tacrolimus and Ischemia

The secondary damage that follows central nervous system (CNS) injury is a target for neuroprotective agents aimed at tissue and function sparing. FK506, a clinically used immunosuppressant, acts neuroprotectively in rat models of brain and spinal cord injury and ischemia. Evidence of in vivo experimental studies highlights the neuroprotective role of FK506 by its direct impact on various cell populations within the CNS. The participation of FK506 in modulation of post-traumatic inflammatory processes is a further potential aspect involved in CNS neuroprotection. In this review we provide an overview of the current laboratory research focusing on the multiple effects of FK506 on neuroprotection following CNS injury.

Topics: Animals; Brain; Disease Models, Animal; Humans; Immunosuppressive Agents; Inflammation; Ischemia; Neuroprotective Agents; Rats; Spinal Cord Injuries; Tacrolimus

A safe and effective preservation solution is a precondition for liver transplantation, which is accepted as the radical treatment for patients with end-stage liver disease. The increasing use of marginal donors and non-heart beating donors as well as the establishment of a national organ allocation network call for better preservation. New preservation solutions like histidine-tryptophan-ketoglutarate (HTK) solution and Celsior solution have been introduced to liver preservation, and protective gene intervention and other modifications have also been investigated. In this article, we review recent advances in liver preservation solutions.. An English-language literature search was conducted using MEDLINE (1990-2005) on liver preservation solution, biliary complication, protective gene and other related subjects.. Although the high viscosity of the University of Wisconsin (UW) solution proved harmful to the hepatic microcirculation, three solutions showed equivalent preservation effects. When the cold ischemia time was short, there were no significant differences among the three solutions in the incidence of biliary complications. So far, modifications of preservation solutions have achieved great success. Several types of protective genes like A20, Bcl-2, Bcl-X(L) and HO-1 were reported to have definite liver protective effects. The addition of other substrates like TNF-alpha antibody, tacrolimus (FK506) and fructose-1,6-bisphosphate (FBP) can also improve the preservation effect. However, addition of insulin to UW solution is harmful to the graft.. In centers with highly-developed transplantation techniques, HTK and Celsior solutions are acceptable in liver preservation. Protective gene modification and addition of substrates like TNF-alpha antibody, FK506 and FBP are prominent approaches to improve liver preservation.

Topics: Adenosine; Allopurinol; Animals; Antibodies; Bile Duct Diseases; Disaccharides; Electrolytes; Fructosediphosphates; Glucose; Glutamates; Glutathione; Histidine; Humans; Insulin; Ischemia; Liver; Mannitol; Microcirculation; Organ Preservation Solutions; Potassium Chloride; Procaine; Raffinose; Tacrolimus; Transformation, Genetic; Tumor Necrosis Factor-alpha

No clinical techniques induce restoration of neurological losses following spinal cord trauma. Peripheral nerve damage also leads to permanent neurological deficits, but neurological recovery can be relatively good, especially if the ends of a transected nerve are anastomosed soon after the injury. The time until recovery generally depends on the distance the axons must regenerate to their targets. Neurological recovery following the destruction of a length of a peripheral nerve requires a graft to bridge the gap that is permissive to, and promotes, axon regeneration. But neurological recovery is slow and limited, especially for gaps longer than 1.5 cm, even using autologous peripheral nerve grafts. Without a reliable means of bridging long nerve gaps, such injuries commonly result in amputations. Promoting extensive neurological recovery requires techniques that simultaneously provide protection to injured neurons and increase the numbers of neurons that extend axons, while inducing more rapid and extensive axon regeneration across long nerve gaps. Although conduits filled with various materials enhance axon regeneration across short nerve gaps, pure sensory nerve graft remains the gold standard for use across long nerve gaps, even though they lead to only limited neurological recovery. Consistent results demonstrate that several immunosuppressive agents enhance the number of axons and the rate at which they regenerate. This review examines the roles played by immunosuppressants, especially FK506, with primary focus on its role as a neuroprotectant and neurotrophic agent, and its potential clinical use to promote improved neurological recovery following peripheral nerve and spinal cord injuries.

Topics: Animals; Axons; Drug Administration Schedule; Humans; Immunophilins; Immunosuppressive Agents; Ischemia; Nerve Regeneration; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Spinal Cord Injuries; Tacrolimus

Our previous rodent studies demonstrated significantly decreased full-thickness necrosis in pedicled dorsal skin flaps with topical tacrolimus as compared with petroleum jelly. Histologically, we found that topical tacrolimus was correlated with increased vascular growth in areas more susceptible to ischemic damage. The purpose of this study was to investigate the potential benefits of pretreatment with tacrolimus. By applying tacrolimus in advance of raising the dorsal skin flaps, we hoped to increase vascularity and thus increase the overall viability of the flaps.. Twenty Sprague-Dawley rats were initially randomized to 4 groups based on timing of tacrolimus treatment (presurgical/postsurgical treatment): control/control (C/C), control/tacrolimus (C/T), tacrolimus/control (T/C), and tacrolimus/tacrolimus (T/T). Treatments consisted of 0.2 g of the control (topical petroleum jelly) and 0.1% topical tacrolimus to the rat dorsum twice per day. After 7 days of presurgical treatment, a cranially based dorsal skin flap measuring 3 × 10 cm was created. Two rats perished during surgery and were excluded for further analysis. Each rat was treated for a further 7 days and sacrificed. Two blinded reviewers marked the total skin flap area as well as areas of viable tissue, reversible ischemia, and full-thickness necrosis. Percentage areas were calculated using Fiji/ImageJ, and statistical analysis was performed in R.. The average viable areas for C/C, C/T, T/C, and T/T were 31.4%, 31.9%, 35.6%, and 22.6%, respectively. The average reversible ischemic area for C/C, C/T, T/C, and T/T was 53.1%, 54.0%, 54.1%, and 71.5%, respectively. The average necrotic area for C/C, C/T, T/C, and T/T was 15.4%, 14.0%, 10.2%, and 5.9%, respectively. For areas of reversible ischemia, T/T arm had higher areas compared with C/T (P = 0.004) and T/C (P = 0.044). There was no significance between treatment arms for areas of viable and necrotic tissue.. We observed higher areas of reversible ischemia for continuous tacrolimus treatment compared with only pre-tacrolimus application or post-tacrolimus application. This suggests that tacrolimus application before and after surgical insult may be associated with improved ischemic survival of the skin. Although we did not observe decreased areas of necrosis for tacrolimus treatment compared with control, this was likely due to the limited number of rats available in each arm to reach significance. Further study is needed to fully elucidate the encouraging trends that were observed.

Topics: Animals; Graft Survival; Ischemia; Necrosis; Petrolatum; Pilot Projects; Rats; Rats, Sprague-Dawley; Soft Tissue Injuries; Surgical Flaps; Tacrolimus

to evaluate the renal toxicity caused by tacrolimus and mycophenolate mofetil (MMF) in a single kidney ischemia and reperfusion model.. experimental study using Wistar rats, submitted to right nephrectomy and left renal ischemia for 20 minutes, separated into groups in the postoperative period (PO): 1) Control (nonoperated); 2) Sham (operated, without PO drug); 3) TAC0.1, TAC1 and TAC10, tacrolimus administered PO at doses of 0.1mg/kg, 1mg/kg and 10mg/kg via gavage, respectively; 4) MMF, administered mycophenolate mofetil 20mg/kg; 5) MMF/TAC1 and MMF/TAC0.5, with an association of mycophenolate mofetil 20mg/kg and tacrolimus 1mg/kg and 0.5mg/kg, respectively. They were killed on the 14th PO and the kidney was removed for tissue oxidative stress analysis, by the dosage of reduced glutathione (GSH), lipoperoxidation (LPO) and protein carbonylation (PCO), and histological analysis by glomerular stereology (Glomerular volume density, Numerical density glomerular and mean glomerular volume). Renal function was evaluated by the measurement of serum creatinine and urea.. both drugs caused alterations in renal function, and the toxicity of tacrolimus was dose-dependent. Subacute toxicity did not show significant glomerular histological changes, and there was renal and compensatory glomerular hypertrophy in all groups except TAC10.. Both drugs cause changes in renal function. Glomerular morphometry and stereology showed negative interference of immunosuppressants during compensatory glomerular hypertrophy.

Topics: Animals; Hypertrophy; Immunosuppressive Agents; Ischemia; Kidney; Mycophenolic Acid; Rats; Rats, Wistar; Reperfusion; Tacrolimus

Tacrolimus and mycophenolate mofetil are immunosuppressive agents widely used on the postoperative period of the transplants.. To evaluate the influence of the association of them on the abdominal wall healing in rats.. Thirty-six Wistar rats were randomly assigned in three groups of 12. On the early postoperative period, four of the control group and three of the experimental groups died. The three groups were nominated as follow: control group (GC, n=8); group I (GI, n=11, standard operation, mycophenolate mofetil and tacrolimus); group II (GII, n=10, standard operation, mycophenolate mofetil and tacrolimus). The standard operation consisted of right total nephrectomy and 20 min ischemia of the left kidney followed by reperfusion. Both NaCl 0.9% and the immunosuppressive agents were administered starting on the first postoperative day and continuing daily until the day of death on the 14th day. On the day of their deaths, two strips of the anterior abdominal wall were collected and submitted to breaking strength measurement and histological examination.. There were no significant differences in wound infection rates (p=0,175), in the breaking strength measurement and in the histological examination among the three groups.. The combination of the immunosuppressive agents used in the study associated with renal ischemia and reperfusion does not interfere in the abdominal wall healing of rats.

Topics: Abdominal Wall; Animals; Immunosuppressive Agents; Ischemia; Kidney; Mycophenolic Acid; Rats; Rats, Wistar; Reperfusion; Reperfusion Injury; Tacrolimus

Skin necrosis is a known postoperative complication of mastectomies. The pathophysiology of tissue necrosis involves lymphatic congestion, followed by venous congestion and ultimately arterial insufficiency. Recent mouse model studies have shown topical tacrolimus to increase growth of lymphatic collateral vessels and decrease lymphedema, potentially obviating the cycle of necrosis and increasing skin survival. The purpose of this study was to investigate the effect of topical tacrolimus on skin flap necrosis in a rat model.. A cranially based dorsal skin flap measuring 3 × 10 cm was raised and reinset on 22 Sprague-Dawley rats. They were then randomized to either the control (topical petroleum jelly) or the treatment (topical 0.1% tacrolimus) arm. In addition, 0.2 g of either ointment was spread over the flap and then covered with an occlusive dressing. Dressings were changed daily with reapplication of both the topical ointment and occlusive dressing. The rats were sacrificed 7 days postoperatively; areas of viable tissue, reversible ischemia, and full thickness necrosis were measured with Fiji software, and comparative analysis was performed with GraphPad statistical software.. The average area of the dorsal flaps in the control and tacrolimus groups was 22.5 and 23.9 cm, respectively. In the control cohort, the average viable area was 42.4%, the average reversible ischemia area was 43.6%, and the average necrotic area was 13.9%. In the tacrolimus cohort, the average viable area was 31.5%, the average reversible ischemia area was 59.3%, and the average necrotic area was 9.2%. Total necrotic area was significantly lower in rats receiving topical tacrolimus as compared with controls (P = 0.015). Furthermore, the ratios of necrotic to reversible ischemia and necrotic to viable tissue were significantly lower in the tacrolimus group as compared with controls (P = 0.003, P = 0.015). There was one incidence of wound dehiscence secondary to rodent self-removal of dressings and suture that required reoperation and reinset.. Topical tacrolimus was associated with significantly less full thickness necrosis as compared with topical.

Topics: Animals; Graft Survival; Ischemia; Mice; Necrosis; Rats; Rats, Sprague-Dawley; Skin Transplantation; Surgical Flaps; Tacrolimus

Allogeneic mesenchymal stromal cells (allo-MSC) are a promising "off-the-shelf" therapy with anti-inflammatory and pro-repair properties. This study investigated humoral immune responses to intramuscular (IM) injections of allo-MSC. Total and isotype-specific anti-donor IgG and donor-specific complement-mediated lysis were determined in sera from healthy mice 2 weeks after single or repeated IM injections of fully mismatched-MHC allo-MSC with comparison to mice receiving syngeneic MSC, allogeneic splenocytes or saline. In mice subjected to hind limb ischemia (HLI), anti-donor IgG was analyzed following IM allo-MSC injection with and without administration of the T-cell immunosuppressant tacrolimus. Recipients of single and repeated IM allo-MSC developed readily-detectable anti-donor IgG. Serum anti-donor IgG levels were similar to those of allo-splenocyte recipients but had higher IgG1/IgG2a ratio and variable capacity for complement-mediated lysis of donor cells. The induced anti-donor IgG bound readily to allo-MSC and this binding was increased following allo-MSC pretreatment with interferon gamma. In mice with HLI, IM injection of allo-MSC into the ischemic limb was also associated with induction of anti-donor IgG but this was abrogated by tacrolimus (FK-506). The results indicate that allo-MSC are inherently immunogenic when delivered intramuscularly to healthy and ischemic mouse hind limb, but induce an IgG1-skewed humoral response that is suppressed by tacrolimus.

Topics: Animals; Antibody-Dependent Cell Cytotoxicity; Cells, Cultured; Histocompatibility Antigens; Immunity, Humoral; Immunosuppressive Agents; Injections, Intramuscular; Ischemia; Isoantigens; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Tacrolimus; Tissue Donors; Transplantation, Homologous

The outcome of scaffold-based stem cell transplantation remains unsatisfied due to the poor survival of transplanted cells. One of the major hurdles associated with the stem cell survival is the immune rejection, which can be effectively reduced by the use of immunosuppressant. However, ideal localized and sustained release of immunosuppressant is difficult to be realized, because it is arduous to hold the drug delivery system within scaffold for a long period of time. In the present study, the sustained release of immunosuppressant for the purpose of improving the survival of stem cells was successfully realized by a nanoparticle-anchoring hydrogel scaffold we developed.

Topics: Animals; Cell Survival; Delayed-Action Preparations; Disease Models, Animal; Endothelial Progenitor Cells; Guided Tissue Regeneration; Hydrogel, Polyethylene Glycol Dimethacrylate; Immunosuppressive Agents; Ischemia; Mice, Inbred BALB C; Nanoparticles; Polylactic Acid-Polyglycolic Acid Copolymer; Tacrolimus; Treatment Outcome

To evaluate renal histological changes and renal function in single kidney rats submitted to renal ischemia-reperfusion and to immunosuppression with tacrolimus and mycophenolate-mofetil.. Experimental study with 80 Wistar rats distributed into control, Sham and six other groups treated with immunosuppressive drugs. Animals undergoing surgery, right nephrectomy and left renal clamping, killed on the 14th day and analyzed for renal histology, urea and creatinine.. The group receiving tacrolimus at higher doses (T3) showed renal histological lesions indicative of early nephrotoxicity, and significant increase in urea and creatinine. The group M (mycophenolate-mofetil alone) and the group M2 (mycophenolate-mofetil combined with half the usual dose of tacrolimus) presented a slight rise in serum urea. The groups using mycophenolate-mofetil alone or combined with tacrolimus showed creatinine levels similar to that of the group T3.. Histologically, the association of injury by ischemia-reperfusion with the use of tacrolimus or mycophenolate-mofetil alone demonstrated a higher rate of renal changes typical of early nephrotoxicity. In laboratory, the combination of injury by ischemia-reperfusion with tacrolimus at higher doses proved to be nephrotoxic.

Topics: Animals; Calcineurin Inhibitors; Creatinine; Immunosuppression Therapy; Immunosuppressive Agents; Ischemia; Kidney; Kidney Diseases; Male; Mycophenolic Acid; Nephrons; Random Allocation; Rats, Wistar; Reperfusion Injury; Tacrolimus; Time Factors; Urea

To evaluate bladder histology in healing and biochemical analysis of rats with single kidney in ischemia/reperfusion, treated with tacrolimus.. Fifty rats randomized into five groups. Three rats died in surgery, 47 rats divided in groups: Control (non-operated, n=10), Sham (operated without drugs, n=8), T1 (operated + tacrolimus 1mg/kg, n=10), T2 (operated + tacrolimus 0.1 mg/kg, n=10), T3 (operated + tacrolimus 10mg/kg, n=9). The surgery was: laparotomy, right nephrectomy, left kidney ischemia/reperfusion, cystotomy followed by bladder suture. After that, rats were submited to gavage daily (Control and Sham with saline solution. T1, T2, T3 with tacrolimus in doses already mentioned). On the 14th day, after death induction, cystectomy was performed and bladder was histologicaly analysed. The serum urea, creatinine and tacrolimus were analysed too.. There was difference in serum tacrolimus in T3 compared to the other groups (p<0.05). There was higher doses of creatinine in T3 group and higher urea in groups with tacrolimus. There were significant differences among all histologic variables comparing groups with and without tacrolimus (p<0.05).. Tacrolimus associated with ischemia/reperfusion is nephrotoxic, suppresses inflammation and seems to delay the healing bladder.

Topics: Animals; Blood Urea Nitrogen; Cicatrix; Creatinine; Immunosuppressive Agents; Ischemia; Kidney; Male; Models, Animal; Nephrectomy; Random Allocation; Rats, Wistar; Reperfusion Injury; Tacrolimus; Urinary Bladder; Wound Healing

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

The protective potential of immunosuppressants has been reported in many experimental models of ischemia both in vivo and in vitro, suggesting a novel therapeutic application of these drugs. Because high-mobility group box 1 (HMGB1) protein has recently been reported to be involved in ischemic brain injury, the purpose of the present study was to determine whether treatment with immunosuppressants could decrease the expression and release of HMGB1 in astrocytes exposed to simulated ischemic conditions (combined oxygen-glucose deprivation, OGD). We also investigated whether immunosuppressive drugs could attenuate necrosis in astrocyte cultures exposed to OGD. Finally, we studied the influence of immunosuppressants on the expression of NFκB, inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2). Cells were treated with cyclosporine A, FK506 and rapamycin (all drugs at concentrations of 0.1, 1 and 10 μM). Our study provides evidence that immunosuppressants decrease the expression and release of HMGB1 in ischemic astrocytes. Our data suggest that HMGB1 release may be partly an active process triggered by oxidative stress because the antioxidant N-acetylcysteine (NAC) clearly attenuated HMGB1 expression and release. Furthermore, we show that the immunosuppressants, at the same concentrations that significantly suppressed HMGB1 expression and release, were also able to prevent the necrosis of ischemic astrocytes and inhibit the expression of inflammatory mediators (NFκ, iNOS and COX-2). These results provide further information about the cytoprotective mechanisms of immunosuppressants on ischemic astrocytes, especially in relation to the pathophysiology of ischemic brain injury. It appears that the protective effects of immunosuppressants can be mediated in part by the suppressing the expression and release of HMGB1 in astrocytes, which leads to the attenuation of ischemia-induced necrosis and neuroinflammation.

Topics: Animals; Astrocytes; Cell Hypoxia; Cells, Cultured; Cyclosporine; Dose-Response Relationship, Drug; Glucose; HMGB1 Protein; Immunosuppressive Agents; Inflammation; Inflammation Mediators; Ischemia; Necrosis; Oxidative Stress; Rats; Rats, Wistar; Sirolimus; Tacrolimus

We investigated whether the immunosuppressive drugs, FK506 and cyclosporine A, increase BDNF protein and/or mRNA expression in ischemic astrocytes and if an increase could be related to changes in the nuclear expression of p-CREB, p-Erk1/2 and p-Akt. The influence of these immunosuppressants on protein and mRNA levels of TrkB and p75(NTR) receptors was also examined. On day 21, cultures of rat astrocytes were subjected to ischemic conditions simulated in vitro (combined oxygen glucose deprivation, OGD) for 8h and exposed to FK506 (10-1000nM) and cyclosporine A (0.25-10microM). FK506 and cyclosporine A (at 1000nM and 0.25microM, respectively) stimulated the expression and release of BDNF in cultured rat cerebral cortical astrocytes exposed to OGD. The immunosuppressants at these doses simultaneously increased p-CREB and p-Erk1/2 expression in the nuclear fraction of astrocytes. The results RT-PCR and Western blot analysis provided further evidence of a modulating influence of the drugs on the expression of trkB and p75(NTR) genes and their protein products in ischemic astrocytes.

Topics: Animals; Astrocytes; Brain-Derived Neurotrophic Factor; CREB-Binding Protein; Cyclosporine; Immunosuppressive Agents; Ischemia; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Receptor, Nerve Growth Factor; Receptor, trkB; RNA, Messenger; Tacrolimus

Calcineurin (CaN) is a calcium/calmodulin-dependent protein phosphatase that has an important role in ischemia-induced apoptosis. The serine/threonine kinase, Akt, which is also known as protein kinase B, has an important role in the cell death/survival pathways. Akt is activated by its phosphorylation, which is positively regulated by phosphatidylinositol 3-kinase (PI3K) and negatively regulated by a class of protein phosphatases (PPs) in tissue. However, the relationship between CaN and Akt after transient ischemia remains unclear. In the present study, we investigated whether CaN is involved in neuronal cell apoptosis and Akt dephosphorylation that occur during ischemic injury. We examined the interdependence between CaN and Akt/protein kinase B (PKB) in the rat retina after transient ischemia. After ischemic damage, we detected changes in levels of CaN, Akt and Bad in rats in the presence or absence FK506, CaN inhibitor. Our results show that CaN cleavage reduced Akt phosphorylation at Thr308 and Ser473, and led to apoptosis via dephosphorylation of the proapoptotic Bcl-2 family member Bad. After treatment with FK506, Akt and Bad dephosphorylation was greatly reduced. The total number of TUNEL-positive neurons was reduced by intravitreal injection of FK506 after transient ischemia. These results indicate that CaN cleavage negatively regulates Akt phosphorylation and is involved in retinal cell apoptosis after transient ischemia.

Topics: Animals; Apoptosis; bcl-Associated Death Protein; Blotting, Western; Calcineurin; Cell Death; Immunohistochemistry; Immunoprecipitation; In Situ Nick-End Labeling; Intraocular Pressure; Ischemia; Male; Oncogene Protein v-akt; Phosphorylation; Rats; Rats, Sprague-Dawley; Retinal Vessels; Tacrolimus

Tacrolimus (Tac), developed in 1990, has been applied as an immunosuppressive agent for liver, heart, and kidney transplantation and is known to have more powerful immunosuppressive effects than cyclosporine (CyA). To evaluate the efficacy of Tac in cadaveric kidney transplants from non-heart beating donors, we present the long-term outcome of patients receiving kidneys with ischemic damage, and compared it with that of CyA. Between July 1990 and December 2000, 55 patients with end-stage renal disease received kidneys from non-heart beating donors (Maastrichy category 3) and were treated with Tac and steroid immunosuppressive therapy. During the same period, we also performed 137 non-heart beating cadaveric renal transplants treated with CyA-based immunosuppressive therapy. The patient survival rate was 98% at 1 yr and 96% at 3-10 yr in the Tac group, and 97% at 1-3 yr, 93% at 5 yr and 85% at 10 yr in the CyA group. The graft survival rate was 91% at 1 yr, 80% at 3 yr, 63% at 5 yr and 34% at 10 yr in the Tac group, and 88% at 1 yr, 75% at 3 yr, 63% at 5 yr and 49% at 10 yr in the CyA group. There was no significant difference in either patient or graft survival rates between the two groups. Acute early rejection in the Tac group was less than that in the CyA group but acute tubular necrosis was the same in both groups. This indicates that Tac is available for cadaveric kidney transplants from non-heart beating donors. In conclusion, Tac is available as an immunosuppressive agent even for kidney transplants from non-heart beating donors.

Topics: Adult; Cadaver; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Ischemia; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Kidney Tubular Necrosis, Acute; Longitudinal Studies; Male; Methylprednisolone; Survival Rate; Tacrolimus; Tissue and Organ Harvesting; Tissue Donors; Treatment Outcome

Microvascular thrombosis is a prominent feature in cardiac delayed xenograft rejection (DXR). We investigated the impact of warfarin or low-molecular-weight heparin (LMWH) anti-coagulation on xenograft function using a heterotopic pig-to-primate model. Donor hearts were from CD46 transgenic pigs and baboon immunosuppression included tacrolimus, sirolimus, anti-CD20 and TPC, an alpha-galactosyl-polyethylene glycol conjugate. Three groups of animals were studied. Group 1 (n = 9) was treated with warfarin, Group 2 (n = 13) with LMWH and Group 3, received no anti-coagulant drugs. The median duration of xenograft function was 20 days (range 3-62 days), 18 days (range 5-109 days) and 15 days (range 4-53 days) in Groups 1 to 3 respectively. Anti-coagulation achieved the targeted international normalized prothrombin ratio (INR) and anti-factor Xa levels consistent with effective in vivo therapy yet, no significant impact on median xenograft function was observed. At rejection, a similar histology of thrombosis and ischemia was apparent in each group and the levels of fibrin deposition and platelet thrombi in rejected tissue was the same. Anti-coagulation with warfarin or LMWH did not have a significant impact on the onset of DXR and microvascular thrombosis. However, a role for specific anti-coagulant strategies to achieve long-term xenograft function cannot be excluded.

Topics: Animals; Animals, Genetically Modified; Anticoagulants; Antigens, CD; Factor Xa; Heart Transplantation; Heparin, Low-Molecular-Weight; Immunoglobulin G; Immunoglobulin M; Immunosuppressive Agents; International Normalized Ratio; Ischemia; Membrane Cofactor Protein; Membrane Glycoproteins; Microcirculation; Myocardium; Papio; Primates; Prothrombin; Sirolimus; Swine; Tacrolimus; Thrombosis; Time Factors; Transplantation, Heterologous; Treatment Outcome; Vitamin K; Warfarin

A retrospective chart review of 1065 consecutive liver allograft recipients in 11 centers from January 1997 to September 1998 was performed. Patients were followed for 3 years or until graft loss. Patients received either tacrolimus (n = 594), cyclosporine (n = 450) or no calcineurin inhibitor (n = 21). Model for end-stage liver disease (MELD) scores at time of transplant were similar between the two groups. During follow-up, more patients switched from cyclosporine to tacrolimus (26.7%) than from tacrolimus to cyclosporine (12.8%; p < 0.0001). Patient and graft survival were equivalent. Corticosteroid use was more common in cyclosporine-treated patients (p < 0.00001). Patients receiving tacrolimus experienced lower serum creatinine levels at months 3 through 36 (p < 0.0001). Systolic blood pressure was lower in patients receiving tacrolimus (p < 0.001) despite a reduced requirement for anti-hypertensive agents (p < 0.0001). In addition, tacrolimus was associated with lower total cholesterol and triglyceride levels for months 3 through 24 and 3 through 12, respectively (p < 0.01), despite a reduced requirement for anti-hyperlipidemic agents. The incidence of new-onset diabetes mellitus was similar in both groups. While both calcineurin inhibitors were associated with excellent patient and graft survival, renal function, blood pressure and serum lipid levels were significantly better with tacrolimus treatment.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Blood Pressure; Cardiovascular Diseases; Cardiovascular System; Child; Child, Preschool; Cholesterol; Cyclosporine; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Ischemia; Kidney; Lipid Metabolism; Liver Diseases; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Tacrolimus; Time Factors; Treatment Outcome; Triglycerides

Dopamine given at moderate doses for inotropy to postischemic hearts has been shown to augment myocyte apoptosis in association with elevated cytosolic calcium. We hypothesize that dopamine-mediated apoptosis occurs through calcium-induced opening of the mitochondrial permeability transition (mPT) pore. We also hypothesize that cyclosporin A (CSA), a calcineurin inhibitor known to block mPT pore opening, would prevent dopamine-induced apoptosis primarily by inhibiting pore opening (cyclophilin D binding).. Isolated perfused rabbit hearts (n = 6/group) were subjected to 30 minutes of 37 degrees C cardioplegic arrest followed by 120 minutes reperfusion (ischemic injury that produces < 3% infarct by triphenyl-tetrazolium chloride [TTC] staining). Four groups were studied: (1) control; (2) dopamine (10 micromol/L) postischemia (dopa); (3) dopamine+CSA (0.2 micromol/L) (CSA+D) group; (4) dopamine+FK-506 (0.2 micromol/L) (FK+D) group. Left ventricular developed pressure and oxygen consumption were measured preischemia and postischemia. Bax, caspase-3 and caspase-9, and poly-ADP-ribose polymerase (PARP) activation were measured by Western blotting. Apoptotic nuclei were quantified by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining.. Dopamine postischemia improved contractile function and heart rate and this was not affected by CSA or FK. However, TUNEL positive nuclei, Bax, caspase-3 and caspase-9 activation, and PARP cleavage were all increased in dopa and FK+D groups, but not in CSA+D.. Cyclosporin is effective in preventing dopamine-induced apoptosis in the postischemic heart. The mechanism is likely due to inhibition of mPT pore opening since FK-506, a potent calcineurin inhibitor that does not bind to cyclophilin, did not prevent this. Low dose cyclosporin may prove useful to prevent dopamine-induced apoptosis resulting in long-term preservation of cardiac function.

Topics: Animals; Apoptosis; Cyclosporine; Disease Models, Animal; Dopamine; Immunosuppressive Agents; Ischemia; Myocardial Stunning; Myocardium; Oxygen Consumption; Rabbits; Reperfusion; Tacrolimus

Ischemia/reperfusion (I/R) carries significant injury to endothelial cells in transplanted organs and is an important factor in chronic rejection. Immunosuppressive drugs, notably cyclosporin A (CyA) and FK506, can potentially augment this injury. Here, our goal was to determine the combined effects of I/R and CyA or FK506 on endothelial cells. Transformed mouse endothelial cells (SVEC 4-10) were subjected to ischemia or I/R for 2-24 hours by incubating cells in 100 per cent N2 (ischemia) followed by 5 per cent CO2 and 95 per cent O2 (reperfusion) for 24 hours. In separate experiments, CyA or FK506 was added to cells subjected to ischemia or I/R. Nonviable cells were determined by Trypan blue exclusion assay. All experiments (done in triplicate) were analyzed by Student's t test. Increasing ischemia times resulted in a greater number of nonviable cells (2% nonviable cells at 0 hours and 57% at 24 hours of I/R). Addition of CyA significantly increased the number of nonviable cells when compared with the control (I/R only) group (P = 0.014). Interestingly, FK506 did not increase the percentage of nonviable cells compared with the control group (P = 0.2). Unlike FK506, CyA augments I/R injury to endothelial cells in vitro. These findings could be relevant in chronic rejection and transplantation.

Topics: Analysis of Variance; Animals; Apoptosis; Calcineurin Inhibitors; Cell Count; Cell Line, Transformed; Cell Survival; Cells, Cultured; Coloring Agents; Cyclosporine; Endothelial Cells; Graft Rejection; Immunosuppressive Agents; Ischemia; Mice; Necrosis; Reperfusion Injury; Tacrolimus; Time Factors; Trypan Blue

The signaling pathways of mitogen-activated protein kinases (MAPKs) are important molecular components responsible for ischemia/reperfusion (I/R) injury in the kidneys. Preconditioning with cyclosporine A (CsA) or FK506 reduces subsequent I/R injury. We studied the effect of preconditioning with CsA or FK506 on MAPK expression in ischemic rat kidneys.. Two separate studies were performed using Sprague-Dawley rats. First, MAPK (extracellular signal-regulated kinase [ERK], jun N-terminal kinase [JNK], p38) expressions were observed at 0, 10, 20, 30, 60, 120, and 1,440 min after I/R injury. Second, the effects of preconditioning with CsA or FK506 on MAPK expressions were observed in rat kidneys with I/R injury. I/R injury was induced by clamping both renal arteries for 45 min. Rats were pretreated with intravenous (IV) CsA (3 mg/kg) or IV FK506 (0.3 mg/kg) 6 hr before I/R injury and killed 30 min later. Expression of MAPK was measured using immunoblot and immunohistochemistry.. MAPK (ERK, JNK, p38) expressions were significantly increased in kidneys with I/R injury compared with sham-operated controls, and immunohistochemistry revealed increased MAPK immunoreactivity in renal tubules of the outer medulla. Kidneys preconditioned with low-dose CsA or FK506 showed significantly increased ERK expression compared with kidneys with I/R injury alone (CsA, 9.5- vs. 4.5-fold; FK506 10.4- vs. 4.5-fold: P<0.05) but showed decreased JNK (CsA, 3.8- vs. 5.3-fold; FK506, 3.4- vs. 5.3-fold: P<0.05) and p38 expression (CsA, 2.5- vs. 3.7-fold; FK506, 2.1- vs. 3.7-fold: P<0.05).. Preconditioning with CsA or FK506 differentially regulates the expression of MAPK in rat kidneys with I/R injury, and this may explain the remarkable protective effects of these agents.

Topics: Animals; Cyclosporine; Immunosuppressive Agents; Ischemia; Ischemic Preconditioning; JNK Mitogen-Activated Protein Kinases; Kidney; Male; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tacrolimus

Topics: Adult; Child; Cyclosporine; Drug Therapy, Combination; Graft Survival; Heart Arrest; Histocompatibility Testing; HLA-DR Antigens; Humans; Immunosuppressive Agents; Ischemia; Kidney; Kidney Transplantation; Middle Aged; Organ Preservation; Postoperative Complications; Renal Dialysis; Tacrolimus; Time Factors; Tissue Donors

The aim of this study was to demonstrate that tacrolimus (FK506) has a hepatoprotective effect by reducing ischemia-reperfusion-induced apoptosis and necrosis, both of which lead to post-surgical liver dysfunction. An ischemia-reperfusion model and primary cultured rat hepatocytes subjected to hypoxic and reoxygenation phases, mimicking the surgical process, were used. c-Jun N-terminal kinase 1/stress-activated protein kinase 1 (JNK1/SAPK1) activation leads to caspase 3 activation, a trigger of apoptosis. The activation status of JNK1/SAPK1 was evaluated by immunoprecipitation or Western-blotting experiments. Apoptosis was assessed by measuring caspase activation and by TUNEL (terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate-biotin nick-end labeling) reaction. Necrosis was assessed histologically. Tacrolimus improved the survival rate of rats subjected to ischemia-reperfusion. After FK506 pretreatment, the liver necrosis rate was reduced, and ischemia-reperfusion-induced JNK1/SAPK1 activation and apoptosis were significantly decreased. In hypoxia-reoxygenation-subjected hepatocytes, tacrolimus reduced JNK1/SAPK1 and caspase 3 activation. In the liver, tacrolimus prevented ischemia-reperfusion-induced apoptosis and necrosis.

Topics: Animals; Apoptosis; Blotting, Western; Caspases; Cells, Cultured; Hepatocytes; Immunosuppressive Agents; In Situ Nick-End Labeling; Ischemia; JNK Mitogen-Activated Protein Kinases; Liver; Male; Mitogen-Activated Protein Kinases; Necrosis; Rats; Rats, Wistar; Reperfusion Injury; Tacrolimus

To assess the windows of therapeutic opportunity for drugs with various chemical actions on fetal growth retardation induced by transient intrauterine ischemia in rats.. At 17 days of gestation, ischemia was induced by 30 min of right uterine artery occlusion. The administration of either alpha-phenyl-N-tert-butyl-nitrone (PBN), FK 506, nifedipine, or MK-801 to pregnant rats was randomly started before occlusion, 1 hour, 3 hours, or 24 hours after recirculation. All of the pups were delivered by cesarean section at 21 days of gestation and were weighed to determine the degree of fetal growth retardation.. The vehicle-treated animals exposed to ischemia showed a significant decrease in fetal body weight compared with the normoxic control animals. The growth disturbances were prevented by nifedipine and MK-801 only when given just prior to ischemia. In contrast, PBN and FK 506 had a protective effect even when given 1 hour and 3 hours after the start of recirculation, respectively.. The present results indicate that treatment with PBN and FK 506 gives relatively wide windows of therapeutic opportunity in fetal growth retardation induced by transient intrauterine ischemia in rats and suggest the possibility of therapeutic intervention after the start of recirculation.

Topics: Animals; Cyclic N-Oxides; Dizocilpine Maleate; Female; Fetal Growth Retardation; Fetal Hypoxia; Ischemia; Neuroprotective Agents; Nifedipine; Nitrogen Oxides; Pregnancy; Random Allocation; Rats; Rats, Wistar; Tacrolimus

Proximal tubular cholesterol levels rise within 18 hours of diverse forms of acute renal tubular injury (eg, myoglobinuria, ischemia/reperfusion, urinary tract obstruction). These increments serve to protect against further bouts of tubular attack (so-called "acquired cytoresistance"). Whether these cholesterol increments are merely transitory, or persist into the maintenance phase of acute renal failure (ARF), has not been previously defined. Furthermore, whether subacute/insidious tubular injury [eg, cyclosporine A (CSA), tacrolimus toxicity], nontubular injury (eg, acute glomerulonephritis), or physiological stress (eg, mild dehydration) impact renal cholesterol homeostasis have not been addressed. This study sought to resolve these issues. Male CD-1 mice were subjected to glycerol-induced ARF. Renal cortical-free cholesterol (FC) and cholesterol ester (CE) levels were determined 3, 5, 7, or 14 days later, and the values contrasted to prevailing blood-urea nitrogen concentrations. The impact of 40 minutes of unilateral renal ischemia plus reflow (3 to 6 days) on mouse cortical FC/CE content was also assessed. Additionally, FC/CE levels were measured in rat renal cortex either 10 days after CSA or tacrolimus therapy, or 48 hours after induction of nephrotoxic serum nephritis. Finally, the impact of overnight dehydration on mouse renal cortical/medullary FC/CE profiles was determined. Compared to sham-treated animals, glycerol, CSA, tacrolimus, ischemia-reperfusion, and nephrotoxic serum each induced dramatic CE +/- FC elevations, rising as much as 10x control values. In the glycerol model, striking correlations (r

Topics: Acute Kidney Injury; Animals; Blood Urea Nitrogen; Cholesterol; Cholesterol Esters; Cyclosporine; Dehydration; Glomerulonephritis; Glycerol; Ischemia; Kidney; Kidney Cortex; Kidney Medulla; Kidney Tubules; Male; Mice; Nephritis; Rats; Rats, Sprague-Dawley; Reperfusion; Tacrolimus

Ischemia/reperfusion (I/R) injury in the early posttransplant period is closely associated with delayed recovery of graft function, increased acute rejection, and late allograft dysfunction. Pharmacological preconditioning with low-dose cyclosporine (CsA) or FK506 was performed to induce ischemic tolerance in rat kidney with I/R injury.. Low-dose CsA (3 mg/kg, administered i.v.) or FK506 (0.3 mg/kg i.v.) were used to induce ischemic tolerance in Sprague-Dawley rats, and the induction of heat shock protein (hsp) 70 by CsA or FK506 was evaluated overtime. Rats were pretreated with CsA or FK506 6 hr before I/R injury when hsp70 was maximally expressed, and were killed 24 hr later. The effect of pharmacological preconditioning on subsequent I/R injury was evaluated in terms of renal function, histopathology score, assays for apoptosis (DNA fragmentation analysis, TUNEL staining, expressions of pro-apoptotic genes, and caspase activity), and the expression of inflammatory cytokine genes (interleukin-1 and tumor necrosis factor-alpha).. Preconditioning with low-dose CsA or FK506 significantly improved renal function and renal histology, compared to rats with I/R injury. Apoptotic cell death (typical DNA laddering and increased TUNEL-positive cells) in rat kidneys with I/R injury, was decreased by pretreatment with low-dose CsA or FK506. Increased expression of pro-apoptotic genes (Fas, Fas-ligand, caspase 1 and 3) and activated caspases in ischemic rat kidneys were decreased after CsA or FK506 pretreatment.. Pretreatment with low-dose CsA or FK506 prevents subsequent I/R injury, and this effect may be related to the induction of hsp70. Pretreatment of renal donors with low-dose CsA or FK506 may result in an improvement in immediate posttransplant function.

Topics: Animals; Apoptosis; Blood Urea Nitrogen; Caspases; Creatinine; Cyclosporine; Dose-Response Relationship, Drug; Gene Expression; HSP70 Heat-Shock Proteins; Immunosuppressive Agents; Interleukin-1; Ischemia; Kidney Transplantation; Male; Rats; Rats, Sprague-Dawley; Renal Circulation; Reperfusion Injury; Tacrolimus; Transplantation Conditioning; Tumor Necrosis Factor-alpha

The immunosuppressant agent FK506 (tacrolimus) has proven to be neuroprotective against brain ischemia, but there are no data on potential neuroprotective effects of FK506 in peripheral nerve ischemia. We examined the potential effects of two doses of FK506 in protecting peripheral nerve from ischemic fiber degeneration. Ischemia in the left sciatic nerve of the rat was produced by injecting 2 x 10(6) microspheres (14 microm) into the left femoral, hypogastric, and superior gluteal arteries in proportions of 47%, 37%, and 17%, respectively. After embolization, FK506 was injected into the left femoral, hypogastric, and superior gluteal arteries in doses of 9.4, 7.4, and 3.4 microg, respectively, for the high-dose group and 4.7, 3.7, and 1.7 microg, respectively, for the low-dose group. The control rats were injected with saline. FK506 treatment resulted in dramatic behavioral improvement in nerve function, in the number of functioning nerve fibers, and in the salvage of a majority of nerve fibers from ischemic fiber degeneration in a dose-dependent fashion. These results suggest that a small dose of FK506 protects peripheral nerve from ischemic fiber degeneration and that it may have potential in the treatment of ischemic neuropathy.

Topics: Action Potentials; Animals; Behavior, Animal; Dose-Response Relationship, Drug; Electrophysiology; Immunosuppressive Agents; Ischemia; Male; Nerve Degeneration; Nerve Fibers; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Tacrolimus; Tibial Nerve

Topics: Adult; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Ischemia; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Pancreas Transplantation; Postoperative Complications; Prednisolone; Radiography; Splanchnic Circulation; Tacrolimus

Topics: Colitis; Colon; Creatinine; Cyclosporine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Ischemia; Kidney Transplantation; Middle Aged; Muromonab-CD3; Mycophenolic Acid; Tacrolimus

Nephrotoxicity is one of the main side effects of calcineurin-inhibitors. The influence of tacrolimus on the renal vasculature has not been well described. We have therefore examined the effects of tacrolimus on renal functional parameters as well as the contribution of the NO-system in a model of ischemic acute renal failure (ARF). Induction of ARF was achieved by clamping both renal arteries of female Sprague-Dawley rats. During the experiment, RBF, GFR, MAP, RVR and FENa were determined during infusion of vehicle, TAC, TAC and the NOS-activator L-arginine, and TAC and NOS-inhibition due to L-NMMA. TAC induced a significant rise in RVR with further decrease of RBF and GFR. Simultaneous L-arginine-infusion could reverse these effects during the infusion without complete restoration to preischemic levels. NOS-inhibition increased MAP and RBF without any effect on GFR. FENa did not differ significantly between the groups. Tacrolimus in the situation of ischemic acute renal failure causes vasoconstriction of pre- and postglomerular vessels with a further deterioration of renal function. L-arginine abolishes the functional deterioration, most likely due to increased NO-liberation.

Topics: Acute Kidney Injury; Animals; Arginine; Blood Pressure; Calcineurin Inhibitors; Constriction; Diuresis; Enzyme Inhibitors; Female; Glomerular Filtration Rate; Immunosuppressive Agents; Ischemia; Kidney; Kidney Glomerulus; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; omega-N-Methylarginine; Rats; Rats, Sprague-Dawley; Renal Artery; Renal Circulation; Tacrolimus; Vascular Resistance; Vasoconstriction

Endothelin-1 (ET-1), a novel vasoconstrictor, possibly plays a role in the mediation of ischemia/reperfusion (I/R) injury. Tacrolimus (FK506) and cyclosporin A (CsA) were reported to maintain tissue microcirculation of the liver subjected to I/R. This study investigated the effects of these immunosuppressants on intestinal I/R in terms of intestinal tissue microcirculation associated with ET-1.. Male S-D rats were pretreated twice with FK506 (0.2 mg/kg), CsA (10 mg/kg) or only saline solution (0.5 mL). The tissue microcirculation in the control was reduced after I/R (29% +/- 10%) accompanied by hypotension, increased tissue ET-1 expression (25.0% +/- 6.4% to 67.9% +/- 5.0% 60 minutes after reperfusion), and increased ET-1 level in the portal blood (3.4 +/- 0.9 to 23.6 +/- 6.1 pg/mL). FK506 suppressed ET-1 expression (27.3% +/- 5.2%, 4.1 +/- 2.2 pg/mL), maintained microcirculation (96% +/- 16%), and blood pressure, reduced histologic damage, and improved survival. CsA had a similar but weaker effect compared with FK506. An additional experiment was performed with BQ485Na (BQ), an ETA receptor antagonist, to evaluate the genuine role of ET-1. BQ showed almost the same effects as FK506.. FK506 and CsA, particularly the former, maintain microcirculation and protect the tissue from I/R injury by suppressing the production and release of ET-1.

Topics: Animals; Azepines; Blood Pressure; Cyclosporine; Endothelin Receptor Antagonists; Endothelin-1; Hypotension; Immunosuppressive Agents; Intestine, Small; Ischemia; Male; Microcirculation; Oligopeptides; Portal System; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptors, Endothelin; Reperfusion Injury; Survival Rate; Tacrolimus; Time Factors

A possible new common action of immunosuppressants, besides suppression of the genes for cytokines like interleukin-2, was investigated in in vivo models. Dexamethasone (0.1 mg/kg, s.c.) failed to suppress ischemic paw edema in mice 1 h after its injection, but maximal suppression was achieved at 3 h (20%) whereafter the suppression decreased at 6 and 18 h (11% and 10%). Pretreatment with oral FK506 (chemical name is recently donated as tacrolimus, 0.1 mg/kg) resulted in 38%, 52%, 23% and 17% suppression at 1, 3, 6 and 18 h, respectively. Cyclosporin A (1 mg/kg), rapamycin (0.1 mg/kg) and deoxyspergualin (1 mg/kg) showed a similar pattern of suppressions after dexamethasone. Transforming growth factor-beta1 (TGF-beta1, 0.3 microg/kg, i.p.) maintained the suppression elicited by an immunosuppressant (42-58%) at 6 h after dexamethasone, whereas transforming growth factor-beta1 and/or an immunosuppressant were not suppressive. Suppression, irrespective of the agent that elicited it, was blocked by nitric oxide (NO) synthase inhibitor, anti-oxidant enzymes and cycloheximide. Endogenous nitric oxide or oxyradicals are essential for the action of dexamethasone in vivo. The four immunosuppressants bound to specific heat-hock proteins (hsp) in the glucocorticoid receptor complex and might enhance the synthesis of anti-inflammatory protein(s).

Topics: Animals; Anti-Inflammatory Agents; Cyclosporine; Dexamethasone; Drug Interactions; Edema; Hindlimb; Immunosuppressive Agents; Ischemia; Male; Mice; Nitric Oxide; Superoxides; Tacrolimus

Prolonged warm ischemic injury in non-heart-beating donors (NHBDs) significantly affects hepatic allograft function after liver transplantation (LTx).. The effects of FK506 and the platelet activating factor antagonist E5880 on postoperative function of hepatic allografts procured from NHBDs were evaluated in porcine orthotopic LTx. In donors, livers were subjected to 90 minutes of warm ischemia and a subsequent 4-hour cold preservation. Group 1 (n = 6) was the untreated control group. In group 2 (n = 4), donors were pretreated with FK506 (0.3 mg/kg). In group 3 (n = 4), donors and recipients were treated with E5880 (0.3 mg/kg). In group 4 (n = 6), pigs were treated with both FK506 and E5880.. All of the recipients in group 1 died within 12 hours. In groups 2 and 3, half of the recipients survived more than 12 hours. In group 4, all of the recipients survived more than 2 days (p < 0.01 compared with group 1). The improved survival seen in group 4 was associated with a reduction in the serum concentrations of glutamic oxaloacetic transaminase and lactate, and a restoration of hepatic energy charge.. The present study suggests that FK506 and E5880 can improve the function of hepatic allografts subjected to prolonged warm ischemia in NHBDs, and that the protective effects of the two drugs seem to be synergistic.

Topics: Adenosine Triphosphate; Animals; Aspartate Aminotransferases; Immunosuppressive Agents; Ischemia; Liver; Liver Transplantation; Piperidines; Platelet Activating Factor; Pyridinium Compounds; Swine; Tacrolimus

Increased production of oxygen free radicals and infiltration of neutrophils into tissue subjected to ischemia-reperfusion have emphasized that neutrophils play a direct role in the development of injury. The present study was designed to elucidate the effect of FK506, a new immunosuppressive drug, on 11 hours of complete ischemia and reperfusion of the inguinal island skin flaps in rats. Group 1 (n = 10) control animals underwent ischemia and reperfusion and no treatment. Group 2 (n = 10) animals received FK 506 0.3 mg/kg/day, and group 3 (n = 9) animals received 0.5 mg/kg/day intramuscularly for 3 days before the ischemia. The effect of the drug was evaluated by measuring flap survival and tissue malondialdehyde content and myeloperoxidase activity and also by histopathologic examination of the skin specimens taken at the 1st and 24th hour after reperfusion. The survival of flaps controlled for 7 days was found to be significantly improved in group 2 (65.0 +/- 10.93 percent) and group 3 (93 +/- 6.25 percent) when compared with the control group (14 +/- 10.12 percent) (p < 0.04 and p < 0.0001). The tissue contents of malondialdehyde and activities of myeloperoxidase were significantly lower in groups 2 and 3 than in the control group. Three days of pretreatment with FK506 significantly reduced neutrophil infiltration in groups treated with either of the doses. These results showed that neutrophils play an important role in island flap survival associated with ischemia-reperfusion injury. Increased neutrophil infiltration was found related with increased levels of malondialdehyde and myeloperoxidase. Flap necrosis and the increase in malondialdehyde, myeloperoxidase, and neutrophil infiltration were improved by FK506 pretreatment, a neutrophil modulating agent.

Topics: Animals; Free Radicals; Graft Survival; Groin; Immunosuppressive Agents; Injections, Intramuscular; Ischemia; Leukocyte Count; Male; Malondialdehyde; Neutrophil Activation; Neutrophils; Peroxidase; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Skin; Skin Transplantation; Surgical Flaps; Tacrolimus

Tacrolimus, an immunosuppressant agent, has been shown to reduce tissue injury and leukocyte accumulation after transient ischemia. This study was designed to evaluate quantitatively the inhibitory effects of tacrolimus on leukocyte rolling and on subsequent leukocyte accumulation in vivo after transient retinal ischemia and the protective effects of tacrolimus on ischemia-induced neural damage.. Retinal ischemia was induced for 60 minutes in anesthetized pigmented rats by temporary ligation of the optic sheath. Tacrolimus was administered at 10 minutes after ischemic induction. At 4, 12, 24, and 48 hours after reperfusion, leukocyte behavior in the retinal microcirculation was evaluated in vivo with acridine orange digital fluorography. After 7 days of reperfusion, ischemia-induced retinal damage was evaluated histologically.. Treatment with tacrolimus suppressed leukocyte rolling; the maximum number of rolling leukocytes was reduced by 60.1% at 12 hours after reperfusion (P<0.05). In tacrolimus-treated rats, the velocity of rolling leukocytes was significantly faster than in vehicle-treated rats (P<0.01). The subsequent leukocyte accumulation was reduced by 61.6% at 24 hours after reperfusion (P<0.01). Histological examination demonstrated the protective effect of tacrolimus on ischemia-induced retinal damage, which was more substantial in the inner retina (P<0.01).. The present study demonstrated the inhibitory effect of tacrolimus on leukocyte rolling and on subsequent leukocyte accumulation and the therapeutic potency to neural injury after transient retinal ischemia.

Topics: Animals; Cell Adhesion; Immunosuppressive Agents; Ischemia; Leukocytes; Male; Microcirculation; Rats; Rats, Inbred Strains; Retina; Retinal Vessels; Tacrolimus; Time Factors

Topics: Animals; Immunosuppressive Agents; Ischemia; Liver Circulation; Reperfusion Injury; Tacrolimus

Topics: Animals; Endothelins; Gene Expression Regulation; Immunosuppressive Agents; Ischemia; Kidney; Kidney Tubules; Male; Microcirculation; Platelet-Derived Growth Factor; Rats; Rats, Sprague-Dawley; Renal Circulation; Tacrolimus; Transforming Growth Factor beta

Topics: Adenine Nucleotides; Animals; Aspartate Aminotransferases; Energy Metabolism; Graft Survival; Ischemia; Liver; Liver Transplantation; Organ Preservation; Piperidines; Platelet Activating Factor; Postoperative Period; Pyridinium Compounds; Swine; Tacrolimus; Temperature; Transplantation, Homologous

An 8-month-old child with an immunodeficiency disorder characterized by abnormal lymphocyte function and by low IgG and IgA levels had combined liver and small bowel transplantation under tacrolimus and steroid immunosuppression for the treatment of short gut syndrome and hepatic cirrhosis. The patient developed an early postoperative episode of Pneumocystis carinii pneumonia, and a subsequent surgical complication, prompting discontinuance of tacrolimus. A skin rash eventually shown to be graft-versus-host disease (GVHD) developed in the flank on the 12th post-transplant day and gradually became generalized. Peritonitis, sepsis, multisystem organ failure including the liver allograft led to death on the 23rd post-operative day. The mechanisms leading to post-transplant GVHD under the specific circumstances in this case are discussed.

Topics: Exanthema; Fatal Outcome; Female; Glucocorticoids; Graft vs Host Disease; Humans; IgA Deficiency; IgG Deficiency; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Infant; Intestine, Small; Ischemia; Liver; Liver Cirrhosis; Liver Transplantation; Lymphocytes; Methylprednisolone; Multiple Organ Failure; Peritonitis; Pneumonia, Pneumocystis; Sepsis; Short Bowel Syndrome; Tacrolimus

The purpose of this study was to investigate the role of neutrophils in ischemic tissue injury and the possible inhibition by pretreatment with FK506, a neutrophilic modulating agent. A dorsal caudally based skin flap (3 x 9 cm) was used as an ischemic injury model in experimental groups. Prior to flap elevation, FK506 at doses of 0.3 mg per kilogram (group 2), 0.5 mg per kilogram (group 3), and 1.0 mg per kilogram (group 4) was given for 3 days intramuscularly. The relationship among neutrophil accumulation (histopathologically), myeloperoxidase (MPO) activity, malondialdehyde (MDA) content (biochemically) of the flap tissue, and flap survival were studied. Skin flaps showed reduced necrosis in the FK506-treated groups (p < 0.08, p < 0.0001, and p < 0.0001 respectively). The increase in accumulation of neutrophils, and MDA and MPO levels (which were induced by ischemia) observed 1 and 24 hours after flap elevation was diminished by FK506 pretreatment. The increased neutrophilic infiltration, and raised tissue MDA content and MPO activity revealed involvement of both free radical production and neutrophils in ischemia. This injury was decreased by FK506, probably by inhibition of neutrophilic chemotaxis, infiltration, and releasing factors.

Topics: Animals; Graft Survival; Immunosuppressive Agents; Ischemia; Male; Malondialdehyde; Neutrophils; Peroxidase; Rats; Rats, Wistar; Skin; Surgical Flaps; Tacrolimus

Bile acids are synthesized and secreted by the liver. During liver failure and hepatic dysfunction, a marked reduction of bile acid synthesis has been shown. The purpose of this study was to determine whether the biliary bile acid pattern was affected by preservation injury and rejection and whether it was a reliable marker for graft function in pediatric liver recipients after liver transplantation.. We prospectively measured the biliary bile acid pattern in 126 serial bile samples obtained from 15 consecutive pediatric liver recipients by reversed phase high pressure liquid chromatography and correlated our results with clinical findings: preservation injury, no rejection, rejection, or infection.. There was a significant change of the bile acid pattern during the first 3 days after transplant. Total biliary bile acids, cholic acid (CA), and CA/chenodeoxycholic acid (CDCA) ratio increased in 12 of 15 patients with mild preservation injury. These changes of the bile acid pattern were markedly delayed in patients with severe preservation injury. During 16 rejection episodes, total biliary bile acid, CA, and CA/CDCA ratio decreased significantly, but returned to normal after successful treatment of rejection. Bacterial infection, observed in nine children, and cyclosporine toxicity, observed in three children, seemed to have no affect on the biliary bile acids.. Liver cell damage as a result of preservation injury or rejection leads to a reduction of biliary CA, resulting in a decrease of total biliary bile acids and the CA/CDCA ratio in pediatric liver recipients. This might be caused by a diminished secretion of bile acids and by a decreased synthesis of bile acids.

Topics: Adolescent; Bile Acids and Salts; Child; Child, Preschool; Cholic Acid; Cholic Acids; Chromatography, High Pressure Liquid; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Ischemia; Liver; Liver Transplantation; Male; Postoperative Complications; Prospective Studies; Tacrolimus

Increased morbidity and mortality following transplantation surgery due to the primary nonfunction and dysfunction of the liver poses a great challenge and has increased the crescendo of research work in this field. In this study, we have tried to address the issue concerning the changes in Ca2+ homeostasis and hepatic microcirculation in 90 min of ischemia followed by reperfusion of the liver after FK506 pretreatment. Twenty dogs divided into two groups; group I (0.15 mg/kg/day FK506 for 3 days, im) and group II (control) were used for the measurement of mitochondrial (mit) and total cellular Ca2+ by atomic absorption spectrophotometer and hepatic microcirculation with laser Doppler flowmeter. Serum AST leakage was significantly (P < 0.05) suppressed in group I at 6 hr after reperfusion. The percentage gain in mit Ca2+ in group I was significantly (P < 0.05) inhibited compared to that in group II at 15 min after reperfusion and also when compared with the preischemic value it was significantly (P < 0.05) elevated at 30 min after reperfusion in group II only. FK pretreatment significantly (P < 0.05) inhibited the overload in total cellular Ca2+ at 15 and 30 min after reperfusion. Moreover, hepatic microcirculation was significantly (P < 0.001) better in group I between 2 and 6 hr after reperfusion. In conclusion, the ameliorating property of FK in ischemia-reperfusion may be explained by prevention of the cellular Ca2+ overload during the perireperfusion period.

Topics: Animals; Calcium; Dogs; Female; Homeostasis; Immunosuppressive Agents; Ischemia; Liver; Liver Circulation; Male; Microcirculation; Reperfusion Injury; Tacrolimus

Topics: Alanine Transaminase; Analysis of Variance; Animals; Cold Temperature; Graft Survival; Ischemia; Lipid Peroxides; Liver; Liver Transplantation; Organ Preservation; Phospholipids; Rats; Rats, Inbred ACI; Reperfusion Injury; Tacrolimus; Transplantation, Isogeneic

We examined the nephrotoxicity of tacrolimus (FK506) in a model of mild warm ischemia. After clamping of both renal arteries of male Sprague-Dawley rats for 20 min, the animals received tacrolimus (3 mg/kg/day i.p.), vehicle of a combination of tacrolimus (3 mg/kg/day i.p.) and diltiazem (12 mg/kg, orally) or vehicle and diltiazem (12 mg/kg, orally). The excretion of urinary enzymes was determined on a daily basis, creatinine clearance at day 10. Tacrolimus significantly increased NAG (N-acetyl-beta-glucosaminidase) excretion and associated histological damage, finally decreasing creatinine clearance. The toxic potential of tacrolimus was markedly enhanced by ischemia. The additional application of diltiazem reduced NAG excretion and histological damage without affecting creatinine clearance. Thus, the protective effect of diltiazem on tacrolimus-induced nephrotoxicity seems to be at least partially a tubular one.

Topics: Acetylglucosaminidase; Animals; Creatinine; Diltiazem; Ischemia; Kidney Tubules; Male; Rats; Rats, Sprague-Dawley; Reperfusion; Tacrolimus

Topics: Female; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Ischemia; Kidney; Kidney Transplantation; Middle Aged; Muromonab-CD3; Postoperative Complications; Tacrolimus

Topics: Adenosine; Allopurinol; Animals; Cell Adhesion; Cold Temperature; Endothelium, Vascular; Glutathione; Graft Survival; Insulin; Ischemia; Leukocytes; Liver Circulation; Liver Transplantation; Microcirculation; Organ Preservation; Organ Preservation Solutions; Raffinose; Rats; Rats, Inbred ACI; Reperfusion Injury; Tacrolimus; Transplantation, Isogeneic

The mechanisms by which polymorphonuclear neutrophils (PMNs) are recruited by the ischemic and reperfused liver are still unknown. The purpose of this study was to determine whether tumor necrosis factor-alpha (TNF) and/or interleukin-1 alpha (IL-1) acted as potential mediators for PMN infiltration after liver ischemia and reperfusion. The potential effect of FK 506, a powerful immunosuppressant, was also studied. Male Sprague-Dawley rats were subjected to 60 and 90 min of total hepatic ischemia, with an extracorporeal porto-systemic shunt. FK 506 (0.3 mg/kg) was intravenously administered 4 hr before ischemia (FK 506 group), and control animals received normal saline solution (NS group). Plasma TNF, IL-1 levels, and PMN infiltration in liver tissue were serially examined at the end of ischemia, 5, 30, 60, and 360 min after reperfusion. The degree of liver necrosis was assessed at 360 min following reperfusion. In the NS group, IL-1 and TNF revealed a transient elevation at 30 and 60 min after reperfusion, following 60 min of ischemia. When the ischemia was increased to 90 min, the IL-1 activity had a rapid elevation (330.5 +/- 129 pg/ml) at 5 min, which remained at high levels (197.8 +/- 70.4 pg/ml) until 6 hr after reperfusion, whereas the TNF activity decreased to normal levels following a similar peak (355 +/- 181.9 pg/ml) at 5 min after reperfusion. The time course of IL-1 release in the NS group, with 90 min of ischemia, correlated directly with the PMN infiltration.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Chemotaxis, Leukocyte; Interleukin-1; Ischemia; Liver; Male; Neutrophils; Portasystemic Shunt, Surgical; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tacrolimus; Tumor Necrosis Factor-alpha

Topics: Adenosine Triphosphate; Animals; Bile; Cold Temperature; Ischemia; L-Lactate Dehydrogenase; Liver; Liver Circulation; Male; Organ Preservation; Portal System; Rats; Rats, Inbred Lew; Regional Blood Flow; Reperfusion Injury; Tacrolimus

Topics: Animals; Graft Survival; Ischemia; Liver; Liver Circulation; Liver Function Tests; Liver Transplantation; Organ Preservation; Regional Blood Flow; Reperfusion Injury; Swine; Tacrolimus; Temperature

Mechanisms by which immunodepressants (Cyclosporine, CsA; FK 506, FK; Azanthioprine, AZA) ameliorate warm ischemic injury of the liver were examined. Female Sprague-Dawley rats were subjected to 60-min of normothermic liver ischemia. Animals were assigned to one of four groups: group I, control with vehicle treatment; groups II, III, and IV, treatment with CsA (10 mg/kg), FK (1 mg/kg), and AZA (1 mg/kg), respectively. The immunosuppressive agents were given per os for 4 consecutive days prior to the induction of hepatic ischemia. In addition to a survival study, plasma levels of endotoxin, serum activities of tumor necrosis factor-alpha (TNF), plasma levels of phosphatidylcholine hydroperoxide (PCOOH) as a lipid peroxide, and serum alanine aminotransferase (ALT) were investigated in blood samples collected from the suprahepatic vena cava. A 7-day survival period was significantly higher in the immunosuppressed animals. Serum TNF levels were elevated and peaked at 3 h following reperfusion. When, the peak values were compared, the animals given immunodepressants had significantly lower levels of TNF (217.0 +/- 40.6 pg/ml for group I, 67.6 +/- 13.7 for group II, 87.9 +/- 28.3 for group III and 89.1 +/- 19.9 for group IV; Mean +/- SEM). Plasma PCOOH levels were also elevated following reperfusion, but with no statistical difference among the groups. Our data suggest that immunodepressants ameliorate warm ischemia/reperfusion injury through modulation of TNF production and not through a diminution of lipid peroxidative injury.

Topics: Alanine Transaminase; Animals; Azathioprine; Cyclosporine; Female; Immunosuppressive Agents; Ischemia; Lipid Peroxidation; Liver; Phosphatidylcholines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tacrolimus; Temperature; Time Factors; Tumor Necrosis Factor-alpha

Topics: Adenosine Triphosphate; Alanine Transaminase; Animals; Aspartate Aminotransferases; Cyclosporine; Dogs; Female; Ischemia; L-Lactate Dehydrogenase; Liver; Male; Reperfusion Injury; Tacrolimus

To examine the role of neutrophils, their presence and the degree of infiltration, as important determinants of ischemia and reperfusion injury of the liver, male Sprague-Dawley rats were subjected to 60 and 90 min of total-liver ischemia. The presence of neutrophils, assessed by the measurement of liver tissue myeloperoxidase (MPO), and the degree of neutrophil liver infiltration, determined by the naphthol AS-D chloroacetate esterase technique, correlated well with animal survival and response to FK506 and cyclosporine administration. Lipid peroxidation, measured by the malondialdehyde (MDA) test in liver tissue, was another factor closely linked with liver function and survival. Pretreatment with FK506 (0.3 mg/kg) and CsA (5 mg/kg) was given at 4 hr and 1 hr before ischemia and at the time of reperfusion. Control ischemic animals showed increased neutrophil liver infiltration, high MPO and MDA liver levels, and diminished overall survival. FK506 and CsA-treated animals had better survival and diminished neutrophil liver infiltration, as well as MPO and MDA levels. The mechanism by which FK506 and CsA protected the animals from severe liver ischemic injury is unknown. Our data indicated that the presence and the degree of infiltration of neutrophils were important components of liver ischemia/reperfusion injury in the rat. So it is possible that one of the fundamental effects of the FK506 and CsA might be through the inhibition of the presence and infiltration of neutrophils in liver tissue.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Cyclosporine; Ischemia; L-Lactate Dehydrogenase; Liver; Male; Malondialdehyde; Microscopy, Electron; Neutrophils; Peroxidase; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Survival Analysis; Tacrolimus

In recent years, there has been growing evidence that tumor necrosis factor-alpha (TNF) plays an important role in the development of hepatic injury after ischemia-reperfusion. We have previously demonstrated that the immunosuppressants, cyclosporine, azathioprine and FK506 (FK), have a protective effect on warm ischemic injury of the rat liver. In the present study, we attempted to elucidate the mechanism for the beneficial effect of FK on liver ischemia, with special reference to the suppression of TNF production. After 60 min and 90 min of warm liver ischemia, the survival rates were significantly improved by FK pretherapy. This was associated with amelioration of hepatic injury, as assessed by histological examinations and determinations of serum AST and lipid peroxide levels in the liver. After 60 min of liver ischemia, TNF was measurable during the reperfusion period in the sera of the control animals, peaking of 6 h after reperfusion (123 +/- 15.8 pg/ml, mean SEM). In contrast, pretreatment with FK significantly suppressed the elevation of serum TNF levels at the same time point (75.8 +/- 13.1 pg/ml, P < 0.05). The present data showed that liver ischemia-reperfusion resulted in TNF production, and that FK could protect the liver from reperfusion injury by suppressing this production of TNF.

Topics: Animals; Female; Immunosuppressive Agents; Ischemia; Liver; Malondialdehyde; Rats; Rats, Sprague-Dawley; Survival; Tacrolimus; Time Factors; Tumor Necrosis Factor-alpha

Topics: Animals; Blood Urea Nitrogen; Injections, Intravenous; Ischemia; Kidney; Male; Metabolic Clearance Rate; Nephrectomy; Rats; Rats, Inbred Lew; Tacrolimus

Topics: Adenosine Triphosphate; Animals; Cyclosporine; Energy Metabolism; Ischemia; Kinetics; Liver; Magnetic Resonance Spectroscopy; Male; Phosphates; Phosphorus; Rats; Rats, Sprague-Dawley; Reperfusion; Tacrolimus; Temperature; Time Factors

Topics: Adenosine Triphosphate; Alanine Transaminase; Animals; Anti-Bacterial Agents; Immunosuppressive Agents; Ischemia; L-Lactate Dehydrogenase; Liver; Liver Circulation; Male; Rats; Rats, Inbred Lew; Tacrolimus

Topics: Animals; Anti-Bacterial Agents; Azathioprine; Cyclosporins; Female; Immunosuppressive Agents; Ischemia; Lipid Peroxidation; Liver; Malondialdehyde; Rats; Rats, Inbred Strains; Tacrolimus; Time Factors

Isolated segments of cat small intestine were subjected to 3 hr of ischemia followed by 1 hr reperfusion (I/R). Mucosal biopsies were obtained for measurement of myeloperoxidase (MPO) activity, an index of tissue neutrophil count, and leukotriene B4 (LTB4) production. Animals were pretreated with either cyclosporin A (CsA) or FK506, which are potent immunosuppressants. Both agents significantly attenuated the neutrophil infiltration induced by I/R. FK506, but not CsA, reduced the elevated mucosal LTB4 production normally observed following reperfusion. The results of this study suggest that FK506 and CsA may be important agents in modulating neutrophil infiltration in acute inflammatory conditions.

Topics: Animals; Cats; Cyclosporine; In Vitro Techniques; Intestine, Small; Ischemia; Leukocyte Count; Leukotriene B4; Neutrophils; Peroxidase; Reperfusion Injury; Tacrolimus

Topics: Animals; Cell Hypoxia; Cell Survival; Cells, Cultured; Cyclosporine; Humans; Ischemia; Liver; Rats; Tacrolimus; Tissue Preservation

Topics: Animals; Anti-Bacterial Agents; Creatinine; Cyclosporins; Drug Synergism; Immunosuppressive Agents; Ischemia; Kidney; Rats; Rats, Inbred Lew; Tacrolimus; Vacuoles

Ischemic damage of the allograft liver is a major problem in clinical liver transplantation. Therefore the identification of hepatoprotective agents is a high priority at most liver transplantation programs. FK 506, a potent new immunosuppressive agent has been reported to possess hepatotrophic activity. To evaluate the putative hepatotrophic activity of FK 506 on experimental hepatic ischemia, rats were subjected to a subtotal hepatectomy following experimental ischemia and subsequent rat survival was assessed. FK 506 (0.3 mg/Kg) administered intravenously 24 hours prior to the induction of hepatic ischemia, reduced the subsequent mortality rate from 100% among controls given saline to only 20% (P less than 0.001). This observation demonstrates that FK 506 enhances the regenerative response of the liver to ischemic injury and may, in addition to its immunologic activity have hepatotrophic activity as well.

Topics: Animals; Anti-Bacterial Agents; Hepatectomy; Immunosuppressive Agents; In Vitro Techniques; Ischemia; Liver; Male; Premedication; Rats; Rats, Inbred Lew; Reperfusion Injury; Survival Rate; Tacrolimus