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1.
G. Toffoli I. Robieux D. Fantin M. Gigante S. Frustaci G. L. Nicolosi M. De Cicco & M. Boiocchi 《British journal of clinical pharmacology》1997,44(3):255-260
Aims In an attempt to reverse multidrug resistance, in a recent trial of verapamil in association with doxorubicin, we used escalating doses of continuous intravenous (i.v.) verapamil under close haemodynamic monitoring. We report the pharmacokinetics of escalating doses of verapamil.
Methods We studied nine patients [
seven males, two females; median age 46 years (range, 31–57)] with advanced adenocarcinoma of the colon and normal renal, hepatic, and cardiac functions. After a loading dose (0.15 mg kg−1 followed by 12 h continuous i.v. infusion at 0.20 mg kg−1 h−1 ), the infusion rate (ko) of verapamil was increased every 24 h (0.25, 0.30, 0.35, and 0.40 mg kg−1 h−1 ). The highest rate was maintained for 48 h. Doxorubicin was given as a continuous i.v. infusion from 12 to 108 h (n=4) or 60 to 108 h (n=5). Blood samples and urine collections were taken every 12 h. Verapamil and nor-verapamil were assayed by high performance liquid chromatography. We calculated systemic clearance of verapamil (CL=ko/Css ) and renal clearance (CLr) of verapamil and nor-verapamil. The Cssvs rate relationship was fitted to a Michaelis-Menten equation: Css=ko(Km+Css )/(V Vm ).
Results CL was dose-dependent and in all nine patients a significant reduction in CL was observed over the dose range (mean CL±s.d. were 0.51±0.31, 0.38±0.16, 0.32±0.18, and 0.27±0.11 l h−1 kg−1, respectively, at 0.25, 0.30, 0.35, and 0.40 mg kg−1 h−1; P=0.0001). Css increased more than proportionally to the dose rate and the Cssvs rate relationship was best defined by a Michaelis-Menten equation (Km=730 μg l−1; V Vm=0.55 mg kg−1 h−1 ), (r=0.994; P=0.006). CLr of verapamil and nor-verapamil was not saturable but the contribution to the elimination was only 2 to 4% of the dose.
Conclusions These findings suggest a non-linear, capacity-limited metabolic clearance of high-dose verapamil. Using escalating infusion rates, high verapamil concentrations (1500–2500 ng ml−1 ) were achieved without major toxicity. Saturable clearance may cause higher bioavailability and slower elimination of verapamil after acute oral overdoses. 相似文献
2.
I?Satish?RaoEmail author Anand?C?Loya KS?Ratnakar VR?Srinivasan 《BMC clinical pathology》2005,5(1):11
Background
Lymph node infarction is known to occur in association with many non-neoplastic and neoplastic conditions however its occurrence in association with DIC is not reported hitherto in the literature. 相似文献3.
Andrea P. Rossi Cesare Caliari Silvia Urbani Francesco Fantin Piero Brandimarte Angela Martini Elena Zoico Giulia Zoso Alessio Babbanini Alfredo Zanotelli Mauro Zamboni 《Nutrients》2021,13(2)
Background: SARC-F and Mini Sarcopenia Risk Assessment (MSRA) questionnaires have been proposed as screening tools to identify patients at risk of sarcopenia. The aim of this study is to test the use of SARC-F and MSRA, alone and combined, as a pre-screening tool for sarcopenia in geriatric inpatients. Methods: 152 subjects, 94 men and 58 women, aged 70 to 94, underwent muscle mass evaluation by dual energy X-ray absorptiometry (DXA), muscle strength evaluation by handgrip, and completed the MSRA, SARC-F and Activity of daily living (ADL) questionnaires. Results: 66 subjects (43.4%) were classified as sarcopenic according to the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) criteria. The 7-item SARC-F and MRSA and 5-item MSRA showed an area under the curve (AUC) of 0.666 (95% confidence interval (CI): 0.542–0.789), 0.730 (95% CI: 0.617–0.842) and 0.710 (95% CI: 0.593–0.827), respectively. The optimal cut-off points for sarcopenia detection were determined for each questionnaire using the Youden index method. The newly calculated cut-off points were ≤25 and ≤40 for MSRA 7- and 5-items, respectively. The ideal cut-off for the SARC-F was a score ≥3. Applying this new cut-off in our study population, sensitivity and specificity of the 7-item MSRA were 0.757 and 0.651, and 0.688 and 0.679 for the 5-item MSRA, respectively. Sensitivity and specificity of SARC-F were 0.524 and 0.765, respectively. The combined use of the 7-item SARC-F and MSRA improved the accuracy in sarcopenia diagnosis, with a specificity and sensitivity of 1.00 and 0.636. Conclusion: 7-item SARC-F and MSRA may be co-administered in hospital wards as an easy, feasible, first-line tool to identify sarcopenic subjects. 相似文献
4.
Animal models of infection should be considered as tools that may be used for many different purposes: investigation of the physiopathology and natural history of infection on one hand, evaluation of the toxicity, pharmacokinetics and activity of antimicrobials on the other hand. Many review articles on the use of animal models of infection for the evaluation of antimicrobial agents have been published (Zak O, O'Reilly T. Animal models in the evaluation of antimicrobial agents. Minireview. Antimicrob Agents Chemother 1991;35:1527-1531), including a recent comprehensive review (O'Reilly T, Cleeland R, Squires E. Evaluation of antimicrobial s in experimental animal infections. In: Lorian V, editor. Antibiotics in Laboratory Medicine, 4th ed. Williams and Wilkins, Baltimore, 1996: 599-759). Therefore, this article will only focus on the contribution of the animal models of infection in: (i) the evaluation of the in vivo activity of antimicrobial agents, using a pharmacodynamic approach. For this purpose, animal models are used to quantify the in vivo bacterial killing and to investigate the different factors influencing the final in vivo activity. (ii) The investigation of the non response to antimicrobial agents in vivo. In this case, animal models are used to investigate the factors limiting the in vivo activity of antimicrobial agents. 相似文献
5.
Marastoni M Guerrini R Balboni G Salvadori S Fantin G Fogagnolo M Lazarus LH Tomatis R 《Arzneimittel-Forschung》1999,49(1):6-12
The solid phase synthesis, based on the Fmoc chemical protocol, was used to prepare ten deltorphin C (Del-C; H-Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2) analogues containing cis- and trans- 2 or 3- or 4- aminocyclohexanecarboxylic acid (ACCA) residues at position 2. ACCA-peptides showed high resistance to degradation by plasma or brain enzymes, negligible affinity for the kappa-binding site and modest delta- and/or mu-receptor affinities. Both [cis-3-ACCA2]Del-C analogues and one trans isomer are the only deltorphin analogues of this series exhibiting an appreciable delta-affinity and selectivity. These data suggest that the presence of a conformationally constrained ACCA residue in position 2 of the "message" sequence of deltorphin C is slightly tolerated. 相似文献
6.
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
7.
J. Delforge S. Sovaila L. Alix A. Didon O. Steichen B. Ranque A. Froissart K. Amadou T. Hanslik B. Cador J.F. Bergmann A. Mekininan C. Goujard S. Gayet P. Cathebras B. Fantin D. Raigniac J.C. Weber A. Bourgarit 《La Revue de médecine interne / fondée ... par la Société nationale francaise de médecine interne》2021,42(2):79-85
IntroductionPatients admitted from emergency units represent a large portion of the population in internal medicine departments. The aim of this study is to identify characteristics of patients and organization of these departments.MethodsBetween June 29th and July 26th 2015, voluntary internal medicine departments from the SiFMI group prospectively filled anonymized internet forms to collect data of each patients admitted in their ward from emergency units, during seven consecutive days.ResultsThree hundred and sixty-five patients from emergency departments were admitted in 18 internal medicine inpatients departments, totalling 1100 beds and 33,530 annual stays, 56% of them for emergency units inpatients. Mean age was 68 years, 54% were women, mean Charlson score was 2.6 and 44% of the patients took at least three drugs. Main causes of hospitalization were infectious (29%) and neurological (17%) diseases. Mean length of stay was 9.2 days. The medical team was composed by a median value of 4,5 [2,75–6,25] senior full-time equivalents, 86% were internists. Each department except one received residents, two third of them were from general medicine.ConclusionThis study highlights a high organizational variability among internal medicine departments and patients, and sets internal medicine as a specialty with a great capacity to achieve an integrative/comprehensive management of patients and to offer a comprehensive basis for physicians in training. 相似文献
8.
Zamboni M Zoico E Fantin F Panourgia MP Di Francesco V Tosoni P Solerte B Vettor R Bosello O 《The journals of gerontology. Series A, Biological sciences and medical sciences》2004,59(4):396-400
BACKGROUND: Leptin has been shown to be linked to adiposity and insulin resistance in middle-aged participants. However, the association between leptin and metabolic syndrome independently of body fat and body fat distribution has not been evaluated in healthy elderly people. METHODS: We studied the independent relation between leptin and the components of the metabolic syndrome in 107 women aged 67-78 years with body mass index (BMI) ranging from 18.19 to 36.16 kg/m2. In all participants, we evaluated BMI, waist and hip circumferences, body composition by dual energy X-ray absorptiometry, fasting, and 2-hour glucose, lipids, insulin, homeostasis model assessment of insulin resistance (HOMA), systolic (SBP), diastolic blood pressure (DBP), and leptin. RESULTS: Significant correlation was found between leptin, BMI, waist circumference, fat mass, DBP, SBP, cholesterol, triglycerides, insulin, and HOMA. After adjusting for age and waist circumference, as well for age and fat mass, leptin was significantly related to insulin levels, HOMA, and cholesterol. In a stepwise multiple regression analysis using insulin levels or HOMA as dependent variables and age, waist circumference, fat mass, leptin, SBP, DBP, cholesterol, and triglycerides as independent variables, leptin entered the regression first, waist circumference second, and age third. CONCLUSION: Our study shows that leptin is significantly related to indices of adiposity in elderly women, and leptin is significantly associated with insulin levels, HOMA, and cholesterol independent of age, body fat, and fat distribution. Leptin, waist circumference, and age together explained 31% and 33% of insulin levels and HOMA variance, respectively, in healthy elderly women. 相似文献
9.
Lower sperm quality and testicular and epididymal structural impairment in adult rats exposed to rosuvastatin during prepuberty
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Gabriel Adan Araújo Leite Marciana Sanabria Marilia Martins Cavariani Janete Aparecida Anselmo‐Franci Patrícia Fernanda Felipe Pinheiro Raquel Fantin Domeniconi Wilma De Grava Kempinas 《Journal of applied toxicology : JAT》2018,38(6):914-929
The increase of obesity, bad eating habits and the lack of physical exercises are highly related to dyslipidemias. Rosuvastatin is a lipid‐lowering drug and has been indicated to prevent cardiovascular diseases and to treat dyslipidemias due to its higher efficiency to reduce serum cholesterol concentrations. This study aimed to evaluate the reproductive adverse effects on sexual maturity due to rosuvastatin exposure in juvenile male rats during prepuberty. Three groups were randomly formed with newly weaned rats: control, whose rats received saline solution 0.9% and rosuvastatin at doses of 3 or 10 mg kg–1 day–1, administered orally by gavage, from postnatal day 21 until preputial separation (average of 45 days for controls and 49 days for statin‐treated animals), indicative of puberty onset. Male rats were maintained until sexual maturity and were killed on postnatal day 110. In the rosuvastatin‐treated groups, the results showed diminished follicle‐stimulating hormone, luteinizing hormone and testosterone concentrations, increased estradiol and prolactin concentrations, histopathologic alterations on testis and epididymis and decreased sperm quality. Moreover, statin‐exposed groups showed decreased expression of androgen receptor on testis and epididymis and lower expression of aquaporin‐9 on epididymal epithelium. In conclusion, administration of rosuvastatin to prepubertal male rats provoked long‐term hormonal deregulation and impaired reproduction at adulthood. 相似文献
10.
P.O. Fernagut W.G. Meissner M. Biran M. Fantin F. Bassil J.M. Franconi F. Tison 《Synapse (New York, N.Y.)》2014,68(3):98-106
Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by a progressive degeneration of the striatonigral, olivo‐ponto‐cerebellar, and autonomic systems. Glial cytoplasmic inclusions (GCIs) containing alpha‐synuclein represent the hallmark of MSA and are recapitulated in mice expressing alpha‐synuclein in oligodendrocytes. To assess if oligodendroglial expression of human wild‐type alpha‐synuclein in mice (proteolipid promoter, PLP‐SYN) could be associated with age‐related deficits, PLP‐SYN and wild‐type mice were assessed for motor function, brain morphometry, striatal levels of dopamine and metabolites, dopaminergic loss, and distribution of GCIs. PLP‐SYN displayed age‐related impairments on a beam‐traversing task. MRI revealed a significantly smaller brain volume in PLP‐SYN mice at 12 months, which further decreased at 18 months together with increased volume of ventricles and cortical atrophy. The distribution of GCIs was reminiscent of MSA with a high burden in the basal ganglia. Mild dopaminergic cell loss was associated with decreased dopamine turnover at 18 months. These data indicate that PLP‐SYN mice may recapitulate some of the progressive features of MSA and deliver endpoints for the evaluation of therapeutic strategies. Synapse 68:98–106, 2014. © 2013 Wiley Periodicals, Inc. 相似文献