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1.
G M Pacifici A Viani M Franchi S Santerini A Temellini L Giuliani M Carrai 《British journal of clinical pharmacology》1990,30(3):427-435
1. The activities of microsomal glucuronyltransferase and thiomethyltransferase, and those of cytosolic sulphotransferase, acetyltransferase, glutathione transferase and thiomethyltransferase were measured in abnormal (cirrhosis and chronic hepatitis) and normal livers. 2. Glucuronyltransferase and sulphotransferase were investigated with 2-naphthol and ethinyloestradiol as substrates. p-Aminobenzoic acid, benzo(a)pyrene-4,5-epoxide and 2-mercaptoethanol were the substrates of acetyltransferase, glutathione transferase and thiomethyltransferase, respectively. 3. Enzyme activities are expressed as nmol min-1 incubation mg-1 protein and the averages (+/- s.d.) are given. With 2-naphthol as substrate, the glucuronyltransferase activity was 6.55 +/- 4.10 (abnormal liver, n = 33) and 7.81 +/- 4.02 (normal liver, n = 26) (NS); whereas sulphotransferase activity was 0.28 +/- 0.18 (abnormal liver, n = 35) and 0.68 +/- 0.43 (normal liver, n = 26) (P less than 0.01). Glucuronyltransferase activity towards ethinyloestradiol was 102.5 +/- 56.9 (abnormal liver, n = 30) and 107 +/- 59.9 (normal liver, n = 26) (NS), whereas sulphotransferase activity was 57.2 +/- 36.0 (abnormal liver, n = 35) and 122 +/- 67.6 (normal liver, n = 28) (P less than 0.01). Acetyltransferase activity was 0.84 +/- 0.83 (abnormal liver, n = 35) and 3.84 +/- 1.65 (normal liver, n = 26) (P less than 0.01). Glutathione transferase activity was 0.83 +/- 0.68 (abnormal liver, n = 35) and 2.90 +/- 1.59 (normal liver, n = 25) (P less than 0.01) and thiomethyltransferase activity was 1.00 +/- 0.69 (abnormal liver, n = 34) and 3.99 +/- 1.49 (normal liver, n = 25) (P less than 0.01). 4. Liver disease lowers the activities towards the substrates studied of sulphotransferase, acetyltransferase, glutathionetransferase and thiomethyltransferase but not that of glucuronyltransferase.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
2.
Paolo De Simone Paola Carrai Lidiana Baldoni Stefania Petruccelli Laura Coletti Luca Morelli Franco Filipponi 《Liver transplantation》2005,11(9):1080-1085
We report the results of a retrospective review of the outpatient pretransplantation workup for United Network for Organ Sharing (UNOS) 3 patients adopted at a liver transplantation (LT) center and illustrate the efficiency indicators used for quality evaluation and cost-analysis. A single-center, pre-LT evaluation workup was performed on an outpatient basis at a cost per patient evaluation of 2,770 Euros (). Objective measures were: the number of patients admitted to and excluded from each phase of the algorithm; the rate of patients admitted to pre-LT evaluation out of the total of referred patients (the referral efficiency rate); the rate of waitlisted patients out of those admitted to pre-LT evaluation (the evaluation efficiency rate); the rate of waitlisted patients out of those referred for LT (the process efficiency rate); and the cost per waitlisted patient, as the ratio of the cost per patient evaluation to the evaluation efficiency rate. From January 1, 1996, to October 1, 2004, 1,837 patients were referred for LT on an outpatient basis. Based on preemptive evaluation of the available clinical data, 412 patients (22.4%) were excluded from pre-LT evaluation and 1,425 (77.6%) were admitted to preliminary consultation. Among these, 603 (42.3%) were excluded from and 822 (57.7%) were admitted to pre-LT evaluation with a referral efficiency rate of 44.7% (822 of 1,837). Out of the patients evaluated for LT, 484 were waitlisted with a cost-utility and evaluation efficiency rate of 58.8% each (484 of 822). Of the 1,837 patients originally addressed for LT 484 were waitlisted, yielding a process efficiency rate of 26.3% (484 of 1,837) and a cost per waitlisted patient of 4,710.8. In conclusion, the 3 indicators allowed monitoring of the efficiency of the pre-LT evaluation algorithm. The current process efficiency rate at our center is low (26.3%), but avoiding early referrals we might increase it to 31.6%, with a 12% net saving on costs per waitlisted patient (from 4,710.8 to 4,165.4). 相似文献
3.
Jordi Ortiz Lawrence W. Fitzgerald Maura Charlton Sarah Lane Louis Trevisan Xavier Guitart William Shoemaker Ronald S. Duman Eric J. Nestler 《Synapse (New York, N.Y.)》1995,21(4):289-298
In previous studies, we have demonstrated that chronic administration of morphine or cocaine produces some common biochemical adaptations in the ventral tegmental area (VTA) and nucleus accumbens (NAc), components of the mesolimbic dopamine system implicated in the reinforcing actions of these and other drugs of abuse. Since this neural pathway is also implicated in the reinforcing actions of ethanol, it was of interest to determine whether chronic ethanol exposure results in similar biochemical adaptations. Indeed, as seen for chronic morphine and cocaine treatments, we show here that chronic ethanol treatment increased levels of tyrosine hydroxylase and glial fibrillary acidic protein immunoreactivity, and decreases levels of neurofilament protein immunoreactivity, in the VTA. Also like morphine and cocaine, ethanol increases levels of cyclic AMP-dependent protein kinase activity in the NAc. These actions of ethanol required long-term exposure to the drug, and were in most cases not seen in the substantia nigra or caudate-putamen, components of the nigrostriatal dopamine system studied for comparison. Altered levels of tyrosine hydroxylase in catecholaminergic cells frequently reflect altered states of activation of the cells. Moreover, increasing evidence indicates that ethanol produces many of its acute effects on the brain by regulating NMDA glutamate and GABA receptors. We therefore examined the influence of chronic ethanol treatment on levels of expression of specific glutamate and GABA receptor subunits in the VTA. It was found that long-term, but not short-term, ethanol exposure increased levels of immunoreactivity of the NMDARl subunit, an obligatory component of NMDA glutamate receptors, and of the Glu Rl subunit, a component of many AMPA glutamate receptors; but at the same time, long-term ethanol exposure decreased immunoreactivity levels of the α1 subunit of the GABAA receptor complex. These changes are consistent with an increased state of activation of VTA neurons inferred from the observed increase intyrosine hydroxylase (TH) expression. These results demonstrate that chronic ethanol exposure results in several biochemical adaptations in the mesolimbic dopamine system, which may underlie prominent changes in the structural and functional properties of this neural pathway related to alcohol abuse and alcoholism. © 1995 Wiley-Liss, Inc. 相似文献
4.
F. Carmassi M. Morale F. De Negri M. Carrai 《Journal of molecular medicine (Berlin, Germany)》1995,73(2):89-93
Patients with liver failure can present both thrombotic and hemorragic complications because of the deficiency in coagulation factors and inhibitors (protein C and S, antithrombin III) and impairment of fibrinolytic balance. Here we report the case of a 63-year-old man with liver cirrhosis, recurrent thrombosis, and features of low-grade consumption coagulopathy, showing severe antithrombin III deficiency (about 30% of normal values). Treatment with antithrombin III (2000 U/day) and low doses of heparin (5000 U b.i.d.) was successful in modulating the coagulation system toward an antithrombotic effect. After discharge from hospital the ambulatory treatment with antithrombin III concentrates (2000 U twice a week) allowed the attainment of antithrombin III activity of about 60% and prevented the patient from recurrence of venous thrombosis.Abbreviations
AT-III
Antithrombin III
-
DIC
Disseminated intravascular coagulation
-
TAT complexes
Thrombin-antithrombin III complexes
-
PAI-1
Plasminogen activator inhibitor-1 相似文献
5.
The activity of histidine-decarboxylase (HD) and histamine-N-methyl-transferase (HMT) was studied in the hypothalamus and cerebral cortex of rats from birth to adulthood. Development patterns were compared in sea-level controls and in rats born and maintained continuously in a natural hypoxic environment (at a high altitude of 3800 m, PO
2 13%) to determine whether chronic stress alters the development of the enzymes for histamine. When expressed in terms of total activity, both enzyme activities were low at birth and progressively increased with age in the two areas studied. When expressed in terms of specific activity, the developmental pattern of the enzymes better reflected that of histamine: for example, at birth, high HD activity and low HMT corresponded to high histamine levels; at 7 days, low HD activity and high HMT corresponded to low histamine levels. It is suggested that a feedback mechanism may operate between endogenous histamine levels and the activity of its synthesizing and catebolizing enzymes.Exposure to chronic stress failed to alter enzymatic activity during the first postnatal week, but significantly influenced it in later development and adulthood. In the hypothalamus stress induced HD activity in the developing animals but depressed it in the adults. In the cerebral cortex, HMT rather than HD was stimulated by stress, but here again the effects were age-dependent. The sensitivity of histaminergic enzymes to environmental stimulation provides indirect supportive evidence for neurotransmitter role of histamine. 相似文献
6.
7.
Stefano Thellung Alessandra Barzizza Guido Maura Maurizio Raiteri 《Naunyn-Schmiedeberg's archives of pharmacology》1993,348(4):347-351
Summary The glutamatergic mossy fibre granule cell pathway has been investigated in rat cerebellar slices. Exposure to 35 mM KCI, a concentration of K+ known to elicit Ca2+-dependent releases of excitatory amino acids from cerebellar slices, raised cGMP levels. The cGMP response was decreased in a concentration-dependent manner by D-(–)-2-amino-5-phosphonopentanoic acid (D-AP5) and by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) indicating the involvement of ionotropic glutamate receptors of both the N-methyl-D-aspartate (NMDA) and the non-NMDA type. The K+-evoked production of cGMP was potently inhibited (EC50 = 1.21 nM) by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a selective 5-HT2 receptor agonist. The effect of DOI (0.01 M) was antagonized by 0.03 M of the 5-HT2 receptor antagonists ketanserin and methiothepin. At concentrations higher than 0.1 M, both antagonists increased on their own the cGMP response elicited by high-K+. This effect was insensitive to tetrodotoxin.It had been previously shown that rat mossy fibre endings release glutamate upon depolarization and that such release can be inhibited by activation of 5-HT2 receptors sited on the mossy fibre endings. Altogether the available data suggest the following conclusions: (a) the glutamate/aspartate endogenously released in cerebellar slices during K+ depolarization increase cGMP synthesis through the activation of both NMDA and non-NMDA receptors; (b) a portion of the cGMP response can be prevented by 5-HT2 receptor activation and may reflect the activity of the mossy fibre-granule cell pathway. Thus serotonin is likely to exert a potent inhibitory control of the excitatory mossy fibre input to the cerebellum by acting at receptors of the 5-HT2 type.
Correspondence to M. Raiteri at the above address 相似文献
8.
Jinee Rizzo Alexandra M. Levine Geoff R. Weiss Tillman Pearce Maura Kraynak Robert Mueck Susan Smith Daniel D. Von Hoff John G. Kuhn 《Investigational new drugs》1996,14(2):227-234
Summary Mitoguazone is a unique chemotherapeutic agent whose activity is believed to result primarily from the competitive inhibition of S-adenosyl-methionine decarboxylase leading to a disruption in polyamine biosynthesis. Initial clinical trials demonstrated that the dose-limiting toxicities (mucositis and myelosuppression) of Mitoguazone were both dose and schedule dependent. Early pharmacokinetic studies of Mitoguazone in man revealed a prolonged half-life. Concurrent with a recent Phase II trial of Mitoguazone in patients with AIDS related non-Hodgkin's lymphoma, the single dose pharmacokinetics of Mitoguazone were characterized. Twelve patients received 600 mg/m2 of intravenous Mitoguazone over 30 minutes on an intermittent every 2 week schedule. Blood, urine, cerebrospinal fluid (CSF), pleural fluid and tissue samples were collected and analyzed by HPLC. Mitoguazone was cleared from the plasma triexponentially with a harmonic mean terminal half-life of 175 hours and a mean residence time of 192 hours. Peak plasma levels occurred immediately post-infusion, ranged from 6.47 to 42.8 g/ml, and remained (for an extended period) well above the reported concentration for inhibition of polyamine biosynthesis. Plasma clearance averaged 4.73 l/hr/m2 with a relatively large apparent volume of distribution at steady-state of 1012 l/m2 indicating tissue sequestration. Renal excretion of unchanged Mitoguazone accounted for an average of 15.8% of the dose within 48 to 72 hours post-administration. Detectable levels of drug were present in random voided samples eight days post-dose. Mitoguazone levels in CSF ranged from 22 to 186 ng/ml post-dose with CSF/plasma ratios ranging from 0.6% to 7%. The pleural fluid/plasma ratio was approximately 1. Tissue levels of Mitoguazone were highest in the liver followed by lymph node, spleen and the brain. 相似文献
9.
Silvana Chiara Maria Teresa Nobile Maura Vincenti Rita Lionetto Alberto Gozza Maria Cristina Barzacchi Ornella Sanguineti Lazzaro Repetto Riccardo Rosso 《Cancer chemotherapy and pharmacology》1998,42(4):336-340
To evaluate toxicity and efficacy of chemotherapy in elderly patients (≥65 years of age) with advanced colorectal cancer,
data from two consecutive trials conducted between 1984 and 1995 at the National Institute for Cancer Research were analysed
comparing the results of treatment in those 65 years of age or older and in those younger than 65 years. Of 215 patients recruited,
82 elderly patients (median age 70 years, median performance status 1) received one of the following regimens based on 5-fluorouracil
(5-FU): (1) weekly 5-FU 600 mg/m2 i.v. bolus (30 patients); (2) weekly 5-FU 600 mg/m2 bolus plus leucovorin (LV) 500 mg/m2 2-h i.v. infusion (28 patients); (3) Weekly 5-FU 2600 mg/m2 24-h continuous i.v. infusion plus LV 100 mg 4-h i.v. infusion and 50 mg orally every 4 h for five doses (24 patients). Overall,
1071 chemotherapy cycles were administered with a median number of 12 courses per patient. The main side effects were diarrhoea,
observed in 38% of patients, stomatitis in 24% of patients and hand-foot syndrome in 13% of patients, and haematological toxicity
affected only 15% of patients. No patient suffered grade IV toxicity. In three patients chemotherapy was discontinued because
of toxicity (two patients suffered grade III diarrhoea, one patient grade III hand-foot syndrome). No significant difference
in toxicity was evident between patients older than or younger than 65 years. Analysis of median dose intensity demonstrated
no difference between the two groups. Overall objective response was observed in 18% (95% confidence limits 11–29) of elderly
patients (15/82) in comparison with 23% (95% CL 17–32) of patients <65 years of age (31/133 pts). In conclusion, chemotherapy
in elderly patients with advanced colorectal cancer is a safe and effective treatment with acceptable toxicity and comparable
objective response rates.
Received: 6 January 1998 / Accepted: 27 February 1998 相似文献
10.
Luigi Quintieri Cristina Geroni Marianna Fantin Rosangela Battaglia Antonio Rosato William Speed Paola Zanovello Maura Floreani 《Clinical cancer research》2005,11(4):1608-1617
PURPOSE: Nemorubicin (3'-deamino-3'-[2'(S)-methoxy-4'-morpholinyl]doxorubicin; MMDX) is an investigational drug currently in phase II/III clinical testing in hepatocellular carcinoma. A bioactivation product of MMDX, 3'-deamino-3',4'-anhydro-[2'(S)-methoxy-3'(R)-oxy-4'-morpholinyl]doxorubicin (PNU-159682), has been recently identified in an incubate of the drug with NADPH-supplemented rat liver microsomes. The aims of this study were to obtain information about MMDX biotransformation to PNU-159682 in humans, and to explore the antitumor activity of PNU-159682. EXPERIMENTAL DESIGN: Human liver microsomes (HLM) and microsomes from genetically engineered cell lines expressing individual human cytochrome P450s (CYP) were used to study MMDX biotransformation. We also examined the cytotoxicity and antitumor activity of PNU-159682 using a panel of in vitro-cultured human tumor cell lines and tumor-bearing mice, respectively. RESULTS: HLMs converted MMDX to a major metabolite, whose retention time in liquid chromatography and ion fragmentation in tandem mass spectrometry were identical to those of synthetic PNU-159682. In a bank of HLMs from 10 donors, rates of PNU-159682 formation correlated significantly with three distinct CYP3A-mediated activities. Troleandomycin and ketoconazole, both inhibitors of CYP3A, markedly reduced PNU-159682 formation by HLMs; the reaction was also concentration-dependently inhibited by a monoclonal antibody to CYP3A4/5. Of the 10 cDNA-expressed CYPs examined, only CYP3A4 formed PNU-159682. In addition, PNU-159682 was remarkably more cytotoxic than MMDX and doxorubicin in vitro, and was effective in the two in vivo tumor models tested, i.e., disseminated murine L1210 leukemia and MX-1 human mammary carcinoma xenografts. CONCLUSIONS: CYP3A4, the major CYP in human liver, converts MMDX to a more cytotoxic metabolite, PNU-159682, which retains antitumor activity in vivo. 相似文献