Class of 2006 Abstract / Background: Approximately 2% of the population has hypothyroidism, and are treated with a levothyroxine product. Unlike other medications, levothyroxine products have not been considered substitutable due to their narrow therapeutic window. Objectives: To compare the bioequivalence study findings from studies conducted by the manufacturer of Synthroid to those conducted by other investigators. Methods: Studies comparing levothyroxine product bioequivalence were found and divided according to time period, study design, and major funding party. Results: Ten studies excluded due to a change in Synthroid formulation. Six steady state studies and 3 single dose studies were left. Conclusions: Although data suggests bioequivalence between all studied levothyroxine products, there was not enough data to make a conclusion.

Hypothyroidism is the most common endocrine disease in dogs and has been shown to have a hereditary nature in many breeds. Previous studies have documented decreased fertility in bitches with experimentally-induced hypothyroidism, decreased viability at birth, increased periparturient mortality, and reduced birth weight in pups born to hypothyroid dogs. Hypothyroid women have an increased demand for exogenous thyroxine throughout gestation in order to maintain normal plasma concentrations of thyroid hormones and produce neuropsychologically normal children. This study was performed to determine if pregnancy causes a similar need for increased levothyroxine dosages in dogs to maintain a euthyroid state. Serum was harvested from blood collected from six bitches with experimentally-induced hypothyroidism that were receiving standard thyroid hormone replacement therapy and from four euthyroid control bitches. Thyroid function tests performed on these samples included total thyroxine (T4), free T4 (FT4), thyroid stimulating hormone (TSH), and 3,5,3'-triiodinine (T3). Thyroid concentrations were measured from ovluation through the end of pregnancy. All bitches whelped normal litters. Euthyroid bitches had no significant alterations in their hormone concentrations throughout pregnancy. None of the supplemented hypothyroid bitches had clinical signs of hypothyroidism throughout the study. Serum concentrations of T4 and FT4 were elevated at multiple sample points during gestation. The results from this study indicate that standard levothyroxine supplementation is adequate to maintain a euthyroid state during pregnancy in experimentally-induced hypothyroid dogs. In addition, there is no evidence that canine thyroid profiles in euthyroid dogs are altered during gestation. / Master of Science

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / O tratamento de escolha para o hipotireoidismo à a levotiroxina sÃdica. Estudos de biodisponibilidade com medicamentos com caracterÃsticas hormonais tÃm grande importÃncia na garantia do controle da qualidade dos fÃrmacos disponÃveis à populaÃÃo. Logo, o objetivo deste estudo foi: Determinar a biodisponibilidade de duas formulaÃÃes de 150 &#956;g de levotiroxina sÃdica em indivÃduos sadios; apÃs Ãnica administraÃÃo de 600 &#956;g, por via oral e comparÃ-las .A pesquisa consistiu de um estudo aberto, randomizado, cruzado, com dois tratamentos, dois perÃodos (duas seqÃÃncias), nos quais os 24 voluntÃrios, saudÃveis e de ambos os sexos, receberam, em cada perÃodo distinto, a formulaÃÃo teste do Achà LaboratÃrios FarmacÃuticos S.A. ou a formulaÃÃo referÃncia da Sanofi-Synthelabo Ltda. (Puran ÂT4). Foi utilizado o imunoensaio de eletroquimioluminescÃncia para dosar as concentraÃÃes dos hormÃnios T3 (liotironina) e T4 (levotiroxina) nas amostras de soro dos voluntÃrios e posterior determinaÃÃo dos parÃmetros farmacocinÃticos. Os resultados da anÃlise de variÃncia (ANOVA) da Levotiroxina demonstraram um significante efeito de perÃodo com diminuiÃÃo dos nÃveis sÃricos do T4, no segundo internamento, independente da aleatorizaÃÃo (p<0,05). As razÃes das mÃdias geomÃtricas do Cmax e ASC0-48h das formulaÃÃes teste e referÃncia foram 92,97% e 97,87%, respectivamente. Os intervalos de confianÃa de 90% foram de 88,70â 97,44% e 93,10 - 102,88%, respectivamente. As formulaÃÃes de comprimidos de 150microg de levotiroxina sÃdica estudadas apresentaram biodisponibilidades semelhantes, quando administradas em dose Ãnica de 600microg, por via oral a voluntÃrios sadios; sendo entÃo consideradas bioequivalentes.

No description available.

Yes / Background: The most commonly reported symptom of hyperthyroidism is weight loss; successful treatment increases weight. Weight gain faced by patients with hyperthyroidism is widely considered a simple reaccumulation of premorbid weight, whereas many patients feel there is a significant weight “overshoot” attributable to the treatment. We aimed to establish if weight gain seen following treatment for hyperthyroidism represents replenishment of premorbid weight or “overshoot” beyond expected regain and, if there is excessive weight gain, whether this is associated with the applied treatment modality. Methods: We calculated the risk of becoming obese (body mass index [BMI] >30 kg/m2) following treatment for hyperthyroidism by comparing BMI of 1373 patients with overt hyperthyroidism seen in a secondary care setting with the age- and sex-matched background population (Health Survey for England, 2007–2009). Next, we investigated the effect of treatment with an antithyroid drug (ATD) alone in regard to ATD with radioactive iodine (131I) therapy. We modeled the longitudinal weight data in relation to the treatment pathway to thyroid function and the need for long-term thyroxine replacement. Results: During treatment of hyperthyroidism, men gained 8.0 kg (standard deviation ±7.5) and women 5.5 kg (±6.8). At discharge, there was a significantly increased risk of obesity in male (odds ratio = 1.7 [95% confidence interval 1.3–2.2], p < 0.001) and female (1.3, 1.2–1.5, p < 0.001) patients with hyperthyroidism compared with the background population. Treatment with 131I was associated with additional weight gain (0.6 kg, 0.4–0.8, p < 0.001), compared with ATD treatment alone. More weight gain was seen if serum thyrotropin (TSH) was markedly increased (TSH >10 mIU/L; 0.5 kg, 0.3–0.7, p < 0.001) or free thyroxine (fT4) was reduced (fT4 ≤ 10 pmol/L (0.8 ng/dL); 0.3 kg, 0.1–0.4, p < 0.001) during follow-up. Initiation of levothyroxine was associated with further weight gain (0.4 kg, 0.2–0.6, p < 0.001) and the predicted excess weight gain in 131I-induced hypothyroidism was 1.8 kg. Conclusions: Treatment for hyperthyroidism is associated with significant risks of becoming obese. 131I treatment and subsequent development of hypothyroidism were associated with small but significant amounts of excess weight gain compared with ATD alone. We advocate that the discussion over the weight “overshoot” risk forms part of the individualized treatment decision-making process.

This study tested the hypothesis that levothyroxine supplementation increases plasma von Willebrand factor (vWf) concentration and enhances vWf function. The effects of levothyroxine administration were evaluated in 8 euthyroid Doberman Pinschers with plasma vWf concentration <30%. Levothyroxine (0.04mg/kg PO q12hours) and placebo were administered for 30 days in a 2-period, 2-treatment, double-blinded, crossover design with a 30-day washout period between treatments. Buccal mucosal bleeding time (BMBT), vWf antigen concentration (vWf:Ag), vWf collagen binding activity (vWf:CBA), Factor VIII coagulant activity (FVIII:C), serum total thyroxine (T4), free thyroxine (fT4), 3,5,3â -triiodothyronine (T3), and thyroid stimulating hormone were measured on days 0, 2, and 30 of each treatment period. The dogs had markedly low plasma vWf:Ag concentrations (mean 8.9%; reference range 70-180%) and vWf:CBA (mean 11.1%; reference range >70%). All dogs had FVIII:C activity within reference range. The response to placebo versus active levothyroxine treatment revealed no significant differences between groups at any time for BMBT, vWf:Ag, vWf:CBA, and FVIII:C. Serum total thyroxine, fT4, and T3 were significantly higher in the levothyroxine-treated group compared to the placebo group at days 2 and 30. Thyroid stimulating hormone was significantly lower in the levothyroxine-treated group compared to the placebo group at days 2 and 30. Levothyroxine (0.04mg/kg) caused laboratory evidence of hyperthyroidism but did not affect plasma FVIII:C and vWf:Ag concentration or the vWf-dependent functional parameters of collagen binding and BMBT. The results of this study do not reveal a direct action of levothyroxine supplementation on plasma vWf concentration or activity in euthyroid Doberman Pinschers. / Master of Science

Η θεραπεία με λεβοθυροξίνη (LT4) έχει στενό θεραπευτικό παράθυρο. Απόκλιση δοσολογίας μπορεί να οδηγήσει σε υπό-θεραπεία ή σε τοξικότητα. Οι δόσεις υποκατάστασης ή καταστολής λεβοθυροξίνης εξαρτώνται τόσο από την απορρόφηση της λεβοθυροξίνης, όσο και από την άλιπη μάζα σώματος. Όσον αφορά τις θέσεις απορρόφησής της από το γαστρεντερικό σωλήνα, οι γνώσεις μας προέρχονται από περιορισμένες μελέτες χορήγησης ραδιοσημασμένης θυροξίνης. Σκοπός της παρούσης εργασίας ήταν να καθορίσει τις φαρμακοκινητικές παραμέτρους της LT4 σε άτομα με νοσογόνο παχυσαρκία, να συγκρίνει αυτές με τις αντίστοιχες νορμοβαρών ατόμων και να μελετήσει τις θέσεις απορρόφησης της λεβοθυροξίνης στο γαστρεντερικό σωλήνα εκμεταλλευόμενοι το πλεονέκτημα των βαριατρικών επεμβάσεων στους ασθενείς με κλινικά σοβαρή παχυσαρκία, στις οποίες αφαιρείται άλλοτε άλλο τμήμα του γαστρεντερικού σωλήνα. Μέθοδος. Μελετήσαμε 62 ευθυρεοειδικά άτομα με αρνητικά αντισώματα κατά της θυρεοειδικής υπεροξειδάσης, 38 ασθενείς με νοσογόνο παχυσαρκία (ομάδα SOS) και 24 υγιείς εθελοντές (ομάδα αναφοράς). Οι 32 ασθενείς από την ομάδα SOS, υπεβλήθησαν σε επιμήκη γαστρεκτομή (10 άτομα), σε γαστρική παράκαμψη κατά Roux-en-Y (7 άτομα) και σε χολοπαγκρεατική εκτροπή με δημιουργία μακρών ελίκων (15 άτομα). Σε όλα τα άτομα χορηγήθηκε από το στόμα διάλυμα 600mcg νατριούχου λεβοθυροξίνης, μετά από ολονύκτια νηστεία, και μετρήθηκαν οι τιμές των Τ4 και T3 του πλάσματος στους χρόνους 0, 0.5, 1, 1.5, 2, 2.5, 3 και 4 ώρες μετά τη χορήγηση του διαλύματος. Η ίδια διαδικασία ακολουθήθηκε και 35 ημέρες μετά το χειρουργείο. Αποτελέσματα. Οι φαρμακοκινητικές παραμέτροι Επιφάνεια Κάτω από την Καμπύλη και Μέγιστη Συγκέντρωση της Τ4 ήταν χαμηλότερες μετά τη χορήγηση του διαλύματος LT4 (p<0,01 και p<0,05), ενώ ο Χρόνος Μέγιστης Συγκέντρωσης της Τ4 μεγαλύτερος στην ομάδα SOS σε σύγκριση με την ομάδα των νορμοβαρών (p<0,01). Μετεγχειρητικά στην ομάδα που υπεβλήθη σε επιμήκη γαστρεκτομή, η ΕΚΚ της Τ4 ήταν μεγαλύτερη (p<0,01), ενώ η ΜΣ και ο ΧΜΣ ήταν παρόμοιοι πριν το χειρουργείο και 35 ημέρες μετά το χειρουργείο. Στην ομάδα που υπεβλήθη σε γαστρική παράκαμψη κατά Roux-en-Y, μετεγχειρητικά η ΕΚΚ, η ΜΣ και ο ΧΜΣ της Τ4 ήταν παρόμοια. Στην ομάδα που υπεβλήθη σε χολοπαγκρεατική εκτροπή και δημιουργία μακρών ελίκων, η ΕΚΚ και η ΜΣ της Τ4 ήταν μεγαλύτερες μετεγχειρητικά (p<0,001), ενώ ο ΧΜΣ ήταν παρόμοιος. Συμπεράσματα. Άτομα με νοσογόνο παχυσαρκία πιθανώς να χρειάζονται μεγαλύτερες δόσεις καταστολής ή υποκατάστασης με LT4 σε σχέση με νορμοβαρή άτομα εξαιτίας, εκτός των άλλων παραγόντων, επηρεασμένων φαρμακοκινητικών παραμέτρων της λεβοθυροξίνης.. Οι φαρμακοκινητικές παράμετροι της απορρόφησης της λεβοθυροξίνης είναι βελτιωμένες μετά από βαριατρική επέμβαση. Η λεβοθυροξίνη απορροφάται κύρια από το απώτερο τμήμα της νήστιδας και από τον ειλεό, ενώ το στομάχι και το δωδεκαδάκτυλο δεν εμπλέκονται άμεσα στην απορρόφηση της λεβοθυροξίνης. / Levothyroxine (LT4) has a narrow therapeutic window so that slightly changes in the treatment dose could have significant clinical consequences. Suppressive or replacement doses of LT4 are affected by the rate and extend of the active ingredient absorbed, as well as by the lean body mass. Concerning the absorption sites of levothyroxine, the data are limited and our knowledge based on studies of radio isotopic thyroxine in intestinal tract. Aim of this study was to determine the pharmacokinetic parameter of LT4 in severely obese individuals, compare them with similar data in lean control subjects, as well as to study the consequences of bariatric surgery on the pharmacokinetic parameters of LT4 and to identify the parts of the gastrointestinal tract implicated in its absorption. Method. We studied 62 euthyroid subjects, who had negative tests for anti-thyroid peroxidase antibodies. Thirty eight of these were severely obese but otherwise healthy (SOS-group). Twenty four were healthy controls subjects (control group). Thirty two subjects of the SOS group, underwent sleeve gastrectomy (SG; n=10); Roux-en-Y gastric bypass (RYGBP;n=7) or biliopancreatic diversion with gastric bypass and long limbs (BPD-LL;n=15). Subjects received 600mcg oral solution of sodium LT4 after an overnight fast. Serum T4 and T3 were measured 0; 0.5; 1; 1.5; 2; 2.5; 3 and 4 hours after LT4 administration. The same procedure was repeated 35 days after surgery. Results. The Area Under the Curve (AUC) and the peak plasma Concentration (Cmax) of T4 after LT4 administration were lower; whereas the Time to reach Cmax (Tmax) from the baseline was higher in the SOS than in the control group. Following surgery; in the SG group; the mean AUC was higher (p<0.01); whereas Cmax and Tmax were similar to pre surgery. In the RYGBP group; mean AUC; Cmax und Tmax were similar. In the BPD-LL group; mean AUC and Cmax were higher 35 days after surgery than before (p<0.001); whereas Tmax was similar. Conclusions. Severely obese individuals may need higher LT4 suppressive or replacement doses than normal weight individuals due, among other factors, impaired LT4 pharmacokinetic parameters. The pharmacokinetic parameters of LT4 absorption are improved following bariatric procedures that result in malabsorption.T4 is absorbed primarily from lower part of the jejunum and from the ileum, whereas stomach and duodenum are not involved directly in the absorption of LT4.

Hashimoto Thyroiditis (HT) or chronic lymphocytic thyroiditis is an autoimmune disease that causes the destruction of the thyroid gland by inflammatory infiltrates and consequently loss of function. This disease is spread worldwide and predominantly affects females. The consequences of alterations in its activity range from cretinism to the vascular changes. It is known that the enzymes ectonucleoside diphosphohydrolase triphosphate (E-NTPDase, EC 3.6.1.5, CD39), ecto-5'nucleotidase (EC 3.1.3.5, CD73) and adenosine deaminase (ADA, EC 3.5.4.4) are involved in regulating the immune response and thrombotic events, since they regulate extracellular levels of adenine nucleotides and nucleoside. Since HT patients have an autoimmune response and present microvascular changes, the objective of this study was to evaluate the influence of purinergic signaling in the regulation of microvascular dysfunction triggered by the disease determining the activity of the ectoenzymes involved in the metabolism of ATP in platelets from patients with HT in treatment with levothyroxine. Samples were collected from patients with HT treated with levothyroxine and from a control group. In this study we determined the activity of the enzymes E-NTPDase, ecto-5'-nucleotidase and E-ADA; detected the expression of the enzyme in platelets and E-NTPDase; and measured hormone levels of TSH and fT4 in patients with HT treated with levothyroxine and control group. Results obtained in the enzyme activity showed that patients with HT in hormone replacement with levothyroxine presented no significant changes when compared with the control group. In conclusion, levothyroxine used in patients with HT may reverse the effects of hypothyroidism when used regularly in these patients, while maintaining the enzyme activity in basal levels. / A Tireoidite de Hashimoto (TH) ou tireoidite linfocítica crônica é uma doença autoimune que causa a destruição da glândula tireóide por meio de infiltrados inflamatórios e consequente perda da função. Esta patologia encontra-se difundida mundialmente e acomete prevalentemente o sexo feminino. As consequências das alterações de sua atividade vão desde cretinismo à alterações vasculares. Sabe-se que as enzimas ectonucleosídeo trifosfato difosfo-hidrolase (E-NTPDase; E.C. 3.6.1.5; CD39), ecto-5 nucleotidase (E.C.3.1.3.5; CD73) e adenosina desaminase (ADA; E.C.3.5.4.4) participam tanto da regulação da resposta imune quanto de eventos trombóticos, uma vez que regulam os níveis extracelulares dos nucleotídeos e nucleosídeo da adenina. Visto que, pacientes portadores da TH possuem uma resposta autoimune e também apresentam alterações microvasculares, o objetivo deste estudo foi avaliar a influência da sinalização purinérgica na regulação das disfunções microvasculares desencadeadas pela doença, através da determinação da atividade de ectoenzimas envolvidas no metabolismo do ATP em plaquetas de pacientes com TH em tratamento com levotiroxina. Foram coletadas amostras de pacientes com TH em tratamento com levotiroxina e um grupo controle. Neste estudo determinamos a atividade das enzimas E-NTPDase, ecto-5 -nucleotidase e E-ADA, verificamos a expressão da enzima E-NTPDase em plaquetas e dosamos os níveis hormonais de TSH e fT4 em pacientes com TH em tratamento com levotiroxina, bem como do grupo controle. Os resultados obtidos na atividade das enzimas e na concentração dos nucleotídeos e nucleosídeo da adenina, não demonstraram alterações significativas quando comparamos os pacientes com TH em reposição hormonal com levotiroxina, com o grupo controle. Em conclusão, sugere-se que a levotiroxina usada em pacientes com TH pode reverter os efeitos do hipotireoidismo quando usada regularmente por estes pacientes, mantendo as atividades das enzimas em níveis basais.

The objective of this study was to define if there is a mutual influence between the daily dose of levothyroxine, positivity/negativity of thyroid antibody, BMI, waistline, hip measurement and other anthropometric parameters. It was also to analyze if the daily dose of levothyroxine is being influenced by degree of hypothyroidismimportance. Methodology: There were 44 patients examined having hypothyroidism and who have been cured with levothyroxine so that their thyroid function has been normal at the time. I have examined those patients' body height, weight, BMI, waistline and hipline. Under the supervision of the medicine doctor I used records available for each of patients regarding concentration of TSH, TPOAb and TgAb, which were defined with patients' blood by a method of immunoassay. Results: The average daily dose of levothyroxine in all patients sample has showed a positive correlation with BMI (Spearman rho coef. 0,429, P value=0,004) and with waistline of women (Spearman rho coef. 0,332, P value=0,028). The concentration of thyroidantibody did not show a statistical relevance regarding the dependence with the dose of levothyroxine, BMI or other anthropometric parameters.The highest average daily dose of levothyroxine was confirmed for examined patients after total thyroidectomy (median of...

Drug interactions of drugs used in thyroid diseases Author: Veronika Teťáková1 Tutor: PharmDr. Josef Malý, Ph.D.1 1 Department of Social and Clinical Pharmacy, Charles University, Faculty of Pharmacy in Hradec Králové Introduction and objectives: Drug interactions are considered to be a significant aspect of pharmacotherapy that can lead to the potentiation of toxicity and side effects of drugs. However, their identification and adequate management of the use of drug combinations hampers a number of obstacles. The aim of this thesis was to summary information about the drug interactions of drugs used in thyroid diseases (levothyroxine, propylthiouracil, thiamazole) and to formulate articles describing the management of interactions in a clinical practice including information for the dispensation of these drugs. To compare the information presented in each database and to determine the degree of conformity between these sources. Methodology: Based on the use of numerous information sources (Micromedex, UpToDate, SPC, Stockley's Drug Interactions) lists of drug interactions of drugs used in thyroid disaeses were established. Information about these interactions were completed by findings from other sources (PubMed®, scientific reports, Google Scholar). The information presented in each of these...