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Application of tacrolimus in children with primary nephrotic

Dec 26, 2016
Primary nephrotic syndrome (primary nephrotic syndrome, PNS) as an immune disease, its pathogenesis is mainly related to immune disorders in children. The current international standard of treatment for children PNS is glucocorticoid based treatment. In the treatment of children with PNS, due to steroid resistance and hormone dependence, as well as glucocorticoid adverse reactions, often need to use immunosuppressive agents. In recent years, emerging new immunosuppressive agents for clinicians to provide more choice. This paper introduces a new type of immunosuppressive agent, tacrolimus, which has received more and more attention. Tacrolimus (tacrolimus, FK506): a new immunosuppressant, because of its immunosuppressive effect is strong, cyclosporine A (Cyclosporine A CsA) 10 ~ 100 times, the adverse reaction was less than CsA, FK506 is currently replacing CsA as the preferred immunosuppression after organ transplantation agent, also used in systemic lupus erythematosus psoriasis, rheumatoid arthritis and other autoimmune diseases. FK506 used in children's PNS reports increasingly common. This article reviews the pharmacodynamics, pharmacokinetics and application of FK506 in PNS in children.
1 tacrolimus profiles
FK506 is a Japanese group by Fujisawa soil fungi wave region extracted from a 23 membered macrolide antibiotics in Osaka in 1984, its molecular formula is C44H69NO12 - H2O. The relative molecular mass of 822.5. Appearance of white crystalline or crystalline powder, insoluble in water, but highly soluble in lipids and other organic solvents. The United States Starzl organ transplantation center of University of Pittsburgh for the first time in 1989 will be FK506 in the clinical trial, 1994 FDA approved FK506 as immunosuppression after liver transplantation for clinical transplantation, then FK506 is widely used in the field of medicine, the use method of oral or intravenous injection.
2 mechanism of action
Tacrolimus by interfering with calcium dependent signal transduction pathway, first with intracellular FK binding protein binding, inhibition of peptidyl prolyl CIS a trans isomerase activity, blocking calcium influx, nuclear factor of activated T cells to phosphorylation, inhibition of T cells G0 to G1 conversion, and then inhibit the proliferation of T cells, the IL-2, IL-2R, IFN- transcription repressor gene by gamma etc.; on the other hand through the inhibition of T cell derived growth factor affecting growth and antibody formation of B cells, eventually causing immunosuppression and the treatment effect is achieved.
3 pharmacokinetics
After oral peak concentration time of about 1H, compared with CsA, FK506 absorption rate of digestive tract is not high. Previous studies have shown that the average oral bioavailability of FK506 in healthy subjects, adults, and children is 20% to. Factors affecting the absorption: (1) food, fasting can accelerate its absorption, high fat, high carbohydrate intake to reduce its absorption. (2) racial differences have been observed: African Americans require higher doses than caucasians. Age and graft type had nothing to do with absorption rate. After intestinal absorption, FK506 was mainly redistributed to erythrocyte, so the whole blood concentration was about 10 to 30 times of plasma concentration, and the plasma protein binding rate was as high as 99%. FK506 is primarily metabolized by the hepatic cytochrome P450-3A enzyme system of demethylation and hydroxylation of [22] active metabolites after 13- is the main n-desmethyl - tacrolimus derivatives, most of the other metabolites no immunosuppressive activity. In normal adult volunteers, the elimination half-life of FK506 was (32 +. 10) H. Metabolites excreted mainly by bile excreted by feces, excreted by urine about 2%. Therefore, the need to reduce the dose of drugs in the liver insufficiency, from the pharmacokinetic point of view, when renal insufficiency does not need to adjust the dose, but for drug induced renal dysfunction, you need to adjust the dose.
4 drug interactions
As long as the drugs and food that affect the cytochrome P450-3A enzyme system of the liver can affect the plasma concentration of FK506. Macrolides, calcium antagonists, HIV protease inhibitors, antifungal drugs, H2 receptor antagonists, proton pump inhibitors such as inhibition of cytochrome P450-3A enzyme can increase the blood concentration, sodium bicarbonate, anticonvulsants, rifampicin, dexamethasone, grapefruit juice could induce metabolic and reduce the blood drug the concentration of methyl prednisolone and FK506 has a synergistic effect, at the same time the use of nephrotoxic drugs (aminoglycosides, CsA, amphotericin B, vancomycin, non steroidal anti-inflammatory) can increase renal toxicity. Because of the high plasma protein binding rate of FK506, it may be replaced with other high protein binding drugs (such as warfarin, oral hypoglycemic agents and non steroidal anti-inflammatory drugs) and affect each other.
5 methods and recommendations
Effective blood concentration of the current Chinese medical science branch of the nephrology Group guidelines recommend FK506 in children with PNS dose of 0.1 to 0.15mg/ (kg * d), Q12h oral, before and after medication 1H fasting. Recommended plasma concentration maintained at 5 ~ 10 g/L, the total course of treatment for 12 to 24 months, if the continuous use of urine protein for 3 months compared with baseline value of <50%, that resistance. Man Chun [26] and so on in the work is also recommended FK506 dose 0.1mg/ (kg * d), valley concentration maintained at 5 ~ 10 g/L Chiu. Clinical application of 6 McCauley [1] for the first time since 1990 reported tacrolimus for the treatment of children with steroid resistant nephrotic syndrome (steroid-resistant nephrotic, syndrome, SRNS), then FK506 PNS for 20 years children reported a total of dozens of articles, but the majority of reported cases or were analyzed retrospectively.
Loeffler and other first times in 2004 carried out a retrospective report, found that 16 cases of SRNS children after FK506 treatment complete remission rate of up to 81%, partial remission rate of up to 13%. Since then reported FK506 efficacy is also more optimistic. At present, FK506 reported number of cases observed in treatment of children PNS is the most China Xia Zhengkun, they reported 65 cases of children with PNS treatment, the total remission rate was 83.1%, of which SDNS the total remission rate was 95.2%, the total remission rate of SRNS was 60.9%, the total remission rate was 83.8% FR. But only a few scholars have studied the long-term observation, Bhimma reported, 22 cases of SRNS were treated with FK506 at 12 months, 8 cases of complete remission, partial remission in 9 cases, stop FK506 treatment after 27.5 months of follow-up, 5 cases of complete remission, partial remission in 10 cases, 2 cases of recurrence, 3 cases died the dialysis related complications. Xia Zhengkun and other follow-up also found 12 cases of recurrence. Isabel Roberti [6] FK506 SRNS for children, after 55 months of follow-up, found that the total remission rate from 91% down to 58%, of which the pathologic types were followed up FSGS after remission rate was 50%, and 40% progression to end-stage renal (average 52 months).
There are 2 articles FK506 and CsA treatment were compared, ManishD Sinha in 2006 compared with 10 patients with refractory SDNS (9 MCD, 1 FSGS) were found in the FK506 treatment of refractory SDNS curative effect is no better than CsA; Swati Choudhry [13] published in 2009, the only one on the FK506 PNS RCT in the treatment of children, they will be 41 cases of SRNS were randomly pided into two groups, were given FK506 and CsA treatment, observation of 1 years, found a combined low dose glucocorticoid treatment efficacy of SRNS, but FK506 in the occurrence of side effects and the risk of relapse is superior to CsA.
6 common adverse reactions
Reported FK506 in children with PNS treatment of common adverse reactions can be: gastrointestinal reactions, elevated blood pressure, neurological symptoms, infection, electrolyte disorders, impaired liver and kidney function, elevated blood glucose, etc.. Pandirikkal et al. Reported 1 patients aged SRNS years old with acute renal failure after oral FK506[dose of 0.15mg/ (kg / day)]1 months after diagnosis of HUS, and renal function returned to normal after withdrawal for 2 weeks (). Sanjeev Gulati et al also reported 1 children with FK506 induced HUS. Bhatia found 1 cases of children with PNS are unknown in the treatment of leukopenia, hormone therapy for 5 weeks is invalid, renal biopsy showed FSGS, CsA combined with obvious side effects after taking FK506, change the treatment course of 7 months when children diagnosed with acute lymphoblastic leukemia, presumably in specific immunosuppression might be under the constitution increased incidence of leukemia. Lavjay Butani reported that 1 cases of children with lymphoma after oral FK506, and children with EB virus antibody negative, I think it can not deny that the occurrence of lymphoma in children with the use of FK506 unrelated.
In addition, tacrolimus drug development in innovation, at present there is a new type of Tacrolimus Sustained-release Capsules (Advagraf), in foreign countries has been confirmed in clinical trials with clinical efficacy and safety of the same with FK506, its advantage is to take only 1 times a day, reduce the patient's medication burden, improve the compliance of children. Bachelor degree in 2011 were treated with Advagraf 8 PNS cases, achieved satisfactory clinical efficacy, also found that the effective blood concentration of different pathological types required can be inconsistent, such as hormone sensitive PNS blood trough concentration from 2 to 3 g/L (the report).
7 problems and prospects of tacrolimus in the treatment of children with PNS, there is a lack of large sample, multi center, prospective, randomized study, and the tacrolimus drug instructions on the indications are limited to a variety of immune rejection after organ transplantation. Current clinical applications are based on clinical guidelines and clinical literature reports.
In conclusion, PNS application of tacrolimus in the treatment of children is to expand, although most of the reported positive opinions, but because the price is more expensive, the influence of physicians and patients as their preferred, as the two or three line agent for SRNS or SDNS, on the evidence accumulation and its long-term efficacy and long-term further clinical side effects of further accumulation of information.

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