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Biomedical subjects

Y Le Meur

Publications and source records attributed to Y Le Meur.

At least 19 recordsLinked to original sources
PubMed2006

Bier's white spots associated with scleroderma renal crisis.

Bier's spots are asymptomatic and permanent white macules, standing on a cyanotic background. These spots are associated with venous stasis and usually appear in physiological conditions. We report the case of a 47-year-old woman with a 2-year history of systemic scleroderma, who developed Bier's white spots associated with a vascular and renal crisis. Interestingly, these spots appeared with the crisis, and disappeared with the treatment and resolution of the crisis. They are probably a result of anatomical and functional damage to the small vessels of the skin. The pathophysiology in the skin is probably the same as that which happens in renal vessels during scleroderma renal crisis.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

Long-term results of monoclonal anti-Il2-receptor antibody versus polyclonal antilymphocyte antibodies as induction therapy in renal transplantation.

We compared the influence of induction therapy on 5-year patient and graft survival as well as on renal function in 100 kidney graft recipients at low immunological risk treated with antilymphocyte globulin (n = 50) versus anti-IL-2R monoclonal antibody (n = 50) in a prospective multicenter study. Long-term immunosuppressive treatment included cyclosporine, mycophenolate mofetil, and a short course of steroids in all patients. Five year graft (86% vs 86%) and patient (94% vs 94%) survivals were identical in both study arms. Moreover, neither serum creatinine or proteinuria were significantly different between the two groups. Our results showed that the choice of the induction therapy seemed to not have a major impact on long-term outcomes among renal recipients at low immunological risk.

Antibodies, Monoclonal↗
PubMed2006

Tolerability of enteric-coated mycophenolate sodium to 1 year in combination with cyclosporine and corticosteroids in renal transplant recipients.

Enteric-coated mycophenolate sodium (EC-MPS) is therapeutically equivalent to mycophenolate mofetil, but delays release of mycophenolic acid until it reaches the small intestine. De novo renal transplant patients taking part in a 12-month, multicenter, randomized study received cyclosporine microemulsion (CsA-ME, early or delayed to day 6), EC-MPS, steroids, and interleukin-2 antagonist induction. Tolerability data relating to EC-MPS are reported. Ninety-seven patients were randomized to early CsA-ME and 100 patients to delayed CsA-ME. Median daily dose of EC-MPS was 1440 mg at all time points throughout the 12-month period. The most frequently reported adverse events were constipation, anemia, urinary tract infection, abdominal pain, leukopenia, and cytomegalovirus infection; there were four malignancies. Fifty patients (24.6%) discontinued EC-MPS prematurely by 12 months, including 42 patients (84%) who discontinued owing to adverse events. No patient discontinued treatment because of gastrointestinal adverse events. Two-thirds of patients (137 [67.5%]) maintained full EC-MPS dose throughout the 12-month study and did not require any dose reduction or dose interruption. EC-MPS is well tolerated in de novo renal transplant recipients when administered in combination with CsA-ME and steroids, with low rates of dose reductions or interruptions. Gastrointestinal adverse events were responsible for dose reduction or interruption in only 5% of patients.

Adrenal Cortex Hormones↗
PubMed2004

Population pharmacokinetic modeling of oral cyclosporin using NONMEM: comparison of absorption pharmacokinetic models and design of a Bayesian estimator.

There have been very few population pharmacokinetic (PopPK) studies and Bayesian forecasting methods dealing with cyclosporin (CsA) so far, probably because of the difficulty of modeling the particular absorption profiles of CsA. The present study was conducted in stable renal transplant patients treated with Neoral and employed the NONMEM program. Its goals were (1) to develop a population pharmacokinetic model for CsA based on an Erlang frequency distribution (which describes asymmetric S-shaped absorption profiles) combined with a 2-compartment model; (2) to compare this model with models combining a time-lag parameter and either a zero-order or first-order rate constant and with a model based on a Weibull distribution; and (3) to develop a PK Bayesian estimator for full AUC estimation based on that "Erlang model." The PopPK model was developed in an index set of 70 patients, and then individual PK parameters and AUC were estimated in 10 other patients using Bayesian estimation. The "Erlang" model best described the data, with mean absorption time (MAT), apparent clearance (CL/F), and apparent volume of the central compartment (Vc/F) of 0.78 hours, 26.3 L/h, and 76 L, respectively (interindividual variability CV = 33, 30, and 48%). Bayesian estimation allowed accurate prediction of systemic exposure using only 3 samples collected at 0, 1, and 3 hours. Regression analysis found no significant difference between the predicted and observed concentrations (10 per patient), and AUC(0-12) were estimated with a nonsignificant bias (0.6 to 8.7%) and good precision (RMSE = 5.3%). In conclusion, the Erlang distribution best described CsA absorption profiles, and a Bayesian estimator developed using this model and a mixed-effect PK modeling program provided accurate estimates of CsA systemic exposure using only 3 blood samples.

Area Under Curve↗
PubMed2001

Plasma levels and metabolism of AcSDKP in patients with chronic renal failure: relationship with erythropoietin requirements.

N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is a physiological inhibitor of hematopoiesis that is maintained at stable levels in normal plasma. Its degradation in vivo and in vitro by angiotensin-converting enzyme (ACE) accounts for the high plasma concentrations of AcSDKP in patients treated with ACE inhibitors. Because ACE inhibitors can induce anemia in some patients, we measured plasma AcSDKP concentrations in 176 patients with chronic renal failure: 120 hemodialysis (HD) and 56 nondialysis (nD) patients, 39 of whom were administered ACE inhibitors. We studied the relationships between AcSDKP levels, hematologic parameters, and recombinant human erythropoietin (rHuEPO) requirements in these patients. AcSDKP levels were significantly greater in HD (10.3 +/- 3.9 pmol/mL) and nD (3.1 +/- 1.8 pmol/mL) patients not administered ACE inhibitors than controls (1.8 +/- 0.2 pmol/mL). In all patients, treatment with ACE inhibitors significantly increased these levels fourfold. HD sessions significantly decreased AcSDKP concentrations by 66% and reduced the predialysis in vitro half-life of AcSDKP (270 +/- 109 minutes) to values (182 +/- 67 minutes) not significantly different from those of controls or nD patients. Most HD patients treated with ACE inhibitors had AcSDKP levels greater than 24 pmol/mL (the greatest concentration found in other nD and HD patients). Only in this group of patients did weekly doses of rHuEPO correlate with AcSDKP levels. Our results show that renal function is essential to maintain stable AcSDKP plasma levels, and at high levels, AcSDKP acts as a uremic toxin causing partial resistance to erythropoietin and inhibiting erythropoiesis.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Application of a gamma model of absorption to oral cyclosporin.

BACKGROUND: Some drugs, such as cyclosporin, exhibit flat and delayed absorption profiles, with a correlation between the delay and the peak width. Such profiles can be described by an absorption model in which the absorption rate is derived from a gamma distribution (of which the classical first-order absorption model is a special case). OBJECTIVE: To develop a model for the pharmacokinetics of extravascular administration of cyclosporin and apply it to a study of the pharmacokinetics of cyclosporin microemulsion in stable renal transplant recipients. PATIENTS AND PARTICIPANTS: 21 renal transplant patients receiving oral cyclosporin microemulsion 75 to 175 mg twice daily. METHODS: The equation of the plasma concentration-time curve after oral administration was expressed as a convolution product between the absorption rate and a multi-exponential impulse response. The convolution integral was computed analytically and expressed in terms of the incomplete gamma function. Cyclosporin was assayed by liquid chromatography/mass spectrophotometry. The model was fitted by nonlinear regression, using a specially developed program. RESULTS: The gamma model yielded a good fit in all of the 21 patients studied. Attempts to fit the same data by a classical exponential with lag-time model failed in most patients. CONCLUSIONS: This model could simplify the Bayesian monitoring of cyclosporin therapy.

Area Under Curve↗
PubMed2000

Factors predicting the long-term success of maintenance cyclosporine monotherapy after kidney transplantation.

BACKGROUND: The theoretical aim of maintenance cyclosporine monotherapy (mCsA) after kidney transplantation is to reduce the incidence of the metabolic complications of corticosteroids and to minimize the adverse effects of excessive long-term immunosuppression. This study was performed in low-immunological-risk cadaveric kidney transplant recipients to evaluate the risks and benefits of mCsA and the long-term graft survival, and to determine the factors predicting success of this policy. METHODS: The multicenter retrospective study was conducted in 329 Caucasian patients receiving mCsA out of 728 first cadaveric kidney transplant recipients. The inclusion criteria were: HLA antibodies < or =25%, serum creatinine <200 micromol/L, and no rejection or only one rejection episode. At the end of the study, we compared the group of patients successfully treated with mCsA (successful group) with those requiring additional immunosuppressive agents (unsuccessful mCsA group). RESULTS: Overall patient and graft survival rates for the 728 first cadaveric graft were 92% and 64%, respectively, at 8 years. Out of 329 patients enrolled in mCsA, 240 were maintained on this treatment and 89 were withdrawn (3 deaths, 18 graft losses, 68 functional grafts). The 8-year graft survival in the 329 enrolled mCsA patients was 84%, 95% in the successful mCsA group, and 70% in the unsuccessful mCsA group. Multivariate analysis showed that the factors predicting success of mCsA were: donor age <40 years (P = 0.001), serum creatinine at mCsA initiation <125 micromol/L (P = 0.02), no rejection episode before mCsA initiation (P = 0.005), and glomerulopathy as the primary renal disease (P = 0.001). CONCLUSION: Numerous kidney transplant recipients with a low immunological risk and good and stable renal function may benefit from discontinuation of prednisone and azathioprine in order to reduce the complications related to these drugs. This therapeutic approach had no adverse impact on the overall long-term graft survival for "low risk" and successful patients.

Adult↗
PubMed1999

Whole blood production of monocytic cytokines (IL-1beta, IL-6, TNF-alpha, sIL-6R, IL-1Ra) in haemodialysed patients.

BACKGROUND: The production of monocytic cytokines by isolated mononuclear cells after stimulation by phytohaemagglutinin (PHA) and lipopolysaccharide (LPS) is generally increased in haemodialysed (HD) patients. We performed whole blood (WB) cultures to evaluate cytokine production by blood cells inside their complex cellular and humoral network. METHODS: Diluted whole blood from HD patients (collected before dialysis) and controls was cultured alone with PHA (2.5 microg/ml) or LPS (1 and 3 microg/ml). Supernatants were collected after 24 and 48 h of culture, and concentrations of IL-1 beta, IL-6, TNF-alpha, sIL-6R and IL-1Ra were determined by ELISA. RESULTS: The low spontaneous production of IL-1beta, IL-6 and TNF-alpha in both patients and controls was not significantly modified by PHA. The lower dose of LPS (1 microg/ml) induced a significant but lower increase in production of IL-1beta, IL-6 and TNF-alpha in patients than in controls. In contrast, while it did not further increase their production in controls, the higher concentration of LPS (3 microg/ml) still increased their production in patients to the same level than in controls. The plasma concentrations of sIL-6R were higher in patients than in controls. In both groups, the sIL-6R concentration did not vary during the culture period whether the cells were stimulated or not with LPS or PHA. This suggests that the increased plasma levels of sIL-6R were not produced by blood cells. Despite a similar significant LPS and PHA induced production of IL-1Ra, the IL-1Ra/IL-1beta ratio was always higher in patients than in controls. CONCLUSION: Monocytes from HD patients in WB cultures are hyporesponsive to PHA and LPS for their IL-1beta, TNFalpha and IL-6 production in contrast to isolated monocytes that demonstrate signs of activation. If it reflects the in vivo situation it could partly explain the immune defect in uraemic and haemodialysed patients. Higher sIL-6R/IL-6 and IL-1Ra/IL-1beta ratios could also participate to the complex immune disturbances of HD patients by reducing the biological activity of two cytokines playing a major role in the immune and inflammatory network.

Blood Cells↗
PubMed1998

[Lymphoproliferative syndromes after renal transplantation].

UNLABELLED: Following kidney transplantation, lymphoproliferative disorders (LD) are encountered at a frequency of 1%. The onset of these LD is correlated with the degree of immunosuppression. The mortality is elevated (> 50%) especially in late forms. Since 1984 we have performed two hundred and seventeen kidney transplantations. The patients received sequential quadruple-drug immunosuppressive therapy: antilymphocyte globulin (ALG), azathioprine, corticosteroids and cyclosporine. A diagnosis of LD was established in ten patients, four were of early onset (within twelve months of transplantation) and six late (after five to nine years). Rejection occurred in two patients, one of which was steroid resistant requiring ALG. Three LD arose from the graft hilum, four had a voluminous tumor mass with extranodal sites: the graft (1), stomach (2), gingiva (1), meninges (1), and bone marrow (1). Histologically there were eight cases of large-cell B lymphoma, 1 mononucleosis-like LD, and a MALT lymphoma. A search for EBV was positive seven times. Treatment consisted of decreasing immunosuppressive therapy only (1), combined with antiviral treatment (1), or with surgical removal of the graft (3), and/or chemotherapy (5). Nine patients are still alive, in complete remission, graft loss occurred in four cases. CONCLUSION: In our series, we found a high frequency of LD. Despite 4 LD with a voluminous tumor mass and unfavorable histological prognosis requiring chemotherapy, all the LD in our series had a favorable outcome.

Adult↗
PubMed1997

[Early menopause].

Early menopause due to an exhaustion of the ovarian follicles before the age of 40 years occurs in approximately 1% of women in this age range. Clinical signs of estrogen deficiency with amenorrhea and sterility are usually confirmed by hypergonadotrope hypogonadism at laboratory tests. The syndrome is to be differentiated from gonadotrophine resistant ovaries and rare gonadotrope adenomas. Ovary biopsy shows more or less complete destruction of the follicles. There are many causes of early menopause including abnormal number or structure of chromosome X in 15-20% of the cases. Certain metabolic disorders and viral infections can also be incriminated. Finally surgery, radiotherapy or chemotherapy can be the cause of iatrogenic menopause. To determine prognosis, the woman's follicular capacity must be estimated. Estrogen therapy is currently the best choice to preserve chances for ovulation and pregnancy. When there is no remaining follicular capacity, ovum donation may be a solution. Finally, all patients should be given hormone substitution therapy due to the long-term risk of estrogen-progesterone deficiency.

Biopsy↗
PubMed1996

Development of enzymo-immunoassays (EIA) for macrophage colony-stimulating factor (M-CSF) and leukaemia inhibitory factor (LIF) by using the same capture and signal generating polyclonal antibody.

Specific high titre polyclonal antibodies rapidly obtained by intralymphnode immunization of rabbits with recombinant M-CSF and LIF (< 60 micrograms/animal) have been used to develop specific, accurate and sensitive EIAs. The same batch of purified anti-M-CSF or anti-LIF Igs has been used for the coating of 96-well plates (capture antibody) and for the quantitative detection of the bound cytokine molecules (soluble biotinylated Igs). The sensitivity (M-CSF: 10 IU/ml, LIF: 20 pg/ml), accuracy (intra-assay-CV: 8.2 to 12.8% for M-CSF; 0 to 19.9% for LIF) and reproducibility (inter-assay-CV: 7.9 to 13.6% for M-CSF; 4.9 to 17.5% for LIF) are equivalent to those for previously published RIAs or EIAs. These assays are highly specific since 11 other cytokines (Epo: 3 IU/ml; G-CSF: 100 IU/ml; CNTF, OSM, SCF, IL-1 beta, IL-2, IL-3, IL-6, IL-11, IL-13: 5 ng/ml) tested in both EIAs were not detectable. Finally, the M-CSF and LIF concentrations measured in various biological fluids were found to be similar to those measured by us and others with different assays. In conclusion, the methodology used for M-CSF and LIF EIAs presented in this work represents a valuable approach for most cytokines, particularly when they are still available in reduced amounts.

Adult↗
PubMed1996

Macrophage colony stimulating factor involvement in uremic patients.

The immunodeficiency of patients with chronic renal failure (CRF) is related to multiple and complex alterations of the cytokine network and of its target cells such as T or B lymphocytes, monocytes, fibroblasts or endothelial cells. Chronic activation of monocytic functions is recognized as a key factor in these immunological disorders. Since macrophage colony stimulating factor (M-CSF) is essential for the activation of several functions of monocytes and macrophages and their production of cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor alpha, we investigated its involvement in patients with CRF. When measured by ELISA, M-CSF serum levels were significantly higher in patients with progressive CRF and those on hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD) than in controls. M-CSF serum levels did not correlate with the degree of renal insufficiency and were probably related to complex alterations in its production and/or degradation by the specific M-CSF receptors of macrophages. In HD patients the M-CSF serum concentrations inversely correlated with the number of circulating lymphocytes and were significantly higher in anemic patients requiring treatment with erythropoietin. Our results suggest that M-CSF may play a role in altering the immune system in uremic patients by maintaining in the circulation and tissues permanently primed monocytes and/or macrophages that can then be triggered to an activated state by secondary stimuli such as endotoxins, complement components, other cytokines or contact with foreign surfaces.

Adult↗