Second harmonic generation from tryptophan-rich short peptides: W(n)K(m) and gramicidin A.

We report the first hyperpolarizability of a series of tryptophan-rich short peptides with the respective sequence KWK, KWWK, KWWWK, KWWKWWK, where W and K stand for tryptophan and lysine. The measurements were performed with the technique of hyper-Rayleigh scattering in the bulk of an aqueous Tris buffer solution at a pH of 8.5 and a salt concentration of 150 mM at the non-resonant fundamental wavelength of 784 nm. The first hyperpolarizability of the different peptides follows a simple additive model scaling with the number of tryptophan residues contained in the peptide. However, it appears that the first hyperpolarizability response of a single tryptophan residue in the peptide strongly differs from that of an isolated tryptophan. Hence, it is therefore demonstrated that the local environment of the tryptophan residues within the peptide strongly influences its nonlinear optical response. A comparison with the first hyperpolarizability of the natural peptide gramicidin A measured in trifluoroethanol (TFE) further confirms the key role of the local environment on the first hyperpolarizability of tryptophan residues in peptides.

Sources of circulating 3,5,3'-triiodothyronine in hyperthyroidism estimated after blocking of type 1 and type 2 iodothyronine deiodinases.

CONTEXT: Graves' hyperthyroidism and multinodular toxic goiter lead to high serum T(3) compared with serum T(4). The source of this high T(3) has not been clarified. OBJECTIVE: Our objective was to assess the role of iodothyronine deiodinase type 1 (D1) and type 2 (D2) for T(3) production and to estimate the sources of T(3) in hyperthyroidism. DESIGN AND SETTING: The study was a prospective, randomized, open-labeled study in a secondary care setting. PATIENTS AND METHODS: Consecutive patients with hyperthyroidism caused by Graves' disease or by multinodular toxic goiter were randomized to be treated with high-dose propylthiouracil (PTU) to block D1, PTU plus KI, or PTU plus sodium ipodate to additionally block D2. T(3) and T(4) were measured in serum, and we estimated the sources of T(3). RESULTS: PTU reduced the T(3)/T(4) in serum to 47.7 +/- 2.5% (mean +/- sem) of the initial value on d 4 of therapy in patients with Graves' disease. The addition of KI to PTU led to a greater fall in T(3) and T(4), but the balance was unaltered. After PTU plus ipodate, T(3)/T(4) on d 4 was lower, 34.1 +/- 1.2% of the initial value. Similar variations were observed in patients with multinodular toxic goiter. Thus, the major source of the excess T(3) was D1-catalyzed T(4) deiodination, with a minor role for D2. It was estimated that the majority of this D1-catalyzed T(3) production takes place in the hyperactive thyroid gland. CONCLUSION: Although thyroidal T(3) contributes only around 20% of total T(3) production in normal individuals, this is much higher in patients with a hyperactive thyroid, ranging up to two thirds. The major part is produced from T(4) deiodinated in the thyroid.

Use of oral cholecystography agents in the treatment of hyperthyroidism of subacute thyroiditis.

AIM: In this study, we describe our experience in treating subacute thyroiditis patients with 2 OCAs (sodium ipodate and sodium iopanoate). METHODS: We studied 10 consecutive patients with subacute thyroiditis treated with 1 of the 2 oral cholecystography agents (OCAs). RESULTS: Hyperthyroidism was controlled and symptoms improved markedly in each case without any evidence of subsequent relapse of thyroiditis after withdrawal of OCAs. Three of the 10 patients had been treated previously with corticosteroids and had demonstrated relapse of thyroiditis and hyperthyroidism after tapering or withdrawal of steroids. We observed no side effects of treatment with OCAs. CONCLUSION: Our data suggest that OCAs are effective and safe agents for management of hyperthyroidism in patients with subacute thyroiditis, even when they have relapsed after treatment with corticosteroids.

Bloqueo de la conversión periférica de Tiroxina a triyodotironina por el iopodato sódico y su empleo en el control agudo del hipertiroidismo / Block of the peripheral conversion of tiroxinE to triyodotironinE for the iopodato sodico and its employment in the acute control of the hyperthyroidism

El presente trabajo se investigó el efecto de iopodato sódico, en 8 sujetos normales y en 21 hipertirodeos con enfermedad de Graves. A los primeros se les administró 3 gramos de iopodato solo por vía oral y a los segundos junto con 30-45 mg fue mertimazol. Posteriormente se determinó la concentración sérica de T4, T3, THS y I, así como también la excreción urinaria de yodo en forma seriada hasta los 45 días después de la administración de este medicamento. Adicionalmente a los estudios hormonales, en los pacientes hipertiroideos se realizó también una evaluación clínica. Utilizando el índice de Crooks, Wayne y Murray (ICWM) y también cardiovascular, antes y durante el tratamiento. En los sujetos normales se observó una caida significativa en los niveles de T3 equivalente al 22 por ciento del valor basal en el primer día y máxima del 35 por ciento al tercer día después de la administración de iopodato, siguiendo luego una curva de recuperación progresiva hasta alcanzar los niveles basales a los 15 días. Los niveles de T4 experimentaron un discreto aumento. Los niveles de TSH también se elevaron significativamente entre el segundo y tercer día. En los pacientes hipertiroideos la respuesta a la administración de iopodato y metimazol fue más marcada, la caída en los niveles de T3 fue 56.7 por ciento al primer día y 60.6 por ciento al tercer día. Los niveles de T4 también sufrieron una disminución progresiva y los valores de TSH se mantuvieron deprimidos durante el periodo de observación. La evolución clínica de los hipertiroideos mostró franca mejoría en estrecha concordancia con los cambios hormonales, en particular con la caída de T3, y en los pacientes con complicaciones cardiovasculares hubo una regresión de la insuficiencia cardiaca y la fibrilación auricular...

Modalidades terapêuticas na doença de Basedow-Graves / Therapeutical approaches in Basedow-Graves disease

Neste artigo säo analisadas as três grandes modalidades terapêuticas do hipertireoidismo - o tratamento clínico, o radioiodo e a cirurgia -, discutindo-se detalhadamente cada uma delas, enfocando seus mecanismos de açäo, vantagens e desvantagens, principais indicaçöes e contra indicaçöes. A abordagem terapêutica também será analisada em grupos especiais como neonatos, crianças e adolescentes, gestantes e idosos

Sodium ipodate (oragrafin) in the preoperative preparation of Graves' hyperthyroidism.

Fourteen Graves' hyperthyroid patients who had been prepared for surgery with sodium ipodate (SI) 500 mg orally twice daily for 3 days were retrospectively studied. SI was administered in combination with propylthiouracil (10 cases) and beta blockers (all cases), which had been previously initiated. Free serum thyroxine (T4) and total triiodothyronine (T3) concentrations were measured before and after SI therapy on the morning of surgery. SI treatment significantly reduced total T3 concentration from 445.9 to 193.4 ng/dL (P < 0.0001) and free T4 concentration from 3.874 to 2.800 ng/dL (P = 0.0003). Preoperatively, only one patient had persistent tachycardia, and intraoperatively this same patient required beta blockers. Blood loss was unremarkable or reduced (average blood loss, 121 mL). On clinical examination glands were firm with normal or somewhat decreased vascularity. On histologic study all glands demonstrated changes consistent with treated Graves' disease. Preoperative treatment with SI appears to be a safe and efficacious method of preparing hyperthyroid patients for surgery.

Ipodate treatment of hyperthyroidism in cats.

OBJECTIVE: To evaluate the efficacy and safety of ipodate in the treatment of hyperthyroidism in cats. DESIGN: Prospective case series. ANIMALS: 12 cats with hyperthyroidism treated at The Animal Medical Center between November 1994 and March 1996. PROCEDURE: Each cat initially received 100 mg of ipodate/d, PO. The drug's effects on clinical signs, body weight, heart rate, and serum triiodothyronine (T3) and thyroxine concentrations were evaluated 2, 4, 6, 10, and 14 weeks after initiation of treatment. A CBC and serum biochemical analyses were performed at each evaluation to monitor potential adverse effects of the drug. Dosage of ipodate was increased to 150 mg/d and then to 200 mg/d at 2-week intervals if a good clinical response was not observed. RESULTS: 8 cats responded to treatment and 4 did not. Among cats that responded, mean body weight increased and mean heart rate and serum T3 concentration decreased during the study period. Among cats that did not respond, mean body weight decreased and mean heart rate and serum T3 concentration were not significantly changed. Serum thyroxine concentration remained high in all cats. Adverse clinical signs or hematologic abnormalities attributable to ipodate treatment were not reported in any of the cats. CLINICAL IMPLICATIONS: Ipodate may be a feasible alternative to methimazole for medical treatment of hyperthyroidism in cats, particularly those that cannot tolerate methimazole and are not candidates for surgery or radiotherapy. Cats with severe hyperthyroidism are less likely to respond to ipodate than are cats with mild or moderate disease, and cats in which serum T3 concentration does not return to the reference range are unlikely to have an adequate improvement in clinical signs.

[Treatment of neonatal hyperthyroidism with calcium iopodate]. / Traitement de l'hyperthyroïdie néonatale par l'iopodate de calcium.

BACKGROUND: Treatment of hyperthyroidism in those neonates born to mothers with Grave's disease is difficult. Calcium ipodate, an agent for oral cholecystography, inhibits extra-thyroid conversion of T3 to T4 and diminishes thyroid secretion. CASE REPORTS: Two neonates with clinical manifestations and biological findings of hyperthyroidism were given calcium ipodate orally, 400 mg every 3 days, from day 26 to 50 for the first patient and from day 9 to 18 for the second in association with a beta blocker. Clinical manifestations disappeared within 2 days and circulating levels of T3 and T4 were normalized within 2-5 days. CONCLUSIONS: This treatment was effective and well-tolerated in both patients and in three others previously reported; it should be confirmed in a larger number of patients and controlled by measuring levels of antibodies directed against thyrotropin-releasing hormone receptors in order to avoid relapse after cessation of treatment as seen in our second patient.

Ipodate therapy in patients with severe destruction-induced thyrotoxicosis.

We describe 4 patients with severe destruction-induced thyrotoxicosis who had a rapid clinical response to oral sodium ipodate (500 mg daily). The underlying thyroid disorders in the patients were postpartum thyroiditis, subacute thyroiditis, silent thyroiditis, and radiation-induced thyroiditis. Ipodate therapy was given for 6 to 10 weeks until restoration of thyroid function to normal. In all patients, an almost complete resolution of symptoms occurred by the third day of ipodate treatment. In the patient with radiation thyroiditis, a daily clinical score of thyrotoxicosis declined within 2 to 3 days. The score remained low as long as the patient was receiving ipodate, but 2 attempts to discontinue ipodate therapy while thyroxine levels were elevated resulted in a rise of the thyrotoxicosis clinical score. This suggests that ipodate therapy, by rapidly reducing triiodothyronine levels through inhibition of the 5' monodeiodination and blockage of the peripheral effects of thyroid hormone, controls severe thyrotoxicosis mediated by destruction and should be considered in this setting in conjunction with beta-adrenergic blockade.

Use of sodium ipodate in management of hyperthyroidism in subacute thyroiditis.

Five hyperthyroid patients (two men and three women) with typical features of subacute thyroiditis were treated with sodium ipodate (Oragrafin; 0.5 g, orally daily or every other day) for 15-60 days; the treatment was stopped when both serum T4 and T3 levels were normal. All patients studied demonstrated a prompt normalization of serum T3, improvement in clinical symptoms of hyperthyroidism, and/or weight gain. We observed no side-effects of treatment with sodium ipodate. Our data suggest that sodium ipodate is a safe and effective agent for management of hyperthyroidism in subacute thyroiditis.

An acute dose of desmethylimipramine inhibits brain uptake of [125I]3,3',5-triiodothyronine (T3) in thyroxine-induced but not T3-induced hyperthyroid rats: implications for tricyclic antidepressant therapy.

The tricyclic antidepressant, desmethylimipramine (DMI), a highly selective inhibitor of presynaptic uptake of norepinephrine (NE), has also been shown to reduce [125I]3,3',5-triiodothyronine (T3) uptake in rat brain synaptosomes. Using DMI as a probe to examine 1) possible noradrenergic influences on thyroid hormone (TH) actions in brain and 2) TH:affective disorder relationships, we found that a single dose of DMI produces a small (7.4-25%) but significant (P < or = .05) decrease in brain uptake of both labeled T3 (T3) and labeled thyroxine (T4) across the spectrum of thyroid states from hypothyroid (HYPO) to euthyroid to T4-induced hyperthyroid. Therefore, it was noted with considerable interest that DMI appeared not to interfere with brain T3 uptake in T3-induced hyperthyroid (T3-HYPER) rats. To confirm this finding, thyroidectomized male rats were made T3-HYPER through administration of T3 (20 micrograms/kg) for 3 weeks or maintained without TH supplement for 6 weeks, becoming HYPO. Rats were given i.v. T3 and 5 min later i.p. DMI or saline. They were decapitated at 3 hr and brains retrieved for radiochemical analysis. Each experiment was run in three separate trials, with three to four rats in each treatment category (DMI or saline). Evaluation by analysis of variance showed that T3 concentrations (percentage of dose) were significantly lower in DMI than in saline-treated rat brain for HYPO (-15%; P = .0034) but not T3-HYPER rats (-2%; P = .6595). These results suggest that, as it does in the case of NE, DMI tends to block TH uptake sites in rat brain. The data also demonstrate a differential affinity for those sites in which T3 > DMI > T4 and suggest that T3 might augment tricyclic antidepressant therapy more effectively than T4.

Sodium ipodate and methimazole in the long-term treatment of hyperthyroid Graves' disease.

A prospective study was conducted to evaluate the effect of prolonged treatment of hyperthryoid Graves' disease with methimazole (MMI) for 12 months or Na ipodate for only 6.6 +/- 1.1 months, since the drug had to be discontinued because of persistent or recurrent hyperthyroidism during treatment. The eight patients who were treated with MMI alone for 12 months became euthyroid, and seven remained in remission for at least 6 months after MMI was discontinued. In contrast, only two of 10 patients treated with Na ipodate alone became euthyroid and remained so during therapy. No ipodate was discontinued in the eight patients who did not respond, and they were then treated with MMI. One patient had recurrent hyperthyrodism after NA ipodate was discontinued, and she was then treated with MMI. MMI was efficacious in treating these nine patients, and all patients were euthyroid by the third month of MMI administration. Five of these nine patients remained euthyroid for at least 6 months after MMI was discontinued, a remission rate that was not significantly different from that observed in the eight patients treated only and initially with MMI (Fisher's Exact Test). There was no significant change in serum thyroid peroxidase antibodies during treatment with MMI alone, Na ipodate alone, or Na ipodate followed by MMI.(ABSTRACT TRUNCATED AT 250 WORDS)

A radioimmunoassay of rat type I iodothyronine 5'-monodeiodinase.

A highly sensitive, specific, and reproducible RIA has been developed to measure rat type I iodothyronine 5'-monodeiodinase (5'-MD). A 16-amino acid peptide (LAP-744) corresponding to a portion of the carboxy-terminal region of the rat liver 5'-MD, as predicted from its cDNA, was synthesized, and rabbits were immunized with the peptide-BSA conjugate. In a final dilution of 1:15,000, our anti-5'-MD antibody bound about 30-35% of a tracer amount of [125I]LAP-744. The detection threshold of the RIA approximated 0.08 pmol LAP-744 or an equivalent amount of 0.08 pmol 5'-MD. Rat liver and kidney microsomes produced dose-response curves that were essentially parallel to that of LAP-744. No inhibition of binding of [125I]LAP-744 to antibody was produced by 0.3 mg or less rat microsomal proteins from testes, heart, brain, muscle, spleen, intestine, lung, placenta, or fetal liver. Recovery of nonradioactive LAP-744 added to spleen microsomes averaged 103%. The coefficient of variation averaged 4% within an assay and 11% between assays. In 16 normal rats studied, the mean (+/- SD) 5'-MD content was 2.4 +/- 0.22 pmol/mg protein in liver microsomes and 2.5 +/- 0.27 pmol/mg protein in kidney microsomes. Fasting of the rat for 2-4 days was associated with a significant reduction in both the activity and the content of the 5'-MD in liver and kidney. Hypothyroidism was also associated with a significant decrease in the activity and content of 5'-MD in both tissues. Significant opposite changes were observed in these parameters in hyperthyroidism. Treatment of the rat with sodium ipodate for 3 days was associated with a significant decrease in both the activity and the content of 5'-MD in liver and kidney. A similar treatment of the rat with propylthiouracil induced a clear reduction in the activity of 5'-MD in liver and kidney, but the content of the enzyme was significantly increased in both tissues. Rats treated with aurothioglucose for 3 days exhibited a significant decrease in 5'-MD activity in liver and kidney microsomes, whereas the tissue content of 5'-MD was not affected. A similar treatment of the rat with methimazole had no significant effect on either the activity or the content of 5'-MD.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of hypothyroidism on rat circadian activity and temperature rhythms and their response to light.

Male rats made hypothyroid by administration of propylthiouracil plus sodium ipodate in drinking water were compared to controls in terms of period of circadian activity and temperature rhythms, amount of gross motor activity, and mean temperature. Animals were studied under entrainment, constant darkness (DD), and constant dim light (LL). There was no difference in the period of the circadian activity rhythm between groups in DD. However, hypothyroid rats showed significant blunting of the period-lengthening response to increasing ambient illumination. As expected, the period of the circadian temperature rhythm increased in controls with increasing ambient illumination. In contrast, the period of the circadian temperature rhythm in hypothyroid animals actually shortened under LL compared to DD. This blunting of the period-lengthening response to increasing ambient illumination of both activity and temperature rhythms in hypothyroid animals could not be explained by differences in activity level or mean temperature between the groups.

Sodium ipodate increases triiodothyronine action in vivo.

Sodium ipodate (IPO) has been shown to bind nuclear T3 receptors (NT3R) in vitro, but previous studies have conflicted in regard to demonstration of this interaction in vivo. We sought evidence for IPO-NT3R binding in vivo by giving large doses of IPO to thyroidectomized (TDX) rats replaced with low doses of T3. We predicted that IPO-NT3R binding would inhibit T3 induced increases in mitochondrial alpha glycerophosphate dehydrogenase activity (alpha-GPDH) in kidney, heart and liver. Three groups of ten euthyroid rats each received 13 daily injections of vehicle, or 6 or 12 mg/100 g body weight of IPO, respectively. Both doses of IPO resulted in decreases in serum T3 and increases in serum TSH. Liver and kidney alpha-GPDH, however, were decreased only in the group receiving 6 mg IPO. In addition, three groups of 30 TDX rats were implanted with osmotic minipumps that contained T3 in the following concentrations: 33, 69 and 96 ng/ul. Ten rats in each group received 13 daily injections of vehicle, or IPO (vide supra). The alpha-GPDH responses were complex in that there was significant interaction between T3 and IPO effects in the kidney (AxB F ratio 5.13, p less than 0.001) and liver (AxB F ratio 2.85, p less than 0.05). The major finding, however, was that alpha-GPDH was not significantly reduced by IPO in any T3 replaced group. Rather, in all three organs, alpha GPDH was significantly increased above that produced by T3 alone by at least one combination of IPO and T3. Changes in serum TSH also suggested that IPO could enhance T3 effects. We conclude that IPO-NT3R binding is not a prominent mechanism via which the drug attenuates T3 effects in vivo. The data suggest that IPO may enhance T3 effects at the cellular level and that this enhancement may not be reflected by routinely monitored serum TSH. The latter observation may have clinical importance.

Identification of thyroxine-sulfate (T4S) in human serum and amniotic fluid by a novel T4S radioimmunoassay.

Recently, we identified significant amounts of thyroxine sulfate (T4S) in fetal sheep serum, meconium, bile, and amniotic and allantoic fluids. Little is known, however, about sulfate conjugation of thyroxine in humans. In this study, we employed a novel, sensitive T4S RIA to address this question. The rabbit antiserum was quite specific; T4, T3, rT3, and 3,3'-T2 showed less than 0.002% cross-reactivity. Other analogs cross-reacted less than 0.0001%. Only rT3S and T3S cross-reacted significantly (9.9% and 2.0%, respectively). The mean serum T4S concentration (ng/dL) was 8.6 in euthyroid subjects, 14.4 in hyperthyroid subjects, 5.0 in hypothyroid subjects, 5.9 in pregnancy, and 4.5 in patients with nonthyroid illnesses. T4S concentration in amniotic fluid from women at 18-19 weeks of gestation (25.5 ng/dL) was higher than that at 14-15 weeks of gestation (14.3 ng/dL). A significant rise in serum T4S was detected in hyperthyroid patients 1 day after ingestion of 1 g of ipodate. These data suggest that T4S is a normal component of human serum and amniotic fluid, and it is mostly derived from T4 peripherally and accumulates when type I 5'-monodeiodinating activity is low in fetuses or inhibited by drugs, such as ipodate.

Therapy of Graves' disease with sodium ipodate is associated with a high recurrence rate of hyperthyroidism.

To evaluate the long-term efficacy of sodium ipodate (IPO) in the treatment of hyperthyroid Graves' disease, we studied 12 consecutive patients with Graves' hyperthyroidism treated only with 500 mg IPO po daily for several weeks to 22 months. Serum thyroid hormone concentrations markedly decreased and serum free T3 values normalized in all patients within 7 days of therapy. Five patients (42%, Group 1) were euthyroid after 6 weeks of IPO treatment and remained so until IPO was discontinued after 22 months. Recurrence of hyperthyroidism after drug withdrawal occurred in only one of these Group 1 patients, who was promptly responsive to a second course of IPO. In contrast, seven of 12 patients (58%, Group 2) relapsed with recurrent hyperthyroidism between 14 and 42 days of IPO therapy. After IPO was withdrawn, these Group 2 patients were treated with methimazole (20-30 mg/day, initial dose), but the therapeutic response was poor and delayed. Two patients were still hyperthyroid after 6 months of methimazole treatment. Elevated serum FT3 concentrations were observed in the Group 2 patients at 21 days following the early normalization of serum FT3 concentrations. No changes in serum thyroglobulin and thyroid microsomal and TSH-receptor autoantibody titers were observed in either groups during IPO therapy. In conclusion, the results of the present study demonstrate that IPO rapidly restores euthyroidism, but its prolonged administration is associated with a high rate of relapse of hyperthyroidism and a poor response to subsequent methimazole treatment and that long-term IPO administration does not affect humoral markers of thyroid autoimmunity.

[Shortened preoperative preparation in diffuse hyperthyroid goiter: experience in 34 patients]. / Preparación preoperatoria abreviada en los bocios difusos hipertiroídeos. Experiencia en 34 pacientes.

Conventional preparation of goitrous hyperthyroid patients using lugol and propranolol may take 2 weeks. This period may be shortened using sodium iopodate and dexamethasone. We used 500 mg of sodium iopodate and 1 mg dexamethasone for 4 days in 34 hyperthyroid patients. Surgical indication derived from failure to medical treatment (68%), large goiter (27%) or adverse reaction to PTU (6%). Clinical euthyroidism was achieved after 4 days in all patients. T3 levels decreased from 482 +/- 26.2 to 137.6 +/- 3.7 ng/dl and T4 from 20.6 +/- 1.04 to 15.2 +/- 0.5 micrograms/dl (p < 0.005). Surgery was uneventful in 33 patients, one subject developed supraventricular tachycardia responsive to verapamil. Electron microscopy of the removed thyroid tissue revealed marked decrease of superficial villi and large phagosomes. Thus, sodium iopodate and dexamethasone are effective and safe for preoperative preparation of hyperthyroid patients.