Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tacrolimus (Tac), which blocks T- and B-cell proliferation by inhibiting calcineurin, was first used for immunosuppression following heart transplant (HT) in 1989. Two multicenter randomized trials have compared Tac to the oil-based cyclosporine (CsA) formulation (both combined with azathioprine and steroids) in HT patients. The two drugs displayed similar patient survival rates and incidences of rejection, nephrotoxicity, diabetes, and infections. The Tac group however, showed a lower incidence of arterial hypertension (and, in one study, of dyslipidemia). A pilot study of Tac in combination with mycophenolate mofetil (MMF) and steroids suggested that maintenance of serum mycophenolic acid levels at 2.5 to 4.5 microg/mL yields lower rejection rates without greater toxicity than previous regimens. Currently, a European multicenter randomized trial is comparing Tac with Neoral CsA, both used in combination with MMF, steroids, and induction antibodies. For patients undergoing primary immunosuppression with CsA, Tac has proved effective for rescue from steroid-resistant acute rejection. It also has tentatively been used without other drugs in selected patients. It is a valid alternative to CsA in current immunosuppressive regimens, because it does not cause gingival hyperplasia or hirsutism and, thus, may improve the quality of life and treatment compliance of female and pediatric patients. It may be preferable to CsA for patients with arterial hypertension or intractable dyslipidemia. Current and future studies will clarify the efficacy and safety of regimens combining Tac with MMF or rapamycin.
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PMID:Tacrolimus in heart transplantation. 1296 69

1. The observation that the immunosuppressants, cyclosporine A (CsA) and tacrolimus, have pressor effects, but sirolimus does not, has led to an hypothesis that generalised sympathoexcitation, resulting from inhibition of calcineurin by CsA and tacrolimus underlies their pressor effects, because sirolimus does not inhibit calcineurin. It is unknown if sirolimus has haemodynamic actions not accompanied by a pressor effect, and whether or not the pressor effects of CsA and tacrolimus are accompanied by similar haemodynamic changes. Therefore, the first aim of our studies was to investigate these possibilities in conscious, chronically-instrumented, male, Sprague-Dawley rats. 2. CsA (5.9 mg kg(-1) bolus i.v.) caused rapid-onset, prolonged hypertension, tachycardia and mesenteric vasoconstriction. There was a slower onset renal vasoconstriction, but no significant change in hindquarters vascular conductance; all the effects of CsA were significantly greater than those of vehicle. CsA given by infusion (over 30 min or 2 h) caused changes qualitatively similar to those above. Repeated administration of CsA over 4 days did not enhance its cardiovascular effects. 3. Pretreatment with the angiotensin (AT(1)) receptor antagonist, losartan, and the endothelin (ET(A) and ET(B)) receptor antagonist, SB 209670, reduced the pressor and mesenteric vasoconstrictor effects of CsA. Additional administration of the alpha-adrenoceptor antagonist, phentolamine, completely inhibited the cardiovascular effects of CsA. 4. Tacrolimus (450 microg kg(-1) bolus i.v.) caused similar peak pressor and tachycardic effects to CsA, but these were much slower in onset, and were maximal when there were no significant regional vasoconstrictions, indicating that the pressor effect was probably due to a rise in cardiac output. However, although propranolol reversed the tachycardic effect of tacrolimus, it did not influence the pressor response. 5. Sirolimus (450 microg kg(-1) bolus i.v.) had no tachycardic action, and only a modest, transient pressor effect, accompanied by equally brief reductions in renal, mesenteric, and hindquarters vascular conductances. 6. The differences between the regional haemodynamic profiles of equipressor doses of CsA and tacrolimus, and the finding that sirolimus has significant cardiovascular actions, indicate that generalised sympathoexcitation, resulting from calcineurin inhibition (with CsA and tacrolimus), is unlikely to be the sole explanation of their pressor effects.
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PMID:Regional haemodynamic effects of cyclosporine A, tacrolimus and sirolimus in conscious rats. 1474 7

This is a retrospective analysis of 16 children started on tacrolimus with various types of treatment-resistant nephrotic syndrome. There are 13 patients with focal glomerulosclerosis, 1 minimal change disease, and 2 IgA nephropathy with nephrosis. The mean age of the children was 11.4 years (range 3.5-18.1 years) with a mean age at diagnosis of 5.6 years (range 1.6-13.3 years). All patients initially received prednisone 2 mg/kg per day. Other therapies for 15 of 16 included cyclosporine (n=15), chlorambucil (n=5), mycophenolate mofetil (n=5), levamisole (n=3), i.v. methylprednisolone (n=3), and cyclophosphamide (n=2). The major indication for the initiation of tacrolimus included treatment resistance/dependence (n=15) and intolerable side effects from other therapies (n=1). The average time from the diagnosis to initiation of tacrolimus was 5.3 years (range 0.3-13.3 years, median 6 years). The initial dosage of tacrolimus utilized was 0.1 mg/kg per day divided into two doses. The mean follow-up period was 6.5 months (range 2.5-18 months). Thirteen patients (81%) went into a complete remission within an average of 2 months (range 0.5-5.5 months), with 3 patients relapsing while on treatment. Three patients did not respond. Of these, 2 had partial remissions (13%) and 1 failed to respond. Adverse events included anemia (n=1), seizure (n=1), worsening or new-onset hypertension (n=5), and sepsis (n=1). All patients remain on tacrolimus. Tacrolimus is an effective, well-tolerated medication for treatment-resistant forms of nephrotic syndrome in children, with a complete remission rate of 81% and a partial remission rate of 13% (totaling 94%).
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PMID:Tacrolimus therapy in pediatric patients with treatment-resistant nephrotic syndrome. 1693 33

Cardiac transplantation is the definitive treatment for eligible patients with end-stage cardiac failure. Techniques have evolved to reduce surgical mortality to under 5%. Immediate and subsequent long-term survival is more dependent on acute and chronic rejection and the complications of immunosuppressive therapy. Ten-year survival is greater than 50%.The success of transplantation over the last 20 years has been largely due to the advances in immunosuppression. The most notable and dramatic milestone was the introduction of cyclosporine in the early 1980s, which resulted in a significant improvement in allograft and patient survival. Cyclosporine is a peptide that inhibits the immune system by suppressing T-helper cell activation via inhibition of calcineurin, a critical intracellular enzyme. Tacrolimus has a similar (but not identical) mechanism of action, and was introduced in the 1990s. Drugs such as cyclosporine and tacrolimus, generically referred to as calcineurin inhibitors, have become the cornerstones of immunosuppressive protocols. As a group, calcineurin inhibitors have adverse effects, including neurotoxicity, hypertension, and nephrotoxicity, which complicate their use. Early renal insufficiency manifests as postoperative oliguria (<50 mL/h urine output) or rising serum creatinine levels. There are a variety of postulated causes for calcineurin inhibitor-associated early renal insufficiency including direct calcineurin inhibitor-mediated renal arteriolar vasoconstriction, increased levels of endothelin-1 (a potent vasoconstrictor), as well as decreased nitric oxide production and alterations in the kidney's ability to adjust to changes in serum tonicity. Once early renal insufficiency occurs, no single treatment has been shown to be effective. Approaches discussed in this paper include reduction in calcineurin inhibitor dosages, as well as various drugs to promote increased renal perfusion such as misoprostol and dopamine. In addition, the paper emphasizes the importance of ruling out other causes of renal insufficiency in the early postoperative period, including volume depletion, depressed cardiac output, and mechanical obstruction to urine flow. Given that there is no highly efficacious treatment for this syndrome, ways to avoid its occurrence are desirable. One paper is referenced that suggests that avoidance of rapid changes in tacrolimus level during the first three days of therapy is associated with a low occurrence of early renal insufficiency.
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PMID:Calcineurin inhibitor-associated early renal insufficiency in cardiac transplant recipients: risk factors and strategies for prevention and treatment. 1496 63

The use of calcineurin inhibitors (CNIs; cyclosporine and tacrolimus) has dramatically increased medium-term life expectancy after heart transplantation but has had only limited impact on long-term outcomes for heart transplant recipients. The original oil-based formulation of cyclosporine has been superceded by a microemulsion formulation (Neoral), which has more predictable pharmacokinetics and allows more precise dose-tailoring. Cyclosporine microemulsion and tacrolimus (Prograf) have a similar efficacy in the prevention of acute rejection of heart transplants, but their use is accompanied by nephrotoxicity and by cardiovascular side effects. The efficacy of immunosuppression can be improved by adjunctive therapy, such as azathioprine, mycophenolate mofetil (MMF; Cellcept), corticosteroids, and induction therapy. One of the most important predictors of patient mortality at >5 years after heart transplantation is cardiac allograft vasculopathy (CAV)/late graft failure, which accounts for 31% of deaths. Neither cyclosporine nor tacrolimus have been shown to prevent the development of CAV. In terms of efficacy, MMF provides a modest advantage over azathioprine in preventing CAV, and the combination of cyclosporine plus MMF results in significantly lower mortality than cyclosporine plus azathioprine. Overall, CNIs have multiple cardiovascular side effects, such as hypertension, hyperlipidemia and new-onset diabetes after transplantation, although cyclosporine and tacrolimus have somewhat different cardiovascular side-effect profiles. The challenge in choosing the best immunosuppressive regimen is to balance efficacy and safety to optimize graft and patient survival over the course of many decades. Because cyclosporine and tacrolimus have similar efficacy against acute rejection the choice of CNI for heart transplant recipients should be based on the relative risk of cardiovascular and renal side effects.
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PMID:Calcineurin inhibitors in heart transplantation. 1509 6

Arterial hyperammonemia and cerebral vasodilatation correlate with cerebral herniation in patients with fulminant hepatic failure (FHF). Tacrolimus is a calcineurin inhibitor that passes the blood-brain barrier and may increase cerebrovascular tone and restrict cerebral ammonia influx. In this study, we determined if tacrolimus prevents cerebral vasodilatation and high intracranial pressure (ICP) in the rat with portacaval anastomosis (PCA) challenged to high arterial ammonia (NH4+) concentration. Seven groups of mechanically ventilated rats, with 6-9 rats in each group, were investigated within 48 hours after construction of a PCA (4 groups) or after sham operation (3 groups). Three groups of the rats received infusion of NH4+ and 4 groups received saline for approximately 180 minutes. Two groups of the PCA rats receiving either NH4+ or saline had an i.v. injection of tacrolimus (0.4 mg/kg) or vehicle before start of NH4+ or saline infusion. Cerebral blood flow (CBF) was monitored by a laser Doppler probe in brain cortex. ICP was monitored by placement of a catheter in the cerebrospinal fluid. CBF and ICP increased in PCA rats receiving NH4+ infusion compared to PCA controls and to all groups of sham-operated animals (P <.05). In the group of PCA rats pre-treated with tacrolimus before receiving ammonia infusion, the increase in ICP was ameliorated compared to the ammonia infused group receiving vehicle (P <.03). Tacrolimus also prevented an increase in CBF in the PCA group receiving NH4+ (P <.05) compared to the control groups. In conclusion, Tacrolimus prevents cerebral vasodilatation and ameliorates intracranial hypertension in PCA rats receiving NH4+ infusion. These findings indicate that tacrolimus could be of clinical value in the prevention of cerebral hyperemia, high ICP, and serious brain damage in patients with FHF.
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PMID:Tacrolimus ameliorates cerebral vasodilatation and intracranial hypertension in the rat with portacaval anastomosis and hyperammonemia. 1523 79

In the control of acute rejection, attention is being focused more and more on the long-term adverse effects of the immunosuppressive agents used. Since cardiovascular disease is the main cause of death in renal transplant recipients, optimal control of cardiovascular risk factors is essential in the long-term management of these patients. Unfortunately, several commonly used immunosuppressive drugs interfere with the cardiovascular system. In this review, the cardiovascular adverse effects of the immunosuppressive agents currently used for maintenance immunosuppression are thoroughly discussed. Optimising immunosuppression means finding a balance between efficacy and safety. Corticosteroids induce endothelial dysfunction, hypertension, hyperlipidaemia and diabetes mellitus, and impair fibrinolysis. The use of corticosteroids in transplant recipients is undesirable, not only because of their cardiovascular effects, but also because they induce such adverse effects as osteoporosis, obesity, and atrophy of the skin and vessel wall. Calcineurin inhibitors are the most powerful agents for maintenance immunosuppression. The calcineurin inhibitor ciclosporin (cyclosporine) not only induces these same adverse effects as corticosteroids but is also nephrotoxic. Tacrolimus has a more favourable cardiovascular risk profile than ciclosporin and is also less nephrotoxic. It has little or no effect on blood pressure and serum lipids; however, its diabetogenic effect is more prominent in the period immediately following transplantation, although at maintenance dosages, the diabetogenic effect appears to be comparable to that of ciclosporin. The diabetogenic effect of tacrolimus can be managed by reducing the dose of tacrolimus and early corticosteroid withdrawal. The effect of tacrolimus on endothelial function has not been completely elucidated. The proliferation inhibitors azathioprine and mycophenolate mofetil (MMF) have little effect on the cardiovascular system. Yet, indirectly, by inducing anaemia, they may lead to left ventricular hypertrophy. MMF is an attractive alternative to azathioprine because of its higher potency and possibly lower risk of malignancies. Sirolimus also induces anaemia, but may be promising because of its antiproliferative features. Whether the hyperlipidaemia induced by sirolimus counteracts its beneficial effects is, as yet, unknown. It may be combined with MMF, however, initial attempts resulted in severe mouth ulcers.
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PMID:Effect of immunosuppressive agents on long-term survival of renal transplant recipients: focus on the cardiovascular risk. 1534 97

1. The numbers of CGN patients have decreased, with a corresponding increase in transplants into IDDM. HTN and MHT have also increased in recent years. 2. Waiting time on dialysis has increased, with an increase in patient age. 3. Transfusions have decreased for all diseases, although less so for SLE. 4. Disease recurrence was highest in FGS, IgA, SLE and CGN. The incidence of recurrence has decreased in recent years. 5. Tacrolimus-MMF and Neoral-MMF were superior to CsA-AZ for all diseases with respect to 5-year graft survival. 6. Systemic diseases such as SLE and IDDM had lower graft survival rates than IgA, PC and ALP. Exclusion of deaths made functional graft survival of all diseases quite similar. 7. Blacks had lower graft survival rates than Whites, Hispanics, and Asians for all diseases. 8. SPK had higher graft survivals than KA in Blacks and Whites. 9. PC patients with HLA-DR1 had a statistically significant higher graft survival than those without DR1 in Whites and Hispanics. 10. IDDM patients with HLA-DR4 had a statistically significantly higher graft survival rates than those without DR4 in Blacks, Whites, Hispanics, and Asians. 11. PC, IgA, and ALP patients had a lower incidence of rejection before discharge than other patients. HTN and IDDM patients had the highest rate of first day non-function and need for dialysis. 12. Need for dialysis and rejection before discharge led to 20 percentage points lower 5-year graft survival compared with those patients who were free of these complications. 13. First day anuria led to 10 percentage point lower 5-year graft survival compared with those with first day diuresis.
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PMID:Effect of primary diseases. 1538 26

The safety and efficacy of tacrolimus (Prograf) in renal transplantation is well established. Achieving longterm patient and graft survival are the ultimate goals following transplantation. Many factors negatively impact long-term transplant outcomes, including graft rejection, renal dysfunction and cardiovascular risk factors (hypertension, hyperlipidaemia, and post-transplant diabetes mellitus (PTDM)). Accordingly, careful consideration of the immunosuppressive strategy and its impact on these factors is critical to optimising outcomes. Clinical trials and registry studies conducted over the past decade have demonstrated tacrolimus to be a cornerstone immunosuppressant in renal transplantation. Compared with cyclosporine treatment, tacrolimus has been shown to be associated with decreased acute and chronic rejection, improved renal function over the long-term post-transplant, and a lower incidence of hyperlipidaemia and hypertension. In early studies, the incidence of PTDM was significantly higher in patients receiving tacrolimus; however, recent large clinical trials have revealed no significant between-group differences in the incidence of PTDM with tacrolimus treatment and cyclosporine microemulsion treatment. Together, these findings may translate into improved long-term transplant outcomes with tacrolimus-based immunosuppression. Although approved only for kidney and liver transplantation in the US, Prograf was the calcineurin inhibitor used in the majority of patients transplanted in 2003: kidney (67%), liver (89%), kidney/pancreas (81%), pancreas (77%), lung (65%), heart/lung (48%), and heart (42%).
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PMID:Tacrolimus based immunosuppression. 1559 82

We evaluate 5-year results of a prospective randomized trial that compared cyclosporine microemulsion (CsA-me) and Tacrolimus (Tac) for primary immunosuppression. One hundred one adult patients undergoing liver transplantation were randomized to receive Tac (n = 50) or CsA-me (n = 51). The most frequent indication for the procedure was cirrhosis due to virus C followed by alcoholism. Survival rates at 1, 3, and 5 years were 86%, 75%, and 72%, respectively; there was no significant difference between CsA-me versus Tac arms. Acute rejection occurred in 30 cases (30%), independent of the type of primary immunosuppression. Serious adverse events were reported significantly more among patients under CsA-me (48 episodes) than under Tac (32 episodes). Nineteen patients were switched to the other calcineurin inhibitor. The switch was much more frequent from CsA-me to Tac (n = 15; 29.4%), mainly because of lack of efficacy (n = 10; 19.6%). There were no cases of chronic rejections in the Tac arm. Four patients were switched from Tac to CsA-me for side effects; only 1 remains alive, after treatment was changed from CsA-me to an antimetabolite. There were no statistical differences in renal dysfunction, diabetes, hypertension, neurologic disorders, new-onset malignancies, or infections. There were no differences in survival or rejection among the intention-to-treat groups. Serious adverse events, total patients with switch of calcineurin inhibitor, as well as switches due to lack of efficacy, were statistically more frequent under CsA-me. Tacrolimus seems to be a more appropriate drug to be used for primary immunosuppression in liver transplantation.
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PMID:Five-year follow-up of a trial comparing Tacrolimus and cyclosporine microemulsion in liver transplantation. 1591 41


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