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M Valenti

Publications and source records attributed to M Valenti.

At least 91 records · Page 5Linked to original sources
PubMed1995

In the search for new antiinflammatory drugs: synthesis and antiinflammatory activity of some Thiazolo(3,2-a)pyrimidine derivatives containing a thioether group.

Our strategy for the exploration of new NSAIDs starts on the synthesis of derivatives of 5-oxo-5H-Thiazolo [3,2-a] pyrimidines. The compounds were achieved by the following methods: (a) condensation of 2-amino-4-alkylthiomethilthiazole with ethyl 4-chloro-3-oxobutanoate (PPA method), (b) triphenyl phosphonium salts preparation, (c) Wittig-reaction of the salts with suitable aldehyde. Synthesized compounds were screened for antiinflammatory activity in the carrageenin rat paw oedema assay according to Winter et al. Some of the new synthesize compounds, at the dose used (50 mg/Kg) reduced meaningfully the oedema. The pharmacological effect varies according to the administration time.

Alkylation↗
PubMed1995

[Transitory swelling of a parotid gland following general anesthesia. Description of a case].

An acute transient swelling of the parotid glands is recorded after general anaesthesia in orthopaedic surgery. The first differential diagnosis is bacterial parotitis; other causes of gland enlargement are viral infections, lymphoma, leukemia, sarcoidosis, Sjogren's syndrome, malnutrition cirrhosis, vomiting, and poor oral hygiene. Excluding the above mentioned conditions, the most probably factors involved in our case are drugs used for anaesthesia, congestion of the venous drainage of the gland because of parasympathetic stimula during tracheal intubation and head positioning during surgery.

Acute Disease↗
PubMed1995

Pharmacological profile of dextrorphan.

Dextrorphan (CAS 125-73-5) is the active metabolite of the antitussive agent dextromethorphan (CAS 125-71-3). The activity of dextromethorphan, its specific pharmacology, acute toxicity and general pharmacology in respect to the central nervous system were investigated in comparison to dextromethorphan. The studies showed that dextrorphan exerts an antitussive activity comparable to the one of dextromethorphan, but a better tolerability and a lower toxicity. These results suggest to use dextrorphan instead of its precursor dextromethorphan in therapy.

Administration, Oral↗
PubMed1995

In vitro synergism between 5-fluorouracil and natural beta interferon in human colon carcinoma cells.

The combination of 5-fluorouracil (FUra) plus IFN-beta was studied in vitro using a human colon carcinoma cell line, HCT-8. Continuous exposure to high concentrations of IFN-beta is cytotoxic to these cells (ED50, 600 +/- 50 IU/ml). A strong synergism (P < 0.002) was observed when a short-term (1-h), high-concentration exposure to fluoropyrimidine (300 or 1000 microM) was followed by IFN-beta given continuously. In fact, the mean ratio between the expected (product of the survival of each agent alone) and the observed clonogenic cell survival rates of the combination was 3.4 (range, 2.4-4.9). Longer exposures to the fluoropyrimidine (24 h, 7 days) produced less than additive effects with IFN-beta, indicating strong schedule dependency for this synergism. The mechanism of interaction was studied at four levels. First, thymidylate synthase (TS) activity, inhibition, and recovery were measured by an in situ assay in cells treated with FUra, IFN-beta, and their combination. When the prolonged infusion of IFN-beta followed a 1-h exposure to FUra, the observed TS inhibition and recovery, at each time point, were very similar to the expected values, indicating that the interactions between these drugs at the level of TS are not the determinant of the synergism. Second, cell cycle analysis was done. During the continuous exposure to IFN-beta, a significant accumulation of HCT-8 cells in S-phase was observed at 24, 48, and 72 h compared to untreated controls (P = 0.003); however, under the same experimental conditions producing synergy in the clonogenic assay, no significant cell cycle perturbations were produced by the combination of FUra followed by IFN-beta compared to those caused by each agent alone. Third, using the alkaline elution test, we also demonstrated that the synergism is not due to enhanced FUra-induced DNA single-strand break frequency in high molecular weight DNA. Finally, nucleic acid incorporation experiments, using tritiated FUra, showed that the cytokine, given continuously (300 IU/ml), enhanced the amount of FUra incorporated into nucleic acids 24 h after a 1-h exposure to 300 and 1000 microM of FUra. The median percentage of enhancement values were 31.6 +/- 11.5%,m for the lower drug concentration and 18. 4 +/- 8.1% for the higher drug concentration tested. These results suggest that the mechanism of this synergism may be related to the ability of IFN-beta to promote the incorporation of intracellular FUra metabolites into nucleic acids and/or to inhibit the cleavage of FUra nucleotides from RNA/DNA.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

A novel trans-platinum coordination complex possessing in vitro and in vivo antitumor activity.

As part of a drug discovery program to discover more effective platinum-based anticancer drugs, a series of platinum complexes of trans coordination geometry centered on trans-ammine(cyclohexylaminedichlorodihydroxo)platinum(IV) (JM335) has been evaluated in vitro against a panel of cisplatin-sensitive and cisplatin-resistant human tumor cell lines (predominantly ovarian). In vitro, against 5 human ovarian carcinoma cell lines, JM335 was comparably cytotoxic to cisplatin itself and over 50-fold more potent than transplatin (mean 50% inhibitory concentrations: JM335, 3.1 microM; cisplatin, 4.1 microM; transplatin, 162 microM). With the use of seven pairs of human tumor cell lines (parent and subline with acquired resistance to cisplatin and encompassing all of the known major mechanisms of resistance to cisplatin) JM335 exhibited a different cross-resistance pattern to that of its cis isomer (JM149). JM335 showed non-cross-resistance in six of the seven resistant lines, cross-resistance in the A2780cisR line possibly being associated with high levels of glutathione. Preliminary intracellular DNA binding studies showed that in contrast to transplatin, JM335 was efficient at forming DNA-DNA interstrand cross-links. In vivo, JM335 produced growth delays in excess of 15 days against 4 of 6 human ovarian carcinoma xenografts and was unique among the complexes studied in retaining some efficacy against a cisplatin-resistant subline of the murine ADJ/PC6 plasmacytoma. JM335 is the first trans-platinum complex to demonstrate marked antitumor efficacy against both murine and human s.c. tumor models and represents a significant structural lead to complexes capable of circumventing cross-resistance to cisplatin.

Animals↗
PubMed1994

A new missense mutation (Cys297-->Phe) of the low density lipoprotein receptor in Italian patients with familial hypercholesterolemia (FHTrieste).

During a survey of the mutations of the low density lipoprotein receptor (LDL-R) gene in Italian patients with familial hypercholesterolemia (FH), we identified a novel point mutation, that creates a new EcoRI site at the 5' end of exon 7, in a heterozygous FH subject (FH-100). The sequence of a cDNA fragment encompassing exon 7 showed the presence of a G-->T transversion in codon 297; this created a new EcoRI site and produced a missense mutation, leading to a Cys297-->Phe substitution in repeat A of the epidermal growth factor (EGF) precursor homology domain of LDL-R. Since the substitution of Cys297 disrupts the intracellular transport of the LDL-R protein, as previously demonstrated by site-directed mutagenesis, we suggest that this mutation is the cause of FH in the FH-100 proband. We screened the DNA of 303 Italian FH patients by amplification of exon 7 from genomic DNA followed by digestion with EcoRI or by Southern blotting. Two individuals (FH-64 and FH-127) were found to be carriers of the Cys297-->Phe mutation. Restriction fragment length polymorphism analysis demonstrated that, in two kindreds (FH-64 and FH-100), the haplotype in linkage with the Cys297-->Phe mutation was the same, suggesting the presence of a common ancestor. The Cys297-->Phe mutation has been designated FHTrieste after the name of the city in Northern Italy from which probands FH-100 and FH-127 originate.

Base Sequence↗
PubMed1994

The effect of drinking coffee and smoking cigarettes on the risk of cirrhosis associated with alcohol consumption. A case-control study. Provincial Group for the Study of Chronic Liver Disease.

In order to assess the interaction between alcohol intake, tobacco smoking and coffee consumption in determining the risk of liver cirrhosis we carried out a hospital-based case-control study involving 115 patients at their first diagnosis of cirrhosis and 167 control patients consecutively enrolled in the General Hospitals of the Province of L'Aquila (Central Italy). The mean life-time daily alcohol intake (as g ethanol consumed daily) was measured by direct patient interviews, whose reproducibility was > 0.80 and similar for cases and controls, as checked by interviewing the relatives of a sample of 50 cases and 73 controls. During the same patient's interview we also measured the mean consumption of coffee (daily number of cups of filtered coffee) and tobacco (life-time daily number of cigarettes smoked). A dose-effect relationship on the risk of cirrhosis was present both for alcohol intake--for which the risk was significantly increased above 100 g of daily intake--and for cigarette consumption. The latter did not however improve the goodness-of-fit of a logistic regression model including alcohol intake as covariate. By contrast, coffee consumption had a protective effect on the risk of cirrhosis and significantly improved the goodness-of-fit of such a model. Abstaining from coffee consumption determined both a significantly increased risk of cirrhosis, even for daily alcohol intake below 100 g, and a multiplicative effect with alcohol intake on this risk. In patients drinking > or = 101 g ethanol daily the relative risk increased from 5.5 (95% confidence interval: 1.4-22.0) for coffee consumers to 10.8 (95% confidence interval: 1.3-58.1) for coffee abstainers.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Drinking↗
PubMed1994

A strong negative association between alcohol consumption and the risk of hepatocellular carcinoma in cirrhotic patients. A case-control study.

We carried out a hospital-based, case-control study to assess the association of both the Hepatitis B Virus (HBV) infection and the lifetime daily alcohol intake with the risk of developing hepatocellular carcinoma (HCC) in patients with liver cirrhosis (LC). Cases were 62 consecutive inpatients of a Gastroenterology Division in whom a first diagnosis of HCC superimposed on LC was made. Two control groups were used: 310 patients without liver disease, matched 1:5 with cases and randomly selected from inpatients of the same hospital, and 97 consecutive asymptomatic inpatients in whom the first diagnosis of LC was made. Alcohol intake was quantified in all subjects by a standardized questionnaire. HBV infection was associated with HCC development in cirrhotics (odds ratio = 6.8; 95% confidence interval = 1.4-32.3), whereas we observed a trend towards a decreased HCC risk at increased alcohol intake values (odds ratio from 1 for lifetime abstainers to 0.2 for drinkers of 175 g/day or more). Our results suggest that alcohol intake is not a direct determinant of HCC, but its role is mediated by LC. Cirrhotics with high alcohol intake do not usually survive long enough to develop HCC.

Age Distribution↗
PubMed1994

Induction of DNA double-strand breaks by 8-methoxycaffeine: cell cycle dependence and comparison with topoisomerase II inhibitors.

We have studied the ability of 8-methoxycaffeine (8-MOC)--one of the most effective caffeine derivatives in inducing chromosomal aberrations--to induce DNA double strand breaks (DSB) in purified human T lymphocytes during the cell cycle. Etoposide- or ellipticine-mediated DNA break frequency was used as a parameter of topoisomerase II activity. DNA-DSB induced by either 8-MOC or VP16 or ellipticine rose co-ordinately with the level of DNA topoisomerase II and with the onset of DNA replication. At concentrations between 10 and 50 microM 8-MOC was approximately 75% as active in terms of DSB as VP16 and ellipticine. By contrast with VP16 and ellipticine, 8-MOC was not cytotoxic. In conclusion, our data suggest that 8-MOC is an agent that efficiently induces DNA-DSB at non-toxic concentrations, and without direct inhibition of topoisomerase II.

Caffeine↗
PubMed1994

Circumvention of atypical multidrug resistance with tumor necrosis factor.

Some "multidrug-resistant" (MDR) cell lines are not associated with a defect in drug accumulation or with the overexpression of P-glycoprotein. These cell lines are defined as "atypical MDR" (at-MDR) and they often express altered or mutated topoisomerase II. We investigated the ability of tumor necrosis factor to reverse at-MDR (in the human ovarian cancer cell line A2780 DX3) on the basis of its efficacy in potentiating in vitro topoisomerase II-targeted drugs, and because there is convincing evidence that the synergy is due to an increased number of topoisomerase-associated strand-breaks as well as to an increased level of extractable topoisomerase.

DNA Damage↗
PubMed1994

New perspectives in the treatment of postmenopausal osteoporosis: ipriflavone.

The efficacy and safety of ipriflavone, a new anti-osteoporotic agent, has been evaluated in an open study in 100 agent, has been evaluated in an open study in 100 osteoporotic women. Ipriflavone was administered as oral capsules dosed at 200 mg, 3 times a day for 12 months. Ninety women completed the study, and the results indicate that the bone mineral density was increased by 2% and 5.8% after 6 and 12 months, respectively. Pain and rachis mobility seemed to be positively influenced by ipriflavone. Only three women complained of side-effects (gastralgia and nausea) and asked to stop the therapy.

Administration, Oral↗
PubMed1994

Family compliance to a treatment programme for alcoholics: a prospective study of prognostic factors.

A total of 198 alcoholic subjects was recruited into a treatment programme according to Hudolin's method. The programme included three steps: (1) presentation of the programme to the alcoholic family (four meetings); (2) a therapeutic community that met weekly over 4 months; and (3) attendance at an on-Treatment Alcoholic Club located close to the family's home residence (weekly self-conducted meetings). Data on the families' compliance to the treatment programme were obtained in January 1993 and the prognostic significance of 11 variables collected during the first step was determined by the proportional hazards regression model. The cumulative proportion of family compliance after 40 months was 36.4%, with similar drop-out rates at each of the three steps of the programme. The prognostic factor which was the major determinant of family compliance to treatment was the active presence of the whole family in the first step, while a good job performance was independently associated with family compliance, being a significant prognostic factor in the second step of the programme. Alcohol abstinence was obtained in 35.9% of the whole study group. This programme provided results for alcohol abstinence which are comparable with methods that require more expensive resources.

Adult↗
PubMed1994

Synthesis and antiulcer activity of some (1S, 5R)-2-thiabicyclo (3, 3, 0) oct-5-ene derivatives.

The preparation of (1S,5R)-2-Thiabicyclo[3,3,0]oct-6-ene derivatives (Sn;n=0,1,2) is described. Spectral and optical data (IR, NMR, Mass, alphaD20) are reported. These compounds can be considered as thiaprostacyclin-like derivatives. Studies of anti-ulcer activity in comparison with two reference compounds (cimetidine, pirenzipine) have shown that all the new compounds own a good anti-ulcer activity. Further studies are in progress to establish the mechanisms of their action.

Animals↗
PubMed1994

[Long-term results of surgical treatment of early cancers of the stomach].

The postoperative course of 172 patients with early gastric cancer operated between 1974 and 1987 was reviewed with a median follow-up of 7 years. The survival probability at the end of 1989 was 0.916 (excluding operative mortality and other causes of death) or 0.876 when the operative mortality was included. Univariate analysis showed a significant survival difference according to the presence or absence of submucosal invasion (p = 0.02, Log-Rank test) and lymph node invasion (p = 0.04, age greater than or less than 50 years (p = 0.03) and according to the type of resection performed (total gastrectomy with gastric and perigastric lymph node dissection or subtotal gastrectomy with incomplete lymph node dissection (p = 0.05). Eleven patients died from cancer recurrence, one is still alive with a recurrence of the gastric stump. The other deaths were due to cancers of other organs (6), cardiovascular disease (2), pneumonia (3), septicaemia (1) and a car accident. Although the prognosis of early gastric cancer is relatively favourable in European countries, patients must be carefully followed for a long period because of recurrences and the high incidence of cancers in other organs.

Adult↗
PubMed1993

Potentiation of TNF-mediated cell killing by mitoxantrone. Relationship to DNA single-strand break formation.

Tumor necrosis factor (TNF) is a pleiotropic cytokine that mediates different cellular responses including cytotoxicity, cytostasis, proliferation, differentiation and expression of specific genes. Recent studies have demonstrated that chemotherapeutic drugs that inhibit the nuclear enzyme DNA topoisomerase II synergize with TNF in tumor cell killing in vitro and in vivo. We now report that a combination of TNF and the topoisomerase II inhibitor Mitoxantrone produced dose-dependent synergistic cytotoxicity against the human ovarian cancer cell line A2774 in a clonogenic assay (1 hr treatment). This result was obtained with simultaneous administration of the drug and the cytokine under test, and is independent of modification of Mitoxantrone uptake. This combination is responsible for an evident augmentation of "cleavable complex" formation. From isolated nuclei, we have isolated also the topoisomerase II activity; we observed an increment when the cells were previously treated with TNF, 2.5 min before nuclear extraction. After 10-30 min of treatment with TNF, the topoisomerase II activity returned to normal values. If TNF is not given with but 30 min before Mitoxantrone, no potentiation of cytotoxicity or break induction is observed. These results suggest that specific timing of the association may be needed also when attempting to translate it to animals and humans.

Cell Death↗
PubMed1993

Preclinical antitumor evaluation of bis-acetato-ammine-dichloro-cyclohexylamine platinum(IV): an orally active platinum drug.

The cytotoxicity of a novel platinum(IV) complex, bis-acetato-amminedichloro-cyclohexylamine platinum(IV) (JM216), has been evaluated in vitro against a panel of human tumor cell lines (predominantly ovarian) representative of models of intrinsic and acquired to cisplatin. In addition, the activity of JM216 administered by the p.o. route has been determined in vivo using the murine ADJ/PC6 plasmacytoma and four human ovarian carcinoma xenograft lines. In vitro, against seven human ovarian carcinoma cell lines, JM216 showed similar cytotoxicity and pattern of cytotoxicity to cisplatin (mean 50% inhibitory concentrations of 3.5 microM for cisplatin and 1.7 microM for JM216). The cytotoxicity of JM216 was more dependent on the time of drug exposure than that of cisplatin, suggesting that extended split-dosing rather than a single bolus administration might be a more appropriate schedule in patients. Using six pairs of acquired cisplatin-resistant and parent human tumor cell lines (four ovarian, one testicular, and one cervical) JM216 exhibited non-cross-resistance (resistance factor of < 1.5) in three whereas tetraplatin exhibited partial or full cross-resistance in all six pairs. Notably, in two of the acquired cisplatin-resistant lines (41McisR and HX/155cisR) where JM216 retained activity, resistance has previously shown to be due primarily to reduced platinum uptake. In vivo, following p.o. administration using the cisplatin-sensitive murine ADJ/PC6 plasmacytoma, JM216 showed antitumor selectivity far superior to that observed for either cisplatin, carboplatin, or tetraplatin. Across four human ovarian carcinoma xenografts of widely differing sensitivity to cisplatin and carboplatin, JM216 exhibited p.o. activity, broadly comparable to that observed for i.v. administered cisplatin and carboplatin and markedly superior to i.p. administered tetraplatin. These antitumor properties suggest that JM216 provides a structural lead to platinum complexes which may circumvent transport-determined acquired resistance to cisplatin and is a suitable candidate as an p.o. administrable platinum complex for phase I clinical trial.

Animals↗
PubMed1993

Early gastric cancer: follow-up after gastrectomy in 159 patients.

The postoperative course of 159 patients with early gastric cancer operated on between 1974 and 1987 was followed for a median of 7.3 years. The cumulative 10-year survival rate(s.e.) calculated using follow-up data to the end of 1989 was 90.6(2.7) per cent excluding operative death and that from causes other than gastric cancer, or 86.3(3.0) per cent when operative mortality was included. The overall 10-year survival rate(s.e.) was 77.3(3.7) per cent. Univariate analysis showed a significant difference in survival rates between cancers confined to the mucosa and those with submucosal invasion (P = 0.02), between patients with and without lymph node metastases (P = 0.05) and between those < or = 50 and > 50 years of age (P = 0.02). Using Cox multivariate analysis and a stepwise procedure for eight variables (sex, age, depth of invasion, lymph node metastases, presence of ulceration, location, histological type, type of surgery), age and histological type had the most significant effect on survival. Seven operative deaths were recorded. Eleven patients died from recurrent cancer and one is still alive with a gastric remnant recurrence. Other causes of death were metachronous primary cancer (six patients), cardiovascular disease (two), pneumonia (three), sepsis (one) and car accident (one). Although the prognosis of early gastric cancer is relatively good in western countries, patients should be carefully followed over a long period for late recurrence and for metachronous cancer, which has a high incidence.

Adult↗