Trombosis de la vena ovárica: casuística en 5 años y revisión de la literatura / Ovarian vein thrombosis: Casuistry over 5 years and literature review

La trombosis de la vena ovárica (TVO) es una complicación infrecuente pero grave en el posparto. Afecta entre el 0,02-0,2% del total de gestaciones, 0,02-0,18% de los partos vaginales, y entre el 1-2% de las cesáreas. Hasta en el 90% de los casos afecta a la vena ovárica derecha, y puede extenderse hasta la vena cava inferior originando complicaciones muy graves. El diagnóstico y tratamiento tempranos son fundamentales. Presentamos los casos de trombosis de la vena ovárica ocurridos en el puerperio durante los últimos 5 años en el Complejo Hospitalario de Pontevedra, y una revisión de la bibliografía existente

The ovarian vein thrombosis (OVT) is a rare but serious complication in the postpartum. It affects between 0.02% and 0.2% of all pregnancies, from 0.02% to 0.18% of vaginal deliveries and between 1% and 2% of caesarean sections. In up to 90% of cases it affects the right ovarian vein and it may extend as far as the inferior vena cava, causing serious complications. Early diagnosis and treatment are crucial. We present the cases of ovarian vein thrombosis having occurred in the postpartum period during the last 5 years in the Complejo Hospitalario de Pontevedra and a review of existing literature

Early non-invasive selection of patients at high risk of severe hepatitis C recurrence after liver transplantation.

BACKGROUND: The early identification of patients at high risk of severe post liver transplant hepatitis C recurrence is relevant, as these patients may be treated using interferon (IFN)-free regimens. METHODS: In a retrospective study with prospectively collected data, we investigated whether the use of several non-invasive methods (fibrosis 4 index [FIB-4], AST-to-platelets ratio index [APRI], enhanced liver fibrosis test [ELF], IFN-γ-inducible protein 10 [IP-10], and transient elastography by Fibroscan) and their combinations 6 months after transplantation could identify those recipients at higher risk of severe recurrence, defined by the presence of significant fibrosis (F ≥2) and/or portal hypertension (hepatic venous pressure gradient ≥6 mmHg) 12 months after transplant. Seventy-two hepatitis C virus (HCV)-infected liver transplant patients and 10 recipients in whom HCV was eradicated before transplantation were included in the study. RESULTS: The levels of all biomarkers were significantly higher in HCV-infected recipients than in controls. Among HCV recipients, levels of biomarkers were significantly higher in patients with severe recurrence. Although there were no statistically significant differences between biomarkers, APRI, ELF, and FIB-4 obtained the highest area under the ROC curve values. The combination of serum biomarkers with Fibroscan increased the negative and positive predictive values, although diagnostic accuracy of individual tests was not significantly improved. CONCLUSIONS: Patients at higher risk of severe HCV recurrence can be identified early, 6 months after transplantation, using readily available non-invasive methods.

Cytokine-based immune monitoring.

Several studies conducted during the last decade have shown that some promising biomarkers and surrogate markers may be useful in implementing personalized immunomodulatory therapies and improving graft and recipient care in solid organ transplantation. The complexity of the immune system response against the implanted graft can change remarkably in the long-term follow-up, and the dynamic balance between T-effector/T-regulatory cell populations determines the outcome of the anti-donor response, risk of rejection, and immunosuppression requirements. For this reason, at any time before and after transplantation, monitoring the T-effector cell activity, associated with an increase in pro-inflammatory cytokine production and release, can be considered as a surrogate marker of the risk of rejection and immunosuppression requirements. Furthermore, infections remain a cause of major complications following transplantation, highlighting the need for developing new approaches aimed at identifying the risk of infection in solid organ recipients. Another main aspect to be considered is that immunosuppressive agents may immunomodulate each treated patient differently. Immunosuppressive drugs show high pharmacokinetic and pharmacodynamic inter-patient variability. Some pharmacodynamic biomarkers such as measurement of the inhibition of target activity can reflect the individual's susceptibility to the treatment. Monitoring a panel of valid biomarkers may provide patient stratification and better immunosuppression treatment selection. After transplantation, therapy should be adjusted based on the prediction of rejection episodes (maintained alloreactivity), prognosis of allograft damage progression, and personal drug response. This review focuses on current knowledge, indicating that monitoring T-cell changes in the production of cytokines such as interferon gamma (IFN-γ) and interleukin (IL)-2, and also the expression of IL-17 by central and effector memory T cells, could be used to predict the risk of rejection and infection, thereby guiding immunosuppressive therapy in transplant recipients.

Activated Regulatory T Cells Expressing CD4(+)CD25(high)CD45RO(+)CD62L(+) Biomarkers Could Be a Risk Factor in Liver Allograft Rejection.

Activated regulatory T cells (aTregs) are nowadays a hot topic in organ transplantation to establish their role during acute rejection (AR) episodes. The aim of this multi-center study was to monitor the frequency of aTregs within the first year after transplantation in a cohort of first-time liver transplant recipients enrolled from 2010 to 2012. aTregs frequency was analyzed by means of flow cytometry. Patients who had AR showed higher levels of aTregs during first year after transplantation in comparison with patients who did not have higher levels. High levels of aTregs in liver recipients might be used as a biomarker of AR; however, further studies must be done to address the potential role of aTregs as biomarkers of AR in liver transplantation.

Should IFN-γ, IL-17 and IL-2 be considered predictive biomarkers of acute rejection in liver and kidney transplant? Results of a multicentric study.

Acute rejection (AR) remains a major challenge in organ transplantation, and there is a need for predictive biomarkers. In the present multicenter study, we prospectively examined a series of biomarkers in liver and kidney recipients. Intracellular expression of IFN-γ, IL-17 and IL-2 and IL-17 soluble production were evaluated both pre-transplantation and post-transplantation (1st and 2nd week, 1st, 2nd and 3rd month). 142 transplant patients (63 liver/79 kidney) were included in the study. Twenty-eight recipients (14 liver/14 kidney) developed AR. Pre- and post-transplantation intracellular expression of %IFN-γ(+) in CD4(+)CD69(+) and in CD8(+)CD69(+) and soluble IL17 identified liver and kidney transplant patients at high risk of AR. Pre-transplantation, %IL-2(+) in CD8(+)CD69(+) also identified kidney patients at high risk. We constructed pre- and post-transplantation risk prediction models, based on a composite panel of biomarkers, which could provide the basis for future studies and will be a useful tool for the selection and adjustment of immunosuppressive treatments.

Intracellular IFN-γ and IL-2 expression monitoring as surrogate markers of the risk of acute rejection and personal drug response in de novo liver transplant recipients.

Biomarker monitoring is needed in transplantation to reflect individual response to immunosuppressive drugs and graft outcome. We evaluated intracellular expression and soluble production of interferon-(IFN)-γ and interleukin-(IL)-2 as predictive biomarkers of acute rejection (AR) and personal drug response. Pharmacokinetic-pharmacodynamic profiles were determined in 47 de novo liver recipients treated with tacrolimus, mycophenolate mofetil and prednisone. Of the 47 patients, AR occurred in nine. There were no differences in drug concentrations between rejectors and non-rejectors. A pre-transplantation cut-off value of 55.80% for %CD8(+)-IFN-γ(+) identified patients at high risk of AR with a sensitivity of 75% and a specificity of 82%. In the first week post-transplantation, patients with a % inhibition for soluble IFN-γ, %CD8(+)-IFN-γ(+) and %CD8(+)-IL2(+) lower than 40% developed AR, showing low susceptibility to immunosuppressive drugs. Therefore, effector-T-cell response monitoring may help physicians to identify personal response to treatment and patients at high risk of AR.

Prospective study of biomarkers of immune response in lung transplant recipients.

INTRODUCTION: Studies on biomarkers of tolerance in organ transplantation have been widely performed during the last decade. AIM: To assess biomarkers in relation to evolution of the immune response among lung transplant recipients. METHODS: This multicenter study included 27 lung transplant recipients followed before as well as at 7, 14, 30, 60, 90, and 180 days posttransplantation. Biomarkers of the immune response based on flow cytometry technology were validated in each center. They included intracellular cytokine expression, regulatory T-cell level, as well as lymphocyte surface antigen and CD28 expressions. RESULTS: The 13 patients who developed acute rejection episodes showed increased numbers of regulatory T cells at 12 months posttransplant. Sixteen patients experiencing infections displayed decreased expression of CD69 on CD8 T cells within the first year of follow-up. CONCLUSION: High Treg levels in the peripheral blood of lung transplant recipients were associated with an increased risk of rejection but not infection. Inversely, we observed low levels of activated CD8 T cells in infected patients.

Desarrollo de síndrome de hiperestimulación ovárica grave tras la administración exógena de gonadotropina coriónica humana / Severe ovarian hyperstimulation syndrome after exogenous administration of human chorionic gonadotropin

El síndrome de hiperestimulación ovárica grave esuna entidad clínica que puede ocurrir tras la administraciónde gonadotropina coriónica humana, utilizadapara inducir la ovulación en las pautas de estimulaciónovárica de la fecundación in vitro. Presentamos el casode una mujer de 27 años, que tras recibir tratamientocon gonadotropina y ser sometida a fertilización in vitroconsiguiendo gestación, presentó un cuadro clínico dedolor abdominal, ascitis, edemas en miembros inferiores,disnea, derrame pleural bilateral y síndrome de distrésrespiratorio del adulto. La paciente precisó ingreso en launidad de cuidados intensivos y ventilación mecánica,así como la realización de legrado uterino para frenar laprogresión del cuadro(AU)

Severe ovarian hyperstimulation syndrome can occurafter administration of human chorionic gonadotropinused to induce ovulation in the context of in-vitrofertilization protocols. We report the case of a 27-yearoldwoman who had received gonadotropin treatment.In-vitro fertilization was successful but she developedabdominal pain, ascites, lower limb edema, dyspnea,bilateral pleural effusion, and adult respiratory distresssyndrome. The patient was admitted to the intensive careunit, where mechanical ventilation was started. Uterinedilatation and curettage was required to halt the process(AU)

Textiloma: en el diagnóstico diferencial de masas abdominales / Textiloma in the differential diagnosis of abdominal masses

Presentamos un caso de diagnóstico inicial de masa pélvica de probable origen ginecológico, etiquetada de mioma uterino como hipótesis diagnóstica principal, en que los hallazgos intraoperatorios descartan esta posibilidad y no confirman ninguna otra, difiriendo el diagnóstico hasta el informe final del anatomopatólogo en que describe una masa de origen textil persistente desde la apendicectomía realizada 18 años antes. Se demuestra así la discordancia existente entre el diagnóstico inicial y el definitivo, además de la necesidad de plantear el cuerpo extraño intraabdominal en el diagnóstico diferencial de este tipo de masas en pacientes intervenidos quirúrgicamente con anterioridad (AU)

We present a case of a pelvic mass of probable gynecological origin, whose principal suspected diagnosis was uterine myoma. Intraoperative findings excluded this diagnosis but failed to confirm other possibilities. The definitive diagnosis was delayed until the pathological report described a mass caused by a textile foreign body retained since an appendicectomy performed 18 years previously. The present report illustrates the discrepancy between the initial and definitive diagnosis, as well as the need to include an intraabdominal foreign body in the differential diagnosis of this type of mass in previously operated patients (AU)

Metástasis de carcinoma de cérvix sobre cicatriz: dos casos clínicos / Incisional skin metastasis from a cervical carcinoma: report of two cases

La recidiva del cáncer de cérvix sobre la cicatriz quirúrgica abdominal tras cirugía es un hecho extremadamente raro. Actualmente, hay muy pocos casos publicados en la literatura médica. La supervivencia de estas mujeres es corta, pues el carcinoma de cérvix sobre cicatriz se considera como una recidiva de la enfermedad. El tratamiento en estos casos varía: cirugía, quimioterapia o radioterapia. A continuación se presentan 2 casos tratados quirúrgicamente y con tratamiento adyuvante. En la actualidad, ambas mujeres están vivas (AU)

Recurrence of cervical carcinoma in an abdominal surgical scar after radical surgery is extremely uncommon. Few reports have been published in the literature and survival in these patients is short; consequently this entity is considered to be a carcinoma recurrence. Treatment varies and may consist of surgery, chemotherapy or radiation. We present two cases treated with surgery and adjuvant therapy. Currently, both patients are still alive (AU)

[Severe ovarian hyperstimulation syndrome after exogenous administration of human chorionic gonadotropin]. / Desarrollo de síndrome de hiperestimulación ovárica grave tras la administración exógena de gonadotropina coriónica humana.

Severe ovarian hyperstimulation syndrome can occur after administration of human chorionic gonadotropin used to induce ovulation in the context of in-vitro fertilization protocols. We report the case of a 27-year-old woman who had received gonadotropin treatment. In-vitro fertilization was successful but she developed abdominal pain, ascites, lower limb edema, dyspnea, bilateral pleural effusion, and adult respiratory distress syndrome. The patient was admitted to the intensive care unit, where mechanical ventilation was started. Uterine dilatation and curettage was required to halt the process.

Pharmacokinetics and pharmacodynamics in renal transplant recipients under treatment with cyclosporine and Myfortic.

INTRODUCTION: Efficacious prophylaxis of acute rejection episodes (ARE) requires adequate exposure to each component of the immunosuppressive treatment from the first days after renal transplantation. The aim of the present study was to evaluate the correlation between cyclosporine (CsA) and mycophenolic acid (MPA) exposure based upon pharmacokinetics (PK) and pharmacodynamics (PD) and 6-month biopsy-proven acute rejection (BPAR) episodes and chronic allograft nephropathy on 6 month protocol biopsies. PATIENTS AND METHODS: We examined twenty-two first or second de novo renal transplant recipients treated with steroids, Sandimmune Neoral (CsA) and Myfortic (720 mg twice a day). PK (C0, C2, and AUC(0-12h)) for both drugs were determined on days 7, 90, and 180. Calcineurin activity, interleukin-2 and interferon-gamma synthesis as well as %CEM were tested at days 7 and 180. CsA dosages were adjusted by C2 monitoring. Collected data included: BPAR during the first 6 months and Banff histological parameters on the 6-month protocol biopsies. RESULTS: Eighteen of 22 patients completed 1 year follow-up under treatment. The 6-month BPAR was 18% (4/22). Six-month protocol biopsies in 50% of 14 recipients showed chronic allograft nephropathy 1. At day 7, CsA C2 and AUC median values were 138 ng/mL and 6377 ng x h/mL, while C0 MPA was 1.0 microg/mL and AUC = 23.9 microg x h/mL. CsA C2 medians at 3 and 6 months were 1468 and 1720 ng/mL. MPA-AUC reached therapeutic targets at 3 months (32.3 microg x h/mL) and was 48.3 microg x h/mL at 6 months. Patients with BPAR showed lower CsA AUC (P = .06) and a significantly lower baseline inhibition of calcineurin activity (P < .005) than patients with no BPAR. An increase in mesangial matrix in 6-month protocol biopsies correlated with higher CsA C2 (P = .01). All biomarkers evaluated were significantly inhibited compared with the standard population. CONCLUSIONS: When Myfortic is administered together with CsA, it is advisable to begin with higher doses (720 mg x 3 days) to reach adequate PK targets and improve BPAR rates. To prevent chronic allograft nephropathy, lower CsA C2 should be targeted from 3 months.

Monitoring gene therapy by external imaging of mRNA: pilot study on murine erythropoietin.

Gene therapy is anticipated as being an important medical development. Essential to its effectiveness is the appropriate activity (protein expression) in the expected target cells. A noninvasive diagnostic procedure of successful gene expression will be of paramount importance to validate its use or its misuse (eg, sports gene doping). Externally detectable labeled oligonucleotide hybridizing with the messenger RNA generated by the transferred gene has been proposed as a possibility to monitor successful gene therapy. The authors selected the erythropoietin gene (Epo) for a pilot study on erythropoietin protein expression in mouse muscle. Oligonucleotides of peptide nucleic acid (PNA) type capable of antisense binding to unique murine Epo-mRNA sequences were synthesized by solid phase methods, and elongated at the N-terminus with the HIV Tat (48-60) cell penetrating peptide. They were labeled with fluorescence and radioactive tags to verify penetration and longer half-life properties in Epo gene transfected C2C12 mouse muscle cells as compared with corresponding wild-type cells. Downregulation of newly expressed erythropoietin protein in such cells additionally confirmed the penetration and hybridizing properties of the selected labeled oligonucleotide. I-labeled Tat-PNAs were intravenously injected into mice that had previously received the Epo gene into the right tibialis muscle by DNA electrotransfer. Preferential accumulation of radioactivity in the transferred limb as compared with the contralateral limb was ascertained, especially for I-Tat-CTA CGT AGA CCA CT (labeled Tat-PNA 1). This study provides experimental data to support the potential use of external noninvasive image detection to monitor gene therapy. The extension of the approach to more sensitive methods for whole-body external detection such as positron emission tomography appears feasible.

Dopaminergic deficiency in mice with reduced levels of the dual-specificity tyrosine-phosphorylated and regulated kinase 1A, Dyrk1A(+/-).

The dual-specificity tyrosine-phosphorylated and regulated kinase 1A (DYRK1A) gene encodes a protein kinase known to play a critical role in neurodevelopment. Mice with one functional copy of Dyrk1A (Dyrk1A(+/-)) display a marked hypoactivity and altered gait dynamics in basal conditions and in novel environments. Dopamine (DA) is a key neurotransmitter in motor behavior and genetic deletion of certain genes directly related to the dopaminergic system has a strong impact on motor activity. We have studied the effects of reduced Dyrk1A expression on the function of the nigrostriatal dopaminergic system. To characterize the dopaminergic system in DYRK1A(+/-) mice, we have used behavioral, pharmacological, histological, neurochemical and neuroimaging (microPET) techniques in a multidisciplinary approach. Dyrk1A(+/-) mice exhibited decreased striatal DA levels, reduced number of DA neurons in the substantia nigra pars compacta, as well as altered behavioral responses to dopaminergic agents. Moreover, microdialysis experiments revealed attenuated striatal DA release and positron emission tomography scan display reduced forebrain activation when challenged with amphetamine, in Dyrk1A(+/-) compared with wild-type mice. These data indicate that Dyrk1A is essential for a proper function of nigrostriatal dopaminergic neurons and suggest that Dyrk1A(+/-) mice can be used to study the pathogenesis of motor disorders involving dopaminergic dysfunction.

Role of FK778 alone or in combination with tacrolimus or mTOR inhibitors as an immunomodulator of immunofunctions: in vitro evaluation of T cell proliferation and the expression of lymphocyte surface antigens.

We evaluated the in vitro capacity of FK778, alone or in combination with other immunosuppressive drugs: Tacrolimus (TRL); Sirolimus (SRL), Everolimus (EVL), to inhibit clonal expansion of T-lymphocytes and expression of lymphocyte-activation surface antigens; secondly, we compared the immunosuppressive potential of FK778 combined with TRL, SRL and EVL with the same combinations using Mycophenolic acid (MPA) as antimetabolite. Lymphocyte proliferation was assessed by 3H-Thymidine incorporation, in whole blood cultures stimulated with ConA. The effect of FK778 on alloresponse was evaluated by MLC and the expression of lymphocyte surface antigens by cytometry. FK778, TRL, SRL and EVL showed a high in vitro capacity to inhibit lymphocyte proliferation in a concentration-dependent way. Combinations of FK778 with TRL, SRL, or EVL presented an additive effect, especially FK778+TRL. Similar inhibition capacity of the clonal expansion was observed, when FK778 was combined with TRL, SRL or EVL, respecting the same combinations but using MPA instead of FK778. In addition, FK778 inhibited the expression of lymphocyte surface antigens involved in activation, co-stimulatory and apoptosis signals. In conclusion, FK778 inhibits the proliferative response induced by mitogeneic and allogeneic stimuli and the expression of surface antigens. Combinations of FK778 with TRL or mTOR inhibitors presented an additive effect and their action on T cell proliferation was similar to that of combinations with MPA. Since FK778, TRL and mTOR inhibitors present different action mechanisms and involve different cellular targets, these combinations may help prevent episodes of allorejection in organ transplants. FK778 and mTOR inhibitors may represent an alternative treatment for patients with renal failure.

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.

Valor pronóstico de los factores clinicopatológicos Ki67, ciclina D1, ciclina D3 y CDK4 en el carcinoma gástrico / Pronostic value of clinicopathologic factors Ki67, cyclin D1, cyclin D3 and CDK4 in gastric carcinoma

- Propósito: Conocer el valor pronóstico de la ciclina Dl, ciclina D3, cdk4 y Ki67, estudiados por métodos inmunohistoquímicos, junto con las características clinicopatológicos de los carcinomas gástricos.- Métodos y resultados: Realizamos estudio inmunohistoquimicos de material incluido en parafina para ciclina D1, ciclina D3, cdk4 y Ki67 en 74 pacientes con carcinoma gástrico. Las inmunotinciones para ciclinas D1, D3 y cdk4 así el índice de proliferación de Ki67, el grado histológico y el tipo histológico (según la clasificación de Lauren) se compararon con la supervivencia. El 97 por ciento de los casos eran Ki67 positivos, el 29 por ciento para ciclina D1, el 23 por ciento para ciclina D3 y el 35 por ciento para cdk4. El análisis multivariante sólo mostró correlación entre el Ki67 (PI) (p<0,01) y la supervivencia. En el análisis univariante el grado histológico también se correlaciona con la supervivencia (p<0,03). La expresión de ciclina D3 se relaciona con cdk4 (p<0,001) y Ki67 (PI) (p<0,02) y la expresión de ciclina D1 con el grado histológico (p<0,03).- Conclusiones: Nuestros resultados sugieren que un índice de proliferación elevado de Ki67 y el grado histológico son marcadores de mal pronóstico. La sobreexpresión de la ciclina D1 podría tener un importante papel en la proliferación celular. La relación entre ciclina D3, cdk4 y Ki67 podrían explicarse por su papel a lo largo del ciclo celular. (AU)

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.

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.

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.