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Long term treatment of Graves' hyperthyroidism with sodium ipodate.

To investigate the long term usefulness of sodium ipodate (Oragrafin) in the management of Graves' hyperthyroidism, we studied the effects of ipodate (500 mg, orally, daily for 23-31 weeks) on serum T3, T4, rT3, and some clinical parameters in five newly diagnosed Graves' hyperthyroid patients. Mean pretreatment serum T3, T4, and rT3 concentrations were 780 ng/dl, 25.4 micrograms/dl, and 118 ng/dl, respectively. One day after the first dose of ipodate, serum T3 decreased by 62% (P less than 0.01), and it was within the normal range thereafter throughout treatment. The serum T4 concentration decreased by 20% (P = 0.09) at 24 h and by 43% (P less than 0.05) at 14 days. Subsequently, serum T4 was 41-65% lower than before treatment throughout the study; rT3 increased 24 h after the first dose of ipodate (118% above baseline; P = 0.1), remained elevated (97-109%) for 10 weeks, and then gradually decreased to the pretreatment level. A marked gain in body weight [5.1 +/- 1.1 (+/- SEM) kg] occurred in all patients. After discontinuation of ipodate, mean thyroid radioiodine (RAI) uptake values increased serially in four patients and were similar to pretreatment values: pretreatment, 74 +/- 6% (+/- SEM); after 7 days, 66 +/- 8%; after 14 days, 71 +/- 7%; after 28 days, 69 +/- 7%. The fifth patients's RAI uptake was 12-16% (vs. a pretreatment value of 48%) from 7-28 days after the end of a 31-week course of ipodate. He remained euthyroid without further treatment for the subsequent 4 months. We conclude that 1) ipodate (500 mg daily) reduces serum T4 and T3 levels as fast and as much as does the 1-g daily dose studied previously; 2) long term use (for 23-31 weeks) of ipodate for the treatment of Graves' hyperthyroidism is clinically feasible; no adverse effects occurred during or after ipodate treatment; and 3) RAI uptake returns to pretreatment levels as early as 7 days after the discontinuation of ipodate. Hence, use of ipodate does not prevent use of 131I therapy for those patients for whom it is otherwise desirable.

Adult

Further studies on the long-term treatment of Graves' hyperthyroidism with ipodate: assessment of a minimal effective dose.

We have previously described that sodium ipodate (500 mg/day, p.o.) is effective in normalizing serum T3 and T4 levels in most patients with Graves' hyperthyroidism. In this study, we examined serum T3, T4, and rT3 levels in 14 hyperthyroid patients with Graves' disease during treatment with a lower dose (500 mg, every other day, p.o.) of sodium ipodate for a period of 3-30 weeks (mean 15.5 weeks). Three types of responses were observed. In group I (4 patients), both serum T3 and T4 were in the normal range at the end of treatment [baseline: mean +/- SEM T3, 6.8 +/- 0.96 nmol/L (normal 0.92-3.0)] and T4 [256 +/- 44 nmol/L (normal 62-167); post-ipodate: T3, 2.0 +/- 0.46 nmol/L and T4 107 +/- 28 nmol/L]. In group II (n = 5), either serum T3 (3 patients) or serum T4 (2 patients) did not become normal (baseline: T3 7.7 +/- 1.1 and T4 228 +/- 3.9; post-ipodate: T3 2.9 +/- 0.57 and T4 188 +/- 27 nmol/L). In group III (5 patients), neither serum T3 nor serum T4 returned to normal following ipodate treatment (baseline: T3 11.9 +/- 1.8 and T4 260 +/- 23; post-ipodate: T3 7.5 +/- 0.49 and T4 322 +/- 17 nmol/L). The mean serum rT3 concentration increased during ipodate treatment to a peak value of 100% above baseline and remained elevated (20-75% above baseline) throughout the study. Some improvement in hyperthyroidism was suggested by increase in body weight during ipodate treatment in most cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

Comparison of methimazole, methimazole and sodium ipodate, and methimazole and saturated solution of potassium iodide in the early treatment of hyperthyroid Graves' disease.

We have evaluated three regimens for the rapid control (10 days' therapy) of thyrotoxicosis in hyperthyroid Graves' disease: methimazole (MMI, 40 mg/day), MMI and sodium ipodate (MMI + Na Ipodate, 1 g/day and MMI and saturated solution of potassium iodide (MMI + SSKI, 6 drops twice daily). When serum T4 and T3 concentrations were analysed as the percent change from pre-treatment values, the following results were observed. Serum T4 concentration decreased in the three treatment groups and the decrease was similar in the MMI and MMI + SSKI groups but significantly lower than in the MMI + Na ipodate group. The serum T3 concentration decreased to the normal range in all seven MMI + Na Ipodate treated patients by the fourth day of treatment and the per cent decrease in serum T3 from pre-treatment values was significantly greater than in the MMI and MMI + SSKI treated patients. The decrease in serum T3 was similar in the latter two groups. Heart rate decreased in all three groups, but the decrease was significantly more in the MMI + Na Ipodate-treated patients. The present findings suggest that the rapid control of hyperthyroid Graves' disease is similar in patients treated with MMI and MMI + SSKI and that the combination of MMI + Na Ipodate is more efficacious since the decrease in serum T3 concentrations and heart rate was significantly greater in the MMI + Na ipodate-treated patients.

Adult

The effects of sodium ipodate (ORAgrafin) on thyroid function in rainbow trout, Salmo gairdneri.

Immature rainbow trout held at 12 +/- 1 degree were injected intraperitoneally with a fine saline suspension of sodium ipodate (5 mg/100 g body wt) every 3 days. Plasma 3,5,3'-triiodo-L-thyronine (T3) fell to 40% of control levels by Day 1 and remained at about this level for the duration of the study (22 days). Plasma L-thyroxine (T4) level was not altered on Day 1 but was lowered to 50% of control values by Days 7 and 22. Immersion of trout in T4 (2 micrograms/100 ml water) elevated plasma T4 but did not alter the ipodate suppression of plasma T3. Injection of control or ipodate-treated trout with [125I]T4, [125I]T3, or Na131I indicated that in addition to blocking T45'-monodeiodination to T3, ipodate also decreased plasma clearance of T4 and T3 and their removal by the bile. Ipodate did not alter the hepatosomatic index but did depress the hematocrit by 22 days, possibly due to the hypothyroid state. In conclusion, ipodate at a dose of 5 mg/100 g, approximately one-tenth of a lethal dose, is an effective acute and chronic hypothyroid agent to administer to trout.

Animals

The biliary and urinary excretion of sodium tyropanoate and sodium ipodate in dogs: pharmacokinetics, influence of bile salts and choleretic effects with comparison to iopanoic acid.

The biliary and urinary excretion of sodium tyropanoate (Bilopaque) and sodium ipodate (Oragrafin) were studied in unanesthetized bile-fistula dogs using stepwise, increasing, intravenous infusions of the contrast materials. A constant intravenous infusion of sodium taurocholate was administered at the rate of either 0.5 or 2.0 mu moles per min per kg throughout each experiment. The biliary excretion of sodium tyropanoate or sodium ipodate was not effected by the rate of sodium taurocholate infusion. The maximum rate of biliary excretion of sodium ipodate was significantly greater than that of sodium tyropanoate with the low taurocholate infusion, but there was no significant difference between the two with the high taurocholate infusion. With the low taurocholate infusion the maximum biliary excretion rate of sodium tyropanoate (0.956 mu moles per min per kg) and sodium ipodate (1.472 mu moles per min per kg) were significantly greater than the maximum biliary excretion of iopanoic acid (Telepaque) (0.671 mu moles per min per kg). With the high taurocholate infusion the maximum biliary excretion rates of the three contrast agents were not statistically different. Both sodium tyropanoate and sodium ipodate produced an increase in canalicular bile flow (8-11 ml per millimole). These data suggest that in clinical cholecystography sodium tyropanoate and sodium ipodate are not excreted in bile more rapidly than iopanoic acid, except when the rate of biliary excretion of bile salts is low; that is, except in patients who are fasting or those who are on a fat-free diet.

Animals

Multisite inhibition by ipodate of iodothyronine secretion from perfused dog thyroid lobes.

Cholecystographic radiocontrast agents interfere with thyroid hormones in several ways. In the present study 1 mM ipodate induced a rapid sustained and reversible inhibition of the secretion of T4, T3, rT3, 3,3'-diiodothyronine, and 3',5'-diiodothyronine from perfused dog thyroid lobes. This effect was not reproduced by infusion of 3 mM iodide and not affected by 2 mM methimazol or 2 mM perchlorate. One millimolar of ipodate inhibited secretion of T4 to 23.7 +/- 2.8% of control (+/- SE, n = 6), 0.3 mM ipodate to 59.6 +/- 3.01 (n = 4), and 0.1 mM ipodate to 80.4 +/- 5.7% of control (n = 4). In search of the site of action in the thyroid of this inhibitory compound it was found that 1 mM ipodate inhibited TSH-induced increase in thyroidal cAMP, cAMP-induced generation of intracellular colloid droplets, and liberation of T4 and T3 from thyroglobulin by acid proteases and peptidases. These processes are those thought to be inhibited during iodide inhibition of thyroid secretion, via gradual formation of an unknown iodine-containing organic intermediate. It is suggested that the inhibition of thyroid secretion observed in the present study is due to structural similarities between ipodate and this putative iodine-containing mediator of the iodide-induced inhibition of thyroid secretion.

Animals

The effect of repeated administration of ipodate (Oragrafin) in hyperthyroidism.

This report describes the effect of administration of repeated doses of ipodate (Oragrafin; 3 g orally every third day for five doses) in six hyperthyroid patients. Baseline serum concentrations of immunoassayable T3, rT3, and T4, were 926 +/- 206 ng/100 ml, 165 +/- 31 ng/100 ml and 21 +/- 2.7 micrograms/100 ml (mean +/- SEM), respectively. Within 24 h after the first dose of ipodate, serum T3 fell by 54% and it remained between 66-77% below baseline until the third day after the fifth dose; subsequently, there was a gradual recovery from the effect of ipodate. Serum T4 also decreased after ipodate administration; it was 23-31% lower than baseline from the second day after the third dose to the sixth day after the fifth dose. Serum rT3 increased after each dose of ipodate; peak values of 97%-203% above baseline value were observed at 24-48 h after each dose. There was a subjective improvement in clinical symptoms of hyperthyroidism in all cases. Resting pulse rate and pulse pressure dropped significantly (P less than 0.02) by the ninth day of study and remained so thereafter. Body weight increased significantly by the ninth day of the study. The various data suggest that ipodate may serve as a useful adjunct in the early treatment of hyperthyroidism.

Adolescent

Treatment of neonatal hyperthyroidism due to Graves' disease with sodium ipodate.

We describe the effect of administration of repeated doses of sodium ipodate in a newborn infant with hyperthyroidism due to transient Graves' disease. Pretreatment (day 3) serum T4 and T3 concentrations were 49 micrograms/dl and 590 ng/dl, respectively. With 24 h after the first dose of ipodate, serum T3 fell by 40%, and it subsequently ranged from 209-278 ng/dl throughout the 39-day ipodate treatment period. Serum T4 also decreased after ipodate administration to 69% and 41% of the pretreatment value after 72 h and 7 days of treatment, respectively; values thereafter during treatment ranged from 19-22 micrograms/dl. These plateau values are in the upper range of normal for the neonatal period. Rapid clinical improvement occurred as the hyperiodothyroninemia abated. Serum rT3 concentrations increased from 468-672 ng/dl to greater than 1400 ng/dl 24 h after each ipodate dose. Thyroid-stimulating immunoglobulin was present in maternal and cord sera, and the half-life of serum thyroid-stimulating immunoglobulin in the infant was approximately 12 days. Antithyroglobulin and antimicrosomal antibodies were present in the infant at 10 days of age, and the titers decreased progressively thereafter; the half-life for the antimicrosomal antibody titer was 3 weeks. The data suggest that sodium ipodate can be useful for treatment of neonatal hyperthyroidism due to Graves' disease.

Antibodies

Effect of sodium ipodate and iodide on free T4 and free T3 concentrations in patients with Graves' disease.

Graves' hyperthyroid patients were treated daily for 10 days with 1 g sodium ipodate, a cholecystographic agent which exerts a blocking effect on the peripheral conversion of T4 to T3, or with 12 drops of saturated solution of potassium iodide (SSKI). Serum concentrations of free T4 (FT4) and free T3 (FT3) were measured before, during and 5 and 10 days after the administration of each drug. Sodium ipodate treatment induced a rapid decrement of serum FT4 concentrations which declined from 48.9 +/- 6.6 pg/ml to 26.0 +/- 2.7 pg/ml. In these patients serum FT3 concentrations declined from 12.4 +/- 2.0 pg/ml to 2.5 +/- 0.4 pg/ml. Ten days after sodium ipodate withdrawal, serum FT4 and FT3 concentrations returned to baseline values. In patients treated with SSKI serum FT4 concentrations declined from 51.1 +/- 8.8 pg/ml to 11.3 +/- 1.4 pg/ml and FT3 from 15.7 +/- 2 pg/ml to 2.6 +/- 0.3 pg/ml. Moreover, after therapy interruption serum free thyroid hormone concentrations returned to baseline values in these patients. Serum FT4 pattern during the study was not different between the two groups of subjects whereas serum FT3 concentrations were significantly lower in patients treated with sodium ipodate. These findings indicate that SSKI and sodium ipodate are effective in inducing a rapid decrement of serum free thyroid hormone concentrations. Therefore the employment of these drugs may be useful in the treatment of patients with thyroid storm and those undergoing thyroidectomy.

Adult

A study of cardiac effects of thyroid hormones: evidence for amelioration of the effects of thyroxine by sodium ipodate.

We studied the effects of daily ip administration of T4 (200 micrograms/100 g BW) or T3 (50 micrograms/100 g) to the rat (six per group) for 3 days with or without sodium ipodate (6 mg/100 g), propylthiouracil (PTU; 2 mg/100 g), propranolol (0.5 mg/100 g), or amiodarone (2.5 mg/100 g) on cardiac weight, 3',5'-diiodothyronine (3',5'-T2) to 3'-monoiodothyronine monodeiodinating activity (MA), mitochondrial alpha-glycerophosphate dehydrogenase (alpha GPD), and/or cytosolic ornithine decarboxylase (ODC). T4 treatment caused a 28% increase in cardiac weight, about an 11-fold increase in 3',5'-T2 MA, about a 27% increase in alpha GPD activity, and about a 129% increase in ODC activity. Administration of ipodate with T4 abolished all effects of T4 on the heart. PTU abolished the effect of T4 on alpha GPD and markedly reduced its effect on 3',5'-T2 MA and ODC activity; it had little effect on cardiac hypertrophy caused by T4 treatment. Propranolol reduced the increase in cardiac weight following T4 administration from 28% to 11%, but had a modest or no effect on T4-induced changes in other metabolic variables studied. Amiodarone also reduced the effect of T4 on heart weight, but had little or no influence on 3',5'-T2 MA, the only metabolic variable studied. T3 treatment of the rat caused a 35% increase in heart weight, about a 15-fold increase in 3',5'-T2 MA, about a 35% increase in alpha GPD, and about a 100% increase in ODC activity. Ipodate and PTU reduced the increase in 3',5'-T2 MA following T3 administration, but had no appreciable influence on heart weight, alpha GPD, and/or ODC activity. Propranolol and amiodarone had no significant effect on any of the changes studied after T3 administration. It was concluded that: 1) ipodate markedly lessens or abolishes the effects of T4 on the heart; 2) propranolol and amiodarone decrease cardiac hypertrophy in response to T4 administration, but have little or no effect on metabolic changes due to T4; 3) PTU curtails the metabolic effects of T4 on the heart but has little effect on cardiac hypertrophy; 4) none of the drugs studied affects cardiac changes occurring after T3 administration. The changes observed in 3',5'-T2 MA after ipodate and PTU treatment may have been a result of direct interaction of the drugs with the deiodinase.

Amiodarone

Sodium ipodate in the treatment of toxic diffuse goiter. Short-term and long-term effects on thyrotoxicosis.

Iodinated radiocontrast medication has been successful in the treatment of thyrotoxicosis when used for short periods up to 21 days, but experience with long-term use is lacking. In the first part of this study, a group of seven patients each taking 1.5 g. sodium ipodate daily was observed for 21 days and compared to a similar group of seven thyrotoxic patients taking 400 mg. propylthiouracil (PTU) daily. Sodium ipodate brought about a more significant decrease in serum total T3 and T4 levels, and more prominent increase in reverse T3 levels in the first ten days of the treatment. In the second part, a group of seven patients with thyrotoxicosis were given sodium ipodate, 1.5 g, daily for 20 days and 0.75 g. thereafter and were compared to a similar group of seven patients who took PTU, 300 mg. daily for the first 20 days and 150 mg. daily afterwards. Serum thyroid hormone levels decreased in both groups at the end of the first month of treatment, but rose again, along with worsening of symptoms, in five patients on ipodate treatment. Therefore, sodium ipodate, an iodinated radiocontrast agent is unable to control thyrotoxicosis for longer than a month.

Adult

Acute L-thyroxine overdose; therapy with sodium ipodate: evaluation of clinical and physiologic parameters.

Two children with acute L-thyroxine overdose were treated with sodium ipodate, an oral cholecystographic agent. Initial thyroxine (T4) levels were elevated to 98.5 mcg/dL and 134.1 mcg/dL, with associated triiodothyroxine (T3) levels of 354 ng/dL and 402 ng/dL. T3 levels increased to a maximum of 662 ng/dL and 468 ng/dL. With administration of sodium ipodate, the T3 decreased with a simultaneous increase of rT3 level. Sodium ipodate effect lasted 72 hours. No toxic effect was noted. Interestingly, thyroid hormone levels correlated with systolic blood pressure but with no other physiologic parameter. Sodium ipodate appears to be a viable treatment modality for acute thyroid overdose in children.

Acute Disease

Ipodate and 8-anilino-1-naphthalene sulfonic acid block receptor binding of T3 in rat liver.

We have determined that 8-anilino-1-naphthalene sulfonic acid (ANS) and ipodate are effective inhibitor in vitro of 125I-T3 binding to rat hepatic nuclei receptors. Both of these agents are estimated to have a Kd for the T3 receptor of about 1--2 x 10(-4) M. Indirect preliminary studies suggest that ANS is a non-competitive inhibitor and ipodate is a competitive inhibitor of T3 binding. Compounds such as tyropanoate and diatrizoate and iodide had no effect on T3 receptor binding. Further in vivo studies with ipodate suggested that T3 receptor binding inhibition also occurred when ipodate was given intravenously to rats.

Anilino Naphthalenesulfonates

Comparison of the effects of amiodarone and ipodate on the rat heart.

Chronic treatment of rats with amiodarone has been shown to produce hypothyroid-like effects such as a reduction in body and heart weight and increased synthesis of the low ATPase V3-cardiac isomyosin (Bagchi, Brown, Schneider and Banerjee 1987). In this report, we have tested the hypothesis that amiodarone causes these effects through the inhibition of intracellular production of triiodothyronine (T3) from thyroxine (T4) by comparing the effects of amiodarone with those of ipodate, a potent inhibitor of T4 to T3 conversion. Separate groups of rats were given dietary ipodate and amiodarone respectively for six weeks. Both agents increased serum T4 and T4/T3 ratios, a finding consistent with the inhibition of peripheral T4 to T3 conversion. However, ipodate failed to produce hypothyroid-like effects on body weight, heart weight and isomyosin transitions similar to those found in the amiodarone group. These data indicate that the hypothyroid-like effects of amiodarone on the rat heart are not due to the inhibition of intracellular generation of T3 from T4.

Amiodarone

Propylthiouracil, ipodate, dexamethasone and periods of fasting induce different variations in serum rT3 in dogs.

Fasting or administration of propylthiouracil (PTU), ipodate, or dexamethasone are all known to induce a pattern of low serum triiodothyronine (T3) concentrations and high serum reverse T3 (rT3) concentrations in humans. In the present study it was found that this is not a universal phenomenon. In normal dogs exposed to fasting or these various pharmacologic agents, the serum T3 level was always depressed as in humans. However, different variations in serum rT3 levels were observed. Fasting and PTU administration were accompanied by slight decreases in the serum rT3 concentration. A single dose of ipodate did not alter serum rT3 levels, but serum thyroxine (T4) levels increased by more than 50%. Dexamethasone induced a considerable increase in serum rT3 levels, while serum T4 levels were unaltered. The results suggest that the high serum rT3 level nearly always seen in "the low T3 syndrome" in humans is merely a coincidental character of the human species, and that it has little importance for in vivo homeostasis.

Animals

Comparative effects of sodium ipodate and iodide on serum thyroid hormone concentrations in patients with Graves' disease.

Patients with thyrotoxic Graves' disease were treated daily for 10 d with 1 g sodium ipodate, an iodine rich X-ray contrast agent which impairs outer ring (5'-) deiodination of T4 to T3, or with 12 drops of a saturated solution of potassium iodide (SSKI). T4, T3 and reverse T3 (rT3) concentrations were measured before, during, and 5 and 10 d after the administration of each drug. SSKI therapy induced a decrease in the serum T4 concentration from 14.7 +/- 1.3 microgram/dl (mean +/- SE) to a nadir of 7.9 +/- 0.9 on days 9 and 10 of therapy, all values reaching the normal range by day 9; a decrease in the serum T3 concentration from 402 +/- 43 ng/dl to a nadir of 143 +/- 20 on day 10, remaining elevated in all patients until day 5 and decreasing into the normal range in all except one patient on days 9 and 10; and no change in the serum rT3 concentration. Serum T4 and T3 concentrations returned to baseline values 10 d after withdrawal of SSKI. In contrast sodium ipodate therapy induced only a modest decrease in the serum T4 concentration from 15.1 +/- 0.7 micrograms/dl to a nadir on day 9 of 11.3 +/- 1.0 and serum T4 remained above the normal range in most patients until day 8; a striking and rapid decrease (within 12 h) in ther serum T3 concentration from 340 +/- 36 ng/dl to mean values ranging from 79 to 85 during the last 5 d of therapy, with most values below the normal range during the last 3 d; and a marked increase in the serum rT3 concentration from 111 +/- 15 ng/dl to a peak value of 376 +/- 59 on day 5.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

Changes in circulating iodothyronines in euthyroid and hyperthyroid subjects given ipodate (Oragrafin), an agent for oral cholecystography.

A dose (3 g) of sodium ipodate used routinely in oral cholecystography caused a fall in serum 3,5,3'-triiodothyronine and a rise in serum 3,3',5'-triiodothyronine in three patients taking thyroxine (T4), four euthyroid subjects,and four hyperthyroid patients. Serum T4 fell in patients with hperthyroidism, whereas it rose in the other two groups. Sodium ipodate appears to alter peripheral T4 metabolism and, in addition, produces thyroid-inhibiting effects in hyperthyroidism.

Graves Disease

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.

Adolescent