiouracil (5, MTU).
Although these compounds are the most commonly employed drugs in the treatment of hyperthyroidism, the detailed mechanism of their action is still not clear. According to the initially proposed mechanism, these drugs may divert oxidized iodides away from thyroglobulin by forming stable electron donor-acceptor complexes with diiodine, which can effectively reduce the thyroid hormone biosynthesis. It has also been proposed that these drugs may block the thyroid hormone synthesis by coordinating to the metal center of thyroid peroxidase (TPO). After the discovery that the ID-I is responsible for the activation of thyroxine, it has been reported that PTU, but not MMI, reacts with the selenenyl iodide intermediate (E-SeI) of ID-I to form a selenenyl sulfide as a dead end product, thereby blocking the conversion of T4 to T3 during the monodeiodination reaction. The mechanism of anti-thyroid activity is further complicated by the fact that the gold-containing drugs such as gold thioglucose (GTG) inhibit the deiodinase activity by reacting with the selenol group of the native enzyme.
Recently, the selenium analogues 2 (MSeI), 4 (PSeU) and 6 (MSeU) attracted considerable attention because these compounds are expected to be more nucleophilic than their sulfur analogues and the formation of an –Se–Se– bond may occur more readily than the formation of an –Se–S– bond with the ID-I enzyme. However, the data derived from the inhibition of TPO by selenium compounds show that these compounds may inhibit the TPO activity by a different mechanism. Therefore, further studies are required to understand the mechanism by which the selenium compounds exert their inhibitory action. Our initial attempts to isolate 2 were unsuccessful and the final stable compound in the synthesis was characterized to be the diselenide (8). In view of the current interest in anti-thyroid drugs and their mechanism, we extended our approach to the synthesis and biological activities of a number of sulfur and selenium derivatives bearing the methimazole pharmacophore.
The thesis consists of five chapters. The first chapter gives a general introduction to thyroid hormone synthesis and anti-thyroid drugs. In this chapter, the biosynthesis of thyroid hormones, structure and function of heme peroxidases, activation of thyroid hormones by iodothyronine deiodinases are discussed. This chapter also gives a brief introduction to some common problems associated with the thyroid gland, with a particular emphasis on hyperthyroidism. The structure and activity of some commonly used anti-thyroid drugs and the role of selenium in thyroid are discussed. The literature references related to this work are provided at the end of the chapter.
The second chapter deals with the synthesis and characterization of the selenium analogue (MSeI) of anti-thyroid drug methimazole and a series of organoselenium compounds bearing N-methylimidazole pharmacophore are described. The clinically employed anti-thyroid drug, methimazole (MMI), exists predominantly in its thione form, which is responsible for its anti-thyroidal activity. The selenium analogue MSeI, on the other hand, is not stable in air and spontaneously oxidizes to the corresponding diselenide (MSeIox). Experimental and theoretical studies on MSeI suggest that this compound exists in a zwitterionic form in which the selenium atom carries a large negative charge. The structure of MSeI was studied in solution by NMR spectroscopy and the 77Se NMR chemical shift shows a large upfield shift (-5 ppm) in the signal as compared to the true selones for which the signals normally appear in the downfield range (500-2500 ppm). This confirms that MSeI exists predominantly in its zwitterionic form in solution. Our theoretical studies show that the formation of the diselenide (MSeIox) from selenol tautomer is energetically more favored than the formation of the disulfide (MMIox) from the thiol tautomer of MMI. This study also shows that the replacement of the N−H group in MSeI by an N-methyl or N-benzyl substituent does not affect the nature of C−Se bond.
In the third chapter, the inhibition of lactoperoxidase-catalyzed oxidation of ABTS by anti-thyroid drugs and related derivatives is described. The commonly used anti-thyroid agent methemazole (MMI) inhibits the lactoperoxidase (LPO) with an IC50 value of 7.0 µM which is much lower than that of the other two anti-thyroid drugs, PTU and MTU. The selenium analogue of methimazole (MSeI) also inhibits LPO with an IC50 value of 16.4 µM, which is about 4-5 times lower than that of PTU and MTU. In contrast to thiones and selones, the S- and Se-protected compounds do not show any noticeable inhibition under identical experimental conditions. While the inhibition of LPO by MMI cannot be reversed by increasing the hydrogen peroxide concentration, the inhibition by MSeI can be completely reversed by increasing the peroxide concentration. Some of the selenium compounds in the present study show interesting anti-oxidant activity in addition to their inhibition propertities. In the presence of glutathione (GSH), MSeI constitutes a redox cycle involving a catalytic reduction of H2O2 and thereby mimics the glutathione peroxidase (GPx) activity in vitro. These studies reveal that the degradation of the intracellular H2O2 by the selenium analogues of anti-thyroid drugs may be beneficial to the thyroid gland as these compounds may act as antioxidants and protect thyroid cells from oxidative damage. Because the drugs with an action essentially on H2O2 can reversibly inhibit thyroid peroxidase, such drugs with a more controlled action could be of great importance in the treatment of hyperthyroidism.
Figure 2. (A) Concentration-inhibition curves for the inhibition of LPO-catalyzed oxidation of ABTS by MMI and MSeI at pH 7.0 and 30 °C. (B) Plot of initial rates (vo) for the LPO-catalyzed oxidation of ABTS vs concentration of H2O2. (a) Control activity, (b) 40 µM of MSeI, (c) 40 µM of MSeIox, (d) 80 µM of PTU, (e) 80 µM of MTU, (f) 40 µM of MMI. The incubation mixture contained 6.5 nM LPO, 1.4 mM ABTS, 0.067 M phosphatebuffer(pH7).(Refer PDF File)
The fourth chapter describes the inhibition of lactoperoxidase (LPO)-catalyzed iodination of L-tyrosine by anti-thyroid drug methimazole (MMI) and its selenium analogue (MSeI). These inhibition studies show that MSeI inhibits LPO with an IC50 value of 12.4 µM, which is higher than that of MMI (5.2 µM). The effect of hydrogen peroxide on the inhibition of LPO by MMI and MSeI is also discussed. These studies also reveal that the inhibition of LPO-catalyzed iodination by MSeI can be completely reversed by increasing the peroxide concentration. On the other hand, the inhibition by MMI cannot be reversed by increasing the concentration of the peroxide. To under stand the nature of compounds formed in the reactions between anti-thyroid drugs and iodine, the reactions of MSeI with molecular iodine is described. MSeI reacts with I2 to produce novel ionic diselenides, and the nature of the species formed in this reaction appears to be solvent dependent. The formation of ionic species (mono and dications) in the reaction is confirmed by UV-Vis, FT-IR and FT-Raman spectroscopic investigations and single crystal x-ray studies. The major conclusion drawn from this study is that MSeI reacts with iodine, even in its oxidized form, to form ionic diselenides containing iodide or polyiodide anions, which might be possible intermediates in the inhibition of thyroid hormones.
Dication X-ray crystal structure of the monocation X-ray crystal structure of the dication
In the fifth chapter, the synthesis and characterization of several thiones and selones having N,N-disubstituted imidazole moiety are described. Experimental and theoretical studies were performed on a number of selones, which suggest that these compounds exist as zwitterions in which the selenium atom carries a large negative charge. The structures of selones were studied in solution by NMR spectroscopy and the 77Se NMR chemical shifts for the selones show large upfield shifts in the signals, confirming the zwitterionic structure of the selones in solution. The thermal isomerization of some S- and Se-substituted methyl and benzyl imidazole derivatives to produce the thermodynamically more stable N-substituted derivatives is described. A structure–activity correlation was attempted on the inhibition of LPO-catalyzed oxidation and iodination reactions by several thiouracil compounds, which indicates that the presence of an n-propyl group in PTU is important for an efficient inhibition. In contrast to the S- and Se-substituted derivatives, the selones produced by thermal isomerization exhibited efficient inhibition, indicating the importance of reactive selone (zwitterionic) moiety in the inhibition. The inhibition data on another well-known anti-thyroid agent carbimazole (CBZ) support the assumption that CBZ acts as a prodrug, requiring a conversion to methimazole (MMI) for its inhibitory action on thyroid peroxidase.
(Refer pdf file/original thesis)
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