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PubMed1980

Separation of enantiomeric iodinated thyronines by liquid chromatography of diastereomers.

A method for the separation of D,L-triiodothyronine and D,L-tetraiodothyronine optical isomers is described. The iodinated thyronines are coupled with L-leucine and the resulting diastereomers are separated by reversed-phase liquid chromatography. The derivatives are detected in the UV region at 230 nm. The technique can be used for the determination of the optical purity of thyroid hormones. It is possible to determine 0.2% of the L-isomer in D-tetraiodothyronine with a relative standard deviation of 8%. One complete analysis takes about 2 h. The results are in good agreement with those of an enzymatic method.

Animals↗
PubMed1991

Comparison of high-performance liquid chromatographic detection methods for thyronine and tyrosine residues in toxicological studies of the thyroid.

Four high-performance liquid chromatographic methods for the detection of thyroid hormones (iodinated thyronines) and precursors (iodinated tyrosines) have been developed and evaluated. Two methods consist of direct determination of the parent compounds with detection at ultraviolet wavelength (230 nm) and with electrochemical detection. The two other methods consist of a pre-column derivatization (with fluorenylmethyl chloroformate and dabsyl chloride) prior to high-performance liquid chromatographic analysis. The various methods were evaluated based on their practical use and sensitivity. The method with direct ultraviolet detection turned out to be the most practical method. With this method analyses of thyroid homogenates have been performed from rats from a toxicological experiment.

Animals↗
PubMed2001

Could a combined administration of dexamethasone and 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) be a more effective alternative to dexamethasone alone in the prevention of RDS?

OBJECTIVE: To test whether the combined application of dexamethasone (DEXA) and 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) induces the synthesis of surfactant protein A (SP-A) mRNA at a higher rate than both substances given alone? STUDY DESIGN: Organoid culture of fetal rat lungs (Wistar rats; day 19 of gestation) was prepared. After 48h of incubation we added DEXA (10(-5), 10(-7), 10(-8) and 10(-9)mol/l), DIMIT (10(-5), 10(-7) and 10(-9)mol/l) and the combination of DEXA in 10(-8)mol/l with various concentrations of DIMIT. After another 48h of incubation, northern blot and hybridization with a 32P-labeled SP-A cDNA probe was performed. One-way-variance-analysis with a Scheffé-test, Levene-test and one-sample-t-test were used for statistical analysis. RESULTS: DEXA alone above 10(-8)mol/l resulted in a significant increase, DIMIT resulted in a decrease of SP-A mRNA induction. Combined application of DIMIT and DEXA resulted in a significant increase compared to the controls. Compared to DEXA alone in 10(-8)mol/l, we found an increased induction, but the data were not significant. CONCLUSIONS: The combined application of DEXA and DIMIT shows a higher induction of SP-A mRNA than both drugs given alone.

Animals↗
PubMed1985

Prenatal exposure of the fetal rat to excessive L-thyroxine or 3,5-dimethyl-3'-isopropyl-thyronine produces persistent changes in the thyroid control system.

Studies were conducted to determine if brief exposure, in utero, to high levels of T4 or to the synthetic thyromimetic agent 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) can produce permanent disruption of the thyroid control system in a manner analogous to the changes in the "set point" reported to occur due to neonatal T4 exposure in the "neo-T4 syndrome". If such a change were to occur, it could explain the persistent thyroid disturbances seen in the progeny of hypothyroid mother rats. These latter progeny are exposed in utero to both low and high serum T4 levels. Maternal T4 treatment produced a 4-fold elevation in fetal serum T4 accompanied by a large decrease in serum TSH levels. The brief treatment in utero with high doses of T4 or of DIMIT resulted in higher neonatal mortality and the T4-treatment produce subsequent growth stunting. These treatments resulted in suppression of the fetal/neonatal thyroid which was very apparent at 5 days of age. At 30 days post-partum, the thyroid control system of the progeny of the T4 and DIMIT-treated animals was still abnormal with low serum T4 levels accompanied with normal serum TSH and T3 levels. At 60 days of age, serum T4 levels remained low in the progeny of the T4-treated animals and the TSH response to TRH was subnormal in both the progeny of the T4-treated and the DIMIT-treated animals. However, serum and pituitary TSH and serum T3 were normal. The thyroid control system of the rat is sensitive to prenatal exposure to hyperthyroxinemia as it is to postnatal exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

The binding of a thyroid hormone metabolite, 3-monoiodo-L-thyronine, to bovine serum albumin as measured by circular dichroism.

The interaction between a thyroid hormone metabolite, 3-monoiodo-L-thyronine (3-T1) and bovine serum albumin (BSA) was investigated by using the CD method. An enhanced CD band was observed at the absorption wavelength region of 3-T1 around 293 nm suggesting the binding of 3-T1 to the BSA molecule. The ellipticity at 293 nm was measured at various molar ratios of 3-T1 to BSA, and the apparent binding constant and the maximum number of binding sites could be estimated as Kapp = 8.85 +/- 1.07 X 10(4) M-1 and n = 23.8 +/- 0.9 respectively. The CD of a mixture of BSA, 3-T1 and thyroxine (T4) was also studied at various pH's. The pH profile of the two characteristic CD bands at 293 nm and 320 nm, attributed to bound 3-T1 and T4, suggested that the optimum binding condition of 3-T1 was attained at alkaline pH of around 9, while that of T4 was attained over a wide pH range between 5-10. A significant role of the ionized 4'-hydroxyl group of 3-T1 in the binding reaction with BSA is also suggested.

Animals↗
PubMed1982

Maturational effect of triiodothyronine and its analog 3,5-dimethyl-3'-isopropyl-L-thyronine on sucrase activity in the small intestine of the developing rat.

In this study we compared the effect of 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) with that of triiodothyronine (T3) on sucrase activity in the small intestine of the fetal and suckling rat. DIMIT (5 micrograms/100 g BW) was injected into pregnant Sprague--Dawley rats on days 17-20 of gestation and DIMIT (10 and 50 micrograms/100 g BW) and T3 (10 and 50 micrograms/100 g BW) were given subcutaneously to two groups of sucklings on days 4-7 and 11-14. Fetal animals were sacrificed on day 21 of gestation; sucklings on days 8 and 15. Sucrase activity in the proximal, middle, and distal small intestine was assayed. DIMIT and T3 suppressed serum thyroid-stimulating hormone (TSH) in the fetus and suckling. Sucrase activity was increased in all small intestinal segments in the fetal and older suckling groups. In the younger sucklings the effect was seen only in the middle and distal segments. In both fetal and suckling groups the sucrase response was dose related. Thus, DIMIT has a thyromimetic effect on development of sucrase activity. The lack of sucrase reactivity in the proximal segment of the younger (8-day-old) sucklings to the administration of either DIMIT or T3 is interesting but unexplained.

Animals↗
PubMed1986

3,5-Diiodotyrosine and thyronine in the urine of patients with chronic renal disease.

Urinary 3,5-diiodotyrosine (DIT) and thyronine (T0) excretion was investigated in 18 patients with chronic renal disease. In accord with previous findings serum T4 and thyroid hormone binding proteins measured in 17 patients were in the low or normal range. Urinary albumin excretion was elevated in all 18 and T4 binding prealbumin (TBPA) in 15 of the 18. Urinary T0 excretion measured in 12 patients was also significantly lower than normal (mean +/- SD 4.4 +/- 2.6 vs 15.8 +/- 5.8 nmol/24 h renal vs normal 2 P less than 0.001). In contrast urinary DIT excretion was significantly elevated in renal patients compared with normal subjects (2.0 +/- 1.5 vs 0.75 +/- 0.41 nmol/24 h, respectively). Possible sources of the increased DIT are discussed.

Adult↗
PubMed1981

3,5-Dimethyl-3'-isopropyl-l-thyronine therapy in diabetic pregnancy: stimulation of rabbit fetal lung phospholipids.

Diabetes mellitus in pregnancy is associated with neonatal respiratory distress syndrome due to impaired synthesis of fetal lung surfactant. Pharmacologic agents that promote fetal lung maturity are diabetogenic and have limited use in the management of diabetic pregnancy for prevention of respiratory distress syndrome. Maternal administration of a thyroid analog 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) results in significant enhancement of fetal lung phospholipid synthesis and accelerated lung maturity. We therefore studied the effects of DIMIT (0.5 mg/kg per d, s.c.) administration to pregnant alloxan-diabetic rabbits on days 25 and 26 of gestation. DIMIT treatment of diabetic maternal rabbits (DD) was associated with reduction of maternal blood glucose (115 +/- 13 vs. 275 +/- 72 mg/dl, P less than 0.05) and fetal glucose (64 +/- 6 vs. 274 +/- 47 mg/dl, P less than 0.001) compared with saline-injected diabetic (D) mothers. Reduction of fetal insulin levels was also associated with maternal DIMIT therapy in diabetic rabbits (56 +/- 5 (D) vs. 24 +/- 4 microunits/ml, P less than 0.001). Maternal diabetes resulted in significant reduction of fetal lung weight (370 +/- 20 vs. 520 +/- 30 mg, P less than 0.005) and lung protein content (6.5 +/- 0.7 vs. 8.7 +/- 0.7 mg/gm, P less than 0.005), which were restored to normal in offspring of DIMIT-treated diabetic rabbits. Maternal DIMIT administration caused significant reduction in fetal lung glycogen content in control (62 +/- 5.8 vs. 25 +/- 5.9 micrograms/mg protein, P less than 0.001) and diabetic (56 +/- 7 vs. 34 +/- 5 micrograms/mg protein, P less than 0.02) offspring. Whereas maternal diabetes was associated with reduction of all major phospholipid species in fetal lung-comprising surfactant, these were restored with DIMIT therapy. The results demonstrate that short-term maternal administration of DIMIT in pregnant diabetic rabbits not only promotes fetal lung phospholipid synthesis, but also appears to ameliorate maternal hyperglycemia. Thus, DIMIT is of potential benefit in the management of diabetic pregnancy.

Animals↗
PubMed1978

Preparation, purification, and stability of high specific activity 125I-labeled thyronines.

A modified chloramine-T method is described for the preparation of several radioiodothyronines by an exchange reaction, which results in low specific activity preparations, or by an addition reaction, which yields radioiodothyronines with specific activities up to 7 mCi/microgram. Purification by paper chromatography is shown to be more convenient than by LH-20 chromatography and provides better resolution among the various thyronines. Radioiodothyronines with only a single iodine atom in the outer (3,5,3'-triiodothyronine and 3,3'-diiodothyronine) are stable for several months when stored in organic solvents. The least stable radioiodothyronines are those with two 125I atoms in the outer ring (3,3',5'-triiodothyronine (rT3) produced from 3-iodothyronine and thyroxine (T4) from 3,5-diiodothyronine). The stability of rT3 and T4 stored in human plasma at 4 C is much greater than when stored in buffer at the same pH. The use of high specific activity [125I]rT3 has permitted the development of a radioimmunoassay with a sensitivity of 1 pg rT3/ml incubation volume.

Diiodothyronines↗
PubMed1980

Suppression of thyrotropin by 3,5-dimethyl-3'-isopropyl-L-thyronine in euthyroid and hypothyroid rats.

The effect of 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) a nonhalogenated thyroid hormone analog, on plasma and pituitary TSH levels was studied in euthyroid and 5-day-thyroidectomized (T-5d) rats. The minimal dose of DIMIT which suppressed basal plasma TSH for a 24-h period was 5.3 micrograms/100 g BW in the euthyroid rats and 5.2 micrograms/100 g BW in the T-5d group. The equipotent doses of T3 were 1.0 and 1.5 micrograms/100 g BW, respectively. Thus, the apparent DIMIT to T3 molar ratio ranged from 6.6 in the hypothyroid to 10 in the euthyroid group. The suppression of TRH-induced TSH release in the euthyroid rats required a high dose of DIMIT (9.2 micrograms/100 g BW), resulting in a DIMIT to T3 molar ratio of 17. Time-course studies comparing the effects of equipotent doses of DIMIT and T3 on TSH release rates in euthyroid and T-5d rats have shown a maximal suppression by 3--24 h after the administration of both T3 and DIMIT. However, the recovery from the effect was slower after T3. TSH synthesis in the T-5d group was similarly suppressed by DIMIT and T3. DIMIT has significant thyromimetic activity in euthyroid and hypothyroid rats, as evidenced by the suppresion of TSH synthesis and release.

Animals↗
PubMed1982

Treatment of ovine cretinism in utero with 3,5-dimethyl-3'-isopropyl-L-thyronine.

Placental transfer of iodothyronines is minimal in most species. The nonhalogenated thyroid hormone analog 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) was administered to pregnant ewes to determine if this compound could prevent cretinism in the thyroidectomized fetal lamb. Pharmacokinetic studies comparing [125I]T3 and [3H]DIMIT resulted in fetal-maternal ratios for [3H]DIMIT which were 5- to 10-fold higher than the ratios for [125I]T3, suggestive of preferential transport of DIMIT across the placenta. Subsequently, DIMIT was administered to three pregnant ewes after hysterotomy and fetal thyroidectomy at 95-98 days gestation. Intramuscular DIMIT (1200-2000 micrograms/day) caused suppression of maternal T4 concentrations from a mean of 4.9 micrograms/dl before hysterotomy to less than 1 micrograms/dl within 1-2 weeks. All three thyroidectomized lambs had clinical signs of cretinism at birth and died. Skeletal and lung maturation were delayed in these animals, all of whom had undetectable serum T4 concentrations. In contrast to DIMIT's proven thyromimetic activity in other fetal animal models, this thyroid hormone analog failed to prevent cretinism in thyroidectomized fetal lambs even when administered to the ewe at a dose that suppressed maternal thyroid function.

Animals↗
PubMed1983

Transplacental effects of 3,5-dimethyl-3'-isopropyl-L-thyronine on fetal hypothyroidism in primates.

Pregnant Rhesus monkeys treated with 131I at midgestation become hypothyroid and produce fetuses without demonstrable thyroid tissue. In an effort to prevent both maternal and fetal hypothyroidism, we treated 131I-treated pregnant monkeys with 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT), a thyroid hormone analog with structural changes which facilitate placental transfer. Five pregnant monkeys were treated with 131I (mCi/kg) at 83-87 days of gestation. One week later, three monkeys were started on treatment with DIMIT (10 micrograms kg-1 day-1, im) and two on im L-T4 (2 micrograms kg-1 day-1). Treatment was continued until delivery by Caesarian section at 152-157 days of gestation. None of the DIMIT-treated mothers became clinically hypothyroid, nor did they have elevated serum TSH concentrations despite low serum levels of T3 and T4. T4-treated mothers were also maintained clinically and biochemically euthyroid. At delivery, infants of DIMIT-treated mothers had normal respiratory function and skeletal maturation. Basal and TRH-stimulated TSH concentrations were suppressed in two of the three infants. By contrast, both T4-treated infants resembled untreated cretinous newborns and died soon after delivery from respiratory failure. Serum TSH concentrations were elevated and skeletal maturation was markedly delayed in these animals. We conclude that DIMIT administration to 131I-treated monkeys prevents clinical and biochemical hypothyroidism in the mother and prevents the major clinical manifestations of cretinism in the fetus.

Animals↗
PubMed1979

Thyrotropin suppression by 3,5-dimethyl-3'-isopropyl-L-thyronine in man.

The thyromimetic activity of 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT), a nonhalogenated thyroid analog, was studied in adult men using suppression of TRH-induced TSH release to assess this activity. In nine men, aged 30-58 yr, the TSH increment after 500 microgram TRH iv was compared to the TSH response to TRH 24 h after oral administration of 1 mg DIMIT. Eight euthyroid subjects had normal baseline TSH levels of 1.5 +/- 0.2 (SE) microunit/ml that fell significantly to 0.7 +/- 0.2 microunit/ml 24 h after DIMIT (P less than 0.005). Their TSH increments after TRH fell from 15.3 +/- 2.8 to 6.7 +/- 1.6 microunit/ml 24 h after DIMIT (P less than 0.001). One subject with probable Hashimoto's thyroditis had an elevated TSH of 18 microunit/ml, with an exaggerated TSH response to TRH of 72 microunit/ml. His basal TSH fell to 7.6 and his TSH increment fell to 14.3 microunit/ml 24 h after DIMIT. The suppression of TSH was relatively prolonged. In four subjects, the TSH response to TRH was still blunted from 5-12 days after DIMIT. In one subject, the TSH increment returned to normal 15 days after DIMIT. DIMIT had no significant effect on PRL secretion. There was no evidence of toxicity in patients receiving DIMIT. DIMIT has effective thyromimetic activity in man, as shown by its significant and prolonged suppression of TSH secretion.

Adult↗
PubMed1988

A radioimmunoassay for measurement of thyronine and its acetic acid analog in urine.

A sensitive and specific RIA has been developed to measure thyronine (To) in urine. The RIA used an anti-To antibody obtained from a rabbit immunized with a L-To-human serum albumin conjugate and [3H]To as the radioligand. The acetic acid analog of To (ToAc), that is the diphenyl structure with an acetic acid side-chain, cross-reacted strongly with the antibody. Relative to To, it cross-reacted 160% in phosphate-buffered saline, pH 7.4, and 100% in 0.075 mol/L barbital buffer, pH 8.6, containing sodium salicylate (final concentration, 8 mg/mL). The latter conditions were employed for the RIA, and the results reported thus reflect the presence of To and/or ToAc. 3-Monoiodothyronine, 3'-monoiodothyronine, 3',5'-diiodothyronine, and 3,5-diiodothyronine cross-reacted with the anti-To antibody 1.9%, 1.7%, 0.3%, and 0.2%, respectively; the cross-reactivity of other To derivatives and tyrosine and its derivatives was less than 0.05%. Urinary To and/or ToAc excretion in 12 normal subjects averaged 16 +/- 2 (+/- SE) micrograms/day (59 +/- 9 nmol/day) or 14 +/- 2 micrograms/g creatinine (5.9 +/- 0.6 nmol/mmol creatinine). Treatment of urine from normal subjects with beta-glucuronidase or sulfatase did not significantly alter the To content. Column and thin layer chromatographic studies revealed that 83% and 61%, respectively (range, 37-100%), of urinary To immunoreactivity was attributable to ToAc. The mean daily excretion of To in 20 patients with nonthyroidal illness [NTI; 22 +/- 4 micrograms/day (82 +/- 17 nmol/day)] was similar to that in normal subjects, but was elevated when expressed as nanomoles per mmol creatinine (20 +/- 2; P less than 0.001), because creatinine excretion was reduced in the NTI patients. The mean daily urinary To excretion in 13 patients with hyperthyroidism due to Graves' disease was slightly elevated [29 +/- 6 micrograms/day (108 +/- 21 nmol/day); P less than 0.1], but was clearly elevated when expressed as nanomoles per mmol creatinine (37 +/- 8; P less than 0.001), again because creatinine excretion was reduced in these patients. The mean urinary To excretion was subnormal in 13 patients with hypothyroidism and was significantly (P less than 0.005) less than that in the NTI patients regardless of the manner in which the results were expressed. Analysis of pronase hydrolysates of thyroid glands obtained at autopsy from euthyroid patients suggested that the To content of the thyroid approximates only 1.2% that of T4, supporting the thesis that prior iodination of tyrosine is critical for the coupling process in the thyroid.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetates↗
PubMed1999

Effect of dexamethasone, triiodothyronine and dimethyl-isopropyl-thyronine on lung maturation of the fetal rat lung.

Our purpose was to elucidate why clinical studies have up to now failed to demonstrate a positive effect of TRH combined with glucocorticosteroids on fetal lung maturity. Morphological and biochemical lung maturation were determined by electron microscopy, choline incorporation, and surfactant-protein-A m-RNA synthesis in rat lung organoid cultures after exposure with a series of concentrations of dexamethasone, triiodothyronine, and dimethyl-isopropyl-thyronine. Thyroid hormones improved morphogenesis of lung histotypic structures but had a negative effect on surfactant synthesis whereas glucocorticosteroids had a positive effect on the surfactant synthesis but a negative effect on morphogenesis. The combination of both substances even had the most negative effect on morphogenesis. Since morphogenesis of lung histotypic structures is prerequisite for surfactant synthesis and secretion, we hypothesize that a sequential treatment of thyroid hormones to improve morphogenesis followed by the application of glucocorticosteroids might be an option to improve neonatal lung function.

Animals↗
PubMed1984

Transplacental effects of 3,5-dimethyl-3'-isopropyl-L-thyronine on tubulin content in fetal brains in rats.

When 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) (10 ng/(g X day] was administered to pregnant rats, their infants showed signs of hyperthyroidism with suppressed body weight, tachycardia, and tremor at the day of birth. The brain weight did not change but the wet weight of the cerebral cortex was increased in the infants. Tubulin content (per wet weight and per whole tissue) was increased in the cerebral cortex and cerebellum but remained unchanged in the hypothalamus in the DIMIT-treated group. DIMIT-induced hyperthyroidism was shown to affect the development of the fetal brain.

Animals↗
PubMed1990

Effects of sodium bromide on the biosynthesis of thyroid hormones and brominated/iodinated thyronines.

The influence of bromide on thyroid function was studied in iodine-deficient rats, fed on a diet containing 4-16 g/kg sodium bromide for 4 weeks. Measurement of total and free thyroxine and thyroid-stimulating hormone in blood, as well as the thyroid hormones in the thyroid gland, revealed typical signs of hypothyroidism, which were significantly enhanced by bromide intake. Special attention was paid to the possible formation of bromo/iodosubstituted thyronines in the thyroid. These measurements were performed by high-performance liquid chromatography with off-line radioimmunoassay detection. Such thyroid hormone analogues could be detected in all groups of animals with additional bromide intake, but the amounts were found to be too low to compensate adequately for the reduced amounts of thyroid hormones. The results of this study also indicate that bromide toxicity is dependent upon the state of the iodine supply, which should be taken into account for evaluation of acceptable daily intake values for bromide.

Animals↗