The use of thyrogen in the treatment of differentiated thyroid carcinoma: an intraindividual comparison of clinical effects and implications of daily life.

AIM: Withdrawal of levothyroxine with resultant hypothyroidism is still used in preparation for I-131 diagnostic whole-body scan (DWBS) and thyroglobulin (TG)-measurement in patients afflicted with differentiated thyroid cancer (DTC). Recombinant human thyroid-stimulating hormone (rhTSH) enhances TSH stimulation obviating the clinical and economical consequences of hypothyroidism. Primary aim of this study was an intraindividual comparison of diagnostic follow-up measurements under these two sets of conditions by taking clinical and socio-economic parameters into account. Second aim was to determine a clear patient preference for the one method or the other. METHODS: This non-interventional observational study included patients (n=192 signed informed consent, n=128 protocol compliant patients without need for therapeutic intervention) with DTC first treated by thyroidectomy and radioiodine ablation. Control visits including I-131 DWBS were planned at 3-6 months post-thyroidectomy after a phase (KU 1) of thyroid hormone withdrawal (THW) and again after 6-12 months later in a euthyroid state under exogenous stimulation with rhTSH (KU 2). Study design was open, prospective and multicentric. Data collected consisted of patient information (SF-12 (®) Health Survey), thyroid-specific results of clinical examinations and several aspects of daily life, e. g., employment, days of absence from work and other economic aspects. RESULTS: In contrast to KU 1, in KU 2 there is a highly significant improvement (p<0.0001) in all studied clinical symptoms and aspects of managing daily life. A significant increase of the SF-12 (®) health survey score could also be identified. Mental score showed a higher increase than physical score. Included patients were less absent from work before KU 2, (absent 4.5%, median 4 days in euthyroid state [range 2-5 d]), vs. before KU 1 (absent 47.8%, median 10 days in hypothyroid state [range 1-30 d]). After KU 2 7.7% of the euthyroid patients was absent from work (median 5 days) while 37.5% was after KU 1 (median 6 days). CONCLUSION: Included patients benefited subjectively and objectively from the use of rhTSH for diagnostic procedures in the treatment of DTC. A clear preference (127 of 128) of analyzed patients could be identified for exogenous stimulation with rhTSH.

Lithium as an adjunct to radioiodine therapy in Graves' disease for prolonging the intrathyroidal effective half-life of radioiodine. Useful or not?

AIM: Evaluation of intrathyroidal kinetics of radioiodine with and without lithium as adjunct with respect to the increase in radiation dose delivered to the thyroid. PATIENTS, METHODS: 267 patients in three groups were included in the study. Group I with 227 patients served as control group, Group II with 21 patients and Group III with 19 patients were distinguished by an intrathyroidal half-life of radioiodine below 3.5 days in the diagnostic test. Patients in Group III received 885 mg lithium carbonate a day for 2 weeks as adjunct to radioiodine therapy. Both diagnostic and therapeutic radioiodine kinetics were followed up by at least 10 uptake measurements within a minimum of 48 h. Kinetics of radioiodine were defined mathematically as balance of the thyroidal iodine intake and excretion by a two-compartment model. RESULTS: Under therapy the maximum uptake of radioiodine was reduced by nearly 10% in all groups, in Group I, the effective half-life as well as the product of maximum uptake x effective half-life as an equivalent of radiation dose independent of thyroid volume was lowered in the same magnitude. In Group II, the energy-dose equivalent remained constant under therapy. With adjunct lithium in Group III, the effective half-life was prolonged significantly by factor 1.61 +/- 0.49 and the volume-independent energy-dose equivalent by factor 1.39 +/- 0.37. No severe side effects of lithium were observed. CONCLUSION: Using lithium as adjunct to radioiodine therapy increases the radiation dose delivered to the thyroid by 39% on average and nearly 30% of radioiodine activity can be saved in these patients. Lithium is recommended in patients with very short effective half-life in the diagnostic test in order to reduce the activity required and whole-body radiation dose.

[Results of a risk adapted and functional radioiodine therapy in Graves' disease]. / Ergebnisse einer risikoadaptierten und funktionsorientierten Radioiodtherapie bei Morbus Basedow.

UNLABELLED: Aim of this study was to find out, if results of a functional orientated radioiodine therapy in Graves' disease could be optimized using a risk adopted dose concept. PATIENTS, METHOD: 351 patients with Graves' disease were treated for the first time between 11/97 and 8/01. The basic dose was 125 Gy, which was increased up to 250 Gy in a cumulative manner depending on clinical parameters (initial thyroid metabolism, thyroid volume, immunoreactivity). Two different methods of dosimetry were used. Occasional thyreostasis was withdrawn two days before the radioiodine test was started. Follow up was done on average 8 +/- 2.4 (4-17.2) months. TSH > or = 0.27 microIU/mL confirmed as a measure of the success. RESULTS: With improved pretherapeutic dosimetry and a mean target dose of 178 +/- 31 Gy (n=72) therapeutic success occurred in 66.7%, in 51.4% euthyreosis was restalled and in 15.3% of patients hypothyroidism was seen (TSH > 4.20 microIU/mL). With simplified pretherapeutic dosimetry and a mean target dose of 172 +/- 29 Gy (n=279) results were moderately impaired (63.8%, 40.1% and 23.7%). With increasing target dose therapeutic failure increased, as insufficiently adopted risk factors for therapeutic failure turned out the initial thyroid metabolism, the TcTU(s) as the (h)TRAb titer. CONCLUSION: Functional orientated RIT can be optimized by including illness specific characteristics, principal limitations are a high initial thyroid metabolism, a large thyroid volume and a high (h)TRAb-titer.

Clinical impact of retinoids in redifferentiation therapy of advanced thyroid cancer: final results of a pilot study.

Differentiated thyroid cancer is a malignant tumour that has a fairly good prognosis, with patients surviving for many years. Multimodal therapy with surgery, radioiodine therapy and TSH suppressive medication is of proven efficacy. However, loss of differentiation is observed in up to one-third of patients with differentiated thyroid cancer, paralleled by an increase in tumour grading and loss of thyroid-specific functions (thyrotropin receptor, iodine accumulation). Such tumours may no longer be amenable to standard treatment protocols, including TSH suppression and radioiodide therapy. Retinoic acids have been shown to exert re-differentiating effects on thyrocytes in various experimental studies and case reports, and it was on this basis that this pilot study was initiated. Patients with advanced thyroid cancer and without the therapeutic options of operation or radioiodide therapy were treated with 13- cis-retinoic acid at a dosage of 1.5 mg/kg body weight daily over 5 weeks. Parameters for assessment of the therapeutic effect were serum thyroglobulin (TG) levels, radioiodine uptake, and tumour size prior to and after retinoid treatment. Fifty patients were evaluated for response, classified as reduction in tumour size and TG levels, stable disease or disease progression. Thirteen patients showed a clear increase in radioiodine uptake, and eight a mild increase. TG levels were unchanged or decreased in 20 patients. Tumour size was assessable in 37 patients; tumour regression was observed in six, and there was no change in 22. In total, a response was seen in 19 patients (38%). Response to retinoid therapy did not always correlate with increased radioiodine uptake, so other direct antiproliferative effects have to be assumed. The encouraging results of the study and the low rate of side-effects with good tolerability of retinoids warrant further studies with altered inclusion criteria and employment of other redifferentiating drugs or combinations of agents.

[Results of TcTUs-optimized radioiodine therapy in multifocal and disseminated autonomy]. / Ergebnisse der TcTUs-optimierten Radioiodtherapie bei multifokaler und disseminierter Autonomie.

AIM: The presented study prospectively evaluates the efficacy of optimized radioiodine therapy in patients (pts) with multifocal (MFA) and disseminated (DISA) autonomy. The target dose was related to the total thyroid volume and was increased in moderate and nonlinear increments from 150 to 300 Gy dependent on the pretherapeutic Tc-99m pertechnetate thyroid uptake under suppression (TcTUs). Patients with focal autonomy were treated with a target dose independent of TcTUs and were used as control group. METHODS: The data of 641 pts (518 women, 123 men) were evaluated, 466 pts with MFA or DISA and 175 pts with focal autonomy. In pts with MFA and DISA the target dose was increased in four steps: TcTUs < 3%: 150 Gy, > 3-6%: 200 Gy, > 6-12%: 250 Gy and > 12%: 300 Gy. In pts with focal autonomy a fixed target dose of 300 or 400 Gy was applied. The radioactivity to be administered was calculated using a modified Marinelli formula. The follow-up examination was performed at the earliest after four, on average after eight months. Normalization of TSH was the only criterion for successful therapy. RESULTS: The success rate in pts with latent or manifest hyperthyroidism in focal autonomy was 91.5%, therapy was not successful in 5.1% and hypothyroidism occurred in 3.4%. The average success rate in pts with MFA and DISA was 91.5%, therapy failed in 7.5% and a very low rate of 1% with hypothyroidism was seen. CONCLUSION: The presented optimized therapy concept with calculated, nonlinear increase of the target dose according to the TcTUs-level guaranteed even in MFA and DISA a high success rate comparable to that in focal autonomy along with a very low rate of hypothyroidism.

A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A.

One hundred and eighty-one families with multiple endocrine neoplasia type 2A (MEN-2A) or familial medullary thyroid carcinoma (FMTC) have been investigated for mutations in the ret protooncogene in Germany. In 8 families with FMTC or MEN-2A, no mutation could be detected in the cysteine-rich domain encoded in exons 10 and 11 of the ret protooncogene. DNA sequencing of additional exons (no. 13-15) revealed rare noncysteine mutations in 3 families (codons 631, 768, and 844). In contrast to these rare events, heterozygous missense mutations in exon 13, codons 790 and 791, were found in 5 families (4 with MTC only; 1 family with MTC and pheochromocytoma) and 11 patients with apparently sporadic tumors. Two different mutations in codon 790 (TTG-->TTT, TTG-->TTC; Leu790Phe) and one mutation in codon 791 (TAT-->TTT; Tyr791Phe) created a phenylalanine residue. We conclude that codons 790 and 791 of the ret protooncogene represent a new hot spot for FMTC/MEN-2A causing mutations. With the discovery of these considerably common mutations in codons 790 and 791 and the identification of some rare mutations, 100% of the German FMTC/MEN-2A families could be characterized by a mutation in the ret protooncogene.

[Paradoxical effect of radioiodine therapy in functional thyroid autonomy and mild immunothyropathy]. / Paradoxe Effekte der Radiojodtherapie bei funktioneller Schilddrusenautonomie und milder Immunthyreopathie.

AIM: To examine all cases with Graves' disease after radioiodine therapy of autonomously functioning thyroid tissue (AFFT) in order to find the cause. METHODS: We retrospectively studied 1428 pts who were treated between 11/93 and 3/97 with radioiodine for AFTT and who underwent at least one control examination. RESULTS: 15 (1.1%) of all pts developed Graves' disease 8.4 (4-13) months after radioiodine therapy. There was no direct suggestion of Graves' disease (TRAK negative, no endocrine ophthalmopathy) in any pt at the time of radioiodine therapy. More detailed analysis of anamnestic data, however, revealed evidence that immunothyropathy predated radioiodine therapy in 11 of the 15 pts. Paradoxical effects of radioiodine therapy manifested as an increase in immunothyropathy in 14 pts, a deterioration in metabolism in 11 pts and a first occurrence of endocrine ophthalmopathy in 5 pts. CONCLUSION: Exacerbation of preexisting, functional primarily insignificant immunothyropathia is held responsible in most cases for the observed paradoxical effects after radioiodine therapy, resulting in radiation-induced manifest Graves' disease; however no therapeutical consequences are recommended.

Anticholinergic agents. 2. Absolute configurations of 2-methyl-1,1-diphenyl-3-(1-piperidyl)-1-propanol and 2-methyl-1,1-diphenyl-3-(1-pyrrolidyl)-1-propanol. Crystal structures of the corresponding mandelates.

Racemic 2-methyl-1,1-diphenyl-3-(1-piperidyl)-1-propanol (4) and 2-methyl-1,1-diphenyl-3-(1-pyrrolidyl)-1-propanol (5) have been synthesized and optically resolved employing (R)- and (S)-mandelic acid, respectively, as resolving agents. The absolute configurations of the enantiomers of 4 and 5 have been established as (-)-(R) and (+)-(S) by crystal structure analyses of (-)-(R)-2-methyl-1,1-diphenyl-3-(1-piperidinio)-1-propanol (+)-(S)-mandelate and (+)-(S)-2-methyl-1,1-diphenyl-3-(1-pyrrolidinio)-1-propanol (-)-(R)-mandelate. The corresponding methiodides have been prepared.

Tocainide: a severe adverse reaction.

Tocainide is a primary analog of lidocaine with antiarrhythmic properties used to treat ventricular rhythm disorders. A 76-year-old man with benign paroxysmal premature ventricular contractions was treated with tocainide and developed a generalized maculopapular lupoid eruption, bleeding from the lips and gingivae, vertigo, gross tremors of the extremities, fever, and short-term memory loss, which required hospitalization. The patient recovered slowly over three months with no permanent sequelae after discontinuing the drug and receiving rigorous supportive care. His excellent physical status and absence of concomitant illness contributed to an uneventful recovery. Tocainide is a potent cardioactive drug with a long biological half-life and should be used with caution.

Syntheses of (S)-(+)-trihexyphenidyl hydrochloride and (S)-(+)-procyclidine hydrochloride, two anticholinergics, using (S)-(-)-3-cyclohexyl-3-hydroxy-3-phenylpropanoic acid as chiral synthon.

The absolute configuration of the more active (-)-enantiomer of the anticholinergic trihexyphenidyl hydrochloride has been established as (R) by syntheses of (S)-(+)-procyclidine hydrochloride, whose absolute configuration has been established previously, and (S)-(+)-trihexyphenidyl hydrochloride from the same chiral building block, viz. (S)-(-)-cyclohexyl-3-hydroxy-3-phenylpropanoic acid. Both enantiomers of this chiral synthon were prepared by optical resolution of the corresponding racemate, employing (R)- and (S)-1-phenylethylamine, respectively, as resolving agents.

Bioavailability of indomethacin tablets in men volunteers.

Indomethacin bioavailability was compared in 22 healthy men who received two tablet dosage formulations and a capsule formulation of indomethacin in a three-way crossover study. In each study period, 50 mg of the indomethacin formulation (25-mg or 50-mg tablets or 50-mg capsules) was administered as a single dose to fasting subjects. Thirteen blood samples were collected at intervals over 24 hours after each dose. Urine samples were collected for 12 hours before each dose and 48 hours after each dose. Serum indomethacin concentrations were measured by a gas chromatographic procedure. The extent of indomethacin absorption for the two tablet formulations was not significantly different from that for the reference capsule. A trend toward earlier and higher peak serum concentrations with the capsule was observed. There was less than 20% difference in mean values for area under the concentration-time curve (AUC) for the three formulations. More than 75% of the subjects had serum concentrations falling between 75 and 125% of the mean serum concentrations. The extent of absorption of indomethacin from the two tablet formulations was similar to that from the capsule.

The effect of pressure change rate on the eustachian tube function in pressure chamber tests.

The capacity of the Eustachian tube to equilibrate pressure differences across the eardrum was tested repeatedly at different rates of pressure change with the aid of a quantitative impedance method in a pressure chamber. Three recordings of the active and passive pressure equilibration functions were made during chamber pressure changes of 0.3, 0.7 and 1.5 kPa-1s in 53 ears in 28 otologically healthy subjects. The middle ear pressures at which the active and passive equilibrations were achieved increased with increasing rates. The test-retest reliability was not rate dependent as regards the passive pressure equilibration functions, but tended to deteriorate with increasing rates for the active equilibration functions. Advantages and disadvantages of the different rates in such tests are discussed.

Effect of atropine on the eustachian tube function.

The effect of atropine on the eustachian tube function was studied by means of a recently designed method. The results out of 20 examined ears showed that atropine significantly reduced both active and passive functions of the eustachian tube. The findings are discussed and it is concluded that the method used might be a valuable tool in forthcoming studies of pharmacological effects on the eustachian tube function.