Serum thyroglobulin level in patients with diffuse and nodular goiter, after therapeutic application of stable iodine.

This study analysed the changes in serum thyroglobulin levels in euthyroid female patients, suffering from diffuse and scintigraphically functional nodular goiter, after therapeutic administration of two preparations of stable iodine: dried bovine thyroid, containing 100 mcg of iodine in one dragee (Thyral, Yugoslav Pharmacopea) and synthetic Na-salt L-thyroxine (Vobenol, with 100 mcg of iodine, too), for relatively short time of following-up, 8 weeks only. Having in mind the key role of TSH in regulation, all aspects of thyroid gland function, the interrelationship between TSH and thyroglobulin concentrations in those patients were also investigated. Prior to the therapy females had elevated thyroglobulin serum concentrations, caused by existence of diffuse and nodular goiter, which reflected an increase in intraglandular turnover of thyroglobulin (192 +/- 140 mcg/L in GROUP A further treated with Thyral and 121 +/- 14.80 +/- mcg/L in GROUP B, whose patients received Vobenol, mean +/- SD). Positive linear correlation between TSH and Tg levels was not established before therapy. Our data indicate that administration of two different preparations containing stable iodine in doses of 100 mcg every second day, during a two months period, resulted in significant decrease in the size of diffuse and nodular goiter, with diminished complains in a great number of patients. In thyroid humoral status, significant decrease of thyroglobulin concentrations was evident in both analysed groups (62 +/- 48 mcg/L, and 60 +/- 66, respectively). Presented results confirmed positive linear correlation between TSH and thyroglobulin in serum samples, after therapy, especially strong in the group treated with dried bovine thyroid.

Fast, short-term response to TRH stimulation in geriatric patients and its clinical importance.

In 52 geriatric patients, average age of 74 years (range from 65 to 89) suffering from generalised arteriosclerotic disease and hospitalized at the Clinical Institute for Geriatrics, we found normal thyroid gland function, in basal condition. Our data showed that 19.42% of the patients had low triiodothyronine (T(3)) concentrations. Basal serum T(3) level was higher (P < 0.01) in males (1.88 +/- 0.44 nmol/l) in comparison to values in females (1.75 +/- 0.28). Serum thyroxine (T(4)) level was lower in males (P < 0.01), but the concentrations of thyreo stimulating hormone (TSH) was lower in females. The value of thyroid reserve in elderly people, estimated by measuring T(3) and T(4) incretion shortly after thyreotropin releasing hormone (TRH) was done, is sufficient to maintain cuthyroid function, although it is, as a whole, significantly lower if compared with T(4) and T(3) response after TRH tests in middle-aged subjects (n = 26), acting as a control group (P < 0.001). Thyroxine excretion from follicular cells in elderly female patients was faster and amplitude was higher, up to the maximal possible level 93 nmol/l (+/- SD) in 25 min after an injection of TRH. In elderly male patients the maximum of T(4) excretion was 78 nmol/l (P < 0.01) at 60 min.

Direct effects of cytostatic therapy on the functional state of the thyroid gland and TBG in serum of patients.

This study analysed the concentrations of thyroid binding globulin (TBG) in the serum as well as the level of triiodothyronine (T3), thyroxine (T4), thyreostimulating hormone (TSH), thyroglobulin (Tg) and T4/TBG coefficient, before therapy and on the fifth day of therapy in 27 patients of both sexes suffering from neoplasia. The patients were treated with cytostatic antibiotics, alkylating agents and podophyllines derivates, by protocol. Serum T3 gains in concentration already after 5 days since the beginning of treatment (from 1.65 +/- 0.20 to 1.73 +/- 0.18 nmol/l), but it is retained within physiological ranges as well as TSH, rT3 and Tg. Thyroxine remains within the permitted ranges, but slightly decreased after therapy (64.00 +/- 11.00 nmol/l, mean +/- SEM) in comparison to the value before (71.00 +/- 19.00), p(F) less than 0.1. A reduction of concentrations in total serum proteins at an average 7.88% was found. The level of inter-alpha globulin, TBG, in patients with proved malignancy is low before therapy (14.97 +/- 4.73 micrograms/l, mean +/- SEM, in males and 14.83 +/- 3.70 in females) but, with application of cytostatics it decreases considerably to the level of 11.68 +/- 4.46 (p less than 0.05) in males and to 13.68 +/- 3.89 in females (NS). In view of these facts, T4/TBG coefficient remains normal and contributes to the maintenance of euthyroid gland function.

Some extrathyroid regulatory mechanisms' aspects in thyroid humoral state at the delivery.

Thyroid function parameters (triiodothyronine, thyroxine, reverse triiodothyronine, thyroid stimulating hormone, thyroglobulin) and thyroid binding globulin (TBG) were determined in sera of 64 women who had carried a normal pregnancy and delivered at term, as well as in sera of their newborns. Obtained results were compared to the findings of the same parameters in 28 women who delivered at term, but had been receiving gestanges 1 to 5 months prior to the delivery, and in their babies. In both groups, serum triiodothyronine (T3) levels were normal both in mothers and in their babies. Foetal serum reverse triiodothyronine (rT3) levels were higher (1.58 +/- 0.14, means +/- SEM) as compared to serum levels (0.36 +/- 0.04) of the mothers treated with gestagens; similar results were obtained in the mothers with normal pregnancy (0.41 +/- 0.03) and their babies (1.65 +/- 0.15, means +/- SEM). In 13 out of 64 (20%) women with normal pregnancy serum thyroxine (T4) was elevated in delivery at term, with no impact on the clinical course. Of 28 women who were treated with gestagens for 1 to 5 months only 4 had elevated serum T4 on the delivery. Using gestagens, according to our results, contributes to an increase of the newborn TBG levels (27.00 +/- 2.65; means +/- SEM) in a significant way (p less than 1.001) as compared to TBG of the newborn delivered after a normal pregnancy (21.40 +/- 2.55).

Lysinomicin, a new aminoglycoside antibiotic. II. Structure and stereochemistry.

The structure of lysinomicin, a new aminocyclitol antibiotic, was established as 3-epi-2'-N-(L-beta-lysyl)-4',5'-didehydro-6'-de-C-methylfortimi cin B (1) on the basis of spectral evidence and chemical degradation of the antibiotic. In the course of the degradation of 1, three additional compounds with interesting biological properties were obtained: 3-epi-2'-N-(L-beta-lysyl)-6'-de-C-methylfortimicin B (4), 3-epi-4',5'-didehydro-6'-de-C-methylfortimicin B (6) and 3-epi-6'-de-C-methylfortimicin B (7).

4-N-Aminoacylation of substances derived from lysinomicin.

The preparations of 4-N-glycyllysinomicin and several 4-N-aminoacyl derivatives of compounds prepared from lysinomicin are presented. The new substances have lower antimicrobial activities than the original 4-N-unsubstituted lysinomicin derivatives. This result indicates that the structure-activity relationship observed with fortimicin A and fortimicin B does not apply to the lysinomicin derivatives studied.

Diastereomeric fortimicin 1,2-epoxides. The preparation of the 1-deamino-2-deoxyfortimicins A and B and the 1,2-di-epi-fortimicins A and B.

The preparation of 1,2-anhydro-2',6'-di-N-benzyloxycarbonyl-1-deaminofortimicin B-4,5-carbamate (4) and its conversion to the two diastereomeric 2',6'-di-N-benzyloxycarbonyl-1-deamino-2-deoxy-1,2-epoxyfortimicin B-4,5-carbamates 7 and 13 are described. The olefin 4 was used for preparation of 1-deamino-2-deoxyfortimicin A (6d) while the beta-epoxide 13 was used for the preparation of 1,2-di-epi-fortimicin A (17b) and 2-amino-1-deamino-2-deoxy-1-hydroxyfortimicin A (19c). The in vitro antibacterial activities of 6d, 17b and 19c are reported.

Substances derived from 4-de-N-methylfortimicin B.

The preparation of 4-de-N-methylfortimicin A analogs as well as the preparation of 4-de-N-methyl-4-N-(beta-aminoethyl)-4-N-ethylfortimicin B is reported. It was shown that the 4-N-methyl group in fortimicin analogs is essential for antibacterial activity since neither the 4-de-N-methylfortimicin A nor the 4-de-N-methyl-4-N-(beta-aminoethyl)-4-N-ethylfortimicin B exhibited useful biological activity.

6'-N-methylfortimicins A and B and 6',6'-di-N-methylfortimicins A and B.

Selective 6'-N-alkylation of 1,2'-di-N-benzyloxycarbonylfortimicin B was effected by both catalytic and chemical reductive alkylation in the presence of aldehydes. These facile selective 6'-N-alkylations were used as the basis of the preparations of the 6',6'-di-N-methylfortimicins A and B, and the 6'-N-methylfortimicins A and B. Of these new 6'-N-methylated fortimicins, only 6'-N-methylfortimicin A has appreciable antibacterial activity, which was about half that of fortimicin A.

4-N-Aminoacylfortimicins E.

The conversion of fortimicin E, a minor metabolite from the Micromonospora olivoasterospora fermentation which also produces fortimicin A and fortimicin B, to four 4-N-aminoacylfortimicins E was accomplished. The new 4-N-aminoacylfortimicins E showed only weak antimicrobial activity against several Gram-negative and Gram-positive microorganisms.

Modification of seldomycin factor 5 at C-3'.

Attempted removal of the 3'-hydroxyl group of seldomycin factor 5 via displacement of a sulfonate ester has led to 3'-epi-seldomycin factor 5. Removal of the hydroxyl group has been effected by the Barton procedure. The antibacterial activity of 3'-epi- and 3'-deoxyseldomycin factor 5 against various aminoglycoside-resistant strains is discussed.

Spectinomycin modification. IV. 7-deoxy-4(R)-dihydrospectinomycin.

7-Deoxy-4(R)-dihydrospectinomycin (7) has been prepared and its structure firmly established by proton magnetic resonance and high resolution mass spectrometry. This spectinomycin analog is devoid of antibiotic activity.

Fortimicins A and B, new aminoglycoside antibiotics. III. Structural identification.

The structures of fortimicins A and B have been determined by PMR, CMR, mass spectra and CD combined with chemical degradations. Both antibiotics are pseudodisaccharides and incorporate a novel aminocyclitol, fortamine. In contrast to the diaminocyclitol moieties of known aminoglycosides, fortamine is a 1,4-diamine, contains both N- and O-methyl groups and possesses chiro stereochemistry. Both antibiotics are glycosides of 6-epi-purpurosamine B, but fortimicin A differs from fortimicin B by being a glycyl amide.

A new aminoglycoside antibiotic complex--the seldomycins. III. The structures of seldomycin factors 1 and 2+.

The structures of seldomycin factors 1 and 2 have been determined by consideration of chemical degradation and spectral properties. Factor 1, also known as XK-88-1, is shown to be 6-O-(2-amino-2-deoxy-alpha-D-xylopyranosyl) paromamine (1) and factor 2, also known as XK-88-2, is shown to be 4'-deoxy-neamine (2). Mass spectral evidence has been obtained that suggests the most probable structure for seldomycin factor 3, also known as XK-88-3, is 6'-amino-6'-deoxyseldomycin factor 1 (12).

Spectinomycin modification. II. 7-EPI-sectinomycin.

7-Epi-spectinomycin (9) and 7-epi-4(R)-dihydrospectinomycin (10) have been prepared and their structure firmly established by proton magnetic resonance. Both of these spectinomycin analogs are devoid of antibiotic activity.