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Current Drug Metabolism 2018Tacrolimus (Tac, or FK506), a calcineurin inhibitor (CNI), is the first-line immunosuppressant which consists of the footstone as immunosuppressive regimens in kidney... (Review)
Review
BACKGROUND
Tacrolimus (Tac, or FK506), a calcineurin inhibitor (CNI), is the first-line immunosuppressant which consists of the footstone as immunosuppressive regimens in kidney transplantation. However, the drug toxicity and the significant differences of pharmacokinetics (PK) and pharmacodynamics (PD) among individuals are hidden troubles for clinical application. Recently, emerging evidences of Tac pharmacogenetics (PG) regarding drug absorption, metabolism, disposition, excretion and response are discovered for better understanding of this drug.
METHOD
We reviewed the published articles regarding the Tac PG and its effects on PK and PD in kidney transplantation. In addition, we summarized information on polygenic algorithms.
RESULTS
The polymorphism of genes encoding metabolic enzymes and transporters related to Tac were largely investigated, but the results were inconsistent. In addition to CYP3A4, CYP3A5 and P-gp (also known as ABCB1), single nucleotide polymorphisms (SNPs) might also affect the PK and PD parameters of Tac.
CONCLUSION
The correlation between Tac PK, PD and PG is very complex. Although many factors need to be verified, it is envisaged that thorough understanding of PG may assist clinicians to predict the optimal starting dosage, help adjust the maintenance regimen, as well as identify high risk patients for adverse effects or drug inefficacy.
Topics: Animals; Calcineurin Inhibitors; Humans; Immunosuppressive Agents; Kidney Transplantation; Polymorphism, Genetic; Tacrolimus
PubMed: 29380698
DOI: 10.2174/1389200219666180129151948 -
Respirology (Carlton, Vic.) Apr 2021The efficacy of combination therapy with corticosteroids and CNI, TAC and CsA, for PM/DM-ILD has been described retrospectively. However, it remains unknown which CNI... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVE
The efficacy of combination therapy with corticosteroids and CNI, TAC and CsA, for PM/DM-ILD has been described retrospectively. However, it remains unknown which CNI treatment regimens, TAC or CsA regimens, are more effective as initial treatments for patients with PM/DM-ILD.
METHODS
We conducted a prospective multicentre, open-label, randomized, 52-week phase 2 trial. Patients with PM/DM-ILD were randomly allocated to receive PSL plus TAC (TAC group) or PSL plus CsA (CsA group). The primary endpoint was PFS rate in the intention-to-treat population at 52 weeks. The secondary endpoints were OS rate at 52 weeks, changes in pulmonary function tests from baseline to 52 weeks and AE.
RESULTS
Fifty-eight patients were randomly assigned to the TAC group (n = 30) and the CsA group (n = 28). The PFS rates at 52 weeks were 87% in the TAC group and 71% in the CsA group (P = 0.16). The OS rates at 52 weeks were 97% in the TAC group and 93% in the CsA group (P = 0.50). The %FVC at 52 weeks in the per-protocol populations significantly increased in both groups. None of the patients discontinued the treatment due to AE.
CONCLUSION
PSL plus TAC treatment may achieve a better short-term PFS rate compared with PSL plus CsA treatment. Further studies must be conducted to evaluate the long-term efficacy and safety of such treatment.
Topics: Cyclosporine; Dermatomyositis; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Prednisolone; Prospective Studies; Retrospective Studies; Tacrolimus
PubMed: 33179395
DOI: 10.1111/resp.13978 -
Journal of Clinical and Experimental... 2022Liver transplantation (LT) is the standard of care for end-stage liver failure and hepatocellular carcinoma. Over the years, immunosuppression regimens have improved,... (Review)
Review
Liver transplantation (LT) is the standard of care for end-stage liver failure and hepatocellular carcinoma. Over the years, immunosuppression regimens have improved, resulting in enhanced graft and patient survival. At present, the side effects of immunosuppressive agents are a significant threat to post-LT quality of life and long-term outcome. The role of personalized immunosuppression is to reach a delicate balance between optimal immunosuppression and minimal side effects. Today, immunosuppression in LT is more of an art than a science. There are no validated markers for overimmunosuppression and underimmunosuppression, only a few drugs have therapeutic drug monitoring and immunosuppression regimens vary from center to center. The immunosuppressive agents are broadly classified into biological agents and pharmacological agents. Most regimens use multiple agents with different modes of action to reduce the dosage and minimize the toxicities. The calcineurin inhibitor (CNI)-related toxicities are reduced by antibody induction or using mTOR inhibitor/antimetabolites as CNI sparing or CNI minimization strategies. Post-liver transplant immunosuppression has an intensive phase in the first three months when alloreactivity is high, followed by a maintenance phase when immunosuppression minimization protocols are implemented. Over time some patients achieve "tolerance," defined as the successful stopping of immunosuppression with good graft function and no indication of rejection. Cell-based therapy using immune cells with tolerogenic potential is the future and may permit complete withdrawal of immunosuppressive agents.
PubMed: 36340316
DOI: 10.1016/j.jceh.2022.06.007 -
CA: a Cancer Journal For Clinicians 2024The progression of cancer involves a critical step in which malignant cells escape from control by the immune system. Antineoplastic agents are particularly efficient... (Review)
Review
The progression of cancer involves a critical step in which malignant cells escape from control by the immune system. Antineoplastic agents are particularly efficient when they succeed in restoring such control (immunosurveillance) or at least establish an equilibrium state that slows down disease progression. This is true not only for immunotherapies, such as immune checkpoint inhibitors (ICIs), but also for conventional chemotherapy, targeted anticancer agents, and radiation therapy. Thus, therapeutics that stress and kill cancer cells while provoking a tumor-targeting immune response, referred to as immunogenic cell death, are particularly useful in combination with ICIs. Modern oncology regimens are increasingly using such combinations, which are referred to as chemoimmunotherapy, as well as combinations of multiple ICIs. However, the latter are generally associated with severe side effects compared with single-agent ICIs. Of note, the success of these combinatorial strategies against locally advanced or metastatic cancers is now spurring successful attempts to move them past the postoperative (adjuvant) setting to the preoperative (neoadjuvant) setting, even for patients with operable cancers. Here, the authors critically discuss the importance of immunosurveillance in modern clinical cancer management.
Topics: Humans; Monitoring, Immunologic; Neoplasms; Antineoplastic Agents; Immunotherapy
PubMed: 37880100
DOI: 10.3322/caac.21818 -
Frontiers in Immunology 2022Belatacept (Bela) was developed to reduce nephrotoxicity and cardiovascular risk that are associated with the chronic use of Calcineurin inhibitors (CNIs) in kidney... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Belatacept (Bela) was developed to reduce nephrotoxicity and cardiovascular risk that are associated with the chronic use of Calcineurin inhibitors (CNIs) in kidney transplant recipients. The use of Bela with early steroid withdrawal (ESW) and simultaneous CNI avoidance has not been formally evaluated.
METHODS
At 3 months post-transplant, stable kidney transplant recipients with ESW on Tacrolimus (Tac) + mycophenolate (MPA) were randomized 1:1:1 to: 1) Bela+MPA, 2) Bela+low-dose Tac (trough goal <5 ng/mL), or 3) continue Tac+MPA. All patients underwent surveillance graft biopsies at enrollment and then at 12, and 24 months post-transplant. Twenty-seven recipients were included; 9 underwent conversion to Bela+MPA, 8 to Bela+low-dose Tac and 10 continued Tac+MPA. Serial blood samples were collected for immune phenotyping and gene expression analyses.
RESULTS
The Bela+MPA arm was closed early due to high rate of biopsy proven acute rejection (BPAR). The incidence of BPAR was 4/9 in Bela+MPA, 0/8 in Bela+low dose Tac and 2/10 in Tac+MPA, P= 0.087. The Bela+low-dose Tac regimen was associated with +8.8 mL/min/1.73 m increase in eGFR compared to -0.38 mL/min/1.73 m in Tac+MPA, P= 0.243. One graft loss occurred in the Bela+MPA group. Immunophenotyping of peripheral blood monocyte count (PBMC) showed that CD28CD4 and CD28CD8 T cells were higher in Bela+MPA patients with acute rejection compared to patients without rejection, although the difference did not reach statistical significance.
CONCLUSIONS
Our data indicate that, in steroid free regimens, low-dose Tac maintenance is needed to prevent rejection when patients are converted to Bela, at least when the maneuver is done early after transplant.
Topics: Humans; Abatacept; Calcineurin; Calcineurin Inhibitors; CD28 Antigens; CD8-Positive T-Lymphocytes; Immunosuppressive Agents; Kidney Transplantation; Leukocytes, Mononuclear; Mycophenolic Acid; Steroids; Tacrolimus; Drug Substitution
PubMed: 36601111
DOI: 10.3389/fimmu.2022.1096881 -
Cureus Mar 2022New-onset diabetes mellitus (NODM) is a common long-term complication after liver transplantation (LT). It is thought to be drug-induced in most cases, no matter the... (Review)
Review
New-onset diabetes mellitus (NODM) is a common long-term complication after liver transplantation (LT). It is thought to be drug-induced in most cases, no matter the underlying disease that cause liver failure and indicated transplantation. Standard post-transplantation (PT) immunosuppressive regimens include prolonged use of calcineurin inhibitors (CNIs), namely tacrolimus (TAC), alongside corticosteroids to avoid acute and chronic graft rejection. This combination is well known for its diabetogenicity. Significant differences between the applied regimens stand out concerning the duration and dosages to prevent the metabolic side effects of these drugs in the long run without compromising the graft's survival. Studies were collected after an extensive research of PubMed database for this very specific topic using the following MeSH keywords in multiple combinations: "Liver Transplantation," "Diabetes Mellitus," "NODM," "Tacrolimus," "Cyclosporine A," and "Steroids." In addition, we used the same keywords for regular searches in Google Scholar. Only the relevant English human studies between 2010 and 2020 were collected except for review articles. Duplicates were eliminated using Mendeley software. Twelve relevant studies directly related to the targeted topic were collected and discussed, including five retrospective cohorts, four prospective cohorts, one clinical trial, one prospective pilot, and one case report. Their topics included primarily the factors increasing the risk of new-onset diabetes mellitus after liver transplantation (NODALT), TAC-based immunosuppression and its relative blood levels affecting the possible development of NODALT, the role of cyclosporine in substituting TAC regimen, and the effect of different steroids-avoiding protocols on the prevention of NODALT. The reviewed studies suggested that lowering the serum concentration of tacrolimus (cTAC) throughout the PT period and eliminating the corticosteroids regimen as early as possible, among other measures, can significantly impact the rate of emergence of NODM. This traditional review tackles the most recent studies about NODALT to establish a comprehensive view on this issue and guide clinicians and researchers for the safest immunosuppressive regimen to date, while maintaining a balanced metabolic profile.
PubMed: 35510006
DOI: 10.7759/cureus.23635 -
BMC Nephrology Oct 2019The purpose of this study was to determine efficacy and safety of cyclosporine A (CsA) for patients with steroid-resistant nephrotic syndrome (SRNS). (Comparative Study)
Comparative Study Meta-Analysis Review
BACKGROUND
The purpose of this study was to determine efficacy and safety of cyclosporine A (CsA) for patients with steroid-resistant nephrotic syndrome (SRNS).
METHODS
The Cochrane Library and PubMed were searched to extract the associated studies on Oct 10, 2018, and the meta-analysis method was used to pool and analyze the applicable investigations included in this study. The P(opulation) I(ntervention) C(omparison) O(utcome) of the study were defined as follows: P: Patients with SRNS; I: treated with CsA, cyclophosphamide (CYC), tacrolimus (TAC) or placebo/not treatment (P/NT); C: CsA vs. placebo/nontreatment (P/NT), CsA vs. CYC, CsA vs. TAC; O: complete remission (CR), total remission (TR; complete or partial remission (PR)), urine erythrocyte number, proteinuria levels, albumin, proteinuria, serum creatinine, and plasma cholesterol, etc. Data were extracted and pooled using RevMan 5.3.
RESULTS
In the therapeutic regimen of CsA vs. placebo/nontreatment (P/NT), the results indicated that the CsA group had high values of CR, TR, and low values of proteinuria, serum creatinine, and plasma cholesterol when compared with those in the placebo group. In comparing CsA vs. cyclophosphamide (CYC), the results indicated that the CsA group had higher TR than the CYC group. In comparing CsA vs. tacrolimus (TAC), the results revealed insignificant differences in CR, and TR between the CsA and TAC groups. The safety of CsA was also assessed. The incidence of gum hyperplasia in CsA group was higher than that in the P/NT group, with no differences in incidence of infections or hypertension between CsA and P/NT groups. There was no difference in the incidence of hypertension between the CsA and TAC groups.
CONCLUSIONS
CsA is an effective and safe agent in the therapy of patients with SRNS.
Topics: Cholesterol; Creatinine; Cyclophosphamide; Cyclosporine; Drug Resistance; Gingiva; Humans; Hyperplasia; Hypertension; Immunosuppressive Agents; Infections; Nephrotic Syndrome; Proteinuria; Steroids; Tacrolimus
PubMed: 31646979
DOI: 10.1186/s12882-019-1575-8 -
Lupus Science & Medicine 2016Current guidelines do not mention tacrolimus (TAC) as a treatment option and no consensus has been reported on the role of TAC in lupus nephritis (LN). The present study... (Review)
Review
Current guidelines do not mention tacrolimus (TAC) as a treatment option and no consensus has been reported on the role of TAC in lupus nephritis (LN). The present study aimed to guide clinical judgement on the use of TAC in patients with LN. A meta-analysis was performed for clinical studies investigating TAC regimens in LN on the basis of treatment target (induction or maintenance), concomitant immunosuppression and quality of the data. 23 clinical studies performed in patients with LN were identified: 6 case series, 9 cohort studies, 2 case-control studies and 6 randomised controlled trials (RCTs). Of the 6 RCTs, 5 RCTs investigated TAC regimens as induction treatment and 1 RCT as maintenance treatment. Five RCTs investigated TAC in combination with steroids and 2 TAC with mycophenolate plus steroids. All RCTs were performed in patients of Asian ethnicity. In a meta-analysis, TAC regimens achieved a significantly higher total response (relative risk (RR) 1.23, 95% CI 1.12 to 1.34, p<0.05) and significantly higher complete response (RR 1.48, 95% CI 1.23 to 1.77, p<0.05). The positive outcome was predominantly defined by the largest RCT investigating TAC with mycophenolate plus steroids. Regarding safety, the occurrence of leucopoenia was significantly lower, while the occurrence of increased creatine was higher. Clinical studies on TAC regimens for LN are limited to patients of Asian ethnicity and hampered by significant heterogeneity. The positive results on clinical efficacy of TAC as induction treatment in LN cannot be extrapolated beyond Asian patients with LN. Therefore, further confirmation in multiethnic, randomised trials is mandatory. Until then, TAC can be considered in selected patients with LN.
PubMed: 28123768
DOI: 10.1136/lupus-2016-000169 -
AIDS and Behavior Nov 2018Despite documented effectiveness of pre-exposure prophylaxis (PrEP), PrEP uptake remains low among at-risk populations. The 2015 CDC report estimates that about 1.2... (Review)
Review
Despite documented effectiveness of pre-exposure prophylaxis (PrEP), PrEP uptake remains low among at-risk populations. The 2015 CDC report estimates that about 1.2 million people in the US have indications for PrEP. However, only 49,158 or 4% of the targeted population are currently using PrEP. Efforts to optimize uptake of PrEP may be facilitated by the development of a comprehensive theoretical framework which can be used to understand reasons for poor uptake and to develop interventions to maximize PrEP uptake and adherence. This article reviews research on correlates of PrEP uptake and presents findings organized within an Information-Motivation-Behavioral Skills (IMB) model framework. In the context of PrEP uptake, the IMB model asserts that to the extent that at-risk groups are well-informed about PrEP, motivated to act on their knowledge, and have necessary behavioral skills to seek out and initiate PrEP regimen, they will successfully overcome obstacles to initiate and adhere to PrEP. The article proposes an adaptation the IMB model for PrEP uptake, provides empirical support for the adapted IMB model extracted from related research, and discusses its application in PrEP uptake interventions.
Topics: Adult; Female; HIV Infections; Health Knowledge, Attitudes, Practice; Humans; Male; Motivation; Patient Acceptance of Health Care; Pre-Exposure Prophylaxis; Self Efficacy; Vulnerable Populations
PubMed: 29557540
DOI: 10.1007/s10461-018-2095-4 -
Transplantation Aug 2021Although the population of older transplant recipients has increased dramatically, there are limited data describing the impact of immunosuppression regimen choice on...
BACKGROUND
Although the population of older transplant recipients has increased dramatically, there are limited data describing the impact of immunosuppression regimen choice on outcomes in this recipient group.
METHODS
National data for US Medicare-insured adult kidney recipients (N = 67 362; 2005-2016) were examined to determine early immunosuppression regimen and associations with acute rejection, death-censored graft failure, and mortality using multivariable regression analysis in younger (18-64 y) and older (>65 y) adults.
RESULTS
The use of antithymocyte globulin (TMG) or alemtuzumab (ALEM) induction with triple maintenance immunosuppression (reference) was less common in older compared with younger (36.9% versus 47.0%) recipients, as was TMG/ALEM + steroid avoidance (19.2% versus 20.1%) and mammalian target of rapamycin inhibitor (mTORi)-based (6.7% versus 7.7%) treatments. Conversely, older patients were more likely to receive interleukin (IL)-2-receptor antibody (IL2rAb) + triple maintenance (21.1% versus 14.7%), IL2rAb + steroid avoidance (4.1% versus 1.8%), and cyclosporine-based (8.3% versus 6.6%) immunosuppression. Compared with older recipients treated with TMG/ALEM + triple maintenance (reference regimen), those managed with TMG/ALEM + steroid avoidance (adjusted odds ratio [aOR], 0.440.520.61) and IL2rAb + steroid avoidance (aOR, 0.390.550.79) had lower risk of acute rejection. Older patients experienced more death-censored graft failure when managed with Tac + antimetabolite avoidance (adjusted hazard [aHR], 1.411.782.25), mTORi-based (aHR, 1.702.142.71), and cyclosporine-based (aHR, 1.411.782.25) regimens, versus the reference regimen. mTORi-based and cyclosporine-based regimens were associated with increased mortality in both older and younger patients.
CONCLUSIONS
Lower-intensity immunosuppression regimens (eg, steroid-sparing) appear beneficial for older kidney transplant recipients, while mTORi and cyclosporine-based maintenance immunosuppression are associated with higher risk of adverse outcomes.
Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Alemtuzumab; Antilymphocyte Serum; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Receptors, Interleukin-2; Registries; Young Adult
PubMed: 33214534
DOI: 10.1097/TP.0000000000003547