Tacrolimus Ciclosporin

Amongst the —> immunosuppressive agents besides the —> glucocorticoids the modern nontoxic drugs have become drugs of choice including ciclosporin, tacrolimus or ascomycin. 

Lipid-based carrier systems have been investigated to improve treatment of inflammatory skin diseases such as atopic eczema and psoriasis by glucocorticoids and T-cell inhibitors such as ciclosporin and tacrolimus. 

Although ciclosporin and tacrolimus applied systemically improve psoriatic lesions, they are clearly less active when applied topically. Therefore, liposomal preparations have been developed. Indeed, ciclosporin penetrates deeper strata of rodent and human cadaver skin more efficiently when incorporated into liposomes [51], Moreover, tacrolimus concentrations in murine skin have increased ninefold, and skin graft survival prolonged, if the drug is liposome encapsulated [52]. This indicates that topical psoriasis therapy with tacrolimus may become possible. At present, topical tacrolimus is confined to the less recalcitrant forms of mild eczema. 

Concentration dependent toxicity Aminoglycosides Cytotoxic agents Ciclosporin Digoxin Lithium Tacrolimus Theophylline Warfarin... 

Rosiglitazone is not metabolized by CYP3A4 and interactions with drugs such as ciclosporin and tacrolimus are therefore not expected. Several studies have confirmed this. 

Rosiglitazone 4 mg/day, increased to 8 mg/day after 1 week, was given to 10 patients with glucose intolerance who had received a renal transplant ciclosporin and tacrolimus whole blood concentrations were unchanged (139). 

In 22 patients with recent renal transplants using rosi-glitzone 4 and 8 mg/day there were no significant changes in blood ciclosporin and tacrolimus concentrations (141). 

Tacrolimus + sirolimus, tacrolimus + mycophenolate mofetil, and ciclosporin + sirolimus have been compared in recipients of their first kidney transplant (52). One-year patient and graft survival did not differ. Ciclosporin + sirolimus was associated with increased serum creatinine concentrations, reduced creatinine clearance, more frequent protocol discontinuation, more antihyperlipidemic drug therapy, and a higher incidence of post-transplant diabetes mellitus. 

The risk of post-transplant diabetes mellitus is greater with tacrolimus than with ciclosporin, but this was mostly true in black patients and during the initial months after transplantation (1084). In one study, insulin sensitivity, alpha and beta cell function, and beta cell reserve were studied in 14 hepatitis C-positive patients with liver transplants, who took tacrolimus or ciclosporin maintenance for 1 year (1085). The patients were matched for low prednisolone dosage (1.1 mg/day versus 1.3 mg/day), body mass index, lean body mass, and sex, and compared with eight controls. Insulin sensitivity and insulin secretory reserve were significantly different from controls, but there was no significant difference between ciclosporin and tacrolimus. 

The incidence, mechanism, and risk factors of tacroli-mus-associated diabetes mellitus are still debated. In 58 patients investigated 1-3 years after liver transplantation there was a significantly higher incidence of diabetes mellitus with tacrolimus (n = 32) compared with ciclosporin (n = 26) (1086). Newly-diagnosed diabetes... 

In a pooled analysis of four randomized trials of tacrolimus versus ciclosporin after renal transplantation, the prevalence of post-transplant diabetes mellitus at 1 year (two studies, 532 patients) was five times higher with tacrolimus than with ciclosporin (OR = 5.0 95% Cl = 2.0, 12.4) (1094). In the opinion of the US FDA, diabetes mellitus after transplantation was a significant hazard in tacrolimus-treated patients, even though about half of the patients were no longer taking insulin at 2 years after transplantation (1095). 

The exact mechanisms of tacrolimus-induced diabetes are unknown. In one renal transplant patient with genetic susceptibility, tacrolimus was associated with insulin-dependent diabetes mellitus and the simultaneous occurrence of anti-glutamic acid decarboxylase antibody (1096). Within 2 months after conversion from tacrolimus to ciclosporin, the antibody was no longer detected and the patient s insulin requirements fell dramatically. Tacrolimus-induced direct beta cell toxicity, with... 

Diabetes mellitus after transplantation occurred more often in hepatitis C virus-positive patients taking tacrolimus than in those taking ciclosporin (58 versus 7.7%). In hepatitis C virus-negative patients, the rates of diabetes mellitus were similar. The authors concluded that hepatitis C is strongly associated with diabetes mellitus after renal transplantation because of the greater dia-betogenicity of tacrolimus. 

In a meta-analysis of 16 studies of patients who were taking tacrolimus (n — 1636) or ciclosporin (n = 1407) the incidence of type 1 diabetes mellitus was significantly higher among those taking tacrolimus (10% versus 4.5%)... 

The effect was observed in those with renal transplants (9.8% versus 2.7%) and those with other organ transplants (11.1% versus 6.2%), and among patients who were taking equal doses of concomitant medications in both treatment arms (12% versus 3%). Further factors associated with diabetes mellitus after kidney transplantation were older recipient age, a cadaveric organ, hepatitis C antibody status, an episode of rejection, and the use of tacrolimus (versus ciclosporin) cumulative glucocorticoid dose and calcineurin inhibitor trough concentration were not associated factors (1100). 

In contrast to its effects on glucose metabolism, tacrolimus offers potential advantages over ciclosporin for lipid disorders (1101). Compared with ciclosporin-based immunosuppressive regimens, total cholesterol and LDL cholesterol serum concentrations were lower in patients taking tacrolimus for 1 year (1102). Both findings were considered to result from a significant glucocorticoidsparing effect of tacrolimus. 

Hyperuricemia has been reported in association with ciclosporin and tacrolimus. In two cases there was a direct association between tacrolimus and gout after liver transplantation (1103). 

Webster AC, Woodroffe RC, Taylor RS, et al. Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients meta-analysis and meta-regression of randomised trial data. BMJ. 2005 331 810. 

Tacrolimus is a macrolide antibiotic from Streptomyces tsukubaensis. In principle, it acts like ciclosporin. At the molecular level, however, its receptor is not cyclophilin but a so-called FK-binding protein. Tacrolimus is likewise used to prevent allograft rejection. Its epithelial penetrability is superior to that of ciclosporin, allowing topical application in atopic dermatitis. 

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. 

CICLOSPORIN TACROLIMUS t plasma concentrations of cidosporin Tacrolimus is probably a more powerful inhibitor of CYP3A4 than cidosporin Avoid co-administration... 

PROTEASE INHIBITORS CICLOSPORIN, SIROLIMUS, TACROLIMUS t levels with protease inhibitors Inhibition of CYP3A4-mediated metabolism of these immunomodulating drugs Monitor clinical effects closely and check levels... 

ACICLOVIR/ VALACICLOVIR ANTICANCER AND IMMUNOMODULATING DRUGS- 1. CICLOSPORIN 2. MYCOPHENOLATE 3. TACROLIMUS 1.1 nephrotoxicity 2. Possible T efficacy 3. t levels with protease inhibitors 1. Additive side-effect 2. Competition for renal excretion 3. Inhibition of CYP3A4-mediated metabolism of tacrolimus 1. Monitor renal function prior to concomitant therapy and monitor cidosporin levels 2. Monitor renal function particularly if on >4g valaciclovir 1 dose of aciclovir if there is a background of renal failure 3. Monitor clinical effects closely check levels... 

Astralagus 2. Echinacea 3. Liquorice 4. Milk thistle 5. Neem 6. Sea buckthorn 1. Ciclosporin 2. Azathioprine 3. Methotrexate 4. Tacrolimus 5. Dadizumab 6. Cyclophosphamide Possibility of graft rejection 1 blood level unknown mechanism (astralagus). Other mechanisms alkyl amides from echinacea modulate tumour necrosis factor alpha mRNA expression in human monocytes/macrophages via the cannabinoid type 2 receptor Unknown mechanism (milk thistle is known to l cyclosporine levels neem L effects of azathioprine, prednisolone and dadizumab sea buckthorn may 1 effect of cyclophosphamide) Induces metabolizing enzymes, CYP3A4 and P-gp (St John s wort L ciclosporin and tacrolimus levels) Avoid concomitant use of the herb... 

Additive renal toxic effects may occur with immunosuppressants (e.g. azathioprine, ciclosporin, tacrolimus), ACE inhibitors, penicillamine, irinotecan and aminoglycoside antibiotics. A deterioration of renal function may even occur after the topical use of NSAIDs. Guidelines are variable for the use of NSAIDs with differing degrees of renal function, as assessed by creatinine clearance measurements. 

With the exception of ciclosporin and tacrolimus, all the above cause nonspecific immunosuppression so that the general defences of the body against infection are impaired. 

Tacrolimus is a macrolide immunosuppressant agent that is isolated from a bacterium. It acts like ciclosporin and is used to protect and treat liver and kidney grafts when conventional immunosuppressants fail. Such rescue treatment may be graft-or life-saving. Tacrolimus may cause nephrotoxicity, neurotoxicity, disturbance of glucose metabolism, hyperkalaemia and hypertrophic cardiomyopathy. 

Amphotericin colloidal dispersion has been compared with amphotericin deoxycholate in a prospective, randomized, double-blind study in the empirical treatment of fever and neutropenia in 213 patients (25). Patients were stratified by age and concomitant use of ciclosporin or tacrolimus and then randomized to receive ABCD (4 mg/kg/day) or amphotericin deoxycholate (0.8 mg/ kg/day) for 14 days. Renal dysfunction was less likely to develop and occurred later with ABCD than with amphotericin deoxycholate. Likewise, the absolute and percentage fall in the serum potassium concentration from baseline to the end of therapy was greater with amphotericin deoxycholate than ABCD. However, probable or possible infusion-related hypoxia and chills were more common with ABCD than amphotericin deoxycholate. There was a therapeutic response in 50% of the patients who received ABCD and 43% of those who received amphotericin deoxycholate. Thus, ABCD was of comparable efficacy and less nephrotoxic than amphotericin deoxycholate, but infusion-related events were more common with ABCD. 

Tacrolimus (FK 506), a macrolide immunosuppressant, has adverse effects similar to those of ciclosporin, including nephrotoxicity. Increased nephrotoxicity can be expected when it is given with amphotericin (156). 

Although the pattern of long-term toxicity of ciclosporin and tacrohmus is remarkably similar for most serious adverse effects (particularly nephrotoxicity), a higher incidence of several minor adverse effects with ciclosporin, namely hirsutism, gingivitis or gum hyperplasia, has been thought to underlie a moderate but significant decrease in the quahty of life with ciclosporin compared with tacrolimus (2). 

Neurological symptoms were observed in 12-25% of liver-transplant patients and in 29% of bone marrow transplant patients, but severe neurotoxicity occurred only in about 1% (18,19/21). They usually appeared within the first month of treatment, but were sometimes delayed (19). Particular attention should be paid to prompt recognition of severe neurotoxicity, because abnormalities of the white matter can occur. Patients usually improved rapidly after temporary ciclosporin withdrawal or dosage reduction, and tacrolimus has sometimes been used successfully instead (SEDA-21, 383) (18). However, recurrence of seizures and persistent electroencephalographic abnormahties were found in 46 and 70% of pediatric transplant patients respectively who had had ciclosporin acute encephalopathy and seizure syndrome and who were followed-up for 49 months (22). 

Endogenous ligands for ciclosporin and tacrolimus, known as immunophilins, are found in very high concentrations in the basal ganglia, and ciclosporin can alter dopamine phosphorylation in the medium-sized neurons in the striatum. Changes in basal ganglia glucose metabolism have been studied in a patient with severe ciclos-porin-related tremor (36). 

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