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Biomedical subjects

M Ballabio

Publications and source records attributed to M Ballabio.

At least 37 records · Page 2Linked to original sources
PubMed1989

Urinary metabolites of rifabutin, a new antimycobacterial agent, in human volunteers.

1. Metabolites of the antimycobacterial agent 4-deoxo-3,4-[2-spiro-(N-isobutyl-4-piperidyl)]-(1H)-imidazo-(2,5-dihydro )- rifamycin S (rifabutin) were isolated from human urine after administration of a single oral dose of the drug. Some of these metabolites were identified by direct inlet mass spectrometry, 1H-n.m.r. spectrometry and, in two cases, by chromatographic comparison with reference compounds. 2. Unchanged drug, 25-O-deacetyl rifabutin and four other metabolites were identified in human urine. 25-O-Deacetyl rifabutin was the main urinary metabolite, other metabolites were characterized as oxidized, and oxidized-deacetylated derivatives. 3. Routes of metabolic transformation were: (a) deacetylation at position 25, (b) oxidation of methyl groups 31 or 32 or at the piperidine nitrogen, and (c) combination of these.

Adult↗
PubMed1988

Ontogenetic development of the 5 alpha-reductase in the rat brain: cerebral cortex, hypothalamus, purified myelin and isolated oligodendrocytes.

In the central nervous system of the rat, the 5 alpha-reductase, the enzyme which converts testosterone into dihydrotestosterone, appears to be concentrated in the white matter and in particular to be associated with myelin. In order to verify whether a temporal correlation might exist between the formation of myelin membranes and the variations of the 5 alpha-reductase activity observed in the brain, the enzymatic activity was studied in the cerebral cortex and in the hypothalamus of male rat in the age range of 3-60 days, in myelin purified from animals of 15-60 days of life and in oligodendrocytes (i.e. in the cells responsible for the formation of the myelin) isolated from the brain of adult and very young rats (7th day of life, when the myelination process is not yet initiated). The results show that the formation of 5 alpha-androstane-17 beta-ol-3-one (DHT) in the cerebral cortex and in the hypothalamus has a peak activity in the first two weeks of life, before the beginning of the myelination process; purified myelin has an enzymatic activity always much higher than that present in the cerebral cortex and in the hypothalamus and shows a peak in the formation of DHT in the first period of myelinogenesis, on the third week of life. Finally the oligodendrocytes of young rats possess a much higher ability to convert testosterone into the 5 alpha-reduced metabolites than the oligodendrocytes of adult animals. A possible involvement of this enzyme in the myelin function may be hypothesized.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1988

Testosterone 5 alpha-reductase activity in the rat brain is highly concentrated in white matter structures and in purified myelin sheaths of axons.

Previous results obtained in this laboratory indicate that in the rat brain the 5 alpha-reductase, the enzymatic activity involved in metabolizing testosterone into 5 alpha-androstan-17 beta-ol-3-one (dihydrotestosterone), is particularly concentrated in the white matter. In the present experiments, this enzymatic activity was studied in the following white matter structures, which were microdissected using the punch technique of Palkovits: anterior commissure (CA), fornix (FX), habenulo-interpeduncular tract (HP), corpus callosum (CC), stria medullaris (SM), optic chiasm (CO), fimbria of the hippocampus (FI), cerebral peduncle (PC), pontine fibers (FP), cerebellar medulla (CMD) and corticospinal tract (TCS). Moreover brain myelin was isolated and purified by sucrose density gradient ultracentrifugation. The results obtained confirm that, in the rat brain, the enzymes involved in testosterone 5 alpha-reduction are preferentially localized in the white matter. However, clearcut differences in the metabolic activity exist between the different structures examined so far. DHT formation increases rostro-caudally, so that the highest activity has been recorded in the white matter structures punched at the level of pons (FP), medulla oblungata (TCS) and cerebellum (CMD). The high metabolic activity associated with the white matter structures appears to be linked to the presence of myelin, since the specific activity of the enzyme is particularly elevated in purified preparations of myelin sheaths.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1987

Differential distribution of the 5-alpha-reductase in the central nervous system of the rat and the mouse: are the white matter structures of the brain target tissue for testosterone action?

In the brain of several animal species testosterone is converted into a series of 5-alpha-reduced metabolites, and especially into 17-beta-hydroxy-5-alpha-androstan-3-one (DHT), by the action of the enzyme 5-alpha-reductase. The formation of DHT has never been evaluated in the white matter structures of the brain, which are composed mainly of myelinated axons. The experiments here described were performed in order to study, in the rat and the mouse, the DHT forming activity of several white matter structures, in comparison with that of the cerebral cortex and of the hypothalamus. Two sampling techniques were used in the rat: microdissection under a stereo-microscope from frozen brain sections of fragments of corpus callosum, optic chiasm and cerebral cortex; fresh tissue macrodissection of subcortical white matter, cerebral cortex and hypothalamus. Only macrodissection was used in the mice. The data show that, independently from the sampling technique used, there are considerable quantitative differences in the distribution pattern of the 5-alpha-reductase activity within different brain structures. Both in the rat and in the mouse, the enzyme appears to be present in higher concentrations in the white matter structures, than in the cerebral cortex and in the hypothalamus. The present results clearly show that the subcortical white matter and the corpus callosum are at least three times as potent as the cerebral cortex in converting testosterone into DHT. An even higher 5-alpha-reductase activity has been found in the optic chiasm. Further work is needed in order to understand the possible physiological role of DHT formation in the white matter structures.

Animals↗
PubMed1987

Thyrotropic activity of crude hCG in FRTL-5 rat thyroid cells.

The presence of thyroid stimulating activity in partially purified hCG was investigated using, as bioassay system, iodide uptake in rat thyroid FRTL-5 cells. The biological responses evoked by hCG were tested after neutralisation with monoclonal and polyclonal antisera to hTSH and hCG, and after fractionation on Sephadex G-100. The molar amounts of TSH and hCG in respective preparations were calculated assuming an activity of 30 IU/mg and 19 IU/mg, respectively, for bTSH and hTSH, and of 14,000 IU/mg for hCG. A dose-dependent response, paralleling that evoked by bTSH, was observed in a concentration range of 0.1-4 mumol/l hCG; 1 mumol of hCG was equivalent to 50 pmol of bTSH and 132 pmol of hTSH. The thyrotropic activity coeluted with hCG immunoactivity on Sephadex G-100. Incubation with monoclonal anti-hTSH antibodies did not affect the stimulatory ability of hCG preparation, indicating that it was not due to hTSH contamination. Similarly, a pretreatment with monoclonal and polyclonal anti-hCG antibodies did not significantly alter the iodide uptake response induced by hCG. These results indicate that the thyrotropic activity in partially purified hCG is not due to the presence of aspecific contaminants, but to a substance structurally related to hCG in terms of molecular weight. However, it appeared to differ from hCG immunologically, suggesting the hypothesis that minor modifications in the molecular structure may confer thyrotropic activity on hCG, altering its immunoreactive potency.

Animals↗
PubMed1986

Endocrine, biochemical, and morphological studies of a pituitary adenoma secreting growth hormone, thyrotropin (TSH), and alpha-subunit: evidence for secretion of TSH with increased bioactivity.

A 40-yr-old man who had acromegaly and hyperthyroidism due to a GH/TSH-secreting pituitary adenoma is described. Serum free T4 was 2.8 ng/dl, free T3 was 1.1 ng/dl, and TSH was 1.2-1.5 microU/ml; the latter was measured in an immunoradiometric assay with a sensitivity of 0.07 microU/ml. Serum TSH was immunologically identical to standard TSH and did not decrease during a T3 suppression test. Serum free alpha-subunit and the molar alpha-subunit to TSH ratio were high (6.1 ng/ml and 31.2, respectively). TRH administration induced significant increases in both GH (+129%) and alpha-subunit (+156%) levels. Conversely, dopamine infusion resulted in a decrease in serum GH (-66%) and alpha-subunit (-43%) levels, and subsequent administration of the dopamine antagonist sulpiride induced significant increases in both GH and alpha-subunit (+393% and +106%, respectively). Similarly, somatostatin infusion inhibited GH (-43%) and alpha-subunit (-61%) secretion. Serum TSH levels were not affected by TRH, dopamine, or somatostatin. The biological to immunological activity ratio of serum TSH purified by immunoaffinity chromatography and measured in an adenylate cyclase assay was significantly increased compared to that in serum from hypothyroid or euthyroid subjects [biological to immunological activity ratio, 6.9 +/- 0.2 (+/- SD) vs. 4.4 +/- 1.1; P less than 0.001]. In gel chromatography, the apparent mol wt of the patient's TSH was smaller than that of the controls. After adenomectomy, all of the altered parameters of pituitary function became normal. Double gold particle immunostaining of the adenomatous tissue showed that all of the cells contained secretory granules positive for GH and alpha-subunit, while very few cells were positive for TSH beta as well as GH and alpha-subunit. These data indicate that in this patient serum TSH had an apparent mol wt smaller than that of normal TSH and an increased biological activity which, along with the autonomous TSH secretion, account for hyperthyroidism in the presence of low normal TSH levels; alpha-subunit originated from the same adenomatous cells that secreted GH but not TSH, thus explaining the in vivo observation that alpha-subunit responses to several agents were dissociated from TSH responses and parallel to GH responses; and TSH and GH were colocalized in a minority of the neoplastic cells.

Adenoma↗
PubMed1986

Bicyclic compounds with potential antiulcer and/or antisecretory activity. II. 1(or 3),4,6,7-Tetrahydro-1(3)H-pyrano[3,4-d]imidazoles and 1(or 3),4,6,7-tetrahydro-1(3)H-thiopyrano[3,4-d]imidazoles.

Owing to our current interest in synthesizing and evaluating the antiulcer and antisecretory activity of bicyclic compounds, a series of 1(or 3),4,6,7-tetrahydropyrano- and 1(or 3),4,6,7-tetrahydrothiopyrano-[3,4-d]imidazoles was synthesized and tested. The biological results were compared with those of some previously described 4,5,6,7-tetrahydroimidazo-[4,5-c]pyridine and 4,5,6,7-tetrahydrobenzimidazole derivatives.

Animals↗
PubMed1985

New anthracycline glycosides obtained by the nitrous acid deamination of daunorubicin, doxorubicin and their configurational analogues.

The new anthracyclines 7-O-(2,3,5-trideoxy-3-C-formyl-alpha-L-threo-pentofuranosyl)daunomyci none (8) and -adriamycinone (10) have been obtained upon nitrous acid deamination of daunorubicin and doxorubicin respectively. Deamination of the L-ribo analogue of daunorubicin (6) gave a mixture of 2,3,6-trideoxy-L-glycero-hexopyranosid-4-ulose (alpha-L-cinerulosyl) (11) and 2,6-dideoxy-alpha-L-arabino-hexopyranosyl (12) glycosides. The corresponding adriamycinone glycosides 13 and 14, obtained by deamination of the doxorubicin L-ribo analogue 7, were found to display an outstanding antileukemic activity in mice.

Animals↗
PubMed1983

Excess of beta-subunit of thyrotropin (TSH) in patients with idiopathic central hypothyroidism due to the secretion of TSH with reduced biological activity.

alpha-Subunit and beta-subunit of TSH were measured in the sera of five patients with idiopathic central hypothyroidism due to the secretion of biologically inactive TSH, in seven normal controls matched for bone age and sex, and in five subjects with mild primary thyroid failure before and after TRH (200 micrograms, iv) stimulation. Basal serum alpha-subunit concentration in patients did not differ from that in normal controls (mean +/- SD, 0.40 +/- 0.20 vs. 0.38 +/- 0.28 ng/ml; P, NS), whereas TSH and TSH-beta were significantly higher in patients (TSH, 1.51 +/- 0.74 vs. 0.59 +/- 0.53 ng/ml, P less than 0.025; TSH-beta, 0.56 +/- 0.18 vs. 0.10 +/- 0.02 ng/ml, P less than 0.001). The concentration of TSH-beta was also significantly higher in patients with central hypothyroidism than in subjects with mild primary thyroid failure (0.56 +/- 0.18 vs. 0.24 +/- 0.08 ng/ml; P less than 0.01), although serum TSH levels did not differ in the two groups (1.51 +/- 0.74 vs. 2.16 +/- 0.52 ng/ml; P, NS). alpha-Subunit was significantly higher in primary hypothyroid subjects (1.50 +/- 0.87, P less than 0.05 compared with patients with central hypothyroidism). After TRH, alpha-subunit, TSH, and TSH-beta net increases (peak) were significantly higher in patients with central hypothyroidism than in normal controls (alpha-subunit: 0.95 +/- 0.5 vs. 0.47 +/- 0.19 ng/ml, P less than 0.05; TSH: 7.1 +/- 3.1 vs. 2.9 +/- 1.8 ng/ml, P less than 0.005; TSH-beta: 0.89 +/- 0.35 vs. 0.22 +/- 0.18 ng/ml, P less than 0.005), whereas they did not significantly differ from those recorded in hypothyroid controls. The beta/alpha ratio, which was 1.67 +/- 0.86 in patients and 0.35 +/- 0.18 in normal controls (P less than 0.005), slightly decreased after TRH to 1.24 +/- 0.78 in patients, but remained unchanged in normal controls (0.39 +/- 0.1). After TRH the alpha-subunit peak occurred at 20 min both in patients and in controls, whereas TSH and TSH-beta peaked at 60 min in patients and at 20 min in controls. One patient was given oral TRH (40 mg/day for 4 weeks). The beta/alpha ratio fell from 1.85 to 0.13. Interestingly, serum thyroid hormones, which did not increase after iv TRH and after the first doses of oral TRH, showed a definite increase. Sera from two patients were filtered on Sephadex G-100: in one of them TSH-beta eluted in the same position as labeled reference standard, whereas in the other one radioimmunoassayable TSH-beta eluted near the void volume. The above data indicate that in patients with idiopathic central hypothyroidism due to biologically inactive TSH there is an excess of circulating TSH-beta and suggest that TRH is implicated in the secretion of TSH of full biological potency.

Adult↗
PubMed1983

Metabolic and pharmacological studies with N-methyl-N'-methyl-2'-allyl-2-benzoyl-4-chloro-glycinanilide (F 1797).

Three metabolites (F 1756, diazepam and N-desmethyl-diazepam) of N-methyl-N'-methyl-2'-allyl-2-benzoyl-4-chloro-glycinanilide (F 1797), a new potential anxiolytic agent, are formed by N-desmethylation or cyclisation in the rat. They were compared with F 1797 for their antileptazol activity in order to assess their contribution to the effect of the parent compound. F 1756 had little effect in this test. However, diazepam and N-desmethyl-diazepam formed after F 1797 certainly contributed to its antileptazol effect.

Anilides↗
PubMed1982

Antileptazol activity and kinetic of CP 1414 S (7-nitro-2-amino-5-phenyl-3-H-,1,5-benzodiazepine-4-one) in the rat and mouse.

The antileptazol effect of CP 1414 S (7-nitro-2-amino-3-phenyl-3H-1,5-benzodiazepine-4-one) a newly developed 1,5 benzodiazepine, lasts longer in mice than in rats. After intraperitoneal injection (10 mg/kg) brain levels of the drug were higher and persisted for longer in the mouse than in the rat. Although it cannot be excluded tht possible metabolites of CP 1414 S may contribute to the anticonvulsant effect of CP 1414 S, in both species the protective effect correlates well with the brain concentrations of the drug.

Animals↗
PubMed1982

Species differences in the kinetics and metabolism of fenfluramine isomers.

After single oral doses of racemic fenfluramine to man and animals (male CD-COBS Sprague-Dawley rat, male CD1-COBS mice and male beagle dogs) plasma and/or brain concentrations of the d- and l-isomers and their deethylated metabolite were measured by gas-liquid chromatography. In rat and mouse d-fenfluramine had a longer half-life (T 1/2) and gave a larger area under the curve (AUC) than the l-isomer. These differences were consistent with stereoselective N-deethylation of l-fenfluramine. Thus, in both species the plasma and brain AUC of the l-metabolite were double that of the d-form. In man and dog slight or no differences were seen between te kinetic and metabolic profiles of the isomers. Comparison of the plasma concentrations time curve of fenfluramine showed slower elimination in man than in the other species. The T 1/2 of the d-isomer was 2.6 hr in rat, 2.5 +/- 0.2 hr in the dog. 4.3 hr in the mouse and 17.8 +/- 0.9 hr in man. The deethylated metabolite norfenfluramine was present in plasma or brain, or both, of all the species examined as a major metabolite of the drug. At the oral doses of racemic fenfluramine tested the ration of the AUC for d-norfenfluramine to d-fenfluramine was 4.4, 2.0, 0.8, 0.3, and the dog, rat man and mouse respectively. The T 1/2 of the metabolite was longer than that of the parent drug in all these species. Similar studies with d-fenfluramine indicated that its kinetic profile was identical to that of d-fenfluramine administered in the racemic form. The l-isomer therefore does not change the absorption, distribution and metabolism of the d-isomer which should be considered as the active form.

Adult↗