tacrolimus and Stroke

Topics: Animals; Fibrinolytic Agents; Humans; Immunosuppressive Agents; Stroke; Tacrolimus; Thrombolytic Therapy

FK506 is a candidate drug for acute stroke. For such drugs, any decision to proceed to clinical trial should be based on a full and unbiased assessment of the animal data, and consideration should be given to the limitations of those data. Such an assessment should include not only the efficacy of a drug but also the in vivo characteristics and limits to that efficacy. Here we use systematic review and meta-analysis to assess the evidence for a protective effect of FK506 in animal models of stroke. In all, 29 studies were identified describing procedures involving 1759 animals. The point estimate for the effect of FK506 was a 31.3% (95% confidence interval 27.2% to 35.4%) improvement in outcome. Efficacy was higher with ketamine anaesthesia and temporary ischaemia and was lower in rats, in animals with comorbidities, and where outcome was measured as infarct size alone. Reported study quality was modest by clinical trial standards, and efficacy was lower in high-quality studies. These findings show a substantial efficacy for FK506 in experimental stroke, but raise concerns that our estimate of effect size might be too high because of factors such as study quality and possible publication bias.

Topics: Animals; Disease Models, Animal; Immunosuppressive Agents; Stroke; Tacrolimus

Neurodegenerative diseases, whether acute or chronic, are a tremendous medical problem in the modern world. Therapies are rare and only applied after a vast amount of neurons are lost. Many efforts have been made to develop new strategies to treat these disorders, but so far, there has been no breakthrough. A characteristic shared by some experimental neuroprotective substances is the induction of the heat shock response, in particular the expression of the heat shock proteins Hsp70 and Hsp27. These Hsps protect cells from cell death induced by various noxious stimuli and inhibit various cellular death pathways. Gene therapy, transgenic mice and drugs inducing Hsps in the brain decrease the infarction area after ischemia and protect neurons and nonneuronal cells of the brain. Furthermore, recent data hint toward a protective role of Hsps in chronic neurological diseases. The induction of Hsps as a possible treatment for stroke, Alzheimer's disease and Huntington's disease is discussed.

Topics: Alzheimer Disease; Animals; Apoptosis; Benzoquinones; Heat-Shock Proteins; Humans; Huntington Disease; Lactams, Macrocyclic; Neuroprotective Agents; Quinones; Stroke; Tacrolimus

Topics: Cerebral Infarction; Cyclosporine; Humans; Immunosuppressive Agents; Ligands; Neuroprotective Agents; Stroke; Tacrolimus

Varicella and zoster, produced by varicella-zoster virus (VZV), are associated with an increased risk of stroke that may be due to persistent inflammation and hypercoagulability. Because substance P is associated with inflammation, hypercoagulability, and atherosclerotic plaque rupture that may contribute to increased stroke risk after VZV infection, we measured serum substance P in simian varicella virus-infected rhesus macaques. We found significantly increased and persistent serum substance P concentrations during varicella and zoster compared with pre-inoculation, supporting the hypothesis that VZV-induced increases in serum substance P may contribute to increased stroke risk associated with VZV infection.

Topics: Animals; Biomarkers; Gene Expression; Herpesvirus 3, Human; Immunosuppressive Agents; Inflammation; Macaca mulatta; Male; Risk; Stroke; Substance P; Tacrolimus; Varicella Zoster Virus Infection; Virus Activation; Whole-Body Irradiation

To determine risk factors for early neurologic complications (NCs) after liver transplantation from perspective of recipient, donor, and surgeon.. In all, 295 adult recipients were enrolled consecutively between August 2001 and February 2014 from a single medical center in Taiwan. Any NC in the first 30 d post-liver transplantation, and perioperative variables from multiple perspectives were collected and analyzed. The main outcome was a 30-d NC. Generalized additive models were used to detect the non-linear effect of continuous variables on outcome, and to determine cut-off values for categorizing risk. Risk factors were identified using multiple logistic regression analysis.. In all, 288 recipients were included, of whom 142 (49.3%) experienced at least one NC, with encephalopathy being the most common 106 (73%). NCs prolonged hospital stay (35.15 ± 43.80 d vs 20.88 ± 13.58 d, P < 0.001). Liver recipients' age < 29 or ≥ 60 years, body mass index < 21.6 or > 27.6 kg/m(2), Child-Pugh class C, history of preoperative hepatoencephalopathy or mental disorders, day 7 tacrolimus level > 8.9 ng/mL, and postoperative intra-abdominal infection were more likely associated with NCs. Novel risk factors for NCs were donor age < 22 or ≥ 40 years, male-to-male gender matching, graft-recipient weight ratio 0.9%-1.9%, and sequence of transplantation between 31 and 174.. NCs post- liver transplantation occurs because of factors related to recipient, donor, and surgeon. Our results provide a basis of risk stratification for surgeon to minimize neurotoxic factors during transplantation.

Topics: Adrenal Cortex Hormones; Adult; Age Factors; Body Mass Index; Brain Diseases; Case-Control Studies; Consciousness Disorders; Delirium; Female; Graft Rejection; Hepatic Encephalopathy; Humans; Immunosuppressive Agents; Intraabdominal Infections; Length of Stay; Liver Transplantation; Male; Mental Disorders; Middle Aged; Mycophenolic Acid; Myelinolysis, Central Pontine; Neurotoxicity Syndromes; Posterior Leukoencephalopathy Syndrome; Postoperative Complications; Preoperative Period; Psychotic Disorders; Risk Assessment; Risk Factors; Seizures; Sex Factors; Stroke; Tacrolimus; Taiwan; Tissue Donors

Since the proportion of patients given thrombolytic therapy with tissue plasminogen activator (t-PA) is very limited because of the narrow therapeutic window, the development of new therapies for ischemic stroke has been desired. We previously reported that liposomes injected intravenously accumulate in the ischemic region of the brain via disruption of the blood-brain barrier that occurs under cerebral ischemia. In the present study, we investigated the efficacy of a liposomal neuroprotective agent in middle cerebral artery occlusion (MCAO) rats to develop ischemic stroke therapy prior to the recovery of cerebral blood flow. For this purpose, PEGylated liposomes encapsulating FK506 (FK506-liposomes) were prepared and injected intravenously into MCAO rats after a 1-h occlusion. This treatment significantly suppressed the expansion of oxidative stress and brain cell damage. In addition, administration of FK506-liposomes before reperfusion significantly ameliorated motor function deficits of the rats caused by ischemia/reperfusion injury. These findings suggest that FK506-liposomes effectively exerted a neuroprotective effect during ischemic conditions, and that combination therapy with a liposomal neuroprotectant plus t-PA could be a promising therapeutic strategy for ischemic stroke.

Topics: Animals; Brain Ischemia; Disease Models, Animal; Infarction, Middle Cerebral Artery; Liposomes; Male; Neuroprotective Agents; Oxidative Stress; Polyethylene Glycols; Rats; Rats, Wistar; Reperfusion Injury; Stroke; Tacrolimus

Cyclosporin A (CsA) has direct effects on neural stem and progenitor cells (together termed neural precursor cells; NPCs) in the adult central nervous system. Administration of CsA in vitro or in vivo promotes the survival of NPCs and expands the pools of NPCs in mice. Moreover, CsA administration is effective in promoting NPC activation, tissue repair and functional recovery in a mouse model of cortical stroke. The mechanism(s) by which CsA mediates this cell survival effect remains unknown. Herein, we examined both calcineurin-dependent and calcineurin-independent pathways through which CsA might mediate NPC survival. To examine calcineurin-dependent pathways, we utilized FK506 (Tacrolimus), an immunosuppressive molecule that inhibits calcineurin, as well as drugs that inhibit cyclophilin A-mediated activation of calcineurin. To evaluate the calcineurin-independent pathway, we utilized NIM811, a non-immunosuppressive CsA analog that functions independently of calcineurin by blocking mitochondrial permeability transition pore formation. We found that only NIM811 can entirely account for the pro-survival effects of CsA on NPCs. Indeed, blocking signaling pathways downstream of calcineurin activation using nNOS mice did not inhibit CsA-mediated cell survival, which supports the proposal that the effects are calcinuerin-independent. In vivo studies revealed that NIM811 administration mimics the pro-survival effects of CsA on NPCs and promotes functional recovery in a model of cortical stroke, identical to the effects seen with CsA administration. We conclude that CsA mediates its effect on NPC survival through calcineurin-independent inhibition of mitochondrial permeability transition pore formation and suggest that this pathway has potential therapeutic benefits for developing NPC-mediated cell replacement strategies.

Topics: Animals; bcl-Associated Death Protein; Calcineurin; Cell Count; Cell Survival; Cyclosporine; Male; Mice, Inbred C57BL; Neural Stem Cells; Nitric Oxide Synthase Type I; Recovery of Function; Signal Transduction; Spheroids, Cellular; Stroke; Tacrolimus

Neuroprotective and/or neuroregenerative activity of FK506, its derivatives, and to a lesser extent cyclosporin A (CsA) in animal models of neurodegenerative diseases of different etiology have been reported. Here, we verified a hypothesis that the most likely mechanism of their neuroprotective action is inhibition of the early steps of inflammatory activation of microglia by interference with mitogen-activated protein kinase (MAPK) signaling. The effect of immunosuppressants on lipopolysaccharide (LPS)-induced changes in morphology, proliferation, and motility of rat primary microglial cultures was evaluated. FK506 and CsA directly inhibited LPS-induced microglia activation and inflammatory responses. While both drugs efficiently reduced the expression of iNOS and the release of nitric oxide, only FK506 strongly inhibited the expression of Cox-2 and secretion of the mature form of IL-1β. FK506 strongly reduced LPS-induced activation of MAPK, and its downstream signaling crucial for inflammatory responses. Comparative analysis of global gene expression in rat ischemic brains and in LPS-stimulated microglial cultures revealed many genes and signaling pathways regulated in the same way in both systems. FK506 treatment blocked a majority of genes induced by an ischemic insult in the cortex, in particular inflammatory/innate immunity and apoptosis-related genes. Microglia-mediated inflammation is considered as one of the most important components of brain injury after trauma or stroke; thus, effective and multifaceted blockade of microglial activation by FK506 has clinical relevance and potential therapeutic implications.

Topics: Animals; Cyclooxygenase 2; Immunosuppressive Agents; Inflammation; Interleukin-1beta; Lipopolysaccharides; Microglia; Mitogen-Activated Protein Kinases; Rats; Stroke; 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

Cardiovascular disease is an important cause of morbidity and death in kidney transplant recipients. This study examines the Framingham risk score's ability to predict cardiac and stroke events. Because cyclosporine and tacrolimus have different cardiovascular risk profiles, these agents were also examined.. A prospective cohort evaluation of 540 patients were followed for a median of 4.7 yr in an outpatient kidney transplant clinic. Baseline Framingham risk scores were calculated and all cardiovascular outcomes were collected.. Rates per 100 patient-years were 1.79 for cardiac and 0.78 for stroke events. The ratio of observed-to-predicted cardiac events was 1.64-fold higher [95% confidence interval (CI) 1.19 to 2.94] for the cohort, 2.74-fold higher (95% CI 1.70 to 4.24) in patients age 45 to 60 with prior cardiac disease or diabetes mellitus, but not higher in other age subgroups. Stroke was not increased above predicted. Risk scores for cardiac (c = 0.65, P = 0.003) and stroke (c = 0.71, P = 0.004) events were modest predictors. 10-yr event scores for cardiac (9.3 versus 13.5%, P < 0.001) and stroke (7.1 versus 10.0%, P = 0.002) were lower for tacrolimus compared with cyclosporine-treated patients. However observed cardiac events were higher in tacrolimus recipients (2.50, 95% CI 1.09 to 5.90) in an adjusted Cox model.. Although risk scores are only modest predictors, patients with the highest event rates are easily identified. Treating high-risk patients with cardioprotective medications should remain a priority.

Topics: Adult; Age Factors; Aged; Ambulatory Care Facilities; Cardiovascular Agents; Cyclosporine; Diabetes Complications; Disease-Free Survival; Female; Health Status Indicators; Heart Diseases; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Predictive Value of Tests; Proportional Hazards Models; Prospective Studies; Risk Assessment; Risk Factors; Stroke; Tacrolimus; Time Factors

Tacrolimus (FK506), an immunosuppressive drug, has been shown to exert a potent neuroprotective activity when administered immediately after occlusion of the middle cerebral artery (MCA) in a nonhuman primate model of stroke. Here, we assessed the neuroprotective efficacy of tacrolimus with delayed treatment using the same model and compared with that of recombinant tissue plasminogen activator (rt-PA). Ischemic insult was induced by photochemically induced thrombotic occlusion of MCA in cynomolgus monkeys, and tacrolimus (0.2 mg/kg) and/or rt-PA (1.0 mg/kg) was intravenously administered 2 h after MCA occlusion. In another experiment, tacrolimus (0.1 mg/kg) was administered 4 h after MCA occlusion. Neurological deficits were monitored for 28 days after the ischemic insult and cerebral infarct volumes were measured with brain slices. With drug administration 2 h after the ischemic insult, tacrolimus significantly reduced neurological deficits and infarct volumes in the cerebral cortex without affecting the recanalization pattern in the MCA, however, rt-PA did not significantly improve neurological deficits or infarct volumes, even though it increased the recanalization rate of the occluded MCA. Combined treatment with tacrolimus and rt-PA exerted additional protection. Administration of tacrolimus 4 h after the ischemic insult still showed significant amelioration of neurological deficits. These results suggested that tacrolimus had a wider therapeutic time window than rt-PA in the nonhuman primate stroke model.

Topics: Animals; Brain; Cerebrovascular Circulation; Drug Administration Schedule; Drug Combinations; Fibrinolytic Agents; Injections, Intravenous; Macaca fascicularis; Male; Nervous System; Neuroprotective Agents; Recombinant Proteins; Stroke; Tacrolimus; Tissue Plasminogen Activator

FK-506 confers a neuroprotective effect and is thought to extend the time window for thrombolytic treatment of cerebral ischemia. These effects have not been assessed in an embolic stroke model. In addition, clinical studies have raised concern that FK-506 may increase the risk of hemorrhagic transformation by damaging vascular endothelial cells. We investigated whether combined administration of recombinant tissue plasminogen activator (rt-PA) and FK-506 would extend the therapeutic time window without increasing the hemorrhagic transformation in a rat embolic stroke model. Male Sprague-Dawley rats (n=66) were subjected to embolic infarction and assigned into eight groups. Six of the groups were treated with or without FK-506 (0.3 mg/kg) administration at 60 min after embolization, together with and all six groups received systemic rt-PA administration (10 mg/kg) at 60, 90, or 120 min. Two permanent ischemia groups were administered saline either with or without FK-506. Infarct and hemorrhagic volume were assessed at 24 h after embolization. Diffusion-weighted and perfusion-weighted magnetic resonance imaging (MRI) were performed in the groups administered rt-PA at 90 min and a vehicle control group to assess whether FK-506 influenced the effectiveness of MRI in revealing ischemic lesion. FK-506 extended the therapeutic time window for systemic thrombolysis compared to rt-PA alone without increasing the risk for hemorrhage. Combined therapy with FK-506 salvaged some of the MRI, revealing ischemic lesions destined to infarction in the animals treated by rt-PA alone. Single low dose of FK-506 alone did not ameliorate the embolic infarction, but it did prove effective in extending the therapeutic time windows for thrombolysis without increasing the risk of hemorrhagic transformation.

Topics: Analysis of Variance; Animals; Cerebral Hemorrhage; Cerebral Infarction; Disease Models, Animal; Drug Interactions; Embolism; Immunosuppressive Agents; Male; Rats; Rats, Sprague-Dawley; Stroke; Tacrolimus; Thrombolytic Therapy; Time Factors; Tissue Plasminogen Activator

The immunosuppressive agent FK506 (tacrolimus) has neuroprotective properties in an experimental model of cerebral ischemia. To improve the accuracy of clinical studies in acute stroke, a clinical dose setting should be based on the brain concentration, but not on the blood concentration of agents in humans. We have already established a measurement method using PET for FK506 concentration in the normal monkey brain, which could be applicable for human study; however, under ischemic conditions, in this study, we aimed to examine the brain concentration of FK506 in a monkey model of stroke.. Studies were performed on six male cynomolgus monkeys (Macaca fascicularis) and a middle cerebral artery (MCA) occlusion model was used. Regional cerebral blood flow (rCBF) was measured by an intravenous injection of [(15)O]H(2)O 165 min after MCA occlusion. FK506 (0.1 mg/kg) containing [(11)C]FK506 was intravenously injected into the monkeys 180 min after MCA occlusion, and dynamic PET images were acquired for 30 min after administration. FK506 concentrations in the brain were calculated in moles per liter (M) units using the specific activity of injected FK506.. MCA occlusion produced ischemia, confirmed by rCBF measurement before the administration of [(11)C]FK506. Fifteen minutes after FK506 (0.1 mg/kg) administration, the concentrations in the contralateral and ipsilateral cortex were 22.4+/-6.4 and 19.7+/-4.0 ng/g, respectively.. We successfully measured the brain concentration of FK506 in a monkey model of stroke. The difference between the contralateral and ipsilateral concentrations of FK506 was not significant. This characteristic that FK506 readily penetrates ischemic tissue as well as normal tissue might explain the neuroprotective effect of FK506 in the ischemic brain and is suitable for the treatment of stroke patients.

Topics: Animals; Brain Ischemia; Functional Laterality; Immunosuppressive Agents; Infarction, Middle Cerebral Artery; Injections, Intravenous; Macaca fascicularis; Male; Positron-Emission Tomography; Radiopharmaceuticals; Stroke; Tacrolimus

Standard treatment for autoimmune hemolytic anemia (AIHA) due to warm antibodies includes combinations of glucocorticoids, immunosuppressive drugs (mainly azathioprine) and splenectomy. Patients who are refractory or intolerant to these therapies constitute an important therapeutic challenge. Rituximab, an anti-CD20 chimeric monoclonal antibody, can effectively deplete B-cells and is commonly used in B-cell non-Hodgkin lymphoma. In addition, it is being increasingly used in autoimmune disorders, such as idiopathic thrombocytopenic purpura, AIHA, systemic lupus erythematosus or vasculitis. We report a case of warm AIHA associated to primary antiphospholipid syndrome (APS). The patient was refractory to high-dose corticosteroids. Splenectomy was discarded in view of the high risk of thrombotic and/or hemorrhagic perioperative complications, due to the presence of APS. After treatment with four weekly doses of rituximab the patients had a rapid and sustained response which allowed progressive tapering of prednisone dose to 5 mg/d. In addition, IgM anticardiolipin titres decreased from > 600 MPL to < 100 MPL. Thirteen further cases of warm AIHA in adults treated with rituximab have been reviewed, showing excellent tolerance and high response rates. Rituximab may be considered prior to splenectomy in patients with refractory AIHA and high risk of complications following splenectomy.

Topics: Anemia, Hemolytic, Autoimmune; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antiphospholipid Syndrome; Contraindications; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Methylprednisolone; Middle Aged; Postoperative Complications; Prednisone; Remission Induction; Rituximab; Splenectomy; Stroke; Tacrolimus; Vasculitis

Renal transplants (RTs) from elderly donors show a high incidence of delayed graft function, which may be increased by the initial use of calcineurin inhibitors.. The purpose of this study was to assess the safety and efficacy of an immunosuppressive regimen using anti-IL-2R antibodies and mycophenolate mofetil (MMF) with delayed introduction of low-dose tacrolimus in RT from elderly donors to elderly recipients.. This observational study in 13 centers included 78 patients, aged 61+/-7 years (range, 50-77), who received a kidney from a donor with a mean age of 64+/-5 years (range, 55-76), 94% of whom had died from a cardiovascular accident (CVA). Immunosuppression consisted of 1 mg/kg daclizumab in two doses (pre-RT and on day 14) combined with steroids, mycophenolate mofetil (initial dose of 2 g/d), and tacrolimus (0.1 mg/kg per day). Tacrolimus was introduced before day 7 (mean, 5.5 days) and adjusted to a target level of 5 to 8 ng/ml. The mean follow up was 27 weeks.. One graft was lost due to primary renal failure and 28 patients (36.4%) required dialysis due to delayed graft function, although it was generally of short duration (median, 4 days; only 2 cases >2 weeks). Acute rejection was seen in 11 patients (14%), with 9 of these confirmed by biopsy (11%, Banff 1997 grade I or II). Three patients withdrew from the study and two patients died (sepsis and accident). The remaining 72 patients continued follow up with a median 6-month creatinine value of 1.6 mg/dL. Sixty-seven percent of patients had at least one episode of infection, half of which were of urinary tract infections. There were nine cases of CMV infection.. These initial results suggest that this immunosuppressive regimen offers good efficacy with regard to short-term renal function, while maintaining both an acceptable low rejection rate and incidence of serious infections.

Topics: Age Factors; Aged; Cadaver; Cause of Death; Creatinine; Drug Administration Schedule; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Safety; Stroke; Tacrolimus; Time Factors; Tissue Donors