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Biomedical subjects

R Cozzi

Publications and source records attributed to R Cozzi.

At least 37 records · Page 2Linked to original sources
PubMed1998

Cabergoline in acromegaly: a renewed role for dopamine agonist treatment?

OBJECTIVE AND DESIGN: Eighteen active acromegalics entered a prospective open study with cabergoline (CAB), a dopaminergic drug much more potent than bromocriptine (Br). METHODS: CAB was administered for 6 months at doses ranging between 0.5 mg twice weekly and 0.5 mg/day. Clinical-anamnestic characteristics of the patients were: (i) sensitivity to dopamine agonist drugs (10 patients); (ii) resistance to somatostatin analogs (SAs) (8 patients): (iii) intolerance to SA (3 patients). In 2 patients marked hyperprolactinemia was present. RESULTS: Basal GH was 6.6 microg/l (2.2-50) (median (range)), and on treatment it was 3.5 microg/l (1.2-34) (P=0.013). The corresponding IGF-I values were 720 microg/l (410-1438) and 375 microg/l (167-1260) respectively (P=0.00001). Individual GH levels decreased below 2 microg/l in 5 patients, and between 2 and 5 microg/l in another 5 patients. IGF-I levels were suppressed below 50% of baseline in 8 patients and normal age-adjusted IGF-I values were reached in 5 patients (27% of the series). The retrospective comparison with previous chronic treatment with Br in the 10 suitable patients showed a greater effectiveness of CAB (IGF-I decrease on CAB treatment, 46.8%, on Br treatment, 31%, P=0.02). Adenoma shrank in the 3 patients whose pituitary imaging was repeated during CAB. CONCLUSIONS: These results envisage that CAB may represent a worthy therapeutic tool in acromegalic patients, inducing a degree of IGF-I and GH suppression comparable to SAs, administered by the oral route and much less expensive.

Acromegaly↗
PubMed1997

Specificity of the G1 block induced by ethionine in human lymphocytes in vitro: a flow cytometric analysis.

Ethionine is the ethyl analogue of the amino acid methionine. The agent is well known to have a weak demethylating activity. In addition, its capacity to reversibly block the cell cycle progression in G1 human lymphocytes (HL) without interfering with blastic transformation has been reported. In order to better understand the mechanism by which the agent is able to induce cell cycle block, experiments have been performed by using flow cytometry, in HL. In particular the hypothesis of the involvement of a specific target at the G0/G1 boundary was tested by treating HL at different times after blastic transformation. Starting from the 40th hour after PHA stimulation, ethionine loses its blocking capacity in such a way that cells challenged by the agent do not differ from controls in any one of the tested cell cycle-related parameters. We suggest the agent exerts its blocking activity at a specific stage of the transformation pathway.

Cell Differentiation↗
PubMed1997

Effects of tamoxifen on GH and IGF-I levels in acromegaly.

Tamoxifen (TAM), a non steroid partially competitive antagonist to the estrogen receptors, has been reported to decrease plasma GH and IGF-I levels both in vitro and in vivo. These data prompted us to evaluate GH and IGF-I changes in acromegaly after acute and chronic TAM administration. Nineteen acromegalic patients (6 M, 13 F, aged 30-70 years) were studied in a prospective open study. Acute TAM test (20 mg po) did not induce any significant change in GH and IGF-I levels. Chronic TAM treatment (20 mg/day for a month and 40 mg/day for another month) induced a transient increase in GH levels (from 9 [3-139] micrograms/l [median, range] to 12 [3-188] micrograms/l, p = 0.0025) and a persistent decrease in IGF-I levels (from 785 [500-1200] micrograms/l to 553 [209-1420] micrograms/l, p = 0.0034). Individual IGF-I values decreased in 13 patients and reached the normal range in 4 of them. At TAM withdrawal hormonal levels increased up to pretreatment values. There was no correlation between GH and IGF-I changes and results were not influenced by age, sex or gonadal status. In this setting it is likely that the observed decrease in plasma IGF-I levels is dependent on TAM activity at the hepatic level.

Acromegaly↗
PubMed1997

Inhibitory effects of galanin on growth hormone (GH) release in cultured GH-secreting adenoma cells: comparative study with octreotide, GH-releasing hormone, and thyrotropin-releasing hormone.

The aim of the present study was to characterize in a large series (N = 12) of cultured somatotrope adenomas the in vitro effects of the neuropeptide galanin on growth hormone (GH) secretion. This was contrasted with two peptides known to be GH secretagogues (GH-releasing hormone [GHRH] and thyrotropin-releasing hormone [TRH]) and a peptide with a known GH-inhibitory effect (the somatostatin analog octreotide). Groups of three wells were incubated for 4 hours with growth medium alone (control incubation), galanin, GHRH(1-29)NH2, TRH, or octreotide. Galanin and octreotide were applied at concentrations of 0.1, 1, and 10 mumol/L, and GHRH and TRH at concentrations of 0.01, 0.1, and 1 mumol/L. Galanin was able to inhibit GH release in nine of 12 cultured somatotrope adenoma cells. This inhibitory effect was clearly dose-dependent in five adenomas. Overall, the mean GH nadir after galanin was -36.1% in nine responder adenoma cultures versus control wells. Octreotide inhibited GH release in five of eight cultured somatotrope adenoma cells. The mean GH nadir after octreotide was -32.7% in five responder adenoma cultures compared with control wells. GHRH and TRH were able to stimulate GH release, respectively, in seven of 11 and in six of seven cultured somatotrope adenoma cells. The mean GH peaks after either GHRH or TRH in responder adenoma cultures were, respectively, +71.5% and +143.7% compared with levels in the control wells. In conclusion, the consistency and potency of the in vitro GH-inhibitory effect of galanin in a large series of somatotrope adenomas are at least similar to those of the most effective available GH-lowering agent, the somatostatin analog octreotide.

Adenoma↗
PubMed1997

Ascorbic acid and beta-carotene as modulators of oxidative damage.

Naturally occurring antioxidants are extensively studied for their capacity to protect organisms and cells from damage induced by oxygen reactive species. In fact, oxidative stress is considered a cause of aging, degenerative disease and cancer. We have focused our attention on two agents, ascorbic acid and beta-carotene, commonly considered to be antioxidants, but whose protective activity against cancer is insufficiently known. This paper reports on the ability of these agents to act against damage induced by H2O2 and bleomycin, in Chinese hamster ovary cells cultivated in vitro. Cytogenetic and cytofluorimetric analyses were performed. Both vitamins proved effective in reducing H2O2-induced sister chromatid exchanges, but increased H2O2- and bleomycin-induced chromosomal aberrations. Cytofluorimetric data, in contrast, showed that ascorbic acid and beta-carotene act as scavengers of endogeneous and H2O2-induced oxygen species.

Animals↗
PubMed1997

Damage proneness induced by genomic DNA demethylation in mammalian cells cultivated in vitro.

Variations in the genomic DNA methylation level have been shown to be an epigenetic inheritable modification affecting, among other targets, the sister chromatid exchange (SCE) rate in mammalian cells in vitro. The inheritable increase in SCE rate in affected cell populations appears as a puzzling phenomenon in view of the well established relation between SCE and both mutagenesis and carcinogenesis. In the present work we demonstrate that, in a treated cell population, demethylation could be responsible for the inheritable induction of damage proneness affecting both damage induction and repair. Normal and ethionine or azacytidine treated Chinese hamster ovary cells, subclone K1 (CHO-K1), were challenged with UV light (UV) or mitomycin-C (MMC) at different times from the demethylating treatment. The SCE rate was measured with two main objects in view: (i) the induction of synergism or additivity in combined treatments, where mutagen (UV or MMC) pulse is supplied from 0 to 48 h after the end of the demethylating treatment; and (ii) the pattern of damage extinction, for the duration of up to six cell cycles after the end of the combined (demethylating agent + mutagen) treatment. Results indicate both a synergism in SCE induction by mutagens in demethylated cells even if supplied up to four cell cycles after the end of the demethylation treatment and a delay in recovery of induced damage, compared with normally methylated cells. These data are discussed in the light of the supposed mechanism of SCE increase and of the possible biological significance in terms of mutagenesis and carcinogenesis.

Animals↗
PubMed1996

Effects of terguride on anterior pituitary function in parkinsonian patients treated with L-dopa: a double-blind study versus placebo.

In a randomized double-blind study, 20 parkinsonian patients (suffering from the disease for 2-18 years), chronically treated with levodopa (500-750 mg/day for 0.5-12 years), received terguride (1 mg b.i.d.) or placebo for 4 weeks. Growth hormone (GH), prolactin (PRL), thyroid-stimulating hormone (TSH), and insulin-like growth factor (IGF-I) secretions were studied before and after the morning dose of levodopa (250 mg p.o.), both before and at the end of study period. At the beginning of the study, basal hormonal levels were within normal limits, and levodopa administration induced a significant suppression in PRL and TSH levels (both p < 0.01)) and a significant increase in GH (p < 0.01). The same results were observed at the end of the study period in the placebo group. Addition of terguride induced a significant suppression in basal PRL levels (p < 0.01), whereas levodopa-induced hormonal changes were unaffected. These data suggest that the hypothalamic dopaminergic function that controls anterior pituitary hormones is preserved in parkinsonian patients, regardless of both the duration of the disease and the long-term treatment with levodopa. The strong additional prolactin-lowering effect of terguride indicates long-lasting dopaminergic effects, as is already known from hyperprolactinemic conditions. The dopaminergic effects of levodopa on TSH, GH, and IGF-I secretion were unchanged by terguride treatment. The anti-dopaminergic effects of terguride observed in the motor system in animal studies, as well as in levodopa-induced dyskinesias in parkinsonian patients, could not be observed in the case of the dopaminergic control of anterior pituitary hormones under the conditions of this study.

Aged↗
PubMed1995

Taurine and ellagic acid: two differently-acting natural antioxidants.

Naturally occurring antimutagenic compounds are extensively analyzed for their capacity to protect cells from induced damage. We selected two agents, taurine and ellagic acid, treated in the literature as antioxidants, but whose activity is insufficiently known. This paper reports on the ability of these agents to act against damage induced by mitomycin-C and hydrogen peroxide in Chinese hamster ovary cells cultivated in vitro. Cytogenetic and cytofluorimetric analyses were performed. Ellagic acid proved to have more than one mechanism of action, probably as a scavenger of oxygen species produced by H2O2 treatment, and as a protector of the DNA double helix from alkylating agent injury. In our experimental conditions, taurine seems able to scavenge oxygen species.

Animals↗
PubMed1995

Persistence of increased levels of ribosomal gene activity in CHO-K1 cells treated in vitro with demethylating agents.

The rate of ribosomal gene activity was evaluated by silver staining of the Nucleolus Organisers (NOs) in cultured CHO-K1 cells after a 12 h pulse with two demethylating agents (L-ethionine and 5-azacytidine). Silver staining of the NOs was measured every 24 h, from 24 up to 110 h after seeding. The purpose was to test the hypothesis that drug-induced demethylation is associated to heritable modifications of rDNA activity. Ribosomal gene activity was shown to be significantly increased by both agents. The increase persisted throughout the experiments, thereby suggesting the heritability of this epigenetic modification. The analysis of heritable DNA damage or modification is an important task in studying the risk of cancer onset and the mechanisms of cancer induction. In these studies two main results were obtained: (i) heritable DNA variations can be induced by both mutational and epigenetic changes; (ii) the modified end-point was not negatively selected.

Animals↗
PubMed1995

Persistence of somatostatinergic tone in acromegaly.

It is a matter of debate whether hypothalamic somatostatin (SRIH) secretion in acromegaly is preserved and still regulated by the physiological feedback mechanisms of growth hormone (GH) and insulin-like growth factor I. To gather further information on this, the reproducibility of plasma GH changes induced by growth hormone-releasing hormone (GHRH) administration was evaluated in 15 acromegalic patients. There was a highly significant correlation between the peak/basal ratio (P/B) GH response in the 15 patients administered GHRH on two separate occasions (r = 0.99, p < 0.001). The test was performed also before and after the administration of drugs able to inhibit or stimulate hypothalamic SRIH release, by activating (pyridostigmine) or inhibiting (pirenzepine) cholinergic pathways, respectively. The GHRH-induced GH response (P/B = 2, range 1.1-26.1) was increased significantly by pyridostigmine pretreatment in 30 patients (P/B = 2.6, range 1.3-34.8; p = 0.0045). In nine out of 30 patients an increase of greater than 2 SD of within-subject GHRH variability was observed in response to GHRH plus pyridostigmine when compared to GHRH alone. An inverse correlation (r = -0.37, p < 0.05) was observed between GH response to GHRH alone and after pyridostigmine pretreatment. On the contrary, no change of GHRH-induced GH response was observed in 12 patients after pirenzepine pretreatment (P/B = 1.9, range 1.1-5 and P/B = 2, range 1.3-6 without and after pirenzepine pretreatment, respectively). These data suggest that in acromegaly the somatostatinergic tone does not seem to fluctuate, and that it can be inhibited often by cholinergic pathway activation but not increased further by cholinergic suppression.

Acromegaly↗
PubMed1993

Desmutagenic activity of natural humic acids: inhibition of mitomycin C and maleic hydrazide mutagenicity.

Humic acids are natural components of organic matter widespread in the environment. In spite of the incomplete knowledge about their composition, increasing interest in humic acid activity is justified by their ubiquity. Four different humic acids have been tested in Chinese hamster ovary cells in vitro, both alone and in combination with two well-known mutagens (mitomycin C and maleic hydrazide). Data about sister-chromatid exchanges, mitotic and proliferation indices were collected. Our results, on the whole, indicate: (i) a slight mutagenicity and toxicity of tested humic acids, probably due to chlorination during sample preparation; (ii) a desmutagenic rather than antimutagenic activity of the tested humic acids.

Animals↗
PubMed1993

Persistence of sister chromatid exchange by 9-beta-D-arabinofuranosyladenine in Chinese hamster ovary cells cultivated in vitro.

The cytogenetic activity of 9-beta-D-arabinofuranosyladenine (ara-A), a known antitumor agent with an unknown mechanism of action (possibly acting via demethylation and/or decrease in DNA synthesis), has been tested in Chinese hamster ovary (CHO) cells cultivated in vitro, with respect to its ability to induce sister chromatid exchange (SCE). The agent shows no effect on cell cycle parameters (proliferation and mitotic indices) at concentrations up to 100 microM, when administered in pulses ranging from 3 to 12 h. Furthermore, even if administered over the entire treatment period (24 h), a severe cell cycle delay appears only at a concentration of 100 microM. A clear increase in the SCE frequency is produced starting from a concentration of 10 microM, irrespective of the treatment protocol (i.e. pulse versus continuous). This effect on the SCE frequency is maintained for as long as 10 cell cycles after removal of the agent. A partial inactivation of S-adenosyl-L-homocysteine (AdoHcy) hydrolase seems to be produced for as long as 6 h after agent removal. We suggest that under our experimental conditions ara-A exerts its action through a heritable epigenetic modification.

Adenosylhomocysteinase↗
PubMed1993

CV 205-502 in acromegaly.

In a series of acromegalic patients the effects of CV 205-502, a new long-acting dopamine-agonist drug, on growth hormone (GH), insulin-like growth factor I (IGF-I) and prolactin (PRL) levels were evaluated in an open study. After acute administration of CV 205-502 (0.0375 mg, po) in 12 patients. GH levels did not change, whereas PRL values significantly decreased and remained suppressed for 24 h. In the 14 patients who underwent chronic CV 205-502 treatment (at daily doses of 0.150-0.600 mg/day given at bedtime or b.i.d. for up to 12 months). GH and IGF-I levels fell significantly from 60 +/- 17 (mean +/- SEM) micrograms/l to 28 +/- 10 micrograms/l and from 1127 +/- 84 micrograms/l to 738 +/- 57 micrograms/l, respectively (p < 0.05). A retrospective comparison with the results obtained for the same patients during a previous chronic bromocriptine treatment (at daily doses of 5-20 mg given t.i.d. or q.i.d.) did not show any significant difference in the suppression of GH levels between the two treatments; no bromocriptine-resistant patient was CV 205-502 sensitive, even at the highest CV 205-502 dose used. We conclude that in acromegaly chronic treatment with this new dopaminergic drug has a GH- and PRL-lowering effect that is similar to but more prolonged than that of bromocriptine, and normal or near-normal GH and IGF-I levels may be obtained in a few patients with b.i.d. administration. However, no GH-lowering effect is observed in bromocriptine-resistant patients.

Acromegaly↗
PubMed1991

Antimutagenic activities of naturally occurring polyamines in Chinese hamster ovary cells in vitro.

Spermine and spermidine, ubiquitous polyamines present in bacteria and animal cells, are also involved in cell growth. Since they interact with the double helix, they can stabilize the DNA molecule. Recent evidence of the antimutagenic and anticarcinogenic capacity of spermine has focused attention on the mechanism(s) by which such agents can protect cells from induced damages. In the present paper we show the ability of spermine and spermidine to decrease the level of sister chromatid exchanges induced in Chinese hamster ovary cells cultivated in vitro, by treating them with Psoralen + UVA irradiation (able to induce mainly monoadducts and DNA cross-links). Two different mechanisms of polyamine action can be invoked to explain the preservative activity of this class of agents.

Animals↗
PubMed1991

Doxorubicin for acromegaly: a case report.

We report the case of an acromegalic woman, aged 35 years, with a huge GH-secreting tumor, repeatedly treated with neurosurgery and radiotherapy, not responsive to bromocriptine (Br) and octreotide (SMS), whose clinical picture evolved to coma due to endocranic hypertension. Since remnant size was too large to be further treated by surgery, chemotherapy with doxorubicin (DOX) (100 mg i.v. every three weeks up to 0.5 mg/m2 over 7 months) was started. Treatment was followed by a rapid improvement of clinical picture with resumption out of coma, progressive decline of GH levels (from 800 ng/ml to 15 ng/ml) and a slight shrinkage of tumor. No side effects were observed during DOX administration. We suggest that in those few acromegalic patients resistant both to SMS and Br, and with poor prognosis, DOX may be effectively used.

Acromegaly↗
PubMed1990

Prolactin response to growth hormone-releasing hormone during chronic thyrotropin-releasing hormone infusion in the treatment of amyotrophic lateral sclerosis.

In six patients suffering from amyotrophic lateral sclerosis we evaluated changes of T4, T3, TSH, PRL, and GH during treatment by continuous iv infusion of TRH for at least 15 days. No clinical improvement was detected. A significant rise of thyroid hormone levels was observed, as well as an upward trend of basal TSH levels and no change of basal PRL and GH levels. TRH acute test-induced TSH and PRL responses became blunted. Treatment provoked also the onset of a responsiveness of PRL to GHRH. The reduced TSH and PRL responses to acute TRH test during treatment could be explained by a down-regulation of TRH pituitary receptors. On the contrary, the onset of PRL responsiveness to GHRH is at present without a satisfactory explanation.

Amyotrophic Lateral Sclerosis↗
PubMed1990

Resistance to a long-acting somatostatin analog (SMS 201-995) reversed by surgery in acromegaly.

A 42-year-old woman had acromegaly and a large macroadenoma with supra- and parasellar extension. Her GH levels (median 85 ng/ml, range 63-170 ng/ml) were not responsive to TRH (200 micrograms iv), GHRH (100 micrograms iv) and bromocriptine (Br 2.5 mg po) acute tests; Sm-C level was 8 U/ml. She was treated with octreotide (SMS) (up to 1500 micrograms daily) for 3 months. No changes of clinical, biochemical and radiological findings were seen, therefore she underwent transsphenoidal surgery. After surgery, hypopituitarism and diabetes insipidus appeared: GH levels remained high (median 45 ng/ml; range 37-56 ng/ml), but became responsive to Br acute test. The patient was given SMS again, and this resulted in clinical improvement, marked reduction of GH and Sm-C levels and slight shrinkage of the residual tumor. Speculative hypotheses about this previously unreported phenomenon might be either an excess of both GHRH and somatostatin, caused by a primary increase of dopaminergic tone, or a primary excess only of GHRH; in both cases the surgical lesion of the hypothalamic-pituitary region might have impaired the neurohormones inflow to the residual pituitary and so let SMS and Br exert their inhibitory actions on GH secretion.

Acromegaly↗