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G Giardina

Publications and source records attributed to G Giardina.

At least 37 records · Page 2Linked to original sources
PubMed1995

Mutant p53 protein overexpression is associated with poor outcome in patients with well or moderately differentiated ovarian carcinoma.

BACKGROUND: It has been shown that the p53 gene is mutated in 30-80% of ovarian carcinomas and that the genetic alterations most often manifest as an accumulation of mutant p53 protein in tumor tissue. The prognostic significance of these findings for patients with ovarian cancer, however, must be established clearly. METHODS: Mutant p53 protein in 90 consecutive epithelial ovarian carcinomas was quantitatively analyzed using a time-resolved immunofluorometric procedure. In contrast to immunohistochemical techniques, this method uses two anti-p53 antibodies. The Cox model was used to evaluate the strength of the associations between the prognostic markers and disease relapse or death at univariate and multivariate levels. Kaplan-Meier survival curves were calculated for patients who were p53-positive or negative and for subgroups with a different clinical stage, histologic grade, or residual postsurgical tumor. RESULTS: The positivity rates for p53 included 1/21 (5%) with Stage I disease, 1/6 (17%) with Stage II, 29/51 (57%) with Stage III, and 8/12 (67%) with Stage IV (total = 39/90, 43%). Patients with p53-negative tumors had a significantly longer disease free survival than did patients with p53-positive tumors (P = 0.03); these results were similar for overall survival (P = 0.06). Multivariate analysis revealed that the presence of postsurgical residual tumor was the only predictor significantly associated with poor patient outcome. However, when patients were divided into groups based on histologic grade, patients with well (G1) and moderately (G2) differentiated tumors had a significantly higher risk of cancer relapse and death if mutant p53 protein was present in their tumors compared with patients who were negative for mutant p53 protein (< 0.01). CONCLUSIONS: The immunofluorometric measurement of mutant p53 protein accumulation in epithelial ovarian carcinomas of a low histologic grade was associated significantly with an increased risk for cancer relapse and death. A similar trend also was suggested for early stage disease and in the absence of residual tumor after surgery. These increased risks, however, were not found for patients with high grade or advanced stage cancer or for those with residual tumor. To the authors' knowledge, this is the first report suggesting that p53 tumor protein accumulation is a marker of poor prognosis in a subset of patients with ovarian cancer.

Adult↗
PubMed1995

Central and peripheral analgesic agents: chemical strategies for limiting brain penetration in kappa-opioid agonists belonging to different chemical classes.

Over the past decade there has been great interest by the pharmaceutical industry in the development of novel analgesics which act by activation of central kappa-opioid receptors. However, in view of the spectrum of unwanted CNS effects associated with such agents, recent efforts have been focused on peripherally-selective compounds with limited ability to cross the blood-brain barrier (BBB). In this review, the authors consider the chemical strategies and associated synthetic procedures employed by various research groups to produce hydrophilic compounds with retained kappa-opioid agonist activity. Physico-chemical (clogP, delta logP) and biological methods (antinociception following administration by peripheral and central routes; ex-vivo binding to detect plasma and brain levels of the drugs) utilized to assess brain penetration are described and compared. Overall, in-vivo ratios correlate better with delta logP values than with clogP.

Analgesics↗
PubMed1994

Selective kappa-opioid agonists: synthesis and structure-activity relationships of piperidines incorporating on oxo-containing acyl group.

This study describes the synthesis and the structure-activity relationships (SARs) of the (S)-(-)-enantiomers of a novel class of 2-(aminomethyl)piperidine derivatives, using kappa-opioid binding affinity and antinociceptive potency as the indices of biological activity. Compounds incorporating the 1-tetralon-6-ylacetyl residue (30 and 34-45) demonstrated an in vivo antinociceptive activity greater than predicted on the basis of their kappa-binding affinities. In particular, (2S)-2-[(dimethylamino)methyl]-1-[(5,6,7,8-tetrahydro-5-oxo-2- naphthyl)acetyl]piperidine (34) was found to have a potency similar to spiradoline in animal models of antinociception after subcutaneous administration, with ED50s of 0.47 and 0.73 mumol/kg in the mouse and in the rat abdominal constriction tests, respectively. Further in vivo studies in mice and/or rats revealed that compound 34, compared to other selective kappa-agonists, has a reduced propensity to cause a number of kappa-related side effects, including locomotor impairment/sedation and diuresis, at antinociceptive doses. For example, it has an ED50 of 26.5 mumol/kg sc in the rat rotarod model, exhibiting a ratio of locomotor impairment/sedation vs analgesia of 36. Possible reasons for this differential activity and its clinical consequence are discussed.

Analgesia↗
PubMed1994

Response to second-line weekly cisplatin chemotherapy in ovarian cancer previously treated with a cisplatin- or carboplatin-based regimen.

Response to a second-line weekly cisplatin chemotherapy in ovarian cancer previously treated with cisplatin- or carboplatin-based regimens was analysed in a clinical series observed between 1984 and 1991. Women who achieved pathological complete response or pathological optimal partial remission after first-line cisplatin- or carboplatin-based regimens were treated at recurrence or progression, occurring at least 4 months after first-line treatment, with second-line chemotherapy. A total of 72 women were included in the analysis. Second-line chemotherapy regimens were: cisplatin 1 mg/kg weekly for seven courses plus epirubicin 70 mg/m2 intravenously (i.v.) every 3 weeks for three courses (28 subjects), cisplatin 1 mg/kg plus etoposide 90 mg/m2 i.v. weekly for a total of seven courses (11 subjects) and cisplatin 1 mg/kg weekly for nine courses plus carboplatin 250 mg/m2 every 3 weeks for three courses (33 subjects). Of the 72 women, 22 (31%, 14 clinical, 8 pathological) had a complete response and 28 (39%), a partial response (24 clinical, 4 pathological). The 24-month cumulative survival probability was 63% in women with complete response, 32% in those who had partial response, but all the 22 non-responders died within 24 months from diagnosis of recurrence (log rank test P < 0.05). The frequency of complete response and partial response increased with the interval between first diagnosis and recurrence: among the 33 women who had recurrent disease to < 18 months from first diagnosis, complete response or partial response was obtained in 20 (61%) subjects, this figure was 67% (14 out of 21 women) among subjects who had recurrent disease between 18 and < 36 months from first diagnosis and 89% (16/18) among those who had recurrence > or = 36 months. In comparison with women who had recurrence 4- < 18 months from first diagnosis, the OR of response was 1.3 (95% CI 0.4-4.1) for those who had recurrence between 18 and < 36 and 5.2 (95% CI 1.1-24.3) for those who had recurrence > or = 36 months from surgery (chi 1(2) trend p < 0.05). Survival rate after the end of second line chemotherapy for women who relapsed 4- < 18 months, 18- < 36 or 36 months or more after surgery were, respectively, 24, 20 and 67% (log rank test, P < 0.05). Age at first diagnosis, histology, stage, and grading of the disease at first diagnosis and site of recurrence were not associated with response to second-line therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Opiate receptors within the blood-brain barrier mediate kappa agonist-induced water diuresis.

Data suggest that kappa opioid agonist-induced water diuresis involves inhibition of vasopressin (AVP) secretion; however, it is not clear whether this action involves kappa receptors in the neurohypophysis or receptors behind the blood-brain barrier (BBB). We have investigated the site of action using three selective kappa agonists, BRL 52656 (S(-)-2-(1-pyrrolidinylmethyl)-1-(4-trifluoromethylphenyl) acetyl piperidine hydrochloride), BRL 53114 ((-)-1-(4-trifluoromethylphenyl) acetyl-2-(1-pyrrolidinymethyl)3,3- dimethyl piperidine hydrochloride) and BRL 52974 (4-(1-pyrrolidinylmethyl)5-(3,4-dichlorophenyl)acetyl-4,5,6,7-t etrahydroimidazo [4,5-c] pyridine), with varying abilities to cross the BBB. Chemical and functional assays indicate that BRL 52974 has limited ability to cross the BBB, whereas BRL 53114 and BRL 52656 can freely penetrate. BRL 52974 was significantly less potent than BRL 52656 and BRL 53114 in causing a water diuresis in conscious rats. The ED10S (i.v. doses to cause a positive free water clearance of 10 microliters/min.100 g) for BRL 52974, BRL 52656 and BRL 53114 were 181, 9 and 3.4 mg/kg, respectively. Furthermore, in dogs BRL 52656 and BRL 53114 but not BRL 52974 (30 micrograms/kg i.v.) were able to cause a significant water diuresis. The data demonstrate that opiate receptors behind the BBB are primarily involved in kappa agonist-induced water diuresis and possibly inhibition of AVP secretion.

Animals↗
PubMed1992

Substituted 1-(aminomethyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinolines: a novel class of very potent antinociceptive agents with varying degrees of selectivity for kappa and mu opioid receptors.

This study describes the synthesis of a series of novel substituted 1-(aminomethyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinolines, and discusses their structure-activity relationships (SARs) using binding affinity for opioid receptors and antinociceptive potency as the indices of biological activity. The introduction of a hydroxy substituent in position 5 of the isoquinoline nucleus generated a compound, 40, which is 2 times more potent than the previously disclosed unsubstituted analogue 39 in mouse models of antinociception. A QSAR analysis of the 5-substitution clearly demonstrates that antinociceptive activity is inversely associated with the lipophilicity of the substituents. The substituted compounds described herein are less selective for the kappa opioid receptors than the unsubstituted isoquinoline 39. For example, the 5-hydroxy-substituted compound 59 shows high affinity for kappa opioid receptors (Ki kappa = 0.09 nM) and a Ki mu/Ki kappa ratio of only 5. However, a multiple linear regression analysis demonstrates a lack of correlation between antinociceptive activity and affinity for the mu opioid receptor. On the other hand, the correlation between binding affinity to kappa opioid receptor and antinociceptive activity was statistically significant.

Analgesics↗
PubMed1992

Enantiospecificity of kappa receptors: comparison of racemic compounds and active enantiomers in two novel series of kappa agonist analgesics.

Two novel series, Ia,b and IIa,b, of kappa opioid antinociceptive agents have recently been described. 2a,b,3a,b,c The biological activities of 16 racemic compounds and their corresponding (-) enantiomers are now compared in a battery of tests. Enantiomers of unsubstituted piperidines Ia were synthesized starting from S(-) pipecolic acid, whereas the enantiomerically pure substituted piperidines (Ib), tetrahydroisoquinolines (IIa), and thienopiperidines (IIb) were, in general, obtained after diastereomeric crystallization of the corresponding tartrate salts. The absolute stereochemistry of one representative enantiomer from series IIa was determined to be (1S) by X-ray crystallographic analysis. Antinociceptive activity in the mouse abdominal constriction and tail-flick tests following subcutaneous administration, and binding affinity for kappa and mu receptors, were found to reside predominantly in the (-) enantiomers. Consequently, racemic compounds showed approximately half potency of the corresponding enantiomers. This potency difference was less clear after oral administration presumably due to small differences in bioavailability of the two corresponding enantiomers. For compounds with some affinity also for mu receptors (Ki less than 1,000 nM), the kappa/mu selectivity was maintained within each enantiomeric pair, in contrast to results found for other kappa agonists.

Analgesics↗
PubMed1992

[The effect of antihypertensive therapy on the seasonal variations in arterial pressure in hypertensive patients].

To evaluate the influence of antihypertensive therapy (AHT) on blood pressure (BP) seasonal variations, we have analyzed the systolic and diastolic BP values in 145 hypertensives, 112 males and 33 females, aged 23-65 years, in the 10-year period 1981-1990. All patients received medical treatment and were examined for at least 5-7 consecutive years. The year was divided in 2 (cold and warm months) and 4 periods in relation to mean monthly environmental temperature (10 degrees C, 13 degrees C, 18 degrees C and 23 degrees C). Systolic and diastolic BP was higher in cold months (142/93 vs 137/88 mmHg, p less than 0.05). In cold periods AHT was increased in 11% of patients and decreased in 8%. In the warm periods AHT was decreased in 11% of patients and increased in 6%. The AHT reduction in the warm months was not significantly different in comparison to that of cold months. Vice versa, the AHT increase in cold months was greater than that of warm periods (p less than 0.001). In the 10-year period considered, 18% of patients reduced AHT in the warm period and increased it in the cold period. It was also found a small correlation between diastolic blood pressure and wind, which is, in our country, mostly the mistral. Betablockers, calcium-antagonists and the association betablocker-diuretics showed a seasonal BP variation, while patients treated by diuretic had the same BP both in winter and in summer. A small negative correlation was observed between systolic and diastolic BP and temperature in patients treated by all antihypertensive drugs except the diuretics.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

(2S)-1-(arylacetyl)-2-(aminomethyl)piperidine derivatives: novel, highly selective kappa opioid analgesics.

This paper describes the synthesis and structure-activity relationships as kappa opioid analgesics of a novel class of 1-(arylacetyl)-2-(aminomethyl)piperidine derivatives. The active conformation of the pharmacophore, with a torsional angle (N1C2C7N8) of 60 degrees, was defined with computational studies and 1H NMR. A quantitative structure-activity relationship study of the arylacetic moiety substitution indicated that the presence of an electron-withdrawing and lipophilic substituent in para and/or meta positions is required for good analgesic activity and kappa affinity. The lead compounds (2S)-1-[(3,4-dichlorophenyl)acetyl]-2-(pyrrolidin-1-ylmethyl )piperidine hydrochloride and (2S)-1-[4-(trifluoromethyl)phenyl]acetyl]-2-(pyrrolidin-1-ylmet hyl) piperidine hydrochloride are the most kappa/mu selective (respectively 6500:1 and 4100:1) and among the most potent (Ki kappa 0.24 and 0.57 nM, respectively) kappa ligands identified so far. In the mouse tail flick model of antinociception, compound 14 (ED50 = 0.05 mg/kg sc) was 25 times more potent than morphine and 16 times more potent than the standard kappa ligand U-50488.

Analgesics↗
PubMed1991

(1S)-1-(aminomethyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinoline and heterocycle-condensed tetrahydropyridine derivatives: members of a novel class of very potent kappa opioid analgesics.

The synthesis and structure-activity relationship (SAR) of a novel class of kappa opioid analgesics, 1-(aminomethyl)-2-(arylacetyl)-1,2,3,4- tetrahydroisoquinolines and (aminomethyl)-N-(arylacetyl)-4,5,6,7-tetrahydrothienopyridines+ ++, are described. These compounds, formally derived by the condensation of a benzene or thiophene ring on the piperidine nucleus of the recently described compounds 1, are from 3 to 7 times more potent as antinociceptive agents and with a longer duration of action than the original lead compounds. A similar N2-C1-C9-N10 pharmacophore torsional angle of approximately 60 degrees was also found for this class of compounds by using X-ray and 1H NMR analyses. The same absolute configuration (S) at the chiral center of the active (-) enantiomers was determined by X-ray crystallographic analysis. A varied degree of kappa receptor selectivity was a feature of this novel class of antinociceptive agents (mu/kappa ratio from 44 to 950 according to the nature of the basic moiety). SAR analysis indicated that the presence of electron-withdrawing and lipophilic substituents in para and/or meta positions in the arylacetic moiety and the pyrrolidino or dimethylamino basic groups are required to optimize biological activity. The lead compounds 28, 30, and 48 are among the most potent antinociceptive agents (ED50 ca. 0.020 microM/kg sc) and kappa ligands (Ki(kappa) ca. 0.20 nM) identified so far.

Analgesia↗
PubMed1990

[Neoadjuvant chemotherapy of infiltrating carcinoma of the bladder: our experience].

From January 1987 until October 1989, 96 patients have been treated with radical cystectomy for locally advanced bladder cancer. Nineteen, out of 96 underwent chemotherapy (either M-VAC or M-VEC) before cystectomy. Five had T1G3 bladder tumor. After chemotherapy the results had been the following: 5 complete responses (CR) 26%, 7 partial responses (PR) (37%) and no changes in 7 patients (37%). During the first two courses of chemotherapy, 36 administrations out of 152 scheduled should have not been done because of drug toxicity. The seven patients who had no changes had a drug administration reduced of 41% with respect of a rate of reduction of 12% in the group of patients who had complete response. The urinary diversion after cystectomy were performed with a neobladder according to Reddy in 4 patients, with a colon conduit in 1 patient and with an ileal conduit in 12 patients. All the patients survived the surgery. We did not notice any difference in the follow up after surgery in those patients treated before cystectomy with chemotherapy with respect to the patients who underwent cystectomy without chemotherapy. Despite the fact that by now we can not state any conclusion about the efficacy of neoadiuvant chemotherapy, due both to the short follow up and to the small number of patients treated, we should however perform cystectomy in all the patients after chemotherapy because up to now we have no evidence that a conservative treatment of the bladder after chemotherapy could be safe.

Antineoplastic Combined Chemotherapy Protocols↗