OBJECTIVETacrolimus (FK506) is an immunosuppressive drug, which is widely used to prevent rejection of transplanted organs. However, chronic administration of FK506 leads to hypertension in solid organ transplantation patients, and its molecular mechanisms are much more complicated. In this review, we will discuss the above-mentioned molecular mechanisms of FK506-induced hypertension in solid organ transplantation subjects.

DATA SOURCESThe data analyzed in this review were mainly from relevant articles without restriction on the publication date reported in PubMed. The terms "FK506" or "tacrolimus" and "hypertension" were used for the literature search.

STUDY SELECTIONOriginal articles with no limitation of research design and critical reviews containing data relevant to FK506-induced hypertension and its molecular mechanisms were retrieved, reviewed and analyzed.

RESULTSThere are several molecular mechanisms attributed to FK506-induced hypertension in solid organ transplantation subjects. First, FK506 binds FK506 binding protein 12 and its related isoform 12.6 (FKBP12/12.6) and removes them from intracellular ryanodine receptors that induce a calcium ion leakage from the endoplasmic/sarcoplasmic reticulum. The conventional protein kinase C beta II (cPKCβII)-mediated phosphorylation of endothelial nitric oxide (NO) synthase at Thr495, which reduces the production of NO, was activated by calcium ion leakage. Second, transforming growth factor receptor/SMAD2/3 signaling activation plays an important role in Treg/Th17 cell imbalance in T cells which toget converge to cause inflammation, endothelial dysfunction, and hypertension following tacrolimus treatment. Third, the activation of with-no-K(Lys) kinases/STE20/SPS1-related proline/alanine-rich kinase/thiazide-sensitive sodium chloride co-transporter (WNKs/SPAK/NCC) pathway has a central role in tacrolimus-induced hypertension. Finally, the enhanced activity of renal renin-angiotensin-aldosterone system seems to play a crucial role in the pathophysiology of FK506-induced hypertension.

CONCLUSIONFK506 plays a predominant role in the pathophysiology of hypertension in solid organ transplantation subjects.

Humans ; Hypertension ; chemically induced ; Immunosuppressive Agents ; adverse effects ; therapeutic use ; Organ Transplantation ; adverse effects ; Tacrolimus ; adverse effects ; therapeutic use

Treatment of myelodysplastic syndrome (MDS) remains unsatisfactory. It is possible that immunosuppressive therapy might be effective for a certain subset of patients with MDS. In this review 105 patients with MDS who were treated with cyclosporin A (CsA) including 90 RA, 5 RARS, 10 RAEB, were analyzed. The dose of CsA was 2 - 12 mg/(kg x d) for at least three months. Hematological improvement was observed in 64 patients (61%), and complete remission was observed in 14 patients (13.3%). These results indicated that CsA immunosuppressive therapy may be useful for IPSS low, intermediate-1 and intermediate-2 MDS patients.
Cyclosporine ; adverse effects ; therapeutic use ; Humans ; Immunosuppressive Agents ; therapeutic use ; Myelodysplastic Syndromes ; drug therapy ; immunology

OBJECTIVETo evaluate the efficacy and safety of leflunomide in comparison with methotrexate (MTX) on patients with rheumatoid arthritis (RA) in China.

METHODSFive hundred and sixty-six patients with active rheumatoid arthritis were randomly assigned to receive leflunomide at 20 mg once daily or MTX at 15 mg once weekly in a controlled trial. Five hundred and four patients completed the 12-week treatment and some patients continued the treatment for 24 weeks.

RESULTSBoth leflunomide and MTX could improve the symptoms, signs, and joint function, but there were no changes in X-ray observations of patients with rheumatoid arthritis. In the leflunomide group, the overall rates of effectiveness at 12 weeks and 24 weeks were 86.94% and 92.31% respectively; the rates of remarkable improvement were 64.95% and 79.81% respectively. In the MTX group, the overall rates of effectiveness at 12 weeks and 24 weeks were 84.04% and 83.15% respectively; the rates of remarkable improvement were 56.81% and 75.28% respectively. According to intent-to-treat analysis, the ACR 20% response rates at 12 weeks and 24 weeks in the leflunomide group were 62.54% and 67.18% respectively, compared with 60.08% and 61.32% respectively in MTX group. No statistical differences were shown in the efficacy between the two groups (P > 0.05). The adverse events in the leflunomide group were gastrointestinal symptoms, skin rash, alopecia, nervous system symptoms, decreased leukocyte count, and elevation of alanine aminotransferase (ALT). Most of these side effects were mild and transient. The incidence of adverse events in the leflunomide group was 16.84%, significantly lower than that in MTX group (28.17%, P = 0.002).

CONCLUSIONSLeflunomide is effective in the treatment of RA with less adverse events than MTX. Its efficacy is similar to MTX, but the incidence of adverse events and the rate of withdrawal due to adverse events were lower in the leflunomide group than in MTX group.

Antirheumatic Agents ; adverse effects ; therapeutic use ; Arthritis, Rheumatoid ; drug therapy ; Female ; Growth Inhibitors ; adverse effects ; therapeutic use ; Humans ; Immunosuppressive Agents ; adverse effects ; therapeutic use ; Isoxazoles ; adverse effects ; therapeutic use ; Male ; Methotrexate ; adverse effects ; therapeutic use ; Middle Aged

Idiopathic myelofibrosis a Philadelphia-negative chronic myeloproliferative disorder. Potentially curative therapies, such as stem-cell transplantation, are reserved only for a minority of patients. Currently palliative therapies such as androgen and hydroxycarbamide are commonly used but with poor results. Thalidomide has anti-angiogenic effect and also can inhibit cytokines, and therefore plays a certain role in the treatment of a subset of idiopathic myelofibrosis.
Angiogenesis Inhibitors ; adverse effects ; therapeutic use ; Humans ; Immunosuppressive Agents ; adverse effects ; therapeutic use ; Primary Myelofibrosis ; drug therapy ; Thalidomide ; adverse effects ; therapeutic use ; Treatment Outcome

BACKGROUND/AIMS: Infliximab has been shown to be effective and safe for treating refractory luminal and fistulizing Crohn's disease (CD). The aim of this study was to report the efficacy and adverse effect of infliximab therapy in patients with CD at our center. METHODS: Medical records of thirteen patients who were treated with infliximab for refractory luminal or fistulizing CD were reviewed. Clinical response was classified as complete response, partial response and nonresponse. RESULTS: Seven patients were treated for fistulizing CD, four patients for luminal CD, and two for both. The mean time of follow-up was 13.1 months (3.3-28.1 months). Clinical response was seen in 10/13 (77%); complete response 7/13 (54%), partial response 3/13 (23%), nonresponse 3/13 (23%). Mean time to response was 27.1 days (10-41 days). 4 of 10 responders (40%) maintained remission over 30 weeks. Those who started on immunosuppressive treatment more than 3 months before infliximab infusion achieved lower early recurrence rate (14%) compared with those less than 3 months (67%) (p=0.039). Steroid tapering was successful in 7/12 (58%). Five patients required surgical therapy; three nonresponders, one partial responder and one who recurred after initial complete response. Initial responders required less surgery than nonresponders (p=0.035). Acute infusion reactions were seen in 2/40 infusions (5%). One patient developed herpes zoster 20 weeks after infliximab infusion. During follow-up peried, no patient developed serious infection, tuberculosis or malignancy. CONCLUSIONS: Infliximab is effective and safe in clinical practice. Concurrent immunosuppressive use is associated with lower rate of early recurrence.
Adult ; Antibodies, Monoclonal/adverse effects/*therapeutic use ; Crohn Disease/*drug therapy ; Female ; Gastrointestinal Agents/adverse effects/*therapeutic use ; Humans ; Immunosuppressive Agents/therapeutic use ; Male

The number of children undergoing successful renal transplantations has been increasing steadily and as a result, general pediatricians are now more likely to encounter children with a kidney allograft in their practice. Although the medical care immediately after transplantation is mostly provided by transplant teams, more and more outpatient care will eventually be performed at the patient's local community. Medical care from general pediatricians is particularly important, especially for children who are residing far from transplant centers. As these children require prolong immunosuppressive therapies and are susceptible to various specific clinical problems, it is imperative for their primary care providers and pediatricians to be knowledgeable about their specific needs and be competent in providing care. This article highlights the roles and common practice related issues that pertain to general pediatricians in the care of pediatric renal allograft recipients.
Child ; Humans ; Immunosuppressive Agents ; therapeutic use ; Kidney Transplantation ; adverse effects ; psychology ; Pediatrics ; Vaccination

Although new immunosuppressive agents have greatly improved the post-transplantation survival, their adverse effects remain a major challenge. Appropriate assessment and monitoring the immune status in post-transplantation patients is therefore essential. This article summarizes the monitoring indicators and reviews recent advances in this field.
Humans ; Immunosuppressive Agents ; adverse effects ; therapeutic use ; Monitoring, Immunologic ; Organ Transplantation ; Postoperative Care

Kidney transplantation has become an important method in treating advanced renal failure. Immunosuppressants play a key tool in this progress. It is important to understand the goal, mechanism, and adverse effects of immunosuppressive therapy, so as to appropriately use these drugs in post-transplantation patients on a customized basis.
Aftercare ; Humans ; Immunosuppressive Agents ; administration & dosage ; adverse effects ; therapeutic use ; Kidney Transplantation ; Long-Term Care

Left ventricular hypertrophy associated with the use of tacrolimus is a rare complication of solid organ transplantation in adult recipients. We present a cardiac transplant recipient who developed severe concentric left ventricular hypertrophy with congestive heart failure related to myocardial hypertrophy on tacrolimus. Hypertrophy improved when the drug was discontinued and replaced with sirolimus.
Adult ; Cardiomyopathy, Hypertrophic ; chemically induced ; diagnosis ; Female ; Heart Transplantation ; adverse effects ; Humans ; Immunosuppressive Agents ; adverse effects ; therapeutic use ; Middle Aged ; Tacrolimus ; adverse effects ; therapeutic use

This study aimed to evaluate the efficacy and safety of mycophenolate mofetil (MMF) or tacrolimus (TAC) compared with azathioprine (AZA) as maintenance therapy for active lupus nephritis (ALN). Patients with ALN who responded to 24 weeks of induction treatment were enrolled. Patients who received MMF or TAC as induction therapy continued MMF or TAC treatment during the maintenance period, whereas those who received intravenous cyclophosphamide were subjected to AZA treatment. The primary endpoint was the incidence of renal relapse. Secondary endpoints included extrarenal flares and composite endpoints (deaths, end-stage renal disease, or doubling of serum creatinine levels). A total of 123 ALN patients (47 in the MMF group, 37 in the TAC group, and 39 in the AZA group) were enrolled. The median follow-up time was 60 months. Ten MMF-treated patients, ten TAC-treated patients, and eight AZA-treated patients experienced renal relapses (P = 0.844). The cumulative renal relapse rates in the MMF group (P = 0.934) and TAC group (P = 0.673) were similar to the renal relapse rate in the AZA group. No significant difference in the incidence of severe adverse event was observed among the groups. Long-term maintenance therapies with MMF or TAC might have similarly low rates of renal relapse and similar safety profiles compared with AZA.
Humans ; Mycophenolic Acid/adverse effects* ; Azathioprine/adverse effects* ; Tacrolimus/therapeutic use* ; Lupus Nephritis/complications* ; Immunosuppressive Agents ; Treatment Outcome ; Recurrence