tacrolimus and Hyperplasia

The purpose of this study was to determine efficacy and safety of cyclosporine A (CsA) for patients with steroid-resistant nephrotic syndrome (SRNS).. The Cochrane Library and PubMed were searched to extract the associated studies on Oct 10, 2018, and the meta-analysis method was used to pool and analyze the applicable investigations included in this study. The P(opulation) I(ntervention) C(omparison) O(utcome) of the study were defined as follows: P: Patients with SRNS; I: treated with CsA, cyclophosphamide (CYC), tacrolimus (TAC) or placebo/not treatment (P/NT); C: CsA vs. placebo/nontreatment (P/NT), CsA vs. CYC, CsA vs. TAC; O: complete remission (CR), total remission (TR; complete or partial remission (PR)), urine erythrocyte number, proteinuria levels, albumin, proteinuria, serum creatinine, and plasma cholesterol, etc. Data were extracted and pooled using RevMan 5.3.. In the therapeutic regimen of CsA vs. placebo/nontreatment (P/NT), the results indicated that the CsA group had high values of CR, TR, and low values of proteinuria, serum creatinine, and plasma cholesterol when compared with those in the placebo group. In comparing CsA vs. cyclophosphamide (CYC), the results indicated that the CsA group had higher TR than the CYC group. In comparing CsA vs. tacrolimus (TAC), the results revealed insignificant differences in CR, and TR between the CsA and TAC groups. The safety of CsA was also assessed. The incidence of gum hyperplasia in CsA group was higher than that in the P/NT group, with no differences in incidence of infections or hypertension between CsA and P/NT groups. There was no difference in the incidence of hypertension between the CsA and TAC groups.. CsA is an effective and safe agent in the therapy of patients with SRNS.

Topics: Cholesterol; Creatinine; Cyclophosphamide; Cyclosporine; Drug Resistance; Gingiva; Humans; Hyperplasia; Hypertension; Immunosuppressive Agents; Infections; Nephrotic Syndrome; Proteinuria; Steroids; Tacrolimus

Atopic dermatitis (AD) presents a large unmet need for treatments with better safety and efficacy. To facilitate development of topical therapeutics, we need an efficient model for assessing different formulations and concentrations. The "plaque model" has been successfully implemented in patients with psoriasis, another common inflammatory disease, to assess the efficacy of topical treatments. This model has not been validated for AD, which has higher placebo responses and less stable lesions than psoriasis.. We aimed to assess changes in molecular signatures of intrapatient target lesions treated with topical therapeutics.. We enrolled 30 patients with mild-to-moderate AD in a randomized, double-blind, intraindividual comparison of 3 approved agents applied blindly at the investigator site daily for 14 days: pimecrolimus, betamethasone dipropionate, clobetasol propionate, and a vehicle/emollient control. Changes in total sign scores (TSSs), transepidermal water loss, and tissue biomarkers (determined by using RT-PCR and immunohistochemistry) were evaluated.. TSSs showed improvements of 30%, 40%, 68%, and 76% at 2 weeks with vehicle, pimecrolimus, betamethasone, and clobetasol, respectively, with parallel changes in transepidermal water loss (P < .05). Significant differences versus vehicle values were limited to steroids (P < .0001). Steroids (particularly clobetasol) restored epidermal hyperplasia and terminal differentiation versus minimal changes with vehicle or pimecrolimus (P < .001). Levels of cellular infiltrates and cytokines (IL-13, IL-22, and S100As) were similarly reduced only by steroids (P < .001). TSS improvement correlated with changes in hyperplasia, infiltrates, and differentiation markers.. We detected significant clinical and tissue differences between agents, providing a novel approach to study the differential effects of topical formulations using a limited sample size.

Topics: Administration, Topical; Adult; Aged; Anti-Inflammatory Agents; Betamethasone; Biomarkers; Cell Differentiation; Clobetasol; Cytokines; Dermatitis, Atopic; Female; Humans; Hyperplasia; Male; Middle Aged; Placebo Effect; Psoriasis; Skin; Tacrolimus; Young Adult

The aim of this study was to determine the safety and efficacy of a novel pimecrolimus-eluting stent in a porcine coronary model and in a phase I clinical trial.. Rapamycin- and paclitaxel-eluting stents reduce the need for repeat intervention by limiting neointimal hyperplasia but might cause delayed healing, pre-disposing patients to late stent thrombosis. Because inflammation plays a key role in restenosis, pimecrolimus, an anti-inflammatory drug, might reduce restenosis without adversely affecting re-endothelialization.. We evaluated a novel polymeric pimecrolimus-eluting stent covered with a thin parylene C diffusion barrier in a porcine coronary model and in a phase I human clinical trial. The clinical study was a prospective, nonrandomized, first-in-human hypothesis-generating study that enrolled 15 patients who had a single de novo native coronary stenosis.. At 28 days and 3 months in the porcine model, histopathologic indicators predicted safety and biocompatibility when stents coated with polymer only, drug only, and 2 drug-polymer formulations were compared with bare-metal stents (BMS). In the phase I clinical trial, 15 patients had successful implantation of pimecrolimus-eluting stents. By 6 months, no patient suffered death, myocardial infarction, or stent thrombosis. However, the angiographic restenosis (61%), mean late loss (1.44 mm), and repeat target lesion revascularization (53%) were significantly higher than historical BMS controls. Whereas the primary end point was percent volume obstruction, restenosis was so severe that operators performed intravascular ultrasound examination in only 6 patients.. Pimecrolimus-eluting stents induced an exaggerated neointimal hyperplasia at 6 months in comparison with historical controls.

Topics: Adult; Aged; Angioplasty, Balloon, Coronary; Animals; Cardiovascular Agents; Coated Materials, Biocompatible; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Disease Models, Animal; Drug-Eluting Stents; Feasibility Studies; Female; Humans; Hyperplasia; Male; Middle Aged; New Zealand; Polymers; Prospective Studies; Prosthesis Design; Registries; Risk Assessment; Severity of Illness Index; Swine; Tacrolimus; Time Factors; Treatment Outcome; Ultrasonography, Interventional; Xylenes

The aim of this study was to examine the impact of overlapping bare-metal stent (BMS) and three different formulations of drug-eluting stent (DES) on intimal hyperplasia (IH) response of patients with diabetes mellitus (DM).. Forty-nine DM patients treated with overlapping BMS (19 lesions), sirolimus-eluting stent (SES 12 lesions), paclitaxel-eluting stent (PES 8 lesions) or tacrolimus-eluting stent (TES 10 lesions) were studied. Baseline and 9-month follow-up volumetric intravascular vascular ultrasound (IVUS) and quantitative coronary angiography (QCA) analysis were performed in the entire stented segment and in the overlapped (OL) and non-overlapped (non-OL) subsegments. Clinical outcomes were evaluated at 1-year follow-up.. Post-procedure (PO-) QCA measurements were similar in all stent groups, and between OL and non-OL subsegments in each individual type of stents. Percent IH was lower in SES and PES vs. BMS (p < 0.05). Percent IH was significantly greater in OL subsegment compared with non-OL subsegment in BMS (p < 0.05), but not in all type of DES groups. SES showed significantly less %IH compared with PES and TES in OL and non-OL subsegments. Vessel area at the OL remained unchanged from PO to FU in all type of DES and BMS groups. There were no aneurysm formation and no stent thrombosis up to 1-year follow-up.. Overlapping BMS is associated with enhanced IH response in diabetic patients, whereas overlapping DES, particularly SES and PES, appear effective to inhibit IH without detectable late vascular adverse effects.

Topics: Analysis of Variance; Coronary Angiography; Coronary Disease; Diabetes Complications; Drug-Eluting Stents; Female; Humans; Hyperplasia; Imaging, Three-Dimensional; Male; Paclitaxel; Prospective Studies; Sirolimus; Stents; Tacrolimus; Treatment Outcome; Tunica Intima; Ultrasonography, Interventional

The introduction of the potent immunosuppressive drugs tacrolimus (FK) and cyclosporine (CSA) has markedly improved the outcome of solid organ transplantation. However, these drugs can cause posttransplantation diabetes mellitus. Abnormalities in the glucose metabolism are of particular significance in pancreas transplantation.. We studied 26 pancreas allograft biopsies, performed 1-8 months posttransplantation, from 20 simultaneous kidney-pancreas transplant recipients, randomized to receive either FK or CSA. The biopsies were studied by light microscopy, immunoperoxidase stains for insulin and glucagon, in situ DNA-end labeling for detection of apoptosis, and electron microscopy. The islet morphology was correlated with the mean and peak levels of CSA and FK in serum, with corticosteroid administration and with glycemia.. On light microscopy cytoplasmic swelling, vacuolization, apoptosis, and abnormal immunostaining for insulin were seen in biopsies from patients receiving either FK or CSA. The islet cell damage was more frequent and severe in the group receiving FK than in the group receiving CSA (10/13 and 5/13, respectively) but the differences were not statistically significant. Significant correlation was seen between the presence of islet cell damage and serum levels of CSA or FK during the 15 days previous to the biopsy, as well as with the peak level of FK. Toxic levels of CSA or FK and administration of pulse steroids were associated with hyperglycemia when these occurred concurrently (P=0.005). Toxic levels of CSA or FK by themselves were associated with hyperglycemia in a minority of cases (8 and 26%, respectively). Electron microscopy showed cytoplasmic swelling and vacuolization, and marked decrease or absence of dense-core secretory granules in beta cells; the changes were more pronounced in patients on FK. Serial biopsies from two hyperglycemic patients receiving FK and evidence of islet cell damage demonstrated reversibility of the damage when FK was discontinued.. The structural damage to beta cells demonstrated in this study is similar to morphological and functional abnormalities previously described in experimental animal models and can at least partially account for the glucose metabolism abnormalities seen in patients receiving these drugs. Toxic levels of CSA or FK and higher steroid doses potentiate each others' diabetogenic effects.

Topics: Adult; Biopsy; Cyclosporine; Female; Follow-Up Studies; Humans; Hyperglycemia; Hyperplasia; Immunosuppressive Agents; Islets of Langerhans; Male; Microscopy, Electron; Middle Aged; Pancreas Transplantation; Tacrolimus; Time Factors; Transplantation, Homologous; Vacuoles

Post-operative complications of vascular anastomosis procedures remain a significant clinical challenge and health burden globally. Each year, millions of anastomosis procedures connect arteries and/or veins in vascular bypass, vascular access, organ transplant, and reconstructive surgeries, generally via suturing. Dysfunction of these anastomoses, primarily due to neointimal hyperplasia and the resulting narrowing of the vessel lumen, results in failure rates of up to 50% and billions of dollars in costs to the healthcare system. Non-absorbable sutures are the gold standard for vessel anastomosis; however, damage from the surgical procedure and closure itself causes an inflammatory cascade that leads to neointimal hyperplasia at the anastomosis site. Here, we demonstrate the development of a novel, scalable manufacturing system for fabrication of high strength sutures with nanofiber-based coatings composed of generally regarded as safe (GRAS) polymers and either sirolimus, tacrolimus, everolimus, or pimecrolimus. These sutures provided sufficient tensile strength for maintenance of the vascular anastomosis and sustained drug delivery at the site of the anastomosis. Tacrolimus-eluting sutures provided a significant reduction in neointimal hyperplasia in rats over a period of 14 days with similar vessel endothelialization in comparison to conventional nylon sutures. In contrast, systemically delivered tacrolimus caused significant weight loss and mortality due to toxicity. Thus, drug-eluting sutures provide a promising platform to improve the outcomes of vascular interventions without modifying the clinical workflow and without the risks associated with systemic drug delivery.

Topics: Animals; Hyperplasia; Nanofibers; Neointima; Rats; Sutures; Tacrolimus

Topics: Administration, Cutaneous; Dermatologic Agents; Facial Dermatoses; Female; Humans; Hyperplasia; Ink; Lip; Middle Aged; Ointments; Tacrolimus; Tattooing

A collection of plasma cells in the skin can represent a broad spectrum of disease entities. Secondary syphilis, primary cutaneous plasmacytoma, primary cutaneous plasmacytosis, cutaneous lymphoid hyperplasia and nodular amyloidosis are considered possible differential diagnoses. The primary cutaneous plasma cell disorders can range from malignant to benign plasma cell neoplasms. The malignant conditions are neoplastic diseases having monoclonal proliferations, rapid progression and fatal outcome while the benign plasma cell disorders usually show polyclonality, chronicity and benign process, including plasmacytosis. We present a case of cutaneous plasmacytosis. The patient was a 34-year-old man, presented with disseminated reddish-brown plaques and nodules on the right side of the hips, inguinal groove, and the thigh. Histopathologically, mature plasma cells perivascular infiltrates were observed mainly in the dermis. Polyclonality of infiltrating plasma cells with coexistence of both kappa and gamma chain-positive cells demonstrated with immunohistochemistry, as well as CD20+++, CD38++++, CD79a++++, CD138++, Ki67<30%. The diagnosis, cutaneous plasmacytosis, was established by the pertinent laboratory findings. Primary cutaneous plasmacytosis was an uncommon reactive lymphoplasmacytic disorder of uncertain etiology. Cutaneous plasmacytosis is a rare disease characterized by peculiar multiple eruptions and hyper gamma globulinemia. It has been mainly described in patients of Japanese descent, with only few reports in Caucasians and Chinese, although information concerning the disorder was limited to individual case reports. Cutaneous plasmacytosis is a rare disorder, which is characterized by multiple red to dark-brown nodules and plaques on the trunk and usually associated with polyclonal hyper gamma globulinaemia. Primary cutaneous plasmacytosis or cutaneous plasmacytosis was thought to be a reactive process with unknown etiology. Histologically, lesions contain dense perivascular infiltration of mature polyclonal plasma cells without any atypia, in the dermis and subcutaneous fat. The clinical course is chronic and benign without spontaneous remission. Available treatments for cutaneous plasmacytosis include psoralen ultraviolet A radiotherapy, systemic chemotherapy and intralesional steroid injection. The patient with cutaneous plasmacytosis in this report was treated with tacrolimus ointment and psoralen ultraviolet A.

Topics: Adult; Humans; Hyperplasia; Immunosuppressive Agents; Male; Plasma Cells; Plasmacytoma; Skin; Skin Diseases; Tacrolimus

Sebaceous hyperplasia, a benign proliferation ofsebaceous glands, has been well documented in organ transplant recipients treated with cyclosporine. Sebaceous hyperplasia has not been strongly associated with any other immunosuppressive medications. We report a case of eruptive sebaceous hyperplasia in a renal transplant recipient with no previous exposure to cyclosporine that was recently started on tacrolimus, mycophenolate mofetil, and prednisone. To our knowledge, this is the first report of eruptive sebaceous hyperplasia in a renal transplant recipient who was immunosuppressed with tacrolimus and had no prior exposure to cyclosporine.

Topics: Adult; Humans; Hyperplasia; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Prednisone; Sebaceous Gland Diseases; Sebaceous Glands; Tacrolimus

Neointimal hyperplasia (NIH) remains one of the leading causes of graft failure after vascular anastomoses. Cytotoxic drugs, such as rapamycin and tacrolimus, have been shown to inhibit the development of NIH. In this study, the aim was to test the impact of a sustained releasing tacrolimus-chitosan-eluting suture on the development of NIH in a rat model.. In vitro tacrolimus release tests for a 7/0 tacrolimus-chitosan coated PVDF suture were confirmed for 1 month without an initial burst release. Endothelialisation over the aortotomy line occurred in both groups. The area of neointima was significantly reduced in group T compared with group C (ratio 0.22 ± 0.12 vs. 0.42 ± 0.11; p = .017) 1 month post-operatively. Likewise, the percentage of PCNA immunostaining significantly decreased in group C compared with group T (3.83 ± 2.85% vs. 11.17 ± 7.78%; p = .026). The cells constituting NIH were positive for ASMA immunostaining.. Tacrolimus-chitosan-eluting suture is shown to be an effective way to reduce NIH without interfering with normal endothelialisation.

Topics: Actins; Animals; Aorta; Cardiovascular Agents; Coated Materials, Biocompatible; Equipment Design; Hyperplasia; Male; Neointima; Proliferating Cell Nuclear Antigen; Rats, Wistar; Solubility; Suture Techniques; Sutures; Tacrolimus; Time Factors

Topics: Animals; Drug-Eluting Stents; Hyperplasia; Immunosuppressive Agents; Neointima; Rats; Sutures; Tacrolimus; Tunica Intima

Nodular lymphoid hyperplasia (NLH) of the gastrointestinal tract is a rare disease usually reported in patients with congenital or acquired immunodeficiency and chronic gastrointestinal infections. However, no case of NLH in a patient receiving immunosuppressive therapy has been reported to date. We describe the case of a woman who developed chronic diarrhea related to NLH 9 years after liver transplantation. Other causes of diarrhea and NLH were excluded. Her immunosuppressive regimen consisted on mycophenolate mofetil (MMF) and tacrolimus. Reduction of MMF dose improved symptoms but led to a rising aminotransferase level. Given the risk of graft rejection, MMF at full dose was resumed and she was started on symptomatic treatment for diarrhea. The role of immunosuppressive drugs in the pathogenesis of NLH may be related to the reduction of T- and B-lymphocyte proliferation and decreasing antibody production. NLH will further develop to compensate functionally inadequate lymphoid tissue, as reported in congenital immunodeficiency states.

Topics: Diarrhea; Duodenum; Female; Gastrointestinal Diseases; Graft Rejection; Humans; Hyperplasia; Immunosuppressive Agents; Intestinal Mucosa; Liver Transplantation; Lymph Nodes; Middle Aged; Mycophenolic Acid; Postoperative Complications; Tacrolimus

Sirolimus (rapamycin) is used in drug-eluting stent strategies and proved clearly superior in this application compared with other immunomodulators such as pimecrolimus. The molecular basis of this action of sirolimus in the vascular system is still incompletely understood. Measurements of cell proliferation in human coronary artery smooth muscle cells (hCASM) demonstrated a higher antiproliferative activity of sirolimus compared with pimecrolimus. Although sirolimus lacks inhibitory effects on calcineurin, nuclear factor of activated T-cell activation in hCASM was suppressed to a similar extent by both drugs at 10 μM. Sirolimus, but not pimecrolimus, inhibited agonist-induced and store-operated Ca(2+) entry as well as cAMP response element binding protein (CREB) phosphorylation in human arterial smooth muscle, suggesting the existence of an as-yet unrecognized inhibitory effect of sirolimus on Ca(2+) signaling and Ca(2+)-dependent gene transcription. Electrophysiological experiments revealed that only sirolimus but not pimecrolimus significantly blocked the classical stromal interaction molecule/Orai-mediated, store-operated Ca(2+) current reconstituted in human embryonic kidney cells (HEK293). A link between Orai function and proliferation was confirmed by dominant-negative knockout of Orai in hCASM. Analysis of the effects of sirolimus on cell proliferation and CREB activation in an in vitro model of arterial intervention using human aorta corroborated the ability of sirolimus to suppress stent implantation-induced CREB activation in human arteries. We suggest inhibition of store-operated Ca(2+) entry based on Orai channels and the resulting suppression of Ca(2+) transcription coupling as a key mechanism underlying the antiproliferative activity of sirolimus in human arteries. This mechanism of action is specific for sirolimus and not a general feature of drugs interacting with FK506-binding proteins.

Topics: Aorta; Calcium Channels; Calcium Signaling; Cardiovascular Agents; Cell Proliferation; Coronary Vessels; Cyclic AMP Response Element-Binding Protein; Dose-Response Relationship, Drug; Gene Knockout Techniques; HEK293 Cells; Humans; Hyperplasia; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NFATC Transcription Factors; ORAI1 Protein; Phosphorylation; Sirolimus; Stents; Tacrolimus; Time Factors; Tissue Culture Techniques; Transcription, Genetic; Transfection

We investigated whether tacrolimus (FK506) can inhibit neointimal formation in arterialised vein grafts in rats.. Lewis iliolumbar veins were implanted into the abdominal aorta of isogeneic rats. Animals in the treatment groups had daily intramuscular injections of tacrolimus at 0.2 mg/kg (group B) and 0.1 mg/kg (Group C), respectively. The control group A had no treatment. Light microscope evaluations of arterialised vein grafts were performed 30 days after operation. We determined the presence of endothelial cells, the thickness of intima and media, and the degree of infiltration by MHC class II positive, CD4 positive, and CD8 positive cells into the adventitia.. The intimal thickness in group B (5.0±1.0 µm) was statistically lower (P < 0.05) when compared to group C (7.0±3.0 µm). The intimal thickness in untreated group A (12.7±7.0 µm) was statistically higher (P < 0.01) when compared to both treated groups B and C, respectively. The medial thickness and degree of adventitial infiltration by MHC class II positive, CD8 positive, and CD4 positive cells did not differ between groups.. Treatment with tacrolimus (FK506) showed a dose dependant inhibition of neointimal hyperplasia in arterialised vein grafts in rats (Tab. 1, Fig. 3, Ref. 22).

Topics: Animals; Aorta, Abdominal; Hyperplasia; Immunosuppressive Agents; Male; Neointima; Rats; Rats, Inbred Lew; Tacrolimus; Tunica Intima; Veins

Topics: Animals; Femoral Artery; Hyperplasia; Immunosuppressive Agents; Neointima; Suture Techniques; Sutures; Swine; Tacrolimus

The purpose is to elucidate the mechanism by which a newly developed tacrolimus-eluting stent (TES) prevents neointimal hyperplasia after stenting.. The three major coronary arteries in juvenile swine were randomized to implantation of either a TES or bare metal stent (BMS). Twelve weeks after stenting, the TES showed 29% less neointimal area than the BMS. Immunohistochemical staining showed that the expression of calcineurin was up-regulated in the neointima and media after stenting, and the TES inhibited this up-regulation. Western blotting demonstrated that the expression of calcineurin, nuclear factor of activated T cell (NFAT), and interleukin-2 (IL-2) was lower with the TES than with the BMS. To confirm the effect of tacrolimus on vascular smooth muscle cells (VSMCs) and its mechanism, cultured rat VSMCs were incubated with 12.5 microM of tacrolimus (tacrolimus group) or without tacrolimus (control group). The cell number of the tacrolimus group was significantly lower than that of the control group at 48 h of incubation. Western blotting demonstrated that tacrolimus decreased the expression of calcineurin, NFATc4, and IL-2 of cultured VSMCs. We confirmed that calcineurin small-interfering RNA (siRNA) decreased cell proliferation and the expression of NFATc4 and IL-2 in cultured VSMCs compared with negative control-siRNA.. The newly developed TES inhibited neointimal hyperplasia after stenting via the calcineurin/NFAT/IL-2 signaling pathway, which is one of several mechanisms through which TES inhibits restenosis. Calcineurin may be an important molecular target to prevent restenosis after stenting.

Topics: Animals; Calcineurin; Cells, Cultured; Coronary Vessels; Drug-Eluting Stents; Hyperplasia; Immunosuppressive Agents; Models, Animal; Muscle, Smooth, Vascular; NFATC Transcription Factors; Rats; Signal Transduction; Swine; Tacrolimus; Tunica Intima

Pulmonary venous obstruction (PVO) after correction of total anomalous pulmonary venous connection (TAPVC) frequently occurs due to intimal-hyperplasia and the required re-operation. We have developed a novel sustained-release drug delivery system, using Tacrolimus-eluting biodegradable nano-fiber (TEBN). It consists of nano-scale fiber composed of biodegradable polymer and Tacrolimus. This study evaluated the effects of TEBN for prevention of venous anastomotic stricture in a rat model to apply to PVO operation. Tacrolimus was incorporated into poly (L-lactide-co-glycolide). The venous stricture model was made by rat inferior vena cava anastomosis. The IVC anastomosis was covered with TEBN with 1.0 wt% Tacrolimus (n=12) or without TEBN as a control (n=12), and evaluated histologically at 1, 2, and 4 weeks after operation. The ratio of intimal area was significantly reduced in the TEBN group compared with the control group (ratio; 1 week: 0.43+/-0.26 vs. 0.07+/-0.04, P=0.04, 2 weeks: 0.39+/-0.19 vs. 0.05+/-0.02, P=0.01, 4 weeks: 0.31+/-0.15 vs. 0.09+/-0.04, P=0.03, control vs. TEBN, respectively). Histological findings showed endothelialization along the inner surface of the vein even in TEBN. The TEBN reduced intimal hyperplasia and preserved endothelialization even in a venous stricture. These results suggested that this strategy might be useful for prevention of recurrent PVO after TAPVC correction.

Topics: Absorbable Implants; Anastomosis, Surgical; Animals; Cardiovascular Agents; Cell Proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Drug-Eluting Stents; Humans; Hyperplasia; Male; Materials Testing; Muscle, Smooth, Vascular; Nanostructures; Polyglactin 910; Prosthesis Design; Pulmonary Veno-Occlusive Disease; Rats; Rats, Wistar; Tacrolimus; Time Factors; Tunica Intima; Vena Cava, Inferior

To report the 4-month angiographic and 6-month clinical follow-up in first-in-man study using the tacrolimus-eluting bioabsorbable polymer-coated cobalt-chromium MAHOROBA stent.. A total of 47 patients with either stable angina or unstable angina, or silent myocardial ischaemia, based on a de novo coronary stenosis that could be covered by a single 18 mm stent in a native coronary artery with a diameter between 3.0 and 3.5 mm were enrolled at three sites. The primary endpoint was in-stent late loss at 4 months. The secondary endpoints include %volume obstruction of the stents assessed by intravascular ultrasound (IVUS) at 4 months and major adverse cardiac events (MACE) at 6 months. Forty-seven patients were enrolled. Procedural success was achieved in 97.9%. At 4-month follow-up, in-stent late loss was 0.99 +/- 0.46 mm, whereas in-stent %volume obstruction in IVUS was 34.8 +/- 15.8%. At 6 months, there were no deaths, but 2 patients suffered from a myocardial infarction and 11 patients required ischaemia-driven repeat revascularization. The composite MACE rate was 23.4%.. This tacrolimus-eluting stent failed to prevent neointimal hyperplasia, despite the theoretical advantages of the tacrolimus, which has less inhibitory effects on endothelial cells than smooth muscle cells.

Topics: Absorbable Implants; Aged; Angioplasty, Balloon, Coronary; Coronary Angiography; Coronary Stenosis; Drug-Eluting Stents; Feasibility Studies; Female; Humans; Hyperplasia; Immunosuppressive Agents; Male; Middle Aged; Prospective Studies; Tacrolimus; Thrombosis; Time Factors; Treatment Outcome; Tunica Intima; Ultrasonography, Interventional

Topics: Angioplasty, Balloon, Coronary; Animals; Cardiovascular Agents; Coated Materials, Biocompatible; Coronary Restenosis; Coronary Stenosis; Drug-Eluting Stents; Humans; Hyperplasia; Polymers; Prosthesis Design; Risk Assessment; Severity of Illness Index; Tacrolimus; Time Factors; Treatment Outcome; Xylenes

Stent-based delivery of tacrolimus has shown neointimal hyperplasia and restenosis reduction; FK506 is a water insoluble macrolide immunosuppressant. The purpose of this study was to evaluate acute and chronic tissue response to a polymer-free FK506 drug-eluting stent implantation in a porcine coronary artery model. Seventy-eight nonatherosclerotic minipigs underwent successful placement of 134 stents (control n = 56; FK506 (1.5 microg/mm(2)) n = 44; FK506 (2.6 microg/mm(2)) n = 34) at 7, 15, 30, 90, or 180 days. Endothelialisation was almost complete at 7 days, complete at 15 days. At 30 and 90 days, mean neointimal thickness, neointimal area, and % stenosis was significantly less for drug-eluting stents compared with controls. At 180 days, histomorphometric values were similar for eluting and control stents. The FK506-eluting stent allows for a complete re-endothelialisation at 15 days and favorably moderate neointimal hyperplasia at 30 and 90 days in the porcine coronary model. Because of a possible limited bioavailability of FK506, long-term inhibition of neointimal formation was not sustained at the considered follow-up.

Topics: Angioplasty, Balloon, Coronary; Animals; Coated Materials, Biocompatible; Coronary Restenosis; Coronary Vessels; Drug-Eluting Stents; Hyperplasia; Immunosuppressive Agents; Materials Testing; Surface Properties; Swine; Swine, Miniature; Tacrolimus; Tunica Intima

To investigate the efficacy of the malononitrilamide FK778 to prevent vascular smooth muscle cell (SMC) migration/proliferation, and vascular fibrosis, the key events in restenosis development using in vivo and in vitro studies.. Since the high rate of restenosis after percutaneous transluminal coronary angioplasty limited its long-term success, the implementation of locally delivered antiproliferative/immunosuppressive agents became advantageous.. Rats underwent balloon denudation of the abdominal aorta and received sirolimus, tacrolimus, or FK778 for 28 days in varying doses. Aortas were harvested for histologic evaluation, profibrotic gene expression, and organ chamber studies. Antifibrotic, antiproliferative and antimigratory effects of the immunosuppressants were further evaluated in vitro.. Histology of untreated animals revealed marked intimal hyperplasia with moderate luminal obliteration. Neointima formation was dose-dependently attenuated by all three agents with FK778 and sirolimus being most efficacious. Organ chamber relaxation studies showed a leftward shift of the nitroglycerin and the acetylcholine dose-responses in all treatment groups, indicating diminished endothelial dysfunction. In vivo, only FK778 treatment revealed a significant downregulation of the TGF-beta/vasorin system which could be explained by upregulation of the TGF-beta-inhibitory mediator SMAD7. In vitro, FK778 showed most potent antiproliferative and antimigratory effects on SMC compared with sirolimus and tacrolimus. Only the antiproliferative effect of FK778 was due to pyrimidine synthesis blockade and could be reversed by uridine supplementation.. The malononitrilamide FK778 proved highly efficacious against restenosis development by targeting two major components of intimal hyperplasia: SMC proliferation/migration and vascular fibrosis. Thus, the introduction of malononitrilamide-loaded stents may be a promising effort for future strategies.

Topics: Alkynes; Animals; Aorta, Abdominal; Carrier Proteins; Cell Movement; Cell Proliferation; Endothelium, Vascular; Graft Occlusion, Vascular; Hyperplasia; Immunosuppressive Agents; Isoxazoles; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nitriles; Rats; Rats, Inbred Lew; RNA, Messenger; Sirolimus; Smad7 Protein; Tacrolimus; Transforming Growth Factor beta1; Tunica Intima; Vasodilation; Vasodilator Agents

Polymer stent coatings may not be suitable for drug elution because of inherent proinflammatory effects. A previous study suggested a beneficial effect of a stent eluting tacrolimus from a nanoporous ceramic aluminum oxide coating in a rabbit restenosis model. We investigated whether this stent is effective in preventing in-stent restenosis in a porcine restenosis model. Thirty-four juvenile swine underwent balloon overstretch injury and were subjected to implantation of either stainless steel (bare) stents, bare stents coated with nanoporous aluminum oxide alone, and coated stents eluting 50 and 180 mug of tacrolimus (FK506). In-stent restenosis was quantified at 1 and 3 months after stent placement by histomorphometry. A significant increase of neointimal hyperplasia was noted with the stents coated with aluminum oxide alone compared with bare stents (2.92 +/- 1.02 and 1.38 +/- 0.51 mm(2), respectively; P < 0.02). In all arteries containing coated stents, particle debris was found in the media and neointima, resulting in augmented vascular inflammation. In the group of stents coated with aluminum oxide, FK506 elution at a dose 180 mug reduced neointimal hyperplasia vs. no drug elution (1.66 +/- 0.49 vs. 2.92 +/- 1.02 mm(2); 180 mug vs. ceramic alone; P < 0.03). At a dose of 50 mug stent-based delivery of FK506, no reduction of neointimal hyperplasia was found (2.88 +/- 1.31 and 2.92 +/- 1.02 mm(2), respectively; P = NS; FK506 vs. ceramic alone). In summary, particle debris shed from a drug-eluting aluminum oxide coating of a stainless steel stent counteracts potential antiproliferative effects of stent-based tacrolimus delivery in a porcine model of restenosis. We propose that stent coatings eluting drugs need to be routinely tested for being tightly anchored into the stent surface. Alternatively, omission of any coating used as a drug reservoir may eliminate inflammatory particle debris after placement of drug-eluting stents.

Topics: Aluminum Oxide; Animals; Coated Materials, Biocompatible; Coronary Restenosis; Graft Occlusion, Vascular; Hyperplasia; Immunosuppressive Agents; Prosthesis Design; Stents; Swine; Tacrolimus; Tunica Intima

Cytotoxic nitric oxide (NO) is produced during ischemia-reperfusion injury and acute and chronic rejection in allografts by expression of inducible (i) NO synthase (NOS). Therefore, continuous inhibition of iNOS may prevent early graft dysfunction and immune injury (rejection) and consequently improve graft survival. FR260330 is a potent and selective inhibitor of iNOS activity that works by preventing iNOS monomers from dimerization. In this study, the authors evaluated the effect of FR260330 in prevention of chronic rejection in a model of rat aortic allografts.. Male Lewis (LEW, RT1l) rats received male ACI (RT1a) aorta allografts or LEW aorta isografts. Fourteen groups (n > or = 6) were involved in this study. FR260330, tacrolimus, or both were administered orally for 14 or 90 days, according to protocol. The degree of intimal proliferation of graft aorta was determined by a computerized image system.. Both low and high doses of FR260330- or tacrolimus-treated grafts showed significantly decreased intima/(intima+media) ratios at day 90 compared with placebo controls. Combination therapy of low-dose FR260330 with low-dose tacrolimus produced a significant decrease of intima/(intima+media) ratios with intact endothelium compared with placebo controls. Anti-alpha-actin immunohistochemical staining demonstrated that one of the mechanisms of intimal proliferation is related to migration of vascular smooth muscle cells.. A selective inhibitor of NOS, FR260330 plays a protective role in chronic aortic allograft rejection in the rat. Combination therapy of low-dose FR260330 with tacrolimus produces significant protection of immune injury and may serve to improve long-term graft survival and function.

Topics: Actins; Animals; Aorta; Body Weight; Chronic Disease; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enzyme Inhibitors; Graft Rejection; Graft Survival; Hyperplasia; Immunosuppressive Agents; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Piperidines; Rats; Rats, Inbred ACI; Rats, Inbred Lew; Tacrolimus; Transplantation, Homologous; Tunica Intima; Tunica Media

Conversion from cyclosporine (CsA) to tacrolimus (TRL) remains challenging in the daily routine due to individual variations in blood concentrations (pharmacokinetics, PK), pharmacodynamics (PD) and in interactions on plasma mycophenolic acid (MPA) concentrations. Therefore, we used our PD assays of lymphocyte function to monitor the conversion of CsA to TRL in heart (HTx) and lung (LTx) transplant recipients.. Patients (six HTx, two LTx) were converted from CsA to TRL because of gingival hyperplasia. All patients were treated with 6 mg BID TRL 24 hours after the last CsA dose and received mycophenolate mofetil BID cotherapy. PK measurements of CsA, TRL, and MPA were done by EMIT. Expression of cytokine production (IL-2, TNF-alpha), lymphocyte proliferation (PCNA), and activation (CD25) was assessed by FACS.. TRL concentrations increased from day 1 to 3, but did not alter MPA concentrations, which were comparably high to MPA concentrations in combination with CsA (day 0). Compared to CsA therapy, increased TRL concentrations did not further inhibit PCNA expression, inhibited CD25 expression less on days 1 and 2 and equally high on day 3, but inhibited expression of IL-2 and TNF-alpha significantly higher on days 2 and 3 (P < .05).. This study shows that monitoring PD of lymphocyte functions after conversion from CsA to TRL in HTx and LTx recipients revealed differences of inhibition of lymphocyte functions. Monitoring PD of lymphocyte function may provide insights in drug interactions of immunosuppressive combination therapy and may help to tailor immunosuppression to avoid toxicity and to enhance efficacy.

Topics: Cyclosporine; Drug Monitoring; Drug Therapy, Combination; Gingival Diseases; Heart Transplantation; Humans; Hyperplasia; Immunosuppressive Agents; Lung Transplantation; Metabolic Clearance Rate; Mycophenolic Acid; Tacrolimus

Modern immunosuppressive agents such as tacrolimus and rapamycin are claimed to be associated with a reduction in vascular narrowing, a central feature of chronic rejection. This study assesses the effect of cyclosporine, tacrolimus and rapamycin on the development of intimal thickening, fibrosis-associated genes and deposition of extracellular matrix (ECM) proteins in a model of intimal hyperplasia. Male Sprague-Dawley rats received either no treatment or 5 mg/kg cyclosporine, 0.1 mg/kg tacrolimus or 0.05 mg/kg rapamycin. Animals underwent left common carotid balloon angioplasty, and intima medial ratios, pro-fibrotic gene expression and ECM accumulation were calculated at 14 and 28 days. Cyclosporine was associated with increased intimal thickening compared to controls ( P < 0.004). Tacrolimus had no effect on intimal thickening, whilst rapamycin significantly inhibited intimal thickening at both 14 and 28 days ( P < 0.004 and P < 0.026, respectively). All groups significantly inhibited matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinases (TIMP)-1, transforming growth factor (TGF)-beta and collagen III expression at 14 days ( P < 0.001), but increased ECM deposition. However, rapamycin marginally reduced ECM deposition compared to cyclosporine ( P < 0.06). Treatment with cyclosporine was associated with worsening of vascular narrowing, whilst rapamycin showed a beneficial reduction in intimal thickening. Treatment with all immunosuppressive agents resulted in increased ECM deposition. Rapamycin may halt the progression of vascular narrowing compared to both cyclosporine and tacrolimus.

Topics: Angioplasty, Balloon; Animals; Carotid Artery, Common; Collagen Type III; Cyclosporine; Extracellular Matrix Proteins; Fibrosis; Gene Expression; Hyperplasia; Immunosuppressive Agents; Male; Matrix Metalloproteinase Inhibitors; Rats; Rats, Sprague-Dawley; Sirolimus; Tacrolimus; Tissue Inhibitor of Metalloproteinases; Transforming Growth Factor beta; Tunica Intima

Allograft vasculopathy remains the leading cause of late allograft failure following transplantation and can be inhibited by the antiproliferative drug rapamycin. This study assessed the efficacy of combining rapamycin therapy with calcineurin inhibition.. Male Sprague-Dawley rats received rapamycin 0.05 mg/kg daily and either tacrolimus 0.1 mg/kg or cyclosporin 5 mg/kg daily, and findings were compared with those in an untreated control group. Animals underwent left common carotid artery balloon angioplasty; the artery was explanted after 2 weeks. Morphometric analysis was performed on transverse sections and the intima : media ratio was calculated. Profibrotic gene expression was measured with competitive reverse transcriptase-polymerase chain reaction at 14 and 28 days. Proliferation was determined with proliferating cell nuclear antigen at 14 and 28 days. Extracellular matrix deposition was quantified with Sirius red.. The combination of rapamycin and tacrolimus was associated with the greatest reduction in intimal thickening. Furthermore, treatment with rapamycin and tacrolimus significantly attenuated extracellular matrix deposition compared with rapamycin and cyclosporin (P < 0.02).. The effects of rapamycin in combination with tacrolimus were better than those observed with rapamycin and cyclosporin.

Topics: Animals; Calcineurin Inhibitors; Carotid Artery, Common; Cell Division; Cyclosporine; Drug Therapy, Combination; Hyperplasia; Immunosuppressive Agents; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Muscle, Smooth, Vascular; Rats; Rats, Sprague-Dawley; Sirolimus; Tacrolimus; Tissue Inhibitor of Metalloproteinase-1; Tunica Intima

Topics: Animals; Aorta, Thoracic; Cryopreservation; Hyperplasia; Inflammation; Microscopy, Electron, Scanning; Rats; Tacrolimus; Transplantation, Homologous; Transplantation, Isogeneic; Tunica Intima; Tunica Media

Topics: Angioplasty, Balloon, Coronary; Animals; Calcineurin Inhibitors; Carrier Proteins; Cell Cycle Proteins; Cell Division; Cell Movement; Clinical Trials as Topic; Clopidogrel; Coronary Artery Disease; Cyclin-Dependent Kinase Inhibitor p27; Down-Regulation; Graft Occlusion, Vascular; Humans; Hyperplasia; Macromolecular Substances; Phosphotransferases (Alcohol Group Acceptor); Platelet Aggregation Inhibitors; Signal Transduction; Sirolimus; Stents; Tacrolimus; Tacrolimus Binding Protein 1A; Ticlopidine; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins; Tunica Media; Vascular Patency

C24-Deoxyascomycin was prepared in a two-step process from ascomycin and evaluated for its immunosuppressant activity relative to ascomycin and FK506. An intermediate in the synthetic pathway, Delta(23,24)-dehydroascomycin, was likewise evaluated. Despite lacking the hydrogen-bonding interactions associated with the C24-hydroxyl moiety of ascomycin, C24-deoxyascomycin was found to be equipotent to the parent compound both in its immunosuppressive potency and in its interaction with the immunophilin, FKBP12. Conversely, Delta(23,24)-dehydroascomycin which also lacks the same hydrogen-bonding interactions did not exhibit this potency. NMR studies were conducted on the FKBP12/C24-deoxyascomycin complex in an attempt to understand this phenomenon at the molecular level. The NMR structures of the complexes formed between FKBP12 and ascomcyin or C24-deoxyascomcyin were very similar, suggesting that hydrogen-bonding interactions with the C24 hydroxyl moiety are not important for complex formation.

Topics: Amino Acid Sequence; Animals; Humans; Hyperplasia; Immunophilins; Immunosuppressive Agents; Lymph Nodes; Lymphocyte Culture Test, Mixed; Magnetic Resonance Spectroscopy; Male; Models, Molecular; Molecular Sequence Data; Nucleotidyltransferases; Peptidylprolyl Isomerase; Protein Binding; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Recombinant Fusion Proteins; Tacrolimus; Tacrolimus Binding Proteins

Topics: Adult; Cyclosporine; Gingiva; Humans; Hyperplasia; Immunosuppressive Agents; Male; Tacrolimus

The potent immunosuppressant ascomycin (1b) was selectively alkylated at the C-32 carbinol, thus providing esters and amides of 32-ascomycinyloxyacetic acid (4, AOAA). These compounds present structural variation at the FKBP/calcineurin interface. While the native carboxylic acid 4 shows no activity in vitro, esters and simple amides of 4 exhibit potent immunosuppression in the human MLR assay. Moreover, amides show inhibitory activity in the rat popliteal lymph node hyperplasia assay. Surprisingly, FKBP binding was weakened by several orders of magnitude when secondary hydrophobic aryl amides of 4 were tested, while maintaining potent immunosuppressive efficacy in vitro.

Topics: Animals; Calcineurin; Carrier Proteins; DNA-Binding Proteins; Heat-Shock Proteins; Humans; Hyperplasia; Immunosuppressive Agents; Lymph Nodes; Lymphocyte Culture Test, Mixed; Rats; Rats, Inbred Lew; Structure-Activity Relationship; Tacrolimus; Tacrolimus Binding Proteins

Ascomycin 2, a close analogue of the immunosuppressant FK506 1, was modified to incorporate a hydroxyl group at the C-33 position. This increased the aqueous solubility of ascomycin by a hundred-fold at pH 7.4 and by approximately 300-fold at pH 6.5. Ascomycin 3 also exhibited an excellent immunosuppressive activity in vitro, as tested in a human mixed lymphocyte proliferation (HuMLR) assay, and in vivo using a rat popliteal lymph node (rPLN) hyperplasia assay.

Topics: Animals; Humans; Hydrogen-Ion Concentration; Hyperplasia; Immunosuppressive Agents; Indicators and Reagents; Lymph Nodes; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Molecular Conformation; Molecular Structure; Rats; Solubility; Structure-Activity Relationship; Tacrolimus

Immune reactions in the gut are associated with increased epithelial cell proliferation. Here we have studied the role of keratinocyte growth factor (KGF; FGF7) and transforming growth factor-alpha (TGF-alpha) in the epithelial cell hyperplasia seen in explants of fetal human small intestine after activation of lamina propria T cells with the superantigen Staphylococcus aureus enterotoxin B (SEB). After the addition of SEB to the explants there is a 10-fold increase in KGF mRNA by 72 h of culture. KGF transcripts were abundant in the lamina propria using in situ hybridization and the culture supernatants contained elevated amounts of KGF protein. SEB had no direct effect on KGF mRNA and protein production by cultured lamina propria mesenchymal cells, but both were upregulated by TNF-alpha. Accompanying the increase in KGF there was also an increase in TGF-alpha precursor proteins in the culture supernatants and the phosphorylated form of the EGFR receptor was also detected in the tissue. Increased TGF-alpha precursor proteins were also detected in the supernatants of control explants stimulated with KGF alone. The direct addition of KGF and TGF-alpha enhanced epithelial cell proliferation and antibodies against KGF and TGF-alpha partially inhibited SEB-induced crypt hyperplasia. These results suggest molecular cross-talk between the KGF/KGFR and the TGF-alpha/EGFR in immune-mediated crypt cell hyperplasia.

Topics: Drug Interactions; Enterotoxins; Epithelial Cells; Fetus; Fibroblast Growth Factor 10; Fibroblast Growth Factor 7; Fibroblast Growth Factors; Growth Substances; Humans; Hyperplasia; Immunosuppressive Agents; Intestine, Small; Lymphocyte Activation; Organ Culture Techniques; RNA, Messenger; Stromal Cells; Superantigens; Tacrolimus; Th1 Cells; Transforming Growth Factor alpha; Up-Regulation

Topics: Adaptation, Physiological; Atrophy; Connective Tissue; Dexamethasone; Gestational Age; Humans; Hyperplasia; Immunosuppressive Agents; Intestinal Mucosa; Intestine, Small; Lymphocyte Activation; Microscopy, Phase-Contrast; Organ Culture Techniques; Pokeweed Mitogens; T-Lymphocytes; Tacrolimus

Topics: Animals; Death; Epithelium; Graft Rejection; Graft Survival; Hyperplasia; Immunosuppression Therapy; Intestinal Mucosa; Intestine, Small; Lymphoproliferative Disorders; Swine; Tacrolimus

The immunosuppressive agent FK-506 has received much attention due to its efficacy and potency in the areas of transplant rejection and autoimmune disease. Calcineurin, a Ca(2+)-calmodulin activated phosphatase, was recently implicated in the immunosuppressive mechanism of FK-506. In our ongoing search for superior immunosuppressive agents, we have synthesized several analogues of FK-506 and tested their mechanistic and immunosuppressive actions. It was found that C-18 hydroxyl analogues of ascomycin, an analogue of FK-506 also called FR900520, bound tightly to immunophilin FKBP-12, but do not show any immunosuppressive activity in vitro or in vivo despite good bioavailability. Further, they reverse the inhibition of calcineurin caused by FK-506/FKBP-12 complex.

Topics: Carrier Proteins; Cell Division; Cells, Cultured; Humans; Hyperplasia; Interleukin-2; Lymph Nodes; Lymphocytes; Structure-Activity Relationship; Tacrolimus; Tacrolimus Binding Proteins

Juxtaglomerular (JG) hyperplasia and tubular damage along with a decrease in the urine creatinine level induced by FK506 in rat kidney have already been reported in previous paper by us. In this paper, we document the relationship of FK506 nephrotoxicity to the change in the production of thromboxane (Tx) A2 and the lipid peroxidation of the cellular membrane in the rat kidney in order to clarify its morphogenesis. The urinary excretion of TxB2 increased with FK506 administration even on day 1 (P < 0.02). Histologically, OKY-046 (thromboxane synthetase inhibitor) decreased tubular damage, although JG hyperplasia was not eradicated, while biochemically the excretion of TxB2 decreased significantly (P < 0.02), and both the decrease in the urine creatinine level and the increase in the N-acetyl-beta,D-glucosaminidase (NAG) index were relatively smaller. Although the FK506-induced morphological and biochemical changes could not be prevented by the continuous administration of superoxide dismutase (SOD) 30,000 U/kg daily, the malondialdehyde content in renal tissue removed 1 h after FK506 administration had increased. These data suggest that FK506 nephrotoxicity is related to the change in the production of TxA2 and lipid peroxidation of the cellular membrane. However, other mechanisms such as the involvement of sympathomimetic effects of FK506 and other vasoconstrictive factors cannot be ruled out.

Topics: Acetylglucosaminidase; Animals; Creatinine; Enzyme Inhibitors; Hyperplasia; Kidney; Kidney Tubules, Proximal; Methacrylates; Rats; Superoxide Dismutase; Tacrolimus; Thromboxane B2

Topics: Animals; Dose-Response Relationship, Drug; Epoprostenol; Hyperplasia; Juxtaglomerular Apparatus; Kidney Diseases; Kidney Tubules; Rats; Rats, Inbred Strains; Tacrolimus; Thromboxane A2; Time Factors

Topics: Acetylglucosaminidase; Animals; Creatinine; Cytoplasmic Granules; Female; Hyperplasia; Kidney; Kidney Tubules; Lysosomes; Microscopy, Electron; Rats; Rats, Inbred Strains; Renin; Tacrolimus