tacrolimus and Nervous-System-Diseases

Therapy for autoimmune demyelinating disorders has evolved rapidly over the past 10 years to include traditional immunosuppressants as well as novel biologicals. Antibody-mediated neuromuscular disorders are treated with therapies that acutely modulate pathogenic antibodies or chronically inhibit the humoral immune response. In other inflammatory autoimmune disorders of the peripheral and central nervous system, corticosteroids, often combined with conventional immunosuppression, and immunomodulatory treatments are used. Because autoimmune neurologic disorders are so diverse, evidence from randomized controlled trials is limited for most of the immunotherapies used in neurology. This review provides an overview of the immunotherapies currently used for neurologic disorders.

Topics: Adjuvants, Immunologic; Adrenal Cortex Hormones; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Azathioprine; Cyclophosphamide; Cyclosporine; Fingolimod Hydrochloride; Glatiramer Acetate; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Immunosuppressive Agents; Interferon beta-1a; Interferon beta-1b; Interferon-beta; Mitoxantrone; Mycophenolic Acid; Natalizumab; Nervous System Diseases; Peptides; Plasma Exchange; Propylene Glycols; Rituximab; Sphingosine; Tacrolimus

Non-immunosuppressive immunophilin ligands (NI-IPLs) are attracting attention as new candidate drugs for neuroprotection and/or neurorestoration, particularly since they do not have the adverse effects of immunosuppressants. However, it is not yet enough to understand that NI-IPLs are useful drugs for treating neurological disorders. In particular, the molecular mechanism of NI-IPL activity in target cells in the brain remains obscure. In this review, we focused on the molecular basis of the neuroprotective properties of IPLs. Our findings suggest that IPLs have neuroprotective effects mediated by multiple beneficial properties such as a glutathione (GSH)-activating effect, a neurotrophic factor (NTF)-activating effect, and an anti-apoptotic effect, but not by an immunosuppressive effect, both in cell cultures and in vivo. In particular, the GSH-activating effect and the NTF-activating effect of NI-IPLs may be essential to the expression of their neuroprotective properties. Thus, NI-IPLs might have a potentially beneficial effect by ameliorating neurological disorders, since they do not cause serious side effects such as immune deficiency.

Topics: Animals; Cyclosporine; Glutathione; Humans; Immunophilins; Immunosuppressive Agents; Ligands; Nerve Growth Factors; Nervous System Diseases; Neuroprotective Agents; Tacrolimus

Immunophilin ligands such as FK506 and Cyclosporin A, used in immunosuppression, are well-characterized drugs. In the past, they had been the center of attention as a putative therapeutic strategy for neuroregeneration and neuroprotection. In contrast to Cyclosporin A, FK506 readily crosses the brain-blood-barrier and, thus together with its derivatives, may represent a novel approach to the treatment of neurological disorders. FK506 exerts profound neuroprotective and neuroregenerative effects in vivo and in vitro. The mechanism underlying neuroregeneration is fairly well understood. It is independent of the inhibition of calcineurin, which is responsible for the immunosuppression, but operates via the binding of FKBP52 and the heat shock protein (Hsp) 90. In contrast, the underlying pathways of neuroprotection are far less understood. Protection is apparently independent of calcineurin, as shown by non-calcineurin inhibiting derivatives, such as V-10,367 and GPI-1046, but the intracellular actions remain to be defined. FK506 has been shown to interfere with the apoptotic pathway of neuronal cells, including inhibiting JNK activity, cytochrome c release, caspase 3 activation, and CD95 ligand expression. These effects are in part mediated by the inhibition of calcineurin and may not contribute to protection. Our recent studies suggest that the protective properties of FK506 and its non-calcineurin inhibiting derivatives are realized by a fast induction of heat shock proteins. The induction of the heat shock response by immunophilin ligands might prove to be an interesting target for neuroregeneration and neuroprotection.

Topics: Animals; Apoptosis; Calcineurin; Drug Evaluation, Preclinical; Forecasting; Heat-Shock Proteins; Immunophilins; Immunosuppressive Agents; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 4; Mitogen-Activated Protein Kinase Kinases; Nervous System Diseases; Neuroprotective Agents; Tacrolimus

FK506 (tacrolimus), initially developed as an immunosuppressant drug, represents a class of compounds with potential high impact for the treatment of human neurological disorders. While immunosuppression is mediated by the 12-kD FK506-binding-protein (FKBP-12), the neurite elongation activity of FK506 involves FKBP-52 (also known as FKBP-59 or Hsp-56), a component of mature steroid receptor complexes: FKBP-52 binds to Hsp-90, which bind to p23 and the steroid receptor protein to form the complex. The brief review focuses on how three classes of compounds (FK506 derivatives, steroid hormones, and ansamycin anti-cancer drugs, e.g., geldanamycin) increase neurite elongation/nerve regeneration (axonal elongation). A model is presented whereby neurite elongation is elicited by compounds that bind to steroid receptor chaperone proteins (e.g., FKBP-52 and Hsp-90) and thereby disrupt mature steroid receptor complexes (comprising FKBP-52, Hsp-90 and p23 in addition to the steroid receptor binding protein). Disruption of the complex leads to a "gain-of-function" whereby one or more of these steroid receptor chaperone proteins (i.e, FKBP-52, Hsp-90 or p23) activates mitogen-associated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) pathway. Thus, the neurotrophic actions of these distinct classes of compounds can be understood from their ability to bind steroid receptor chaperones, thereby providing a unique receptor-mediated means to activate the ERK pathway. These studies thereby shed new light on the intrinsic mechanism regulating axonal elongation. Furthermore, this mechanism may also underlie calcineurin-independent neuroprotective actions of FK506. We suggest that components of steroid receptor complexes are novel targets for the design of neuroregenerative/neuroprotective drugs.

Topics: Animals; Cyclosporine; Humans; Immunophilins; Ligands; Nerve Regeneration; Nervous System Diseases; Signal Transduction; Tacrolimus

Immunophilins are receptors for immunosuppressive drugs like cyclosporin A, FK506, rapamycin and their non- immunosuppressive analogs, which are collectively referred to as "immunophilin ligands" (IPL). Cyclosporin A binds to a class of IP called cyclophilins, whereas the receptors for FK506 and rapamycin belong to the family of FK506- binding proteins (FKBP). The latter are designated according to their molecular weight: FKBP12, 25, 52 etc. FKBP levels in the rat brain are up to 50 times higher than in the immune system. FKBP12 is associated with IP3 and ryanodine receptors present on the endoplasmic reticulum and plays a role in stabilizing calcium release. It has also been proposed to be a modulator of the TGFbeta receptor activity. Crush injury of facial or sciatic nerves in rat leads to markedly increased FKBP12 levels in the respective nerve nuclei and this increase is related to nerve regeneration. Cyclophilin A protects cells from death following expression of mutant Cu/ Zn superoxide dismutase, which is associated with familial amyotrophic lateral sclerosis. Our recent studies show that FKBP12 and FKBP52 are expressed in the human nervous system, especially in the substantia nigra- deep gray matter axis. In neurodegenerative diseases, FKBP12 levels increase in neurons situated in areas of pathology. This IP colocalizes with synaptophysin and alpha- synuclein, suggesting that it may become a novel marker of pathology. Immunophilins participate in axonal transport, synaptic vesicle assembly and may play a role in neuroprotection against abnormal protein aggregation, suggesting a potential avenue of therapeutic interventions.

Topics: Animals; Cyclosporine; Humans; Immunophilins; Nerve Regeneration; Nervous System Diseases; Neurons; Signal Transduction; Tacrolimus

Between 10%-28% of patients who receive the immunosuppressant cyclosporine (CsA) experience some form of neurotoxic adverse event. Both sensorial motoric functions may be adversely affected, and thus patients present with a wide range of neurological and psychiatrical disorders. Mild symptoms are common and include tremor, neuralgia, and peripheral neuropathy. Severe symptoms affect up to 5 % of patients and include psychoses, hallucinations, blindness, seizures, cerebellar ataxia, motoric weakness, or leukoencephalopathy. Tacrolimus is associated with similar neurotoxic adverse events. Neurotoxicity may result in serious complications for some patients, particularly recipients of orthotopic liver transplants. Factors that may promote the development of serious complications include advanced liver failure, hypertension, hypocholesterolemia, elevated CsA or tacrolimus blood levels, hypomagnesemia, and methylprednisolone. Occipital white matter appears to be uniquely susceptible to the neurotoxic effects of CsA; injury to both the major and minor vasculature may cause hypoperfusion or ischemia and local secondary toxicity in the white matter. Calcineurin inhibition by CsA and tacrolimus alters sympathetic outflow, which may play a role in the mediation of neurotoxic and hypertensive adverse events. The symptoms of CsA- and tacrolimus-associated neurotoxicity may be reversed in most patients by substantially reducing the dosage of immunosuppressant or discontinuing these drugs. However, some patients have experienced permanent or even fatal neurological damage even after dose reduction or discontinuation. CsA-sparing and tacroli-mus-sparing drug regimens that use the immunosuppressant mycophenolate mofetil, which has no neurotoxic effects, may reduce the incidence and severity of neurotoxic adverse events while maintaining an adequate level of immunoisuppression.

Topics: Calcineurin Inhibitors; Cyclosporine; Humans; Immunosuppressive Agents; Mental Disorders; Nervous System Diseases; Neurotoxins; Postoperative Complications; Tacrolimus; Transplantation Immunology

Neuroimmunophilin ligands are a class of compounds that hold great promise for the treatment of nerve injuries and neurological disease. In contrast to neurotrophins (e.g., nerve growth factor), these compounds readily cross the blood-brain barrier, being orally effective in a variety of animal models of ischaemia, traumatic nerve injury and human neurodegenerative disorders. A further distinction is that neuroimmunophilin ligands act via unique receptors that are unrelated to the classical neurotrophic receptors (e.g., trk), making it unlikely that clinical trials will encounter the same difficulties found with the neurotrophins. Another advantage is that two neuroimmunophilin ligands (cyclosporin A and FK-506) have already been used in humans (as immunosuppressant drugs). Whereas both cyclosporin A and FK-506 demonstrate neuroprotective actions, only FK-506 and its derivatives have been clearly shown to exhibit significant neuroregenerative activity. Accordingly, the neuroprotective and neuroregenerative properties seem to arise via different mechanisms. Furthermore, the neuroregenerative property does not involve calcineurin inhibition (essential for immunosuppression). This is important since most of the limiting side effects produced by these drugs arise via calcineurin inhibition. A major breakthrough for the development of this class of compounds for the treatment of human neurological disorders was the ability to separate the neuroregenerative property of FK-506 from its immunosuppressant action via the development of non-immunosuppressant (non-calcineurin inhibiting) derivatives. Further studies revealed that different receptor subtypes, or FK-506-binding proteins (FKBPs), mediate immunosuppression and nerve regeneration (FKBP-12 and FKBP-52, respectively, the latter being a component of steroid receptor complexes). Thus, steroid receptor chaperone proteins represent novel targets for future drug development of novel classes of compounds for the treatment of a variety of human neurological disorders, including traumatic injury (e.g., peripheral nerve and spinal cord), chemical exposure (e.g., vinca alkaloids, Taxol) and neurodegenerative disease (e.g. , diabetic neuropathy and Parkinson's disease).

Topics: Animals; Brain Injuries; Carpal Tunnel Syndrome; Cyclosporine; Humans; Immunophilins; Immunosuppressive Agents; Ligands; Nerve Regeneration; Nervous System Diseases; Spinal Cord Injuries; Tacrolimus; Tacrolimus Binding Protein 1A

Topics: Diabetes Mellitus; Humans; Kidney; Neoplasms; Nervous System Diseases; Tacrolimus

An open-label, randomized, 3-way crossover, drug-drug interaction study of the investigational anti-HBV combination agent, emtricitabine/tenofovir DF and the antirejection agent, tacrolimus was conducted in healthy volunteers to evaluate the potential for a pharmacokinetic interaction between these drugs.. Subjects received emtricitabine/tenofovir DF (200/300 mg q.d.) and tacrolimus (0.1 mg/kg/day) alone or in combination for 7 days, with a 2-week washout between successive treatments. Drug concentrations were measured by LC/MS/MS and steady state pharmacokinetic parameters were calculated for each drug using noncompartmental methods.. The 90% confidence intervals (CIs) of the geometric least-squares mean ratio for AUCtau, Cmax and Ctau for each drug together vs. alone were within the predetermined no-effect boundaries of 80 - 125% (representing a maximum 20% effect), other than the upper limit of the 90% CI for tenofovir Cmax, which was just outside the 125% threshold.. It was concluded that there was no clinically relevant pharmacokinetic interaction between emtricitabine/tenofovir DF and tacrolimus when administered together.

Topics: Adenine; Adult; Area Under Curve; Deoxycytidine; Dose-Response Relationship, Drug; Drug Interactions; Emtricitabine; Female; Flatulence; Half-Life; Humans; Immunosuppressive Agents; Male; Middle Aged; Nervous System Diseases; Organophosphonates; Patient Dropouts; Tacrolimus; Tenofovir; Time Factors; Young Adult

This follow-up multicenter analysis is based on 362 pancreas allograft recipients at 14 institutions who were given tacrolimus between 1 May 1994 and 15 November 1995. Three groups were studied: (1) recipients given tacrolimus initially for induction and maintenance therapy (n = 250; 215 without, 35 with, a concurrent bone marrow transplant), (2) recipients who converted to tacrolimus for rescue or rejection therapy (n = 89), and (3) recipients who converted to tacrolimus for other reasons (n = 23). Of 215 recipients without a bone marrow transplant in the induction group, 166 (77%) underwent a simultaneous pancreas-kidney transplant (SPK), 29 (14%) a pancreas transplant alone (PTA), and 20 (9%) a pancreas after previous kidney transplant (PAK). Initial antibody therapy was given to 185 (86%) recipients. All 215 received tacrolimus and prednisone; 202 (94%) also received azathioprine (AZA) and 11 (5%) mycophenolate mofetil (MMF). The most common side effects of tacrolimus were neurotoxicity in 21%, nephrotoxicity in 21%, gastrointestinal (GI) toxicity in 13%, and diabetogenicity in 13% of these recipients. No recipient in this group developed new-onset insulin-dependent diabetes mellitus. Of 89 recipients in the rescue group, 71 (79%) had an SPK, 11 (13%) a PTA, and 7 (8%) a PAK. Before conversion, all had been on cyclosporine (CsA)-based immunosuppression; 74% of them had 2 or more rejection episodes previously. The most common side effects were nephrotoxicity in 27%, neurotoxicity in 26%, GI toxicity in 18%, and diabetogenicity in 8% of these recipients. No recipient in this group developed new-onset insulin-dependent diabetes mellitus. In the induction group patient survival at 1 yr was 98% for SPK, 79% for PTA, and 100% for PAK recipients. According to a matched-pair analysis, pancreas graft survival for SPK recipients at 1 yr was 88% with tacrolimus vs. 73% with CsA (p = 0.002); for PTA recipients, 68% vs. 70% (p > 0.35); and for PAK recipients, 85% vs. 65% (p = 0.13). Graft loss from rejection was not different with tacrolimus vs. CsA in all 3 pancreas recipient categories. At 1 yr, 17% of recipients had converted from tacrolimus to CsA for diabetogenicity, nephrotoxicity, or rejection; 23% had converted from AZA to MMF. The incidence of post-transplant lymphoma was < 2%. In the rescue group, patient survival rates at 1 yr were 96% for SPK, 100% for PTA, and 86% for PAK recipients (p < 0.08). Pancreas graft survival at 1 yr was 89% for SPK, 58% for

Topics: Adult; Anti-Inflammatory Agents; Azathioprine; Bone Marrow Transplantation; Case-Control Studies; Cyclosporine; Diabetes Mellitus; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Gastrointestinal Diseases; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Diseases; Kidney Transplantation; Lymphoma; Male; Muromonab-CD3; Mycophenolic Acid; Nervous System Diseases; Pancreas Transplantation; Prednisone; Prospective Studies; Randomized Controlled Trials as Topic; Survival Rate; Tacrolimus; Transplantation, Homologous

FK506 has been proven effective for prevention and treatment of liver allograft rejection. Herein, we compare FK506-based immunosuppression with an effective quadruple immunosuppressive regimen, including cyclosporine and antithymocyte globulin. The results of a single center participating in the European multicenter FK506 study are reported, including immunosuppressive efficacy as well as toxicity. One-year patient and graft survival was 96.7% and 90.0% for the CsA group and 90.2% and 88.5% for the FK506 group, which is not statistically different. The incidence and severity of acute rejection episodes during the first postoperative year was similar in both treatment groups with 34.4% and 33.3% for the FK506 and CsA treatment group, respectively. Immunosuppressive potency was better for the FK506 group compared with the CsA group according to the incidence of chronic rejection. Furthermore, 5 patients (8.3%) required conversion to FK506 for immunological reasons, i.e., refractory acute or chronic rejection. The incidence of moderate and severe neurotoxicity during the early postoperative period was higher in the FK506 group (21.3%) compared with the CsA group (11.7%), while the incidence of renal insufficiency and acute renal failure was similar (18.0% and 18.3% for the FK506 and CsA treatment groups, respectively). The incidence of CMV infection was significantly higher under treatment with CsA (25.0%) than with FK506 (6.6%) (P < or = 0.05), while the incidence of pneumonia (13.1% and 13.3%), cholangitis (29.5% and 26.7%), and urinary tract infection (39.3% and 28.3% for the FK506 and CsA treatment groups, respectively) was similar in both treatment groups. However, infection was more serious in some cases treated with FK506, and evolved as the main cause of death in the FK506 treatment group. Therefore, caution should be paid to over immunosuppression and toxicity in FK506-treated patients. Regarding the monitoring of FK506, FK506 plasma level failed to be a reliable indicator, and therefore we recommend measurement of whole blood FK506 levels. Our data indicate that immunosuppressive potency of FK506 is greater than that of CsA, especially concerning the incidence of chronic rejection.

Topics: Adolescent; Adult; Aged; Cyclosporine; Cytomegalovirus Infections; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Nervous System Diseases; Opportunistic Infections; Renal Insufficiency; Survival Analysis; Tacrolimus; Transplantation, Homologous

The introduction of cyclosporine A (CsA) and FK506 significantly improved the outcome of liver transplantation. However, the postoperative course and outcome of liver transplant recipients in still compromised by rejection, over-immunosuppression-induced infection and immunosuppression-associated toxicity. In the present study, we evaluated the reason for conversion between immunosuppressive regimens in 121 patients, 60 treated with FK506 and 61 patients treated with CsA-based immunosuppression. Five patients treated primarily with CsA (8.3%) were converted to FK506 therapy because of refractory acute of chronic rejection within 12 months following liver transplantation (LTX). In 2 patients, conversion was performed after Re-LTX. In 4 of these 5 patients, rejection was successfully treated according to histological and laboratory investigations, while in the remaining patient, graft function improved with persisting histological evidence of chronic rejection. Moderate and severe neurologic symptoms during the early postoperative period, i.e. organic brain syndromes (OBS), seizures, hemiparesis, dysphasia, dysathria and cerebellar symptoms were observed in 21.3% of patients treated with FK506 and in 11.7% of patients treated with CsA (p = n.s.). Five patients treated primarily with FK506 were converted to CsA due to severe neurotoxicity. Early postoperative renal insufficiency was observed to a similar extent with 42.6% of FK506- and 36.7% of CsA-treated patients. 8.3% of FK506-treated patients and 11.7% of CsA-treated patients required hemodialysis (p = n.s.) There patients were converted from FK506 to CsA due to persisting renal insufficiency. Moderate and severe neurologic symptoms were observed more frequently under treatment with FK506 than CsA, and all conversions from FK506 to CsA (13.3%) were performed because of neuro- or nephrotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Cyclosporine; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Liver Transplantation; Nervous System Diseases; Survival Rate; Tacrolimus

Since we may soon be able to choose between primarily CsA- or FK506-based immunosuppression, it is important to establish the superior immunosuppressive agent for the individual patient. In the present study, 121 patients, 61 randomly assigned to FK506- and 60 assigned to CsA-based immunosuppression, were analyzed according to the primary diagnosis for liver transplantation. One-year patient survival was similar in all groups. However, the incidence and severity of acute rejection within the 1st year after transplantation was significantly higher in patients transplanted due to HCV disease who were receiving FK506 (58.8%) compared with those patients receiving CsA (27.8%; p < or = 0.05). Furthermore, the incidence of moderate and severe neurotoxicity was significantly higher during the 1st month after LTX in patients transplanted owing to HCV disease treated with FK506 (35.3%) compared with those patients receiving CsA (16.7%; p < or = 0.05). Irrespective of the immunosuppressive regimen, the incidence of early postoperative neurotoxicity was significantly lower in patients transplanted owing to HBV disease, alcoholic cirrhosis and various other liver diseases summarized than in patients transplanted due to HCV disease receiving FK506 therapy. During the 1st year, the incidence and severity of rejection in patients transplanted due to alcoholic cirrhosis and PBC was significantly lower in patients treated with FK506 (11.1% for both groups) compared with those patients receiving CsA (54.5% and 60.0%, respectively; p < or = 0.05. Furthermore, this was accompanied by a lower incidence of toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Cyclosporine; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Liver Transplantation; Nervous System Diseases; Tacrolimus

Neurological complications were examined in a multicentre, randomized, parallel-group study of 545 patients undergoing primary liver transplantation to compare the efficacy and safety of FK 506- and cyclosporin A-based immunosuppressive regimens (CBIR). In an additional analysis, patients were divided into early and late randomized cohorts to detect the influence of protocol amendements that allowed for FK 506 dose reductions. Initial follow-up was for 6 months. Tremor, headache and insomnia were the most frequently reported adverse events involving the neurological system. Whereas these neurological symptoms were observed significantly more often in FK 506-treated patients (P < 0.05 vs. CsA for the overall population), this was no longer the case for the late FK 506 and CBIR cohorts. The risk of FK 506-treated patients developing tremor was related to the initial i.v. dose, the rate of administration of the i.v. dose and the daily dose (P < 0.01). Headache was significantly correlated with the FK 506 dose (P < 0.05), and insomnia was not related to any dosing variable. Major neurological symptoms, including psychosis, convulsion, coma, aphasia and intracranial haemorrhage, were reported with a low frequency (0.4-5.2%), and differences between both treatment groups were neither significant for the overall population nor for the early and late cohorts of FK 506 and CBIR. Data from the late cohorts showed no differences in the overall incidence of neurological adverse events between FK 506- and CBIR-treated patients.

Topics: Cyclosporine; Drug Therapy, Combination; Europe; Graft Rejection; Headache; Humans; Immunosuppressive Agents; Liver Transplantation; Muromonab-CD3; Nervous System Diseases; Sleep Initiation and Maintenance Disorders; Survival Rate; Tacrolimus; Time Factors; Tremor

Topics: Adult; Cyclosporine; Female; Humans; Liver Transplantation; Male; Nervous System Diseases; Tacrolimus

At our institution, tacrolimus is used as a second-line agent for the prevention and treatment of graft-versus-host-disease in the allogeneic hematopoietic stem cell transplantation (HSCT) unit after patients have experienced a serious or intolerable adverse event to cyclosporine. As per our standard practice, tacrolimus is administered via 2-h intermittent IV infusions (IIVs) every 12 h rather than continuous IV infusion. Shorter infusion times are cautioned due to concerns of higher rates of nephrotoxicity, neurotoxicity and infusion-related reactions, although there is a paucity of data to support this claim. Our primary objective was to evaluate the safety of a 2-h IIV of tacrolimus in an adult HSCT population. We retrospectively reviewed the charts of 104 patients who received tacrolimus by IIV (3574 doses; median = 22, range 1-158, IQR = 28) from 2002 to 2016. Primary outcomes collected include rates of nephrotoxicity, neurotoxicity and infusion-related reactions. One (0.9%) grade 2 infusion-related reaction occurred and resolved without discontinuation of tacrolimus. Of 16 incidences (13.6%) of nephrotoxicity, all but 10 (8.5%) cases resolved. Precipitating factors for nephrotoxicity unrelated to tacrolimus were identified in all 10 cases. There were 41 incidences (35%) of neurotoxicity, of which, 8 (6.8%) were considered serious. All neurotoxicity reverted to baseline or resolved completely. We propose that a 2-h IIV of tacrolimus is a safe method of administration in the adult HSCT setting.

Topics: Acute Kidney Injury; Adolescent; Adult; Aged; Cyclosporine; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Incidence; Infusions, Intravenous; Male; Middle Aged; Nervous System Diseases; Patient Safety; Retrospective Studies; Tacrolimus; Young Adult

The cause of post-transplant CNI-NCs is multifactorial and not ascribed solely to CNI toxicity. A total of 90 children (aged <20 years) who underwent LDLT were evaluated to investigate the predictive factors associated with CNI-NCs. Twelve patients (13.3%) developed CNI-NCs after LDLT (age range, 2-15 years). The symptoms of CNI-NCs were seizures, VD, and stupor. The median onset of CNI-NCs was 10 days (range, 5-30 days) post-transplant. In the univariate analysis, higher recipient age at LDLT, donor age and recipient's BW, lower actual GV/SLV and TAC dosage/BW, and higher mean T-Bil and sodium level for 7 days after transplantation were independently significantly associated with TAC-NCs. Multivariate analysis showed that the T-Bil level in the first week after LDLT was the only significant independent predictive factor for TAC-NCs (HR, 1.588; 95% CI, 1.042-2.358; P=.031). In conclusion, CNI-NCs occurred most frequently in children over 5 years and were associated with hyperbilirubinemia for 7 days post-transplant, regardless of TAC levels. The transplant team should refer to a neurologist to define the diagnosis and to collaborate to resolve the neurological problems.

Topics: Adolescent; Age of Onset; Bilirubin; Body Weight; Calcineurin Inhibitors; Child; Child, Preschool; Female; Humans; Hyperbilirubinemia; Immunosuppressive Agents; Infant; Liver Failure; Liver Transplantation; Living Donors; Male; Multivariate Analysis; Nervous System Diseases; Postoperative Complications; Proportional Hazards Models; Retrospective Studies; Risk Factors; Stupor; Tacrolimus

Experimental study with rats.. To evaluate functional and histological effects of tacrolimus (FK 506) and erythropoietin (EPO) after experimental spinal cord contusion injury (SCI).. Brazil.. Wistar rats (n=60) were submitted to SCI with the NYU Impactor system. The control group received saline; the EPO group received EPO; the group EPO+FK 506 received EPO associated with tacrolimus and the group FK 506 received tacrolimus only. The Sham group underwent SCI, but did not receive any drug. Locomotor function was evaluated after SCI by BBB (Basso, Beattie and Bresnahan) weekly and by the motor-evoked potential test in 42 days. The spinal cord was histologically evaluated.. There was a significant difference between treated and the control groups from the seventh day on for BBB scores, with no difference between the groups EPO and EPO+FK 506 by the end of the study. There were significant differences between groups for necrosis and bleeding, but not for hiperemia, degeneration and cellular infiltrate. Axon neuron count was different between all groups (P=0.001), between EPO+FK 506 and FK 506 (P=0.011) and between EPO+FK 506 and Sham (P=0.002). Amplitude was significantly different between all groups except between control and sham. For latency, there was no difference.. This study did not reveal significant differences in the recovery of locomotor function, or in the histological and electrophysiological analysis in animals treated with EPO and tacrolimus after thoracic SCI.

Topics: Animals; Disease Models, Animal; Erythropoietin; Evoked Potentials, Motor; Follow-Up Studies; Immunosuppressive Agents; Locomotion; Nervous System Diseases; Rats; Rats, Wistar; Recovery of Function; Spinal Cord Injuries; Statistics, Nonparametric; Tacrolimus; Time Factors

Topics: Aged; Fatal Outcome; Female; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Nervous System Diseases; Renal Dialysis; Renal Insufficiency; Survival Analysis; Tacrolimus; Time Factors; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome

Early diagnosis and treatment of acute cellular rejection (ACR) after intestinal transplantation (ITx) is challenging. We report the outcome of three patients: two presented mild ACR improved with steroids. One presented steroid-resistant severe rejection, improved after rabbit anti-thymocyte globulin (r-ATG), but unfortunately died for encephalitis caused by opportunistic infections.

Topics: Adolescent; Anastomosis, Surgical; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Basiliximab; Child; Daclizumab; Encephalitis; Fatal Outcome; Female; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Intestinal Diseases; Intestinal Volvulus; Intestines; Male; Nervous System Diseases; Recombinant Fusion Proteins; Short Bowel Syndrome; Tacrolimus

Tropisetron is widely used to counteract chemotherapy-induced emesis. Evidence obtained from human and animal studies shows that tropisetron possesses anti-inflammatory properties. In this study, we assessed the effect of tropisetron on brain damage in a rat thromboembolic model of stroke. Stroke was rendered in rats by introduction of an autologous clot into the middle cerebral artery (MCA). Tropisetron (1 or 3mg/kg); m-chlorophenylbiguanide (mCPBG), a selective 5-HT(3) receptor agonist (15 mg/kg); tropisetron (3mg/kg) plus mCPBG (15 mg/kg); granisetron (3mg/kg); tacrolimus (1mg/kg); or tacrolimus (1mg/kg) plus tropisetron (3mg/kg) were administered intraperitoneally 1h prior to embolization. Behavioral scores and infarct volume as well as myeloperoxidase (MPO) activity and tumor necrosis factor-alpha (TNF-α) level were determined in the ipsilateral cortex 4h and 48 h following stroke induction. Forty-eight hours after embolization, tropisetron (1 or 3mg/kg), tropisetron (3mg/kg) plus mCPBG (15 mg/kg), tacrolimus (1mg/kg), or tacrolimus (1mg/kg) plus tropisetron (3mg/kg) significantly curtailed brain infarction, improved behavioral scores, diminished elevated tissue MPO activity, and reduced TNF-α levels compared to control group (n=6; P<0.05). mCPBG or granisetron had no effect on the mentioned parameters. Tropisetron attenuates brain damage after a thromboembolic event. Beneficial effects of tropisetron in this setting are receptor independent.

Topics: Analysis of Variance; Animals; Biguanides; Blood Gas Analysis; Brain Edema; Brain Infarction; Brain Injuries; Cerebral Cortex; Disease Models, Animal; Dose-Response Relationship, Drug; Immunosuppressive Agents; Indoles; Ischemia; Male; Nervous System Diseases; Peroxidase; Rats; Rats, Wistar; Seizures; Serotonin Antagonists; Stroke; Tacrolimus; Tropisetron; Tumor Necrosis Factor-alpha

Liver transplantation is the only curative treatment in patients with end-stage liver disease. Neurological complications (NC) are increasingly reported to occur in patients after cadaveric liver transplantation. This retrospective cohort study aims to evaluate the incidence and causes of NC in living donor liver transplant (LDLT) patients in our transplant center. Between August 1998 and December 2005, 121 adult LDLT patients were recruited into our study. 17% of patients experienced NC, and it occurred significantly more frequently in patients with alcoholic cirrhosis (42%) and autoimmune hepatitis (43%) as compared with patients with hepatitis B or C (9/10%, P = 0.013). The most common NC was encephalopathy (47.6%) followed by seizures (9.5%). The choice of immunosuppression by calcineurin inhibitor (Tacrolimus or Cyclosporin A) showed no significant difference in the incidence of NC (19 vs. 17%). The occurrence of NC did not influence the clinical outcome, since mortality rate, median ICU stay and length of hospital stay were similar between the two groups. Most patients who survived showed a nearly complete recovery of their NC. NCs occur in approximately 1 in 6 patients after LDLT and seem to be predominantly transient in nature, without major impact on clinical outcome.

Topics: Brain Diseases; Cohort Studies; Cyclosporine; Female; Hepatitis B; Hepatitis C; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Incidence; Liver Cirrhosis, Alcoholic; Liver Diseases; Liver Transplantation; Male; Middle Aged; Nervous System Diseases; Retrospective Studies; Seizures; Tacrolimus; Treatment Outcome

Neurological complications (NCs) represent a serious problem following liver transplantation and may develop either because of various peri-operative factors or the toxicity of immunosuppression. Although the causality assessment of NCs can be particularly difficult in the setting of organ transplantation, calcineurin inhibitors (CNIs) might influence NCs to a certain extent, regardless of the etiology. Therefore, minimizing the influence of CNIs could be a reasonable strategy for alleviating NCs. Based on our hypothesis that lipid supplementation prevents lipophilic CNIs from crossing the blood-brain barrier, soybean oil was administered to five liver transplant patients with NCs. In all of these patients, the neurological symptoms improved without discontinuing or reducing the dose of CNIs. Thus, lipid supplementation might be able to reduce the adverse neurological effects of CNIs.

Topics: Adult; Aged; Blood-Brain Barrier; Calcineurin Inhibitors; Cyclosporine; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Nervous System Diseases; Soybean Oil; Tacrolimus

Among 71 patients, 19 (26.7%) experienced tacrolimus-related complications including 15 neurologic reactions and four problems with nephrotoxicity. Seven of these patients received grafts from cadaveric donors and 12 from living donors. Nine patients were children. The cohort included 5 female and 14 male subjects of mean age 26 +/- 20 (min 6, max 65) years. The common indications for the liver transplantation were cholestatic and metabolic diseases in pediatric patients, and viral hepatitis in adult patients. Blood tacrolimus levels were within the normal range. All patients with neurologic complications received antiepileptic therapy and drug conversion to rapamycin in 4 cases and to cyclosporine (CsA) in 11 cases. Six cases with Wilson disease and all cases with tyrosinemia experienced neurologic complications, which reversed in all but one case. In four cases with nephrotoxicity, we switched to rapamycin. Renal function improved in all cases. Patients with Wilson disease and tyrosinemia were more susceptible to the neurologic side effects of tacrolimus. In these cases we recommend the use of drugs with fewer neurologic side effects. Tacrolimus also has nephrotoxic effects, which can be reversed by converting to rapamycin.

Topics: Cyclosporine; Hepatolenticular Degeneration; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Nervous System Diseases; Postoperative Complications; Psychotic Disorders; Retrospective Studies; Risk Factors; Tacrolimus

The safety and efficacy of tacrolimus (Tac)-based immunosuppressive treatments were studied in 115 pediatric renal transplant recipients (mean follow-up period, approximately 20 months). The acute rejection rate was 22.7% 6 months after transplantation and the steroid-resistant acute rejection rate was 6.4%. The 5-year patient and graft survival rates were 98.6% and 95.9%, respectively. Major adverse effects included infection, ie, cytomegalovirus (CMV) antigenemia (41.7%), renal dysfunction (29.6%), and impaired glucose tolerance (20.9%). The incidences of these adverse events were significantly decreased among patients who had undergone transplantation after March 2000 (n = 43), namely, 30.2%, 18.6%, and 11.6%, respectively.

Topics: Adult; Cadaver; Female; Follow-Up Studies; Glucose Intolerance; Graft Rejection; Humans; Immunosuppressive Agents; Infections; Japan; Kidney Transplantation; Living Donors; Male; Nervous System Diseases; Postoperative Complications; Retrospective Studies; Survival Analysis; Tacrolimus; Time Factors; Tissue Donors

Neurotoxicity is a well-recognized side effect of calcineurin inhibitors. Rapamycin is considered to be significantly less neurotoxic than calcineurin inhibitors (CNIs). The aim of this study was to retrospectively analyze a group of post-liver transplant patients who had been converted to rapamycin because of CNI-related neurotoxicity.. Orthotopic liver transplantation (OLT) was performed in 56 consecutive patients between April 1, 2003, and August 15, 2004. Immunosuppression was administered with tacrolimus, mycophenolic acid, and corticosteroids.. Seven patients were converted to rapamycin due to new-onset neurotoxicity or exacerbation of previous neurological symptoms secondary to CNI. None of the patients had toxic levels tacrolimus (>15 ng/mL) at the time of symptoms, which persisted despite reduction of CNI dose. The indications for conversion were: (1) peripheral neuropathy; (2) seizure; (3) metabolic encephalopathy; and (4) central pontine myelinolysis. All patients showed improvement or resolution of their neurological symptoms after conversion to rapamycin. Two patients died, the first due to a hypoxic event and the second due to central pontine myelinolysis with limited improvement and a family decision to withdraw care. There were no complications directly attributed to rapamycin. Specifically, there were no thrombotic events, wound complications, or biliary leaks. Three patients had a rejection episode that was successfully treated with pulse corticosteroids and low-dose tacrolimus (levels < 5 ng/mL).. Rapamycin can be safely used in OLT recipients with severe neurological symptoms ascribed to or exacerbated by CNIs. Rapamycin monotherapy may be inadequate to control rejection early after transplantation. Rapamycin can be combined with low doses of CNI to prevent rejection.

Topics: Adrenal Cortex Hormones; Adult; Calcineurin Inhibitors; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Nervous System Diseases; Sirolimus; Survival Analysis; Tacrolimus; Treatment Outcome

We examined the frequency, reasons and outcome after conversion from Tacrolimus to Cyclosporine A. From August 1989 to December 1992, 1000 consecutive liver transplantation patients were studied, which included 834 adults (age>18 yr.) and 166 children with mean follow-up of 77 months (range 56 to 96). A prospectively populated electronic database was queried to identify patients that underwent conversion, the clinical indication and outcomes. Thirty-seven out of 834 adult recipients (4.43%), mean age of 48.4+/-12.9 years, 19 male (51.35%) and 18 females (48.64%) required conversion from Tacrolimus to Cyclosporine A baseline immunosuppressive therapy. No pediatric patient required conversion. The mean time interval from liver transplantation to Cyclosporine A conversion was 443.45+/-441.44 days (range 22 to 1641). The clinical indications for conversion included: 20 neurological (54%), 6 gastrointestinal (16%), 5 hematological (14%), and 6 other (16%) scenarios. Seven of the 37 patients (18.9%) died. The causes of death were multi-organ failure (2), sepsis (2), pancreatitis (1), hepatic failure due to relapse of ethanol abuse (1), and unknown cause (1). Nine out of 37 patients (24.32%) had to be reconverted to Tacrolimus (mean 282.22+/-499.79 days; range 15 to 1583 day with a median of 135) after institution of Cyclosporine A; none showed recurrence of the original symptoms. The reasons for these re-conversions were acute cellular rejection (44%, n=4), chronic rejection (11%, n=1), increased hepatic enzymes (33%, n=3) and progressively worsening neurological symptoms (11%, n=1). The frequency of conversion from Tacrolimus to Cyclosporine A was 4.43%. Conversion is safe and efficacious if done in a controlled setting. Additionally, re-conversion to Tacrolimus for lack of efficacy of Cyclosporine A did not appear to be associated with a recurrence of the condition that caused the initial switch.

Topics: Adult; Aged; Cyclosporine; Female; Gastrointestinal Diseases; Graft Rejection; Hematologic Diseases; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Nervous System Diseases; Retreatment; Retrospective Studies; Tacrolimus; Treatment Outcome

Topics: Adolescent; Adult; Aged; Cadaver; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Nervous System Diseases; Postoperative Complications; Retrospective Studies; Seizures; Tacrolimus; Tissue Donors

Although cyclosporine (CsA) made clinical liver transplantation possible, side effects and development of rejection have limited its use. In some patients, conversion to tacrolimus has been necessary to abrogate side effects and to preserve allograft function.. The results of conversion from CsA to tacrolimus were studied retrospectively in 94 liver allograft recipients from a North American and a European transplant center (Duke University Medical Center, Durham, NC, and Hopital Beaujon, Clichy, France).. Forty-seven of 94 patients (50%) were converted for steroid-resistant acute rejection. Conversion was successful in 91% of these patients, whereas 9% of patients developed chronic rejection. A further nine patients were converted for chronic allograft rejection with positive results in eight of nine grafts. Mean serum bilirubin in these nine patients was 8.7 mg/dl before conversion and 2.1 mg/dl 6 months after conversion (P=0.02). Nine patients were converted due to inability to wean steroid. Of these, six patients remains steroid free 1 year after conversion. Twenty-three patients (24%) were converted for nephrotoxicity with a reduction in serum creatinine from 167+/-36 mmol/L to 119+/-28 mmol/L 1 year after conversion (P=0.006). Eight of 11 patients converted for neurotoxicity improved after conversion. Conversion to tacrolimus had no effect on seizure frequency or memory loss.. These results suggest that conversion to tacrolimus from CsA is an appropriate paradigm for graft rescue and treatment of a variety of side effects after liver transplant. However, some situations such as memory loss and hypertension may require other strategies.

Topics: Adult; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Liver; Liver Function Tests; Liver Transplantation; Male; Middle Aged; Nervous System Diseases; Retreatment; Retrospective Studies; Salvage Therapy; Steroids; Tacrolimus

Neurological complications after orthotopic liver transplantation (OLTX) have remained a major concern in a small proportion of patients. The etiology of these complications is often thought to be multifactorial: the influence of calcineurin inhibitors is occasionally thought to play an important role. When neurotoxicity occurs after OLTX under tacrolimus, it is usually a minor complication and responds readily to a reduction in the dosage of or a temporary withdrawal of tacrolimus. However, neurotoxic complications occasionally do not respond to this conventional process. Neoral is a microemulsion formulation of cyclosporine. It has more consistent pharmacokinetic parameters and improved bioavailability when compared with conventional cyclosporine. The aim of the present report was to evaluate the role of Neoral in OLTX recipients with neurotoxic complication who failed to respond to a reduction in the dosage of tacrolimus.. Between August 1995 and November 1997, 330 adults (age >18 years) received primary OLTX under tacrolimus-based immunosuppression (mean age 52.6+/-11.4 years). There were 190 men and 140 women. Twenty-three (7%) patients (mean age 53.2+/-11.8 years; 17 men, 6 women) were converted to Neoral (mean 35+/-41 days after OLTX). These patients were followed until June 1998 (mean follow-up 22.7+/-7.8 months).. Four (17.4%) patients died during the follow-up period, and two patients underwent retransplantation. Neurological symptoms improved in all patients who survived. Adequate trough concentrations were achieved in all patients with p.o. Neoral. Nine (39%) patients experienced rejection episodes after conversion. Six (26.1%) patients were converted back to tacrolimus because of ongoing rejection (n=3), retransplantation (n=2), or persistent nausea and vomiting (n=1) without recurrence of the original neurological complication.. Neurological complications after OLTX disorders that occur under tacrolimus and that fail to respond to a reduction in the dosage can be treated safely by conversion to Neoral. However, the rate of rejection is up to 39%, and patients can often be converted back to tacrolimus without recurrence of the original neurological complication.

Topics: Adult; Aged; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Nervous System Diseases; Postoperative Complications; Reoperation; Retreatment; Tacrolimus; Tomography, X-Ray Computed

When tacrolimus side effects persist despite dose reduction, conversion to cyclosporine-based immunosuppression (CyA) is necessary. We characterized tacrolimus side effects that warranted discontinuation of the drug, and outcomes after conversion. Of 388 liver recipients who received tacrolimus as primary immunosuppression, 70 required conversion to CyA. We recorded indication for conversion, whether conversion was early or late after transplantation, tacrolimus dose and trough blood level at conversion, and incidence of rejection after conversion. Conversion was early in 29 patients (41.4%) and late in 41 (58.6%). Indications for early conversion were neurotoxicity (20), (insulin-dependent) diabetes mellitus (IDDM) (5), nephrotoxicity (3), gastrointestinal (GI) toxicity (6), and cardiomyopathy (1), and for late conversion were neurotoxicity (15), IDDM (12), nephrotoxicity (3), GI toxicity (5), hepatotoxicity (6), post-transplant lmphoproliferate disease (PTLD) (2), cardiomyopathy (1), hemolytic anemia (1), and pruritus (1). All early-conversion patients showed improvement/resolution of symptoms. Among late-conversion patients, 37 (90.2%) had improvement/resolution; in 4 (9.8%), adverse effects persisted. The overall rejection rate was 30%. Sixty-two patients (88.6%) are alive with functioning grafts 686 +/- 362 days (range, 154-1433 days) after conversion. When tacrolimus side effects are unresponsive to dose reduction, conversion to CyA can be accomplished safely, with no increased risk of rejection and excellent long-term outcome.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Cyclosporine; Diabetes Mellitus, Type 1; Female; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Nervous System Diseases; Retrospective Studies; Tacrolimus

Topics: Cholesterol; Cyclosporine; Follow-Up Studies; Humans; Hypertension; Immunosuppressive Agents; Kidney; Liver Function Tests; Liver Transplantation; Nervous System Diseases; Retrospective Studies; Tacrolimus; Triglycerides

Although immunosuppressant immunophilin ligands promote neurite outgrowth in vitro, their neurotrophic activities are clearly independent of their immunosuppressive activity. In the present report, a novel nonimmunosuppressive immunophilin ligand, GPI-1046 (3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate+ ++) is described. In vitro, GPI-1046 bound to FK506 binding protein-12 and elicited neurite outgrowth from sensory neuronal cultures with picomolar potency with maximal effects comparable to nerve growth factor. In vivo, GPI-1046 stimulated the regeneration of lesioned sciatic nerve axons and myelin levels. In the central nervous system, GPI-1046 promoted protection and/or sprouting of serotonin-containing nerve fibers in somatosensory cortex following parachloroamphetamine treatment. GPI-1046 also induced regenerative sprouting from spared nigrostriatal dopaminergic neurons following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice or 6-hydroxydopamine (6-OHDA) toxicity in rats. The rotational abnormality in 6-OHDA treated rats was alleviated by GPI-1046. These neurotrophic actions in multiple models suggest therapeutic utility for GPI-1046 in neurodegenerative diseases.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Carrier Proteins; Cells, Cultured; Chickens; Disease Models, Animal; DNA-Binding Proteins; Dopamine Agents; Heat-Shock Proteins; Male; Mice; Nerve Crush; Nerve Regeneration; Nervous System Diseases; Neurites; Neurons; Oxidopamine; Parkinson Disease; Pyrrolidines; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Serotonin; Tacrolimus; Tacrolimus Binding Proteins; Tyrosine 3-Monooxygenase

Cyclosporine (CsA)-associated side effects include nephrotoxicity, hypertension, neurological disorders, and hyperlipidemia. A considerable share of early and long-term posttransplant morbidity is likely to be drug related.. In 31 patients with stable graft function, conversion from CsA to tacrolimus was implemented due to nephrotoxicity (n=19), hypertension (n=9), and neurological disorders (n=8).. Three months after conversion, a response was evident in 26 patients (84%), whereas 5 patients (16%) were nonresponsive. In 13 of 19 patients (68%) suffering from nephrotoxicity, serum creatinine levels decreased significantly from 2.0+/-0.5 mg/dl to 1.5+/-0.4 mg/dl (P<0.005), whereas in 6 of 19 patients (32%) no improvement was observed. Antihypertensive therapy was reduced in six of nine patients and neurological disorders improved in six of eight patients. When analyzing all patients, average levels of cholesterol and triglycerides were significantly lower after conversion when compared with at the time of conversion (P<0.05). Conversion to tacrolimus reduced drug-related side effects in the majority of patients, while graft function remained stable. Conversion to tacrolimus may be considered for CsA-related side effects as a potential beneficial approach.

Topics: Adult; Aged; Creatinine; Cyclosporine; Drug Therapy, Combination; Female; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Kidney; Liver Transplantation; Male; Middle Aged; Morbidity; Nervous System Diseases; Retrospective Studies; Tacrolimus; Time Factors

The purpose of this study is to describe the neuroimaging (CT and MR imaging) findings in liver transplant patients who develop severe neurologic side effects during immunosuppressive therapy with tacrolimus and to correlate these findings with clinical signs and tacrolimus levels in blood.. Brain CT and/or MR imaging was performed on six patients who developed neurologic symptoms while receiving tacrolimus in the post-transplant period. All patients were evaluated by the neurology staff, and imaging studies were independently interpreted by three neuroradiologists. Trough tacrolimus levels in blood were measured with the IMX immunoassay and were correlated with neurologic symptoms and imaging findings.. Imaging abnormalities were observed in five of six patients during the course of their neurologic illnesses. For each patient, neurologic symptoms began when the tacrolimus level in blood was at a peak, exceeding the therapeutic limit in all but one case. In five patients, neurologic symptoms eventually resolved after the tacrolimus dose was reduced or after the drug was stopped. Multifocal low attenuation of white matter was the predominant finding seen on CT images, and matching hyperintense white matter foci were observed on long-TR MR images. In three patients, clinical recovery was accompanied by reversal of the white matter abnormalities seen on CT and MR images.. Immunosuppressive therapy with tacrolimus may produce neurologic side effects that are associated with brain CT and MR imaging abnormalities. Resolution of symptoms and reversal of imaging findings occur when the tacrolimus dose is reduced.

Topics: Adult; Brain; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Magnetic Resonance Imaging; Male; Middle Aged; Nervous System Diseases; Tacrolimus; Tomography, X-Ray Computed

Topics: Adolescent; Adult; Cyclosporine; Female; Follow-Up Studies; Hepatolenticular Degeneration; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Male; Nervous System Diseases; Postoperative Complications; Prednisolone; Retrospective Studies; Tacrolimus; Time Factors

We report FK506-induced neurotoxicity in 14 of 44 consecutive patients following orthoptic liver transplantation. In 10 of these 14 patients, postural hand tremors were found in the first weeks following surgery, transient apraxia of speech in 3, and generalized tonic-clonic seizures were noted in 2 patients. Other manifestations included nightmares, agitation, and acute delirium. Reduction of the FK506 dose resulted in resolution of symptoms, but in 1 patient mild speech difficulties and in 3 patients a fine tremor remained. Blood and plasma levels of FK506 were similar in patients with and without neurotoxicity. FK506 neurotoxicity in patients with liver transplantation commonly results in transient neurological manifestations. The incidence of neurotoxicity in FK506 is dramatically reduced in maintenance doses of 0.075 mg/kg twice a day.

Topics: Adult; Female; Humans; Liver Transplantation; Male; Middle Aged; Nervous System Diseases; Tacrolimus

The objective of this study was to define the severe neurological complications that occur in recipients of an orthotopic liver transplantation, receiving FK 506 as their primary immunosuppressive agent. To accomplish this, 100 consecutive orthotopic liver transplantation patients were followed prospectively from the time of their transplant until the date of their initial post-orthotopic liver transplantation discharge from hospital. All major neurological complications occurring during this period were recorded and assessed. The frequency of severe neurological complications occurring in these severely ill transplant recipients was 34%. Delirium was noted in 16, coma in 9, seizures in 4, and 5 developed focal motor deficits associated with the finding of a brain abscess, transient ischemic attack or central pontine myelinolysis. At the time at which a major neurologic complication was noted, the blood level of FK 506 was recorded. No direct relationship between FK 506 blood levels and the presence or absence of major neurologic complications of orthotopic liver transplantation could be demonstrated. Based upon this series, it can be concluded that although FK 506 may contribute to the pathogenesis of minor neurological complications seen after orthotopic liver transplantation such as tremors and headaches, the pathogenesis of most of the major neurologic complications occurring after orthotopic liver transplantation is multifactorial and cannot be ascribed solely to FK 506 toxicity.

Topics: Female; Graft Rejection; Humans; Immunosuppression Therapy; Incidence; Liver Transplantation; Male; Middle Aged; Nervous System Diseases; Prednisone; Prospective Studies; Tacrolimus; Time Factors

Nitric oxide (NO) is a potent biological messenger molecule in the central nervous system (CNS). There are several potential sources of NO production in the CNS, including neurons and endothelial cells which express NO synthase (NOS) constitutively. Astrocytes and microglia can be induced by cytokines to express a NOS isoform similar to macrophage NOS (mNOS). Primary mixed glial cultures exposed to lipopolysaccharide (LPS) or a combination of LPS and gamma-interferon (INF-gamma) produce nitrite, a breakdown product of NO formation, in a dose-dependent manner. Nitrite production is detectable at 12 hr, peaks at 48 hr and is sustained for at least 96 hr. The NOS inhibitor, nitro-L-arginine (NArg), inhibits nitrite formation, but the immunosuppressant agent, FK506, does not. In mixed glial-neuronal cultures exposed to 50 ng LPS or 5 ng LPS and 1 microgram INF-gamma, neurons begin to die at 48 hr, approx. 24-36 hr after detectable nitrite production. Neurotoxicity is attenuated by 100 microM NArg. These data indicate that expression of inducible mNOS causes delayed neurotoxicity.

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Cells, Cultured; Cerebral Cortex; Interferon-gamma; Lipopolysaccharides; Nerve Degeneration; Nervous System Diseases; Neuroglia; Neurons; Nitric Oxide Synthase; Nitrites; Nitroarginine; Rats; Tacrolimus

To study the neurological sequelae in liver transplanted recipients, 25 patients were followed up between 5 and 30 months after transplantation and another 14 patients were seen before and after transplantation. Physical examination took special note of tremor and polyneuropathy; additionally, patients estimated concentration and memory, tremor, paraesthesias and sleep disturbances on a self-rating scale. Tremor was reported to be preexistent in 50% of the later FK 506 and cyclosporin group and only temporarily rose afterwards. Twenty-eight percent complained of tremor and 20% said that it interfered mildly with daily activity. Only 2 of 39 patients showed new signs of polyneuropathy. Concentration and memory improved significantly after transplantation. In the second group of patients, MRI, EEG, lumbar puncture and neuropsychological tests were done just before and routinely after transplantation, revealing numerous preexisting neurological deficits with only singular changes afterwards.

Topics: Adrenal Cortex Hormones; Adult; Cyclosporine; Follow-Up Studies; Humans; Immunosuppressive Agents; Liver Transplantation; Middle Aged; Nervous System Diseases; Neurologic Examination; Physical Examination; Postoperative Complications; Tacrolimus; Time Factors

Topics: Actuarial Analysis; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Graft Survival; Humans; Hypertension; Kidney; Kidney Function Tests; Liver Transplantation; Male; Middle Aged; Nervous System Diseases; Potassium; Tacrolimus

Topics: Adult; Cyclosporine; Female; Gastrointestinal Diseases; Humans; Liver Transplantation; Male; Nervous System Diseases; Quality of Life; Retrospective Studies; Tacrolimus

Topics: Bilirubin; Cyclosporine; Humans; Nervous System Diseases; Retrospective Studies; Tacrolimus; Transplantation Immunology