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Biomedical subjects

I Rojo

Publications and source records attributed to I Rojo.

14 recordsLinked to original sources
PubMed2004

New concepts in cyclosporine pharmacokinetic and dynamic monitoring: the impact of concomitant immunosuppression on target C2 concentrations.

BACKGROUND: There is a correlation between cyclosporine (CsA) pharmacokinetics (PK) and pharmacodynamics (PD), especially 2 hours after drug administration. AIM: To evaluate the relationship between CsA PK and PD profiles in two groups of stable renal transplant patients treated with CsA alone or CsA plus mycophenolate mofetil (CsA+MMF), so as to define the best target for C2 and clarify the impact of concomitant immunosuppression. METHODS: Thirty-eight stable renal transplant recipients were treated with CsA (n=20) or CsA+MMF (n=18). Twelve nontreated normal healthy controls (NHC) were also included. Calcineurin activity (CNa), IL-2 production, and CsA levels were measured at 0 and 2 hours postdose. RESULTS: There were no significant differences in median CsA C2 values and CNa between the CsA alone and the CsA+MMF groups (388 microg/L and 497.5 microg/L and CNa 2h; 3.92% alkaline phosphatase [AP]; 3.94% AP, respectively). In vitro production of IL-2 was significantly lower in the CsA+MMF group than in the CsA group (median IL-2 2h: 280.52 ng/L, 169.48 ng/L, P<.001). The correlations (r) between C2 and CNa 2h were: CsA r=0.74; CsA+MMF r=0.84 (P<.001 in both cases). CONCLUSIONS: In stable renal transplant patients, median CsA C2 values below 500 microg/L were associated with inhibition of CNa and IL-2 synthesis. CNa and IL-2 production may be good biological markers of CsA immunosuppression. The measurement of CNa depends mainly on CsA concentration, whereas in vitro IL-2 production reflects the effect of both CsA and MMF. Further studies are necessary to define the optimal C2 target concentration and the possible impact of concomitant immunosuppression.

Calcineurin Inhibitors↗
PubMed2003

Pharmacokinetic and pharmacodynamic correlations of cyclosporine therapy in stable renal transplant patients: evaluation of long-term target C(2).

We investigated the relationship between the pharmacokinetics and pharmacodynamics of cyclosporine in 15 stable renal transplant patients in order to define an effective and safe therapeutic range. The area under the curve of the first 4 h (AUC(0-4)), trough (C(0)) and 2 h (C(2)) levels showed median values of 1655 ng x h/ml, 114 ng/ml and 384 ng/ml, respectively. C(2) showed a strong correlation with AUC(0-4) (r=0.942, p=0.0005). C(0) correlated poorly with C(2) and AUC(0-4) (r=0.596, p=0.019 and r=0.538, p=0.031, respectively). Calcineurine activity (CNa) was 6.74% at 0 h and 3.90% at 2 h, representing significant reductions (82% and 89.6%, respectively; p<0.0005) compared with normal healthy controls (median basal value 37.4%). IL-2 production was 349 pg/ml at 0 h and 276.35 pg/ml at 2 h; both results were significantly lower (reductions of 44.5% and 56.1%, respectively; p=0.04 and 0.005) than the controls of 629.1 pg/ml. IFN-gamma at 2 h post-dose (8.16 UI/ml) was significantly lower (72.1% reduction, p=0.005) than in controls (29.2 UI/ml). There was a good correlation between CNa and IFN-gamma production, particularly at 2 h post-dose (r=0.537, p=0.007), and a fair correlation between CNa and IL-2 concentration (p=0.030, r=0.426). C(2) showed an inverse significant correlation with CNa (Spearman's p=0.000, r=-0.753), IL-2 (p=0.000, r=-0.725) and IFN-gamma (p=0.000, r=-0.701) production. In treated patients, the Emax inhibitory sigmoidal model showed that a C(2) of 279 ng/ml was needed to achieve a 50% inhibition (EC50) of IL-2 and INF-gamma production. The results demonstrated a significant inhibition of calcineurin activity and IL-2 and IFN-gamma production in patients receiving cyclosporine monotherapy compared to healthy controls. A median C(2) value of 384 ng/ml was associated with a good degree of inhibition of CNa and IL-2 and IFN-gamma synthesis, and the lack of rejection episodes and relevant toxicity.

Area Under Curve↗
PubMed2000

Pharmacokinetics and pharmacodynamics of mycophenolic acid in stable renal transplant recipients treated with low doses of mycophenolate mofetil.

Suboptimal doses of mycophenolate mofetil (MMF) are frequently employed in renal transplant (Tx) patients, with drug-related side effects or low weight. The aim of this study was to compare the mycophenolic acid (MPA) pharmacokinetic profile and its pharmacodynamic effect on patients receiving either standard (2 g) or low (1.5 g or 1 g) MMF doses, in order to evaluate the therapeutic efficacy of such low doses in inhibiting IMPDH activity. Twenty-seven stable renal Tx recipients aged 18-65 years, with a post-Tx follow-up of 38.5 +/- 44.8 months (6-166 months), receiving 1 g (n = 10), 0.75 g (n = 7) and 0.5 g (n = 10) MMF twice a day in association with cyclosporine and prednisone, were included. The control group was made up of untreated healthy volunteers (n = 5). Plasma concentrations of MPA were analyzed by reverse-phase HPLC. IMPDH activity was determined in lymphocytes by the measurement of 3H release from [2,8-(3)H] hypoxantine. The mean value of areas under the concentration-time curves (AUC(0-12)) of MPA throughout the 12-h dosing interval in patients treated with 2 g was higher than the corresponding data in patients receiving 1.5 g or 1 g bid, but no statistical differences were observed between the three groups. There was no correlation between MPA-AUC(0-12) values and MMF dose (expressed in g/day or g/kg per day). Predose MPA concentrations correlated only weakly with the respective MPA-AUC(0-12) values (r2 from 0.385 to 0.655), whereas an acceptable correlation was observed between MPA Cmax and MPA-AUC(0-12) (r2 from 0.626 to 0.759) in 2 g, 1.5 g, and 1 g MMF groups. An inverse relationship between MPA concentrations and IMPDH activity was observed. In general, the maximum MPA concentration was achieved from 1 h to 2 h after dosing, and the maximum inhibition of IMPDH was also from 1 h to 2 h after dosing. The evaluation of IMPDH activity demonstrated that there was a significant statistical difference between samples from 0 to 1 h (P = 0.008) and 0 to 2 h (P = 0.04). In conclusion, concentration-time profiles of renal transplant recipients administered 0.75 g and 0.5 g twice a day are slightly lower than those from the 2 g group, but nor significantly. On the other hand, inhibition of IMPDH activity was comparable in the three groups, indicating considerable interindividual pharmacodynamic variability. Pharmacodynamic monitoring of the degree of immunosuppression and its correlation with MPA plasma concentrations will be assessed further in future studies.

Adolescent↗
PubMed2000

Assessment of mycophenolic acid-induced immunosuppression: a new approach.

BACKGROUND: Mycophenolic acid (MPA), a metabolite of mycophenolate mofetil (MMF), is an immunosuppressive agent that inhibits inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the ex novo synthesis of GTP. We measured IMPDH activity in peripheral blood mononuclear cells (PBMCs) from MMF-treated patients to evaluate the efficacy of MMF in individual patients. METHODS: IMPDH activity was measured by (3)H released from [2,8-(3)H]IMP that had been formed in the cells from added [2,8-(3)H]hypoxanthine in PBMCs of 35 renal transplant recipients treated with cyclosporin A and corticoids plus MMF: 2 g (n = 10), 1.5 g (n = 7), 1 g (n = 10), or 0 g (n = 8) per day. An alternative method, based on the capacity of the patients' sera to inhibit spontaneous proliferation of the CEM cell line, was also analyzed. RESULTS: The IMPDH activity of PBMCs in transplanted patients was highly variable. For the method based on CEM cell line proliferation: (a) cell proliferation was inhibited only in MMF-treated patients; (b) there was a clear postdose increase in inhibition; (c) inhibition was not affected by other immunosuppressants in vitro or in vivo; (d) inhibition from predose to predose sample was correlated; and (e) when the MMF dosage was <20 mg. kg(-1). day(-1), two groups of patients were identified, one that maintained a high inhibitory capacity in all dose intervals, and one with periods of low inhibitory capacity. CONCLUSIONS: Measurement of the inhibition of CEM cell line proliferation by sera from MMF-treated patients may be useful for evaluating the relative efficacy of MMF treatment in individual patients, especially those receiving low doses of MMF.

Adult↗
PubMed1998

Nitric oxide production by pig endothelial cells in response to human-derived injury.

BACKGROUND: The hyperacute rejection induced by natural antibodies is the first barrier to the success of pig to human organ xenotransplantation. When this barrier is overcome, an infiltrate of mainly monocytes and natural killer cells can be observed. Nitric oxide (NO) has been described to be involved in allo- and xenorejection, and to participate in the regulation of monocyte infiltration in other models. METHODS: We have studied the capacity of human monocytes and natural antibodies to induce the production of NO by pig endothelial cells, by measuring NO2, a stable end product of NO. RESULTS: Human monocytes can induce HuProVim (HUP), a pig endothelial line, and "in situ, ex vivo" pig endothelial cells to produce NO2. This NO2 production was inhibited by NG-nitro-L-arginine-methylester and NG-monomethyl-L-arginine, inhibitors of NO production. This induction can be observed even if cells are separated by a semipermeable membrane, which indicates that it is a result of soluble factors. Activated cells continue producing NO after triggering for 1 hr. No NO2 production was observed after activation of HUP cells with recombinant human interleukin (IL)-1alpha, IL-1beta, IL-6, IL-10, transforming growth factor-beta1, IL-2, IL-4, interferon-gamma, or recombinant human tumor necrosis factor-alpha (rhTNF-alpha) alone. Only the combination of rhTNF-alpha+rIL-1alpha or rIL-1beta, and rhTNF-alpha+rIL-1alpha+IFN-gamma induces some NO production. Human natural anti-pig antibodies, which had been described to induce cytoskeleton changes on endothelial cells, do not induce NO production. CONCLUSIONS: Our data show that human monocytes induce the production of NO by pig endothelial cells. The inducing signal is soluble and cannot be provided by human anti-pig natural antibodies.

Animals↗
PubMed1990

CD27 induction on thymocytes.

CD27 mAb recognize a disulfide-linked homodimer of 55 kDa present in the majority of T cells and in a minor subpopulation of thymocytes. Although an increase of CD27 expression has been described in activated T cells, this Ag is poorly expressed in long term growing T cells. It has been also reported that CD27- becomes CD27+ upon activation. In the aim to better know the relationship between CD27 expression and the activation and maturation processes, the induction of this Ag in thymocytes was analyzed. The results obtained in this work show that: 1) CD27 is expressed only in thymocytes with high CD3 Ag density. 2) Its expression can be induced in low density CD3 CD4+ CD8+ cells by Con A and in low CD3 Ag density by PMA+ionomycin. 3) PMA alone or in combination with rIL-2 induces CD25 and CD71 expression but not CD27. 4) Unlike CD27, the Ag CD45RA, CD26, and CD76, which are present only in a minor thymocyte subpopulation, are not induced in double positive thymocytes. Because it has been reported that cyclosporin A interferes with thymocytes maturation and blocks the transition from double to single positive cells, its effect was measured on CD27 induction. Cyclosporin A did not inhibit CD25 expression induced by both Con A and PMA+ionomycin, but under these conditions it inhibited the induction of CD27. In this paper we discuss whether CD27 could be implicated in T cell maturation.

Antibodies, Monoclonal↗
PubMed1990

Differential effects of anti-CD45 monoclonal antibody on human B cell proliferation: a monoclonal antibody recognizing a neuraminidase-sensitive epitope of the T200 molecule enhances anti-immunoglobulin-induced proliferation.

We have generated seven monoclonal antibodies (mAb) that recognize the T200 molecule. These mAb have been classified by competitive binding assay in flow cytometry into three groups each reacting with a different epitope of the T200 molecule: (a) 136-4B5, that shows a sialic acid nature, (b) 135-4H9, 135-4C5, 144-2, 155-2 and (c) 72-5D3, 124-2H12b. A heterogeneous effect was observed when they were tested on an anti-immunoglobulin-induced B cell proliferation. Whereas 72-5D3 and 135-4H9 mAb inhibited the proliferative response of B cells, 136-4B5 mAb greatly enhanced it, both effects being dose dependent. We can conclude that anti-CD45 mAb have a different and contrary functional behavior on anti-Ig-induced B cell proliferation, depending on the epitope recognized. The basis for such a difference could reside in the glucidic nature of the epitope recognized by the 136-4B5 mAb.

Antibodies, Anti-Idiotypic↗
PubMed1989

Responsiveness of systemic lupus erythematosus T cells to signals provided through LCA T200 (CD45) and T1 (CD5) antigens.

It is currently unclear whether the T cell defective capacity to proliferate and to secrete interleukin-2 (IL-2) observed in systemic lupus erythematosus (SLE) reflects an intrinsic disorder of the T cell or defects secondary to a monocyte dysfunction. In order to clarify whether the disorder is intrinsic to the T cell, we have studied the proliferative capacity of cells highly depleted of monocytes, activated by Seph-CD3, as 'first signal,' and by monoclonal antibodies (MoAbs) CD45 and CD5 as 'second signal,' in 14 SLE patients. There were no significant differences between SLE patients and healthy volunteers in the response of the monocyte-depleted cells to Seph-CD3+CD45; Seph-CD3+CD5; Seph-CD3+IL-2; and Seph-CD3+phorbol myristate acetate (PMA). However, active SLE compared with non-active SLE had an impaired response of peripheral blood mononuclear cells (PBMC) to Seph-CD3 and to Seph-CD3+IL-2. The good responses obtained to second signals provided through CD45 and CD5 indicate that at least these mechanisms are not intrinsically impaired in SLE T cells. These findings, together with the abnormal response of PBMC suggest that a monocyte dysfunction plays an important role in SLE T cells hyporesponsiveness.

Adolescent↗
PubMed1987

A second signal for T cell mitogenesis provided by monoclonal antibodies CD45 (T200).

The induction of T cell mitogenesis through CD3 is a complex process that requires at least two signals. The first one can be provided by Sepharose-bound CD3. The second one is normally provided by monocytes. The signal provided by Sepharose-bound CD3 is unable by itself to induce mitogenesis in monocyte highly depleted cells (MHDC). We describe here that the monoclonal antibody (mAb) 72-5D3 belonging to CD45 (T200), which was not mitogenic by itself, could replace monocytes when MHDC were activated by Sepharose-bound CD3. That is to say, in the absence of monocytes, mAb 72-5D3 gave a second signal necessary for T cell proliferation. Using eleven anti-CD45 mAb from other investigators we show that this effect is not a peculiar characteristic of 72-5D3 mAb. The effect of the mAb 72-5D3 was only effective in CD4-positive cells and was not observed when MHDC were activated with either soluble CD3 or concanavalin A. As both phorbol myristate acetate and mAb 72-5D3 can replace monocytes, a comparative study of their effects was undertaken. Phorbol myristate acetate but not mAb 72-5D3 induced proliferation of MHDC when recombinant interleukin 2 (rIL2) was added. On the other hand mAb 72-5D3 induced IL2 production in MHDC activated by Sepharose-bound CD3 and increased the IL2 production in Sepharose-bound CD3-activated peripheral blood mononuclear cells. In conclusion, data presented in this report indicate that the T200 molecule could be involved in T cell proliferation by giving a signal that induces the production of IL2 and bypasses the necessity of monocytes.

Animals↗