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Biomedical subjects

P Lefebvre

Publications and source records attributed to P Lefebvre.

At least 19 recordsLinked to original sources
PubMed2003

A randomized study over 13 cycles to assess the influence of oral contraceptives containing ethinylestradiol combined with drospirenone or desogestrel on carbohydrate metabolism.

In this open-label, randomized study we compared the influence of a new oral contraceptive containing 30 microg ethinylestradiol and 3 mg drospirenone (Yasmin) with a reference preparation containing 30 microg ethinylestradiol and 150 microg desogestrel (Marvelon) on variables of carbohydrate metabolism by means of oral glucose tolerance tests at baseline and in the 6th and 13th treatment cycle. The mean levels of fasting glucose and insulin were similar at baseline and after 13 treatment cycles, whereas C-peptide and free fatty acid levels decreased slightly in both groups. All blood glucose and insulin values measured in the oral glucose tolerance tests were within normal ranges, despite a slight increase in the mean areas under the curves of 0-3 h [AUCs (0-3 h)] of both variables from baseline to treatment cycle 13. Differences between both treatments were not statistically significant. The mean AUCs (0-3 h) for C-peptide were not markedly changed in any treatment group. Free fatty acid levels decreased by 42% in the drospirenone group and increased by 48.9% in the desogestrel group, in terms of means of individual changes. Both preparations were well tolerated and equally efficacious regarding contraception and cycle control. The mean body weight was slightly decreased in most cycles during treatment with the drospirenone combination, as compared to baseline, while it was slightly increased versus baseline in all cycles during treatment with the desogestrel combination. The combination with drospirenone had less impact on blood pressure than the combination with desogestrel. In conclusion, Yasmin, a combined low-dose oral contraceptive with 30 microg ethinylestradiol and 3 mg of the novel progestogen drospirenone, as well as the reference Marvelon, containing 30 microg ethinylestradiol and 150 microg desogestrel had little impact on carbohydrate metabolism when used for 1 year. The observed changes were small and not suggestive of a clinically relevant deterioration of carbohydrate metabolism.

Adolescent↗
PubMed2003

[Recent progress in the "fibrinogen hypothesis"].

Several clinical and epidemiological studies have demonstrated that a high level of plasma fibrinogen is an independent risk factor for coronary, cerebral and peripheral artery disease. The role of fibrinogen in cardiovascular diseases is mainly due to thrombotic complications in advanced stages of the atherothrombotic disease. However, fibrinogen also plays an active role in the initiation and development of atheromatous plaques. The relations between fibrinogen and ischemic cardiopathies, other vasculopathies and diabetes mellitus are discussed. The controversial effects of statins on fibrinogen are also described.

Biomarkers↗
PubMed2002

High-dose, single-agent irinotecan as first-line therapy in the treatment of metastatic colorectal cancer.

PURPOSE: The efficacy and safety of single-agent, high-dose irinotecan (CPT-11, Campto) 500 mg/m(2) every 3 weeks were investigated as first-line treatment for advanced colorectal cancer (CRC). PATIENTS AND METHODS: Patients were enrolled into the study to receive a first cycle of therapy with irinotecan at a dose of 350 mg/m(2) every 3 weeks, which could be escalated to 500 mg/m(2) for the second and subsequent cycles depending on toxicity. Efficacy, safety and pharmacokinetics were determined in the intent to treat (ITT) population and the high-dose population (i.e. patients who had received at least three cycles of irinotecan, the second and third at 500 mg/m(2)). RESULTS: Of 49 patients enrolled into the study (ITT population), 31 (63%) received at least three cycles of treatment with cycles 2 and 3 at an irinotecan dose of 500 mg/m(2) (the high-dose population). The response rates (RR) for the ITT and high-dose populations were 24.5% and 35.5%, respectively. The main grade 3/4 toxicities per cycle in the ITT and high-dose populations were neutropenia 22% and 17%, febrile neutropenia 5% and 3%, and diarrhoea 12% and 7%, respectively. The pharmacokinetics of irinotecan and its metabolite SN-38 were investigated in 31 patients in cycle 1 and 22 patients in cycle 2. Irinotecan clearance and SN-38 exposure were not sufficiently correlated with toxicity in cycle 1 to identify patients for dose increase in subsequent cycles. The exposure to irinotecan and SN-38 increased in proportion to dose from 350 to 500 mg/m(2). CONCLUSION: These results suggest that high-dose irinotecan can be safely administered as first-line monotherapy to approximately two-thirds of patients who present with advanced CRC following a selective first cycle.

Adenocarcinoma↗
PubMed2002

Randomized controlled study of the influence of two low estrogen dose oral contraceptives containing gestodene or desogestrel on carbohydrate metabolism.

This study compared the impact on carbohydrate metabolism of two combinedoral contraceptives (COCs). This open-label, single-center trial enrolled participants for a total of 15 cycles. Thirty-six women were randomized to receive either 20 microg ethinyl estradiol (EE) and 75 microg gestodene (GSD) or 20 microg ethinyl estradiol and 150 microg desogestrel (DSG) daily for 21 days out of 28. A glucose tolerance test was performed at baseline and cycles 6 and 13. The area under the curve (AUC) for glucose increased in both study groups. The change was statistically significant (p = 0.036) for the 20 EE/75 GSD group at cycle 6 versus baseline. Fasting blood glucose at cycle 13 was significantly (p < 0.01) higher for both treatment groups compared to baseline. No changes were found for fasting insulin and fasting C-peptide levels or for the AUCs of insulin or C-peptide. Both regimens were well tolerated. Gestodene and desogestrel in combination with 20-microg ethinyl estradiol induce similar changes in carbohydrate metabolism which are smaller than those described earlier for COCs containing higher estrogen doses or more androgenic progestins such as levonorgestrel.

Adult↗
PubMed2002

[Diabetes yesterday, today and tomorrow. Work of the International Federation of Diabetes].

Diabetes mellitus is a frequent disorder affecting individuals of all ages. In children, adolescents and young adults, but also sometimes in older people, Type 1 diabetes is the consequence of insulin deficiency, resulting from an autoimmune process destroying the insulin producing cells in the pancreatic islets of Langerhans. In the adults and older persons (but sometimes also in young individuals), Type 2 diabetes (non-insulin dependent diabetes) occurs in genetically predisposed individuals and is favoured by weight excess and sedentarity. This form of diabetes is undiagnosed in about 50% of those affected. This concise review surveys the history of diabetes, the current situation and the expected changes in terms of epidemiology, prevention and treatment. The role of the International Diabetes Federation (IDF) whose headquarters are located in Brussels, is briefly described, particularly in the scope of its fight against a disease currently affecting 180 millions people worldwide, a figure likely to reach 325 millions at the 2025 horizon.

Diabetes Mellitus↗
PubMed2001

Control of retinoic acid receptor heterodimerization by ligand-induced structural transitions. A novel mechanism of action for retinoid antagonists.

Heterodimerization of retinoic acid receptors (RARs) with 9-cis-retinoic receptors (RXRs) is a prerequisite for binding of RXR.RAR dimers to DNA and for retinoic acid-induced gene regulation. Whether retinoids control RXR/RAR solution interaction remains a debated question, and we have used in vitro and in vivo protein interaction assays to investigate the role of ligand in modulating RXR/RAR interaction in the absence of DNA. Two-hybrid assay in mammalian cells demonstrated that only RAR agonists were able to increase significantly RAR interaction with RXR, whereas RAR antagonists inhibited RXR binding to RAR. Quantitative glutathione S-transferase pull-down assays established that there was a strict correlation between agonist binding affinity for the RAR monomer and the affinity of RXR for liganded RAR, but RAR antagonists were inactive in inducing RXR recruitment to RAR in vitro. Alteration of coactivator- or corepressor-binding interfaces of RXR or RAR did not alter ligand-enhanced dimerization. In contrast, preventing the formation of a stable holoreceptor structure upon agonist binding strongly altered RXR.RAR dimerization. Finally, we observed that RAR interaction with RXR silenced RXR ligand-dependent activation function. We propose that ligand-controlled dimerization of RAR with RXR is an important step in the RXR.RAR activation process. This interaction is dependent upon adequate remodeling of the AF-2 structure and amenable to pharmacological inhibition by structurally modified retinoids.

Dimerization↗
PubMed2001

Phase I and pharmacokinetic study of two sequences of gemcitabine and docetaxel administered weekly to patients with advanced cancer.

PURPOSE: To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and effect of drug sequence on toxicities and pharmacokinetics of the combination of gemcitabine and docetaxel. METHODS: A total of 34 patients with advanced cancers were treated with gemcitabine and docetaxel on days 1 and 8 of each 21-day cycle according to the following dose escalation schedule: level 1, 800 and 30 mg/m2, respectively; level 2, 800 and 40 mg/m2; level 3, 1,000 and 40 mg/m2; and level 4, 1,250 and 40 mg/m2. At each dose level, at least three patients were assigned to one of the two sequences of drug administration: gemcitabine-->docetaxel or docetaxel-->gemcitabine. Once the MTD had been reached, six additional patients, who had received no more than one chemotherapy regimen, were enrolled to dose levels 3 and 4 (gemcitabine-->docetaxel) to determine the MTD in minimally pretreated patients. RESULTS: Neutropenia was the most frequent DLT with an overall incidence of 23.5%. Grade 3/4 neutropenia occurred in 62% of patients (8/13) who had received two or more prior chemotherapy regimens, but not at all (0/15) in patients who had received no more than one prior chemotherapy regimens (P< 0.001). Additional DLTs included grade 4 diarrhea and grade 4 stomatitis in one patient each. The MTD was determined to be gemcitabine 800 mg/m2 and docetaxel 40 mg/m2 in patients who had received two or more prior chemotherapy regimens. However, minimally pretreated patients (no more than one prior chemotherapy regimen) were able to tolerate higher doses with an MTD of gemcitabine 1,250 mg/m2 and docetaxel 40 mg/m2. There were no significant differences in toxicities or pharmacokinetics between the two sequences of administration. Partial and minor responses were observed in 23.5% of patients: non-small-cell lung (two of eight), gastric (two of three), head and neck (one of two), bladder (two of four) and hepatocellular cancer (one of one). CONCLUSIONS: The combination of gemcitabine and docetaxel administered on days 1 and 8 every 21 days was feasible and well tolerated in patients with advanced malignancies. The sequence of administration had no significant effect on the toxicity or pharmacokinetics of either drug. Minimally pretreated patients tolerated higher doses of this combination without significant toxicities. This schedule and combination demonstrated activity in a variety of solid tumors, and merits further evaluation.

Adult↗
PubMed2001

Murine prolactin-like protein E synergizes with human thrombopoietin to stimulate expansion of human megakaryocytes and their precursors.

The aim of this study was to determine the effect of promegakaryocytopoietic murine hormone prolactin-like protein E (PLP-E) on human megakaryocytopoiesis. Human bone marrow CD34+ cells, cultured in serum-free medium with combinations of thrombopoietin (TPO), stem cell factor (SCF), Flt-3 ligand (Flt-3L), and PLP-E, were analyzed via microscopy, flow cytometry, and clonogenic assay. Unlike the situation with mouse cells, PLP-E alone did not promote human megakaryocyte (MK) differentiation, but instead synergizes with TPO to increase colony-forming unit megakaryocyte (CFU-MK), burst-forming unit erythroid (BFU-E), and and colony-forming unit granulocyte erythroid macrophage mixed (CFU-GEMM) expansion, as well as total MK production. These effects can be attributed to an increase in colony frequency, combined with a significantly greater total cell expansion induced by adding PLP-E along with TPO. The number of cells in each CFU-MK colony is an indication of the maturity of the progenitor population, with larger colonies deriving from a more immature progenitor cell. PLP-E significantly expanded immature, intermediate, and mature CFU-MK subsets at 3 days of culture, as well as the intermediate and mature subsets at day 6. PLP-E combined with TPO induced significant expansion of all CFU-MK subsets at all time points. PLP-E further increased the effect of SCF and Flt-3L on TPO-induced total cell and CFU-MK expansion.PLP-E may act as a survival factor for primitive human megakaryocytic and erythroid progenitors. It appears to preserve the highly proliferative immature fraction of the progenitor compartment but by itself does not promote total cell proliferation or human MK production. PLP-E may prove useful in combination with TPO and other cytokines for ex vivo expansion of hematopoietic progenitors to be used in a clinical setting.

Animals↗
PubMed2001

Direct evidence to support the role of antigen-specific CD8(+) T cells in melanoma-associated vitiligo.

Vitiligo is a cutaneous pigmentary disorder characterized by the loss of melanocytes. An autoimmune mechanism is strongly suspected to be involved in this affection given that it is frequently associated with autoimmune hormonal disorders, and because antibodies directed against melanocytic antigens are found in the serum of patients with vitiligo. We examined the role of cellular immunity in melanoma-associated vitiligo by expanding infiltrating lymphocytes from fresh biopsy specimens of vitiligo patches in melanoma patients. The vitiligo-infiltrating lymphocytes were almost exclusively T lymphocytes, and most were CD8(+). Following in vitro expansion, vitiligo-infiltrating lymphocytes remained predominantly CD8(+) and expressed the cutaneous homing receptor CLA. Furthermore, vitiligo-infiltrating lymphocytes had a clonal or oligoclonal T cell receptor profile, possibly reflecting specific antigenic stimulation. Finally, vitiligo- infiltrating lymphocytes specifically recognized differentiation antigens shared by normal melanocytes and melanoma cells. This direct demonstration of CD8(+) T cell involvement in vitiligo suggests that, in melanoma patients, vitiligo may be a visible effect of a spontaneous antitumoral immune response.

Adult↗
PubMed2001

Interleukin-2 inhibits glucocorticoid receptor transcriptional activity through a mechanism involving STAT5 (signal transducer and activator of transcription 5) but not AP-1.

Cytokines and glucocorticoids (GCs) signaling pathways interfere with each other in the regulation of apoptosis and gene expression in the immune system. Interleukin-2 (IL-2), through the Janus kinase/signal transducers and activators of transcription (Jak/STAT) and mitogen-activated protein kinase (MAPK) pathways, activates STAT5 and activated protein-1 (AP-1) transcription factors, respectively, which are known to repress glucocorticoid receptor (GR) activity, at least in part, through protein-protein interactions. In this work, we have analyzed the mechanisms whereby IL-2 down-regulates the GC-induced transactivation of the mouse mammary tumor virus long terminal repeat (MMTV-LTR) in murine CTLL-2 T lymphocytes. Mutagenesis studies revealed that the MMTV-LTR STAT5 binding site (-923/-914) was not required for IL-2-mediated inhibition but identified both glucocorticoid response elements (GREs) and the -104/+1 region as critical elements for this negative response. The DNA binding activities of transcription factors required for GC-mediated activation of the MMTV-LTR promoter and that bind to the -104/+1 region (nuclear factor-1, Oct-1) were not affected by IL-2 treatment. Overexpression of wild-type STAT5B enhanced the effect of IL-2 on MMTV-LTR activity, and a dominant negative form of STAT5B (Y699F) abolished the IL-2-mediated MMTV-LTR inhibition, whereas AP-1 activation had no effect in this system. Direct interaction between liganded GR and STAT5 was observed in CTLL-2 cells in a STAT5 phosphorylation-independent manner. Overexpression of nuclear coactivators CBP (CREB-binding protein) or SRC-1a (steroid receptor coactivator 1a) did not blunt IL-2 inhibitory effects. We suggest that the STAT5-repressive activity on the GC-dependent transcription may involve direct interaction of STAT5 with GR, is dependent on the promoter context and STAT5 activation level, and occurs independently of coactivators levels in T cells.

Animals↗
PubMed2001

[Isolated pulmonary valve endocarditis: a case report].

The authors report the very rare case of isolated pulmonary valve endocarditis in the absence of classical predisposing factors and discuss the therapeutic approach. In the absence of large series, a maximum of information is developed from this new case, especially with respect to its unusual context.

Aged↗
PubMed2001

[Insulin sensitivity and polycystic ovarian syndrome].

Insulinresistance, commonly associated with polycystic ovarian syndrome (PCOS), raises many unresolved debates about its prevalence, mechanism and true pathological role. Low insulin sensibility may have multiple origins among them genetic molecular defects in pathways of cellular insulin effects. A weight gain and android distribution of fat mass may reveal or increase insulin resistance and hyperinsulinemia. The preexisting unbalanced ovarian steroidogenesis secondary to abnormalities in gene coding for enzymes of P450C17 alpha might be the necessary support facilitating the stimulatory effect of hyperinsulinemia or other factors (LH, IGF1) on ovarian androgens. In practice, the phycisian has to know how to evaluate and to treat insulin resistance in view of its implication in dysovulation and, later on, metabolic and cardiovascular risks. Nutritional education and regular physical exercice are the necessary approaches. The efficacy and indications of metformin and thiazolidinediones have to be further evaluated.

Adipose Tissue↗
PubMed2001

[Which contraception to choose for the diabetic woman?].

Low-dose oral contraceptives can be used by a great number of women with IDDM or a previous gestational diabetes mellitus. Others hormonal contraceptives (progestogen-only preparations) are less convenient and the compliance is poor with an increasing risk of gynaecologic side effects. The safety of this contraceptives as regards vascular diabetic complications is not evaluated well. Nulliparous patients with progressive complications can use barrier methods of contraception after education. Macroprogestative contraception is a adequate choice for women within forties. For multiparous diabetic women, intra-uterine devices represent the first choice.

Contraceptives, Oral↗
PubMed2001

Molecular basis for designing selective modulators of retinoic acid receptor transcriptional activities.

Retinoic acid receptors are ligand-regulated transcription factors belonging to the nuclear receptor superfamily, which comprises 49 members in the human genome. all-trans retinoic acid and 9-cis retinoic acid receptors (RARs and RXRs) are each encoded by three distinct genes and several isoforms arise from alternative splicing and the use of different promoters. While RXRs are promiscuous dimerization partners of several other nuclear receptors, RARs are active, in-vivo, when associated to RXRs. Retinoids are therefore regulators of multiple physiological processes, from embryogenesis to metabolism. Different combinations of RXR:RAR heterodimers occur as a function of their tissue-specific expression and their activity is mostly conditioned by the activation status of RAR. These heterodimers are defined as non permissive heterodimers, in opposition to permissive dimers whose transcriptional activity may be modulated through RXR and its dimerization partner. The transcriptional activity of these dimers also relies on their ability to recruit nuclear coactivators and corepressors, which function as multi proteic complexes harboring several enzymatic activities (acetylases, kinases). The structure of the ligand bound to the RAR moiety of the dimer, as well as the nature of the DNA sequence to which dimers are bound, dictate the relative affinity of dimers for coactivators and thus its overall transcriptional activity. RARs are also able to repress the activity of unrelated transcription factors such as AP1 and NF-kappa-B, and therefore have potent anti proliferative and anti inflammatory properties. This review summarizes our current view of molecular mechanisms governing these various activities and emphasizes the need for a detailed understanding of how retinoids may dictate transactivating and transrepressive properties of RARs and RXRs, which may be considered as highly valuable therapeutic targets in many diseases such as cancer, skin hyperproliferation and metabolical disorders (diabetes, atherosclerosis etc).

Animals↗
PubMed2000

Partial restoration of all trans retinoic acid (ATRA) sensitivity by compactin in ATRA-resistant leukemic cells (ATRA-R HL-60).

The resistance to all trans retinoic acid (ATRA) differentiating treatment is a consequence, in most of the cases, of either increased catabolism or down regulation of ATRA uptake. Recently, we have shown that ATRA efficiency to differentiate HL-60 cells was enhanced about 30 times after its incorporation into Low Density Lipoprotein (ATRA-LDL). Here, we attempted to differentiate the ATRA-resistant HL-60 cells by ATRA-LDL at high concentrations up to 10 microM. No significant differentiating effect was observed, although the LDL receptor sites were evidenced in these cells. To increase the number of LDL receptors, the cells were pre-incubated in lipoprotein-deprived serum medium and compactin (2 microM), both ATRA and ATRA-LDL induced gradual increase of cell differentiation (35%+/-1 and 51.5%+/-5 at 10 microM of ATRA and ATRA-LDL respectively). At 2 and 8 microM, the intracellular concentrations of ATRA were respectively three and four times higher when incorporated into LDL. In addition, ATRA-LDL, in the medium, was better protected against degradation than ATRA. The surprising restoration of free ATRA sensitivity after treatment with compactin suggested the implication of new mechanisms unrelated to the LDL-receptor endocytosis but involving the non-sterol pathway.

Antineoplastic Agents↗
PubMed2000

Ex vivo expansion of early and late megakaryocyte progenitors.

Our goal is to produce ex vivo-expanded human megakaryocytes (MK) cells from peripheral blood progenitor cell (PBPC) harvests for use in supplementing conventional autografts. In this paper we show the megakaryocytopoietic productivity of small-scale in vitro serum-free cultures of human CD34+ cells containing MK growth and development factor (MGDF) and stem cell factor (Kit ligand; SCF) +/- granulocyte colony-stimulating factor (G-CSF). Cultures were characterized after 3, 6, 9, and 13 days by flow cytometry and clonogenic assays. CD34+ cells expanded 5.2- and 3.4-fold, and produced 2.2 and 2.4 CD34+/41(+) cells per seeded CD34+ cell after 6 and 9 days in culture, respectively. None were detected at day 13. CD41+ cells expanded exponentially over 13 days. Colony-forming unit-megakaryocyte (CFU-MK) also expanded exponentially, but the proportion of the most primitive CFU-MK dropped from 45% to 1.5% and to <1% after 6 and 9 days, respectively. G-CSF increased total cell expansion, but decreased CD41+ frequency, yielding no gain in MK production. We also found that PB CD34+ cells cultured for 3-6 days are richer in primitive MK progenitors, while those cultured for 9-13 days have greater numbers of more differentiated MKs. Overall, the combination of MGDF+SCF proved sufficient for expanding CD34+/CD41+ cells. As the stage of ex vivo MK differentiation most conducive to optimal platelet production in vivo is not known, we are planning a clinical trial to determine the efficacy of ex vivo-expanded MKs on platelet recovery in relation to MK maturity.

Antigens, CD34↗