New strategies to optimize clinical outcomes with cyclosporine in liver transplantation.
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Cyclosporine↗
Biomedical subjects
G A Levy
Publications and source records attributed to G A Levy.
Genomic characterization, localization, and functional expression of FGL2, the human gene encoding fibroleukin: a novel human procoagulant.
For diseases in which thrombosis plays a pivotal role, such as virus-induced fulminant hepatitis, fetal loss syndrome, and xenograft rejection, the major procoagulant has remained elusive. Here we describe the isolation and functional expression of a distinct human prothrombinase, termed FGL2. The murine fgl2 gene product has been implicated in the pathophysiology of murine fulminant hepatitis. The predicted ORF corresponds to a 439-amino-acid type II integral membrane protein that contains a carboxy-terminal Fibrinogen-related domain. Functional analysis showed that FGL2-encoded protein is indeed a prothrombinase. This enzyme is a serine protease and directly cleaves prothrombin to thrombin. The FGL2 gene is a single-copy gene in the haploid human genome and has two exons separated by a 2195-bp intron expressing two mRNA transcripts of 1.5 and 5.0 kb. The 5'-flanking region contains putative cis-elements including a TATA box, an AP1 site, CEBP sites, Sp1 site, and Ets binding domains. By both radiation hybrid analyses and fluorescence in situ hybridization, human FGL2 was localized to 7q11.23.
Amino Acid Sequence↗
Pharmacokinetics and tolerability of 40-0-[2-hydroxyethyl]rapamycin in de novo liver transplant recipients.
BACKGROUND: 40-0-[2-Hydroxyethyl]rapamycin (RAD), a novel macrolide with potent immunosuppressive and antiproliferative activities, prevents rejection in animal allotransplantation models. This phase I trial assessed the effects of bile diversion, administration route, and time after transplant on RAD pharmacokinetics after single-dose administration in de novo liver allograft recipients. The influence of RAD on cyclosporine (CsA) pharmacokinetics and the safety of RAD were also evaluated. METHODS: Twenty-six de novo liver allograft recipients were assigned to one of four treatment groups based on the presence or absence of a T tube, administration route (nasogastric or nasoduodenal), and timing of RAD administration. Patients received a single 7.5-mg RAD dose on one to three occasions in addition to CsA (Neoral) and corticosteroids. Steady-state cyclosporine profiles with and without RAD coadministration were evaluated. Results. Recipients with bile diversion demonstrated lower peak concentration (Cmax) than those without, but overall drug exposure (AUC) was not altered. Cmax and AUC were not influenced by administration route. A trend towards higher Cmax on postoperative day 3 than on postoperative day 1 was noted, although AUC was not altered. Single-dose RAD coadministration did not affect steady-state CsA pharmacokinetics. RAD was well tolerated and caused few drug-related adverse effects. RAD administration did not increase infection rates or produce clinically significant changes in laboratory parameters. Conclusions. In de novo liver transplant recipients, the overall extent of RAD absorption was not influenced by bile diversion, administration route, or time of administration. CsA pharmacokinetics were not affected by single-dose RAD coadministration. RAD capsules administered in single doses of 7.5 mg were well tolerated and safe.
Administration, Oral↗
Procoagulants in fetus rejection: the role of the OX-2 (CD200) tolerance signal.
The spontaneous loss of normal karyotype embryos may be initiated or prevented by the maternal immune system. In mice, loss between the time of implantation (day 4.5) and formation of a vascularized placenta (day 9.5) when the embryo is too large to survive by diffusion alone, is analogous to occult pregnancy failure in humans. They are called occult because usually the woman does not know she is pregnant. From studies in mice, these early losses have a different mechanism than abortion of a vascularized placenta (analogous to clinically evident human spontaneous miscarriage). The latter depend on the activation of the novel prothrombinase fgl2 on the fetal trophoblast and in maternal decidua by the T helper-1 (Th1) type cytokines TNF- alpha+gamma -interferon that arise from NK cells and NK gammadelta T cells; conversion of prothrombin to thrombin which in turn generates IL8 that activates polymorphonuclear leukocytes leads to embryonic death. These inflammatory processes are counteracted by Th2/3-type cytokines that arise in part from V gamma 1 delta 6 T cells reacting to, as yet, unidentified trophoblast antigens in the presence of the 'tolerance signaling molecule' OX-2. By contrast, peri-implantation losses (between implantation and formation of a vascularized placenta, analogous to occult losses in humans) appear to be dependent upon perforin(+)cells, complement activation, and products of alphabeta T and NK alphabeta T cells, but not on TNF- alpha or procoagulant activation. Similarities and differences between findings in the mouse and human, and the potential evolutionary significance of mechanisms affecting reproductive success are reviewed.
Abortion, Spontaneous↗
Activation of the novel prothrombinase, fg12, as a basis for the pregnancy complications spontaneous abortion and pre-eclampsia.
PROBLEM: Impaired trophoblast invasion during the first trimester of pregnancy is linked to spontaneous abortion, and defective invasion in the second trimester to hypertension + proteinuria (pre-eclampsia). Hypertension developing during the third trimester of human pregnancy represents, in part, a corrective response in the mother to provide adequate placental perfusion for fetal growth when trophoblast has not to invaded and converted the myometrial porprtion of maternal spiral arteries into to low resistance-high capacitance conduits. Deportation of vesicles from hypoxemic trophoblast is thought to cause hypertension plus proteinuria, vascular damage and a systemic coagulopathy. Trophoblast invasion may be inhibited by local cytokines, such as TGF-betas but Thl-type cytokines associated with pre-eclapmsia and spontaneous abortions (e.g., IL-1, TNF-alpha, IFN-gamma) are not known to inhibit migration at in situ concentrations. Trophoblast invasion is also inhibited by the binding of surface integrins to fibronectin and fibrin, and fibrin production is stimulated by these Th1 cytokines via up-regulation of prothrombinases(s) such as fg12 which directly and via TNF-alpha-facilitated inflamation compromise trophoblast cell integrity. We, therefore, asked if fg12 expression and TNF-alpha are increased in first trimester human miscarriage and in third trimester pre-eclampsia. METHODS: fg12 mRNA was detected using in situ hybridization and fg12 protein by immunohistochemistry. TNF-alpha mRNA and protein were similarly tested. The techniques were validated using uterine sections from day 8.5 of CBA x DBA/2 pregnancies, and then were applied to sections of placentae from normal and pre-eclamptic pregnancies with and without intrauterine fetal growth restriction (IUGR). Fibrin was detectectd by immunohistochemistry. RESULTS: Expression of fg12 protein correlated with fg12 mRNA expression in mouse uteri and in placentae from normal human pregnancies. Increased expression of fg12 and TNF-alpha mRNA and protein, and increased fibrin deposition was detected in placental trophoblast. CONCLUSIONS: Activation of fg12 prothrombinase by Th1-type cytokines in pregnancy may lead to spontaneous abortion, or in ongoing pregnancy, to pre-eclampsia and/or IUGR.
Abortion, Spontaneous↗
Long-term immunosuppression and drug interactions.
1. Early patient and graft survival are excellent after liver transplantation. 2. The focus must be on reducing toxicity associated with long-term immunosuppression. 3. Available new drugs offer the potential to reduce toxicity by combination therapy or replacement of toxic agents. 4. Individual patient immunosuppressive protocols should be developed. 5. Drug interactions are common and the source of significant morbidity.
Drug Interactions↗
Fgl2 prothrombinase expression in mouse trophoblast and decidua triggers abortion but may be countered by OX-2.
Spontaneous abortion of normal karyotype embryos in mice and in humans is associated with an increase in uterine T helper (Th) 1 type proinflammatory cytokines, tumour necrosis factor (TNF)-alpha, interferon-gamma and interleukin (IL)-1, and a deficiency of Th2/3 type cytokines, IL-4, IL-10, and transforming growth factor (TGF)-beta2. In mice, Th1 cytokines up-regulate a novel prothrombinase, fgl2, which via thrombin, leads to activation of polymorphonuclear leukocytes that terminate the pregnancy. Here we show that Th1 cytokines up-regulate fgl2 mRNA in fetal trophoblast and secondary decidua of CBA/JxDBA/2 and CBA/JxBALB/c matings, and promote fibrin deposition. This pattern is accompanied by a high rate of abortion. However, the spontaneous abortion rates in abortion-prone CBAxDBA/2 matings and in low abortion rate CBAxBALB/c matings were significantly lower than that expected from the frequency of implantations with high levels of fibrin and fgl2 mRNA(hi). As the glycoprotein OX-2 occurs in the pregnant rat uterus and can deviate cytokine responses to Th2/3, we investigated OX-2 in pregnant CBA/J mice. We found OX-2 mRNA was present at the same sites as fgl2 mRNA, but was reduced in response to Th1 cytokines. Furthermore, anti-OX-2 raised the abortion rate to predicted levels, while recombinant OX-2 dramatically reduced the abortion rate. Fgl2 prothrombinase may provide a mechanism explaining pregnancy loss, and conversely, successful pregnancy may be due in part to OX-2-dependent activation of maternal tolerance mechanisms at the feto-maternal interface.
Abortion, Spontaneous↗
C2 monitoring strategy for optimising cyclosporin immunosuppression from the Neoral formulation.
Profiling of absorption of cyclosporin microemulsion (Neoral) is a concept in therapeutic drug monitoring (TDM) designed to further optimise the clinical benefits of this formulation in transplant recipients. A single blood concentration measurement 2 hours after Neoral administration (C2) has been shown in both liver and kidney transplant recipients to be a significantly more accurate predictor of drug exposure than trough concentrations (C0), and its use results in a reduction in the incidence and severity of cellular rejection. In a prospective trial in de novo renal transplant recipients, patients who achieved target concentrations for area under the concentration-time curve over the first 4 hours postdose (AUC(0-4h)) of 4500 to 5500 ng. h/ml within 5 days of transplantation had a 7% incidence of histological acute rejection, compared with 37% rejection in those patients who did not achieve this target level. Of the single sampling points, C2 correlates best with AUC(0-4h) (r2 = 0.86); C(0) had the poorest correlation. In an international study in 21 centres examining the absorption profiling, C2 samples were the most accurate predictors of AUC(0-4h) and freedom from rejection. In liver transplant recipients receiving Neoral -based maintenance immunosuppression, adoption of Neoral C2 monitoring identifies patients who are both over- and under-dosed, which is not distinguished by C0 measurements. Further adjustment of C2 to recommended targets, even at 5 and 10 years after transplantation, results in reduction in nephrotoxicity without exposing the patient to the risk of rejection. In summary, despite a level of simplicity comparable to C0 measurement, Neoral absorption profiling, and specifically C2 measurement, is a much more sensitive approach to assessing the pharmacokinetics and predicting the clinical effect of this formulation in the individual patient, with a consequent marked reduction in the incidence of acute cellular rejection and improved long term graft function.
Cyclosporine↗
Lamivudine for hepatitis B in liver transplantation: a single-center experience.
BACKGROUND: Liver transplantation for hepatitis B virus (HBV) has been associated with a high rate of reinfection and graft failure. Lamivudine, a potent inhibitor of HBV replication, has been shown to prevent viral recurrence after transplantation. METHODS: The effectiveness of lamivudine monotherapy for the management of HBV recurrence after liver transplantation was assessed. Lamivudine was used in three patient groups: (1) patients started before transplantation and continued after transplantation (n = 13); (2) patients treated after transplantation (n = 15); and (3) patients with de novo hepatitis B after transplantation (n = 4). RESULTS: Median follow-up on lamivudine was 24 months. Active viral replication (HBV-DNA+) was seen in 17 (53%) of 32 at treatment initiation. All lost HBV-DNA at a mean of 2.4+/-1.6 months after lamivudine initiation. Twenty-six (81%) patients remain free of viral recurrence. Six (19%) patients have evidence of breakthrough infection with the YMDD mutant of HBV, two of whom progressed to graft failure. All four patients in group 1 who developed breakthrough had evidence of hepatitis B surface antigen expression in the explanted liver by immunohistochemistry despite being serum HBV-DNA negative before transplantation. No difference was observed among the three groups in DNA clearance or breakthrough rates. CONCLUSIONS: Lamivudine achieves viral DNA clearance in almost all patients. Expression of viral antigens in the liver seems to identify patients at risk of developing HBV-DNA recurrence. Disease-free survival of 81% at 22 months is similar to data with hepatitis B immunoglobulin therapy. Given the safe clinical profile and high efficacy in the prevention of disease recurrence, lamivudine will favorably change the outlook of liver transplantation for HBV.
Adult↗
Molecular and functional analysis of the human prothrombinase gene (HFGL2) and its role in viral hepatitis.
In the present studies, we report the cloning and structural characterization of the HFGL2 gene and its functional role in human fulminant hepatitis. The HFGL2 gene is approximately 7 kb in length with 2 exons. The putative promoter contains cis element consensus sequences that strongly suggest the inducibility of its expression. From the nucleotide sequence of the human gene, a 439-amino acid long protein is predicted. The overall identity between the murine fgl2 and hfgl2 coded proteins is over 70%. About 225 amino acids at the carboxyl end of these molecules are almost 90% identical, and correspond to a well-conserved fibrinogen-related domain. Both HFGL2 and FGL2 encode a type II transmembrane protein with a predicted catalytic domain toward the amino terminus of the protein. Transient transfection of Chinese hamster ovary (CHO) cells with a full-length cDNA of HFGL2 coding region resulted in high levels of prothrombinase activity. Livers from 8 patients transplanted for fulminant viral hepatitis were examined for extent of necrosis, inflammation, fibrin deposition, and HFGL2 induction. In situ hybridization showed positive staining of macrophages in areas of active hepatocellular necrosis. Fibrin stained positively in these areas and was confirmed by electron microscopy. These studies define a unique prothrombinase gene (HFGL2) and implicate its importance in the pathogenesis of fulminant viral hepatitis.
Adolescent↗
Neoral use in the liver transplant recipient.
This review and critical analysis of current trends of immunosuppression management in liver transplantation provides evidence and support for the continued role of Neoral as an indispensable part of immunosuppressive protocols. CyA formulation influences clinical outcomes such as acute rejection; this is confirmed by several multicenter studies. The CyA microemulsion formulation provides more reliable and effective absorption characteristics, and it may provide more rapid and complete immunosuppression in the de novo patient than IV administration. An advanced TDM strategy, particularly a 2-hour post-dose blood level (C-2), can improve the effectiveness and safety of immunosuppression in de novo liver transplant patients. There are potential risks resulting from CyA withdrawal strategies, as there is no evidence supporting this strategy. Neoral is an indispensable part of combination protocols in liver transplantation.
Cyclosporine↗
Neoral absorption profiling: an evolution in effectiveness.
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Absorption↗
Hepatitis C-related cirrhosis: a predictor of diabetes after liver transplantation.
Hepatitis C virus (HCV) infection has recently been suggested to be a risk factor for the development of diabetes mellitus. The aim of our study was to investigate whether the prevalence of diabetes is increased among liver transplant recipients infected with HCV. We compared the prevalence of diabetes among 278 liver transplant recipients whose original cause of liver failure was HCV infection (110 patients), hepatitis B virus infection (HBV; 53 patients), and cholestatic liver disease (CLD; 115 patients). The pretransplantation prevalence of diabetes was higher in the HCV group (29%) compared with the HBV (6%) and CLD (4%) groups (P <.001). The prevalence of diabetes remained higher in the HCV group 1 year after transplantation: 37%, 10%, and 5% in the HCV, HBV, and CLD groups, respectively (P <.001). The cumulative steroid dose during the first year of transplantation was significantly lower in the HCV group compared with the CLD group. Multivariate analysis revealed that HCV-related liver failure (P =.002), pretransplantation diabetes (P <.0001), and male sex (P =.019) were independent predictors of the presence of diabetes 1 year after transplantation. The high prevalence of diabetes persisted in the HCV group, with 41% diabetic at 5 years. The majority of patients with diabetes mellitus (89%) required insulin therapy after transplantation. Patient and graft survival rates were similar among patients with and without diabetes. In conclusion, our study shows that there is a high prevalence of diabetes among liver transplant recipients infected with HCV both before and after transplantation.
Adult↗
Immunosuppression in liver transplantation.
Prevention of graft rejection while minimizing morbidity remains the single most important objective in liver transplantation. Advances in immunosuppression have provided excellent patient and graft survival with relatively low incidences of acute rejection. However, it is apparent that the toxicity of the present immunosuppressive drugs accounts for much of the morbidity after transplantation. Attention is now being focused on combination drug therapies to reduce morbidity while maintaining the excellent results achieved with present immunosuppressive agents.
Adult↗
Outcome of long-term ribavirin therapy for recurrent hepatitis C after liver transplantation.
Ribavirin therapy was initiated at a median of 181 days after liver transplantation in 18 patients with persistent elevation of alanine aminotransferase values and biopsy-proven hepatitis, and continued for 23 months (12-44 months). All patients had a prompt biochemical response, with alanine aminotransferase decreasing by 69%; complete normalization occurred in 5 (28%). Serum hepatitis C virus RNA levels did not change during therapy. Liver biopsies obtained after 17 months (9-38 months) of therapy showed no improvement in necroinflammation. However, worsening of fibrosis occurred in 12 patients; and cirrhosis developed in 5 patients (28%), with 3 patients progressing to graft failure. Biopsies from 27 untreated patients who did not fulfill treatment criteria (median follow-up, 38 months) and 4 patients who received 3 months of ribavirin (44 months) showed cirrhosis in 11 and 75%, respectively. Patient and graft survival rates for treated and untreated patients were similar. Although ribavirin improves alanine aminotransferase, it does not prevent the development or progression of fibrosis in patients with recurrent hepatitis C virus.
Adult↗
Relationship of pharmacokinetics to clinical outcomes.
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Chemistry, Pharmaceutical↗
Neoral/cyclosporine-based immunosuppression.
The introduction of cyclosporine (CsA) has been a major advance. Its use paved the way for successful programs in heart, lung, liver, kidney, and kidney-pancreas transplantation. The recent introduction of Neoral has overcome many of the problems associated with the use of Sandimmune (Novartis, Basel, Switzerland), including poor bioavailability, dependence on bile for absorption, and need for intravenous CsA early in the postoperative period. The use of Neoral has resulted in (1) a marked reduction in the incidence of acute cellular rejection, (2) ability to discontinue steroid therapy in the early posttransplantation period, and (3) low toxicity profiles. In direct comparison with tacrolimus, Neoral was equally efficacious and less toxic. This is even more impressive when one now realizes the monitoring of Neoral has been inadequate, and with more sensitive monitoring tools, including peak CsA level; a surrogate marker for C(max), CsA blood concentrations 2 hours after drug intake; or area under the CsA time-concentration curve, rejection rates may be improved, with improvement in toxicity profiles.
Adult↗
The emerging role of immunoregulation of fibrinogen-related procoagulant Fgl2 in the success or spontaneous abortion of early pregnancy in mice and humans.
PROBLEM: Abortion of chromosomally normal embryos in the CBA X DBA/2 mating combination is triggered by release of Th1 cytokines (tumor necrosis factor [TNF]-alpha, interferon [IFN]-gamma, and interleukin [IL]-1), which cause abortion via a novel prothrombinase, Fgl2, and polymorphonuclear leukocytes. The site of activation may be maternal vascular endothelium on arteries and veins nourishing the placenta. Activation of coagulation is also prominent in spontaneous abortion of chromosomally normal human embryos. We asked where is Fgl2 up-regulated in the uterus in murine abortions, and if similar Fgl2 expression occurs in human pregnancy failure. METHODS: Control CBA X DBA/2 pregnant mice, or from mice injected with TNF-alpha + IFN-gamma on day 7.5 of gestation, were removed on day 8.5, fixed, sectioned, and subject to in situ hybridization for Fgl2. Sections were also stained for fibrin. Elective first trimester termination samples or biopsies taken early in the course of a recurrent miscarriage were similarly fixed, sectioned, and analyzed by in situ hybridization. Control and cytokine-treated mice were anticoagulated with heparin, an activator of antithrombin III, and/or the direct anti-thrombin inhibitor hirudin. RESULTS: Low level Fgl2 expression localized to basal decidua remote from the embryo was noted in control mice; cytokine treatment, which causes greater than 80% of abortions, produced a striking up-regulation in this area as well as in a band at the junction of decidua and myometrium. Trophoblast also became strikingly positive. Fgl2 expression was associated with increased fibrin staining. Anticoagulation significantly protected against abortions, but doses were limited by the complication of retroplacental hemorrhage. In tissue from normal first trimester pregnancy, minimal Fgl2 positivity was seen in some villous syncytiotrophoblast, in villous stroma, cytotrophoblast, and in some cells in decidua. In spontaneous abortion of normal embryo, striking Fgl2 positivity was seen in syncytiotrophoblast and extravillous cytotrophoblast, in association with areas of thrombus formation. CONCLUSIONS: Fgl2 appears to be physiologically expressed and may protect against the internal danger of maternal and/or fetal bleeding during pregnancy and at parturition; a role in inhibiting transplacental traffic is also possible. External dangers in the form of stress, endotoxin, and antigens eliciting Th1 cytokine responses upregulate Fgl2 prothrombinase in trophoblast as well as in decidua, which results in spontaneous abortion of immunogenetically "weaker" embryos.
Abortion, Spontaneous↗