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  1. Choong CL, Wong HS, Lee FY, Lee CK, Kho JV, Lai YX, et al.
    Transplant Proc, 2018 Oct;50(8):2515-2520.
    PMID: 30316389 DOI: 10.1016/j.transproceed.2018.04.024
    BACKGROUND: Inhibition of calcineurin inhibitor (CNI) metabolism with diltiazem reduces the dose of tacrolimus required to achieve its therapeutic blood concentration in kidney transplant recipients (KTRs). This cost-savings maneuver is practiced in several countries, including Malaysia, but the actual impacts of diltiazem on tacrolimus blood concentration, dose-response relationship, cost-savings, and safety aspects are unknown.

    METHODS: This retrospective study was performed on all KTRs ≥18 years of age at our center from January 1, 2006 to December 31, 2015, who were prescribed diltiazem as tacrolimus-sparing agent. Blood tacrolimus trough level (TacC0) and other relevant clinical data for 70 eligible KTRs were reviewed.

    RESULTS: The dose of 1 mg tacrolimus resulted in a median TacC0 of 0.83 ± 0.52 ng/mL. With the introduction of a 90-mg/d dose diltiazem, there was a significant TacC0 increase to 1.39 ± 1.31 ng/mL/mg tacrolimus (P < .01). A further 90-mg increase in diltiazem to 180 mg/d resulted in a further increase of TacC0 to 1.66 ± 2.58 ng/mL/mg tacrolimus (P = .01). After this, despite a progressive increment of every 90-mg/d dose diltiazem to 270 mg/d and 360 mg/d, there was no further increment in TacC0 (1.44 ± 1.15 ng/mL/mg tacrolimus and 1.24 ± 0.94 ng/mL/mg tacrolimus, respectively [P < .01]). Addition of 180 mg/d diltiazem reduced the required tacrolimus dose to 4 mg/d, resulting in a cost-savings of USD 2045.92 per year (per patient) at our center. Adverse effects reported within 3 months of diltiazem introduction were bradycardia (1.4%) and postural hypotension (1.4%), which resolved after diltiazem dose reduction.

    CONCLUSION: Coadministration of tacrolimus and diltiazem in KTRs appeared to be safe and resulted in a TacC0 increment until reaching a 180-mg/d total diltiazem dose, at which point it began to decrease. This approach will result in a marked savings in immunosuppression costs among KTRs in Malaysia.

    Matched MeSH terms: Tacrolimus/administration & dosage*
  2. Thong KM, Chan TM
    Lupus, 2019 Mar;28(3):334-346.
    PMID: 30744523 DOI: 10.1177/0961203319829817
    OBJECTIVES: Infection is an important concern in lupus nephritis treatment, but few studies have focused on this complication. Available data suggest marked variation in occurrence and outcome. This meta-analysis and review aims to provide an overview of infective complications, focusing on the risk factors and outcomes.

    METHODS: Original articles on lupus nephritis Class III/IV/V published in the period January 1980 to December 2016 were identified from the Pubmed/Medline electronic database. Meta-analysis of randomized controlled trials was performed to investigate total and serious infections at different phases of treatment and their associated factors. A descriptive review that included all studies was also performed, providing details on the types of infection, infection-related mortality, and potential impact of different eras on infection rates.

    RESULTS: A total of 56 studies (32 randomized controlled trials) were included. The incidence rates of overall and serious infections were higher during the induction than maintenance phase of therapy, with serious infections occurring at 8.2-50 and 3.5 per 100 patient-years, respectively. Recent data, predominantly from Asia, suggested lower rates of overall infections with induction regimens that included tacrolimus compared with mycophenolate (risk ratio 0.50, 95% confidence interval 0.33-0.76, p = 0.001). Mycophenolate as induction treatment was associated with lower overall infection risks than cyclophosphamide in non-Asians (risk ratio 0.60, 95% confidence interval 0.48-0.75, p 

    Matched MeSH terms: Tacrolimus/administration & dosage
  3. Okuda K, Fu HY, Matsuzaki T, Araki R, Tsuchida S, Thanikachalam PV, et al.
    PLoS One, 2016;11(8):e0160944.
    PMID: 27501378 DOI: 10.1371/journal.pone.0160944
    Immunosuppressive agents are used for the treatment of immune-mediated myocarditis; however, the need to develop a more effective therapeutic approach remains. Nano-sized liposomes may accumulate in and selectively deliver drugs to an inflammatory lesion with enhanced vascular permeability. The aims of this study were to investigate the distribution of liposomal FK506, an immunosuppressive drug encapsulated within liposomes, and the drug's effects on cardiac function in a rat experimental autoimmune myocarditis (EAM) model. We prepared polyethylene glycol-modified liposomal FK506 (mean diameter: 109.5 ± 4.4 nm). We induced EAM by immunization with porcine myosin and assessed the tissue distribution of the nano-sized beads and liposomal FK506 in this model. After liposomal or free FK506 was administered on days 14 and 17 after immunization, the cytokine expression in the rat hearts along with the histological findings and hemodynamic parameters were determined on day 21. Ex vivo fluorescent imaging revealed that intravenously administered fluorescent-labeled nano-sized beads had accumulated in myocarditic but not normal hearts on day 14 after immunization and thereafter. Compared to the administration of free FK506, FK506 levels were increased in both the plasma and hearts of EAM rats when liposomal FK506 was administered. The administration of liposomal FK506 markedly suppressed the expression of cytokines, such as interferon-γ and tumor necrosis factor-α, and reduced inflammation and fibrosis in the myocardium on day 21 compared to free FK506. The administration of liposomal FK506 also markedly ameliorated cardiac dysfunction on day 21 compared to free FK506. Nano-sized liposomes may be a promising drug delivery system for targeting myocarditic hearts with cardioprotective agents.
    Matched MeSH terms: Tacrolimus/administration & dosage
  4. Abu Bakar K, Mohamad NA, Hodi Z, McCulloch T, Williams A, Christian M, et al.
    Pediatr Nephrol, 2019 12;34(12):2557-2562.
    PMID: 31520127 DOI: 10.1007/s00467-019-04346-z
    BACKGROUND: Late acute cellular rejection (LACR) is associated with poorer graft outcomes and non-adherence. Non-adherence to tacrolimus can be indirectly assessed by the intra-patient variability (IPV) of tacrolimus trough levels. The threshold of IPV associated with rejection is not known.

    METHODS: We conducted a case-control study comparing 25 patients with biopsy-proven LACR against 25 stable controls matched for age group, primary diagnosis and time post-transplant. IPV was calculated using coefficient of variance (CV) and mean absolute deviation (MAD) using tacrolimus levels in the preceding 12 months. We also assessed the percentage time for tacrolimus levels

    Matched MeSH terms: Tacrolimus/administration & dosage*
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