ISSN:0163-4356    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Therapeutic drug monitoring in neonate has been hampered by invasiveness of blood samplings raising ethical problems. A methodologic approach has been developped in adults and in children that is still unsufficiently developped in neonates, the Bayesian forecasting of drug plasma concentration. This method is particularly attractive in neonates using a few blood samples from an individual patient and more informations from a prior patient sample representative of the population the individual patient belongs to. The present article aims at reviewing the different procedures and methods to minimize invasiveness during therapeutic drug monitoring in neonate and at reviewing the methods for improving the quality of different dose adjustments using a Bayesian approach.

ISSN:0163-4356    

出版商:OVID    

年代:2002

数据来源: OVID

ISSN:0163-4356    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Many women worldwide use recreational drugs and alcohol. Details on the amounts and schedule of such exposures in pregnancy are often unreliable because of recall issues and shame and fears of legal action. Even when the report on maternal dose is correct, it does not necessarily reflect the amount reaching the fetus. Drugs of abuse accumulate in meconium and are incorporated into fetal hair on its growth. Recent work has documented the sensitivity and specificity of these assays for cocaine and other recreational drugs. Dose-response relationships between cocaine as measured in neonatal hair and head circumference or neurologic sequelae have been recently established. For ethanol, which cannot be measured in hair or meconium, accumulation of its fatty acid ethyl esters in meconium is emerging as a promising test for heavy maternal drinking in the second part of pregnancy. The identification of biologic markers of intrauterine exposure to xenobiotics will allow better understanding of etiology and dose-response relationships.

ISSN:0163-4356    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Highly active antiretroviral therapy, involving treatment with three or four antiretroviral agents, has greatly improved the effectiveness of therapy for human immunodeficiency virus (HIV) infection. It has also extended the number of possible drug interactions that may occur in treated patients. There are 105 possible two-drug interactions among the 15 currently approved antiretroviral agents. Well-characterized interactions involving inhibition of drug metabolism have been exploited to reduce dose size or frequency and to simplify treatment regimens. Many additional interactions are possible with other drugs used to treat or prevent complications of HIV infection. Interactions with methadone and other opiate abuse therapies are also of concern. The usefulness of therapeutic drug monitoring for antiretroviral drugs remains controversial. However, drug measurements before introduction of an interacting drug can establish patient-specific targets that can guide subsequent dosing adjustment.

ISSN:0163-4356    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The intracellular class of proteins that bind the interleukin-2 suppressing drugs (cyclosporin, tacrolimus, and sirolimus) are called immunophilins. It is believed that the drugs do not act directly on T cells to cause immunosuppression. Instead, there is evidence that drug–immunophilin complexes are responsible for the therapeutic effect. In this work, evidence is presented that ubiquitin is an immunophilin. Ubiquitin is a highly conserved protein essential to an important pathway that targets proteins for proteolysis. The interaction of these drugs could cause accelerated proteolysis of a key protein for T-cell upregulation or could cause the inhibition of proteolysis of a T-cell suppressor. It was also shown that when ubiquitin is complexed with tacrolimus, the complex inhibits calcineurin phosphatase, and it is known that immunosuppression with these drugs occurs concurrently with a decrease in the activity of this enzyme. The discovery of ubiquitin as an immunophilin has opened many new avenues to explore in relation to the effects of these drugs.

ISSN:0163-4356    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Major advances in immunosuppression and reductions in the rates of acute rejection have led to increasing graft and patient survival rates during the past two decades. Chronic dysfunction of the renal allograft, however, remains a major clinical problem and probably represents the end result of the complex interplay between donor and recipient factors, immunologic injury, nonimmunologic insults, and drug-induced nephrotoxicity. Optimal function of the renal allograft is obtained by maintaining a balance between underimmunosuppression and acute rejection and overimmunosuppression and drug-induced toxicities. To minimize side effects while maintaining efficacy, immunosuppressive drugs are commonly used as combination therapy. Pharmacokinetic and pharmacodynamic interactions between these agents can affect graft survival and function. The evidence supporting the role of therapeutic drug monitoring as applied to commonly used immunosuppressants in modern transplantation is presented here, and the increasing role of therapeutic drug monitoring in the optimization of graft and patient survival rates in the modern era of renal transplantation is discussed.

ISSN:0163-4356    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Cyclosporine is a critical dose drug for which individualisation by therapeutic drug monitoring is indisputable. Current evidence suggests that a single concentration (C2) taken two hours after cyclosporine administration with the microemulsion formulation better predicts exposure and events than the trough concentration (C0), which is routinely used for adjusting the dosage of this drug. Studies have shown that the greatest calcineurin inhibition and the maximum inhibition of IL-2 production occur in the first 1 to 2 hours after dosing. These findings support the concept that the C2level better reflects immunosuppressive efficacy than the trough concentration. Preliminary data from an outcome study in liver transplant recipients have shown that the incidence of biopsy proven moderate to severe acute rejection was significantly lower in patients managed by C2monitoring compared with those monitored by C0. The critical importance of achieving adequate cyclosporine exposure during the first 3 to 5 posttransplant days to prevent acute rejection has been documented in prospective studies with de novo renal and liver transplant recipients. Conversion of maintenance liver and heart transplant patients to C2monitoring resulted in an amelioration of renal function. Time-dependent target values have been proposed for liver and renal transplant recipients. These require further prospective validation. For routine monitoring of C2levels on-site validated dilution guidelines are necessary for most of the available immunoassays. C2monitoring necessitates further organizational requirements which may be judged differently between transplant centers. In particular during the early posttransplant period C2monitoring is a promising new option to make immunosuppressive therapy with the microemulsion formulation of cyclosporine safer and more efficient.

ISSN:0163-4356    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Expanding the cytokine paradigm beyond the use of calcineurin inhibitors as baseline therapy provides new strategies in immunosuppression. Drugs such as FTY720 alter the sensitivity of lymphocytes to homing chemokines, and agents such as sirolimus (SRL) disrupt downstream cytokine signal transduction. Confirming studies in rodents and nonhuman primates, administration of either FTY720 or both of these drugs afford synergistic interactions with cyclosporine to renal transplant patients to rapidly and dramatically deplete peripheral blood lymphocytes (PBL) but neither granulocytes nor monocytes. Present information suggests that FTY720 facilitates lymphocyte homing mechanisms, leading to T and B cell sequestration in secondary lymphoid structures. Interestingly, FTY720 displays pharmacokinetic characteristics suggesting that therapeutic drug monitoring (TDM) will not be essential for clinical applications. In contrast, SRL is a critical-dose drug that requires TDM. SRL disrupts costimulatory and cytokine-stimulated T cell activation by inhibiting a multifunctional kinase, mammalian target of sirolimus (mTOR). Two pivotal trials including more than 1,300 patients demonstrated that addition of SRL to a CsA-based regimen reduces the incidence, time to onset, and severity of acute rejection episodes. When used alone, SRL seems therapeutically equivalent to CsA. In the coming decade, SRL is likely to be used in a variety of drug combination regimens both simultaneously and sequentially, not only to avert acute rejection episodes, but also to forestall chronic nephropathic processes. These two new agents are likely to usher in a new era of transplant therapy.

ISSN:0163-4356    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

SDZ RAD (everolimus, Certican™) is a novel macrolide immunosuppressant that blocks growth factor-driven transduction signals in the T-cell response to alloantigen. After stimulation of the IL-2 receptor on the activated T-cell, SDZ RAD inhibits p70S6 kinase, acting at a later stage in the T-cell mediated response than do cyclosporine and other calcineurin inhibitors (CNIs). Unlike the CNIs, SDZ RAD is a proliferation signal inhibitor, blocking growth factor-driven proliferation of both hematopoietic and nonhematopoietic cells. These activities are complementary to those of cyclosporine and provide a rationale for the addition of SDZ RAD to cyclosporine-based immunosuppression, with the potential for minimizing CNI nephrotoxicity, reducing the incidence of acute rejection, and favoring long-term graft survival. Potential also exists for beneficial effects on other factors that may influence the development of chronic rejection. These factors include comorbid diseases such as hypertension, which may affect transplant vasculopathy, and opportunistic infection with cytomegalovirus (CMV) and other viruses, which may increase the risk of chronic rejection. The synergistic effect of SDZ RAD and cyclosporine has been confirmed in preclinical models, with graft survival being significantly prolonged in rat models of kidney and heart allotransplantation. Clinical experience with SDZ RAD in cyclosporine-based immunosuppression, including low-dose cyclosporine regimens, has also resulted in predictable and favorable clinical outcomes. Low rates of acute rejection, excellent rates of patient and graft survival, lower incidence of CMV infections, better cholesterol, triglyceride and creatinine profiles, and better renal function have been demonstrated with SDZ RAD and lower doses of cyclosporine (Neoral; Novartis Pharmaceuticals, East Hanover, NJ) in recipients of renal transplants. These findings, combined with good tolerability rates and an acceptable side-effect profile, indicate that the synergistic profile of SDZ RAD in combination with nontoxic dosages of CNI's and IL2 inhibitors will further improve longterm results in renal transplantation.

ISSN:0163-4356    

出版商:OVID    

年代:2002

数据来源: OVID