Tacrolimus reversible

P6rez Men6ndez-Conde C, Alvarez Diaz A, Delgado Silveira E, Bermejo Vicedo T. Leucoencefalopatia posterior reversible secundaria al tratamiento con tacrolimus. [Reversible posterior leuko-encephalopathy secondary to treatment with tacrolimus]. Farm Hosp 2008 32(5) 298-9. 

Cyclosporine and tacrolimus are calcineurin inhibitors that are administered as part of immunosuppressive regimens in kidney, liver, heart, lung, and bone marrow transplant recipients. In addition, they are used in autoimmune disorders such as psoriasis and multiple sclerosis. The pathophysiologic mechanism for ARF is renal vascular vasoconstriction.41 It often occurs within the first 6 to 12 months of treatment, and can be reversible with dose reduction or drug discontinuation. Risk factors include high dose, elevated trough blood concentrations, increased age, and concomitant therapy with other nephrotoxic drugs.41 Cyclosporine and tacrolimus are extensively metabolized by... 

ACE inhibitors and angiotensin-receptor blockers (ARB) have definite benefits in patients with nephropathy and are believed to have renoprotective effects in most patients. Due to their ability to cause an initial bump in serum creatinine, these agents should be used cautiously when employed in combination with the calcineurin inhibitors. The dihydropyridine calcium channel blockers have demonstrated an ability to reverse the nephrotoxicity associated with cyclosporine and tacrolimus (Table 52-8). In general, antihypertensive therapy should focus on agents with proven benefit in reducing the progression of cardiovascular disease and should be chosen on a patient-specific basis.55 See Chapter 2 for further recommendations for treating HTN. 

Drugs that might affect amprenavir include abacavir, aldesleukin, antacids, anticonvulsants, azole antifungals, clarithromycin, cyclosporine, dexamethasone, buffered didanosine, disulfiram, ethanol, indinavir, methadone, metronidazole, nelfinavir, nonnucleoside reverse transcriptase inhibitors, oral contraceptives, rifamycins, ritonavir, saquinavir, St. John s wort, tacrolimus, and zidovudine. 

Insulin-dependent posttransplant diabetes mellitus (PTDMj. lnsulin-dependent PTDM was reported in 20% of tacrolimus-treated kidney patients without pretransplant history of diabetes mellitus in the Phase 3 study. The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at 1 year and in 50% at 2 years posttransplant. Black and Hispanic kidney transplant patients were at an increased risk of development of PTDM. 

Myocardial hypertrophy Myocardial hypertrophy has been reported in association with the administration of tacrolimus and generally is manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. Hypertrophy has been observed in infants, children, and adults. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. 

After kidney transplantation, 15 of 20 children tolerated tacrolimus after switching from ciclosporin for immunological reasons or adverse effects (609). The most frequent adverse effects were neuropsychological and behavioral symptoms in three children, ranging from anorexia nervosa-like symptoms, with weight loss, amenorrhea, depression, and school problems, to severe insomnia and in one child aggressive and anxious behavior. Only the last child was exposed to toxic tacrolimus blood concentrations. All the adverse effects were fully reversible after withdrawal. 

Rapid identification of speech loss linked to tacrolimus may be important, because dosage reduction or withdrawal may be associated with reverse of speech loss. 

In two women aged 37 and 69, acute and reversible tacrolimus nephrotoxicity developed after the addition of clarithromycin for an upper respiratory tract infection (76). 

When itraconazole was withdrawn the effect of itraconazole on the kinetics of tacrolimus took 12 days to reverse. 

Katari SR, Magnone M, Shapiro R, Jordan M, Scantlebury V, Vivas C, Gritsch A, McCauley J, Starzl T, Demetris AJ, Randhawa PS. Clinical features of acute reversible tacrolimus (FK 506) nephrotoxicity in kidney transplant recipients. Clin Transplant 1997 11(3) 237 2. 

Severe recurrent, but usually reversible hjrpertrophic cardiomyopathy has been infrequently reported, both in adults and children (SEDA-19, 352) (SEDA-20, 346). Based on experimental data and one additional case report, the interaction of tacrolimus with calcium channel blockers in the cardiac muscle has been suggested as a possible mechanism (SEDA-21, 390). However, the role of tacrolimus in the development of cardiomyopathy is still hjrpothetical. Echocardiographic abnormalities were relatively common before and after liver transplantation in 12 adult patients, and there was no clear evidence that oral tacrolimus specifically alters cardiac function (13). Other investigators did not show differences in heart weight, ventricular thickness, or valve circumferences between 67 Uver transplant recipients treated with tacrolimus and 72 non-transplanted patients who died from end-stage liver disease (14). In addition, more than 80% of patients in both groups had left ventricular hypertrophy. 

Pure red cell aplasia is an occasional complication of treatment (SED-13, 1131) (SEDA-20, 347) (60). In one case, tacrolimus was thought to have caused reversible pancytopenia with severely reduced granulopoiesis and megakaryocytopoiesis on bone marrow examination (SEDA-21, 391). 

Parvex P, Pinsk M, Bell LE, O Gorman AM, Patenaude YG, Gupta IR. Reversible encephalopathy associated with tacrolimus in pediatric renal transplants. Pediatr Nephrol 2001 16(7) 537 2. 

Tacrolimus causes acute reversible renal dysfunction in renal [661-663,667], hver [290,664-666,679,680], heart [681-683] and pulmonary [684, 685] transplant recipients and in patients with immunologically mediated diseases [686]. Tacrolimus-induced GFR and RBF decrease is associated with an important increase in renal vascular resistance, both in humans and rodents [63,679,687-692]. Calcium channel blockers improved renal function in TAC-treated liver transplant recipients [693] and in animal models of TAC nephrotoxicity [689,694-6%]. Tacrohmus acute nephrotoxicity, similar to CSA, shows normal renal histology or non-specific changes such as isometric cytoplasmic vacuolation in tubular epithelial cells, microcalcification, giant mitochondria and lysosomes, and necrosis and early hyahnosis of individual smooth muscle cells in the afferent arterioles, which revert with drug reduction or discontinuation [697-699]. 

Vincent F, Laskow DA, Neylan JF, Mendez R, Matas AJ. One-year follow-up of an open-label trial of FK506 for primary kidney transplantation. A report of the U.S. Multicenter FK506 Kidney Transplant Group. Transplantation 1996 61 1576-1581. McLaughlin GE, Abitbol CL. Reversal of oliguric tacrolimus nephrotoxicity in children. Nephrol Dial Transplant 2005 20 1471-1415. 

In 1989 tacrolimus (FK 506), a second caldneurin inhibitor started its clinical journey [8]. Tacrolimus has an immunosuppressive effect approximately 100 times more potent than CsA and early clinical trials demonstrate that FK 506 was effective in reversing refractory acute rejection in renal, liver and heart transplantation. Subsequently, this drug showed to be at least as effective as CsA in the primary immunosuppression schedules for solid organ and bone marrow transplantation and, similarly to CsA, proved to be a valuable alternative in the treatment of autoimmune diseases [3,9-11]. At the moment, FK 506 is considered the only drug that can substitute CsA in primary immunosuppression schedules and it is currently used in almost 60% of liver transplantation immunosuppressive prescriptions. 

The nephrotoxicity profile of tacrolimus is very similar to that of CsA. Tacrolimus induces acute and reversible functional changes in renal function, chronic renal irreversible structural injury, electrolyte disturbances, renal tubular acidosis and hemolytic-uremic syndrome. There are some few and important differences tacrolimus induces less hypertension but more glucose metabohsm impairment than CsA [242, 515-521]. Also resembling CsA, tacrolimus association with drugs that interfere with the cytochrome P-450 metabolism or with other nephrotoxic drugs, can precipitate acute renal dysfunction [522-526]. ... 

Tacrolimus can reverse ongoing refractory acute rejection in any type of transplantation, which does not appear to be the case with cyclosporin. 

Nakazato, X, et al.. Reversible posterior leukoencephalop-athy syndrome associated with tacrolimus therapy. Intern Med, 2003. 42(7) p. 624-5. 

A report of severe gingival overgrowth in a kidney transplant patient was attributed to the additive adverse effects of ciclosporin and phenytoin. Ciclosporin was replaced by tacrolimus, which may have fewer oral adverse effects, and almost complete reversal of gingival overgrowth was achieved within 6 months. ... 

Two patients with liver transplants taking tacrolimus developed acute but reversible renal failure, one after taking four Motrin (ibuprofen) tablets (strength not stated) and the other after three 400-mg tablets of ibuprofen taken over 24 hours. Both had stable renal function before taking the ibuprofen. ... 

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