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J Martorell

Publications and source records attributed to J Martorell.

At least 37 records · Page 2Linked to original sources
PubMed2001

Mycophenolic acid plasma concentrations: influence of comedication.

Mycophenolate mofetil (MMF) in combination with cyclosporine (CsA) or Tacrolimus (TAC) has been show to be a potent immunosuppressive agent. The authors assessed the mycophenolic acid (MPA) plasma levels achieved in clinical practice and evaluated the effect of concomitant administration of CsA and TAC . One hundred forty transplant patients (kidney: 120 and lung: 20) received a triple immunosuppression regimen of CsA or TAC, prednisone and MMF. Twenty-two renal transplant patients received double therapy with MMF and prednisone. There was no correlation between MMF dose and MPA trough concentrations (r = -0.0657). The medians (range) of the MPA dose-to-concentration ratio (D/C) in the CsA and TAC groups were 0.90 (0.11-8.33) and 0.56 (0.11-14.3), respectively (p < 0.0001). According to the post transplant period (1-3, 4-6 and >6 months), D/C values were significantly lower in patients receiving MMF and TAC than those receiving MMF and CsA in all three periods. MPA levels in patients treated with MMF and CsA were significantly lower than those obtained in double therapy. The D/C ratio in CsA-treated patients, increased significantly (p = 0.0005) when CsA level increased. There was no relationship between D/C ratio and TAC blood concentrations. These results suggest that CsA exerts an influence on MPA trough levels, although further work is required to characterize the mechanism of interaction.

Adult↗
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

Identification of a novel HLA-Cw*07 variant (Cw*0714) in a German Caucasian family.

We report herein the identification of a new HLA-Cw*07 allele in two members of a German Caucasian family. This novel allele, designated as Cw*0714, differs from Cw*07011 and Cw*0706 by two nucleotide changes: one at codon 66 (AAC-->AAG) in the exon 2, leading to an amino acid change from Asn to Lys; and another silent substitution at codon 99 (TAT-->TAC) in the exon 3. The latest substitution (T-->C at the third position of codon 99) was not seen in any of the HLA-Cw*07 alleles reported so far, thus being characteristic to the new HLA-Cw*0714 allele.

Alleles↗
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↗
PubMed1999

Identification of a novel DRB1-allele (DRB1*0106) by sequence-based typing.

We report herein the identification of a new DRB1 allele using sequence-based typing. The new allele, DRB1*0106, was detected during routine HLA typing of a patient undergoing bone marrow transplantation. DRB1*0106 is identical to DRB1*0101 except for two codons, 71 (AGG-->GCG) and 86 (GGT-->GTG), changing the encoded arginine to alanine and glycine to valine. Both sequences were confirmed by polymerase chain reaction with sequence-specific primers (PCR-SSP). The polymorphism at codon 71 has not been, until now, identified in DRB1*01 alleles, although it is present in all the DRB1*15 alleles as well as DRB1*1309 and DRB1*1424.

Alleles↗
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↗
PubMed1998

Recurrence of immunological markers for type 1 (insulin-dependent) diabetes mellitus in immunosuppressed patients after pancreas transplantation.

BACKGROUND: Type 1 (insulin dependent) diabetes mellitus (IDDM) is an autoimmune disease in which autoantibodies against islet cells develop concomitantly with or even preceding diagnosis. Because the recurrence of diabetes can be the cause of graft failure in patients with pancreas transplantation, we studied the possible recurrence of IDDM immunomarkers after transplantation. METHODS: The following determinations were performed every 1-2 years after transplantation in 50 immunosuppressed IDDM patients with simultaneous kidney and pancreas transplantation (bladder drainage of exocrine secretion): islet cell antibodies (ICA) by direct immunofluorescence, antibodies against glutamic acid decarboxylase (GADab) by radiobinding assay, and the oral glucose tolerance test. The mean follow-up was 4.1+/-6.3 (range 1 to 9 years). RESULTS: GADab were detected in 11 patients after transplantation, 10 of whom had been positive beforehand. ICA reappearance after transplantation was detected in seven patients (14%). The presence of ICA was related to GADab positivity (P=0.001) and HLA DR3 patients (P=0.04), but not with pancreatitis and rejection episodes, immunosuppression induction therapy, or donor HLA haplotype. During follow-up, an abnormal oral glucose tolerance test was more frequent in ICA-positive patients (P=0.02), with no differences in metabolic control or insulin secretion. CONCLUSION: We conclude that GADab persist and ICA reappear despite immunosuppressive therapy in patients with functioning pancreas transplants. The relevance and the risk that this implies for IDDM development should be determined.

Adult↗
PubMed1998

Effect of a platelet-activating factor (PAF) receptor antagonist on hyperacute xenograft rejection; evaluation in a pig kidney-human blood xenoperfusion model.

In pig to human discordant xenotransplantation, PAF may contribute to the pathogenesis of hyperacute xenograft rejection (HXR). We examined the release of PAF and the effect of a PAF receptor antagonist (BN 52021) on HXR in a pig kidney-human blood xenoperfusion model. Pig kidneys were perfused with porcine blood (AUTO group, n = 5), human blood (HETER group, n = 6) or human blood plus BN 52021 (BN group, n = 4), respectively. In contrast to HETER kidneys that never produced urine and were rejected in 15-30 min, the administration of BN 52021 induced a partial recovery of glomerular filtration rate and allowed kidneys to function until the end of the study. The release of PAF and soluble P-selectin, as well as endothelial P-selectin expression and tissue myeloperoxidase (MPO), were much higher in the HETER than in the AUTO group. HETER and BN kidneys displayed similar natural xenoantibody titres, CH50, PAF, soluble P-selectin as well as renal immunoglobulin (IgM, IgG, IgA) and complement (C3, C1q) deposition. However, HETER kidneys displayed a full histologic picture of HXR (mainly interstitial haemorrhage and vascular microthrombi) and BN kidneys had only endothelial cell swelling. Also, BN 52021 administration attenuated glomerular and vascular P-selectin expression and renal tissue MPO activity. We conclude that in the pig kidney-human blood xenoperfusion model, PAF is produced in higher amounts than in the pig kidney-pig blood autologous combination. The administration of BN 52021 exerts a protective effect by means of attenuating the acute inflammatory response and blocking vascular microthrombi formation.

Animals↗
PubMed1998

Parental human leukocyte antigens and implantation failure after in-vitro fertilization.

At present, it is well accepted that maternal recognition of paternally derived fetal antigens occurs during normal pregnancy and may be beneficial for implantation and maintenance of gestation. Thus, we have investigated the compatibility of human leukocyte antigens (HLA) in couples with successive failed in-vitro fertilization (IVF) cycles. Study group 1 included 50 couples with prior primary infertility who had not achieved a pregnancy after > or = 3 (range 3-7, mean 3.7) IVF cycles where at least two embryos (mean 3.3, range 2-4) were transferred in each attempt. An infertile control group (group 2) included 50 infertile couples undergoing IVF with the same indications as couples in group 1, who achieved a viable pregnancy with their first IVF attempt. The results were compared with those found in a population sample including 100 men and 100 women from the local population (group 3). We found a statistically significant (P < 0.05) excess of HLA sharing (> or = 2 antigens) between partners in group 1 as compared to groups 2. There was a trend toward increased HLA sharing in group 1 when groups 1 and 3 were compared. We conclude that some cases of implantation failure after IVF and embryo transfer might be caused by underlying close histocompatibility between partners.

Adult↗
PubMed1996

Elevated soluble CD27 levels in serum of patients with systemic lupus erythematosus.

The CD27 belongs to the NGF-R, a family of type I transmembrane receptors present in most T cells. The soluble form of CD27 can be found in body fluids, and elevation of serum levels is observed in T cell activation. Preliminary studies indicate that measurement of sCD27 levels might be of use in the evaluation of immune responses in vivo. Systemic lupus erythematosus (SLE) is a disease of unknown etiology. T cells from SLE patients have impaired responsiveness to various kinds of stimuli. However, the precise localization of the defect in the activation of SLE remains unclear. In this study we have analyzed the sCD27 serum levels in a SLE population and in a healthy group control. Seventy patients with SLE were prospectively studied. As controls, 20 healthy volunteer blood donors, matched by sex and age, were studied. We developed an enzyme-linked immunosorbent assay (ELISA) to measure sCD27. The mean level (+/-SD) of sCD27 was higher in the SLE patients (48.29 +/- 23.86 u) than that in the control group (36.13 +/- 7.48 u) (P = 0.02). In addition, patients with active SLE revealed higher serum concentration of sCD27 (58.20 +/- 31.06 u) than that of patients in remission (42.77 +/- 16.71 u) (P < 0.01). We found a positive correlation among sCD27 and sCD25 serum levels in SLE patients (r = 0.30, P = 0.01). No significant relation was found for other clinical symptoms or immunological parameters. In conclusion, sCD27 serum levels were increased in SLE patients and this increase was associated with the activity of the disease. Our data are consistent with the hypothesis that the CD27 antigen may constitute a marker of disease activity.

Adolescent↗
PubMed1996

Intravenous immunoglobulin preceding in vitro fertilization-embryo transfer for patients with repeated failure of embryo transfer.

OBJECTIVE: To determine the effectiveness of immunotherapy with high-dose IV immunoglobulin preceding IVF-ET for patients with repeated failure of ET. DESIGN: Prospective, observational. SETTING: Assisted Reproduction Unit of the Hospital Clínic i Provincial in Barcelona, a tertiary care setting. PATIENTS: Twelve consecutive tubal infertility patients experiencing repeated unexplained IVF-ET failure including at least three ETs replacing three to four fresh embryos each. Two women shared three or more human leukocyte antigens (HLA) with the husband. INTERVENTION: During the subsequent new IVF-ET cycle, each patient received 400 mg/kg IV immunoglobulin daily for 5 days during ovarian stimulation, that is, 5 to 7 days before ET. MAIN OUTCOME MEASURES: Clinical pregnancies. RESULTS: No implantation occurred. There were no side effects. CONCLUSIONS: High-dose IV immunoglobulin is not a useful tool for IVF-ET failure.

Adult↗
PubMed1996

Influence of anti-HLA antibodies and positive T-lymphocytotoxic crossmatch on survival and graft rejection in human liver transplantation.

BACKGROUND/AIMS: The role of crossmatching in liver transplantation is controversial. The aim of this study was to investigate retrospectively the effect of sensitization and IgG lymphocytotoxic crossmatching on liver transplantation. METHODS/RESULTS: Over 5 years, 20 of 243 (8.2%) first liver transplants were performed with a positive crossmatch and their outcome was compared with the remaining 223 performed with a negative crossmatch. Women had a higher incidence of positive crossmatch than men (p < 0.001). Significant differences in mean panel reactive antibody of 2.7% and 43.3% were found in negative and positive crossmatch patients, respectively (p < 0.001). Severe early rejection resulting in graft loss occurred in eight of 20 positive crossmatch patients, and only one of 223 negative crossmatch patients (p < 0.001). Five of the remaining positive crossmatch patients suffered several acute rejection episodes some months after liver transplantation. Two of 20 in the positive crossmatch group developed chronic rejection (10%) compared with ten of 223 negatives (4.4%) (N.S). Nine of 16 positive crossmatch female recipients suffered graft loss and seven died, representing 1-year graft and patient survival of 56% and 43%, respectively. Fifteen of 68 negative crossmatch female recipients presented graft loss and 12 died, accounting for 1-year patient and graft survival of 82% and 78% (p < 0.005), respectively. Five patients (20%) displayed positive crossmatch at the time of retransplantation, compared with 24 (10%) who were negative (N.S). CONCLUSION: Our experience confirms the adverse impact of a positive crossmatch in liver transplantation, particularly in female recipients. Candidates with high panel reactive antibody are more likely to display a positive crossmatch, and therefore to develop early severe rejection and graft failure.

Adult↗