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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunosuppressive agents increase the risk of death due to coronary disease or stroke by their ability to cause 3 different adverse effects: dyslipidaemia, hypertension and hyperglycaemia. Post-transplant diabetes mellitus has emerged as a major adverse effect of immunosuppressants. As recipients of organ transplants survive longer, the secondary complications of diabetes mellitus have assumed greater importance. There is a need for a precise definition of post-transplant diabetes mellitus to facilitate inter-centre comparison and to study the natural history of post-transplant diabetes mellitus. We recommend broad criteria to define hyperglycaemia, as a fasting blood glucose level of > 400 mg/dl at any point or > 200 mg/dl for 2 weeks, or a need for insulin treatment for at least 2 weeks. We also recommend serial measurements of HbA1c. Cyclosporin and tacrolimus cause post-transplant diabetes mellitus by a number of mechanisms, including decreased insulin secretion, increased insulin resistance or a direct toxic effect on the beta cell. For corticosteroids, the induction of insulin resistance seems to be the predominant factor. However, few studies have examined the mechanism of diabetogenicity at the molecular level. This may hold the key for pharmacological manipulation of current immunosuppressive regimens which may result in decreased metabolic complications. Corticosteroid sparing regimens have been shown to reduce the metabolic complications of immunosuppressants including post-transplant diabetes mellitus. However, their use should be balanced against the increased incidence of transplant rejections. Post-transplant diabetes mellitus may be organ-specific irrespective of the immunosuppressant used. Tacrolimus causes a high incidence of post-transplant diabetes mellitus in recipients of kidney transplants (upto 20% in some reports); the diabetogenicity of cyclosporin-based regimens is comparable with that of tacrolimus-based regimens in recipients of liver transplants. A few clinical studies in which attempts were made to discontinue cyclosporin resulted in an unacceptable loss of the transplant. In the case of tacrolimus, complete withdrawal of immunosuppression may be possible in selected patients with liver transplants. However, post-transplant recipients who may benefit from this approach are difficult to identify. In some early series, patients received doses of tacrolimus that were approximately 2 to 3 times higher than those currently used, which may have resulted in a higher incidence of post-transplant diabetes mellitus. More recently, it has been shown that tacrolimus was successful in salvaging whole pancreatic grafts which were maintained on cyclosporin. Tacrolimus-based immunosuppression as primary therapy was also used with remarkable success in solitary whole pancreas transplants. Strategies to reduce the metabolic complications of immunosuppressants should be pursued aggressively as this will directly lead to a decrease in long term cardiovascular adverse effects.
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PMID:Post-transplant diabetes mellitus. The role of immunosuppression. 911 92

Tacrolimus (FK506), a potent immunosuppressive drug, is effective in attenuating brain infarction after cerebral ischemia. However, there has been no report characterizing the neuroprotective action and therapeutic time window of tacrolimus systematically using different types of stroke models and extended observation periods. Therefore, we evaluated the neuroprotective effect of tacrolimus in three different animal models of cerebral ischemia: transient and permanent focal ischemia in rats and transient global ischemia in gerbils. Tacrolimus at doses higher than 0.1 mg/kg (i.v.) produced a statistically significant reduction in ischemic brain damage following permanent and transient focal ischemia in rats when administered immediately after the onset of ischemia. Tacrolimus (1 mg/kg, i.v.) demonstrated similar neuroprotective activity even after delayed administration (2 h after permanent or 1 h after transient focal ischemia). The neuroprotective effect of tacrolimus was still present 2 weeks after transient focal ischemia and 1 week after permanent focal ischemia. After transient global ischemia in gerbils, tacrolimus (1 mg/kg, i.v.) given immediately after reperfusion also produced long-lasting neuroprotective effects with a protective time-window of 1-2 h. Taken together, the results clearly indicate that tacrolimus exerts potent, long-term neuroprotective effects with a favorable therapeutic time-window, regardless of the model of cerebral ischemia. These results strengthen the notion that tacrolimus might be of clinical value for the treatment of acute stroke.
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PMID:Neuroprotective action of tacrolimus (FK506) in focal and global cerebral ischemia in rodents: dose dependency, therapeutic time window and long-term efficacy. 1259 Nov 30

Tacrolimus (FK506), an immunosuppressive drug, is known to have potent neuroprotective activity and attenuate cerebral infarction in experimental models of stroke. Here we assess the neuroprotective efficacy of tacrolimus in a nonhuman primate model of stroke, photochemically induced thrombotic occlusion of the middle cerebral artery (MCA) in cynomolgus monkeys. In the first experiment, tacrolimus (0.01, 0.032, or 0.1 mg/kg) was intravenously administered immediately after MCA occlusion, and neurologic deficits and cerebral infarction volumes were assessed 24 hours after the ischemic insult. Tacrolimus dose-dependently reduced neurologic deficits and infarction volume in the cerebral cortex, with statistically significant amelioration of neurologic deficits at 0.032 and 0.1 mg/kg and significant reduction of infarction at 0.1 mg/kg. In the second experiment, the long-term efficacy of tacrolimus on neurologic deficits and cerebral infarction was assessed. Vehicle-treated monkeys exhibited persistent and severe deficits in motor and sensory function for up to 28 days. A single intravenous bolus injection of tacrolimus (0.1 or 0.2 mg/kg) produced long-lasting amelioration of neurologic deficits and significant reduction of infarction volume. In conclusion, we have provided compelling evidence that a single dose of tacrolimus not only reduces brain infarction but also ameliorates long-term neurologic deficits in a nonhuman primate model of stroke, strengthening the view that tacrolimus might be beneficial in treating stroke patients.
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PMID:Tacrolimus, a potential neuroprotective agent, ameliorates ischemic brain damage and neurologic deficits after focal cerebral ischemia in nonhuman primates. 1452 29

Between April 1995-December 2003, 1,324 deceased donor kidney transplantations were performed in 139 transplant institutes in Japan. Of these, 45 transplants were from heart-beating and 1,279 transplants were from non-heart-beating deceased donors (NHBDD). Clinical outcomes for the 1,279 recipients of NHBDD kidney transplants were investigated. The overall 5-year patient and graft survival rates were 90% and 72%, respectively. A total of 112 NHBDD kidney grafts never functioned after transplantation and the recipients had to remain on dialysis. The causes of nonfunction were rejection, primary nonfunction, death, thrombosis and others in the order of the incidence. The major causes of graft loss were nonfunction, death, chronic rejection and acute rejection in that order. Major causes of recipient deaths were pneumonia, sepsis and CVA within 12 months, and heart diseases, sepsis, malignancy and pneumonia more than 12 months after transplantation. Kidneys from female donors, donors aged 15 or less or over age 60, donors with extrinsic causes of death other than head trauma, recipients over age 60 and those with diabetic nephropathy as their original disease were found to be at risk for poor graft survival. The lowest and last donor serum creatinine level did not influence the incidence of nonfunction or graft survival. However, graft survival was significantly poorer among recipients of older "expanded" donor kidneys than for recipients of younger grafts. The warm and total ischemia times should be kept shorter than 30 minutes (better 15 minutes), and 12 hours, respectively to minimize the incidence of nonfunction and early graft loss. It is especially important in cases with WIT over 30 minutes that the total ischemia should be kept within 12 hours. Cannulation before cardiac standstill was important to reduce the incidence of nonfunction and achieve high graft survival rates with NHBDD kidneys. The discontinuance of ventilator support also reduced the incidence of graft nonfunction. The combination of CsA or Tacrolimus and MMF as both the induction and maintenance regimen significantly improved graft survival. The use of either anti-T cell antibodies or basiliximab was also associated with significantly better graft survival for NHBDD kidneys. The combination of basiliximab, CsA and MMF resulted in a graft survival rate of 98% at one and 2 years.
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PMID:Outcomes of kidney transplants from non-heart-beating deceased donors as reported to the Japan Organ Transplant Network from April 1995-December 2003: a multi-center report. 1670 41

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.
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PMID:Therapeutic time window of tacrolimus (FK506) in a nonhuman primate stroke model: comparison with tissue plasminogen activator. 1716 59

FK506 (Tacrolimus) has the potential to decrease cerebral ischemia-reperfusion injury. However, the clinical trial of FK506 as a neuroprotectant failed due to adverse side effects. This present study aimed to conduct the selective delivery of FK506 to damaged regions, while at the same time reducing the dosage of FK506, by using a liposomal drug delivery system. First, the cytoprotective effect of polyethylene glycol-modified liposomes encapsulating FK506 (FK506-liposomes) on neuron-like pheochromocytoma PC12 cells was examined. FK506-liposomes protected these cells from H2O2-induced toxicity in a dose-dependent manner. Next, we investigated the usefulness of FK506-liposomes in transient middle cerebral artery occlusion (t-MCAO) rats. FK506-liposomes accumulated in the brain parenchyma by passing through the disrupted blood-brain barrier at an early stage after reperfusion had been initiated. Histological analysis showed that FK506-liposomes strongly suppressed neutrophil invasion and apoptotic cell death, events that lead to a poor stroke outcome. Corresponding to these results, a single injection of FK506-liposomes at a low dosage significantly reduced cerebral cell death and ameliorated motor function deficits in t-MCAO rats. These results suggest that liposomalization of FK506 could reduce the administration dose by enhancing the therapeutic efficacy; hence, FK506-liposomes should be a promising neuroprotectant after cerebral stroke.
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PMID:Treatment of cerebral ischemia-reperfusion injury with PEGylated liposomes encapsulating FK506. 2324 12

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.
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PMID:Cyclosporin A enhances neural precursor cell survival in mice through a calcineurin-independent pathway. 2505 98