1,721,092 research outputs found
Poor response to thiopurine in inflammatory bowel disease: How to overcome therapeutic resistance? Commentary
No full textThe thiopurine antimetabolites azathioprine and 6-mercaptopurine are commonly used to treat inflammatory bowel disease; however, their administration at conventional doses is associated with adverse events and a lack of response in some patients. Although there is an abundance of data on thiopurine-S-methyltransferase (TPMT) deficiency and adverse hematologic events during treatment with thiopurines, there is still a paucity of information on the molecular causes for nonresponse. Chouchana et al. present a patient with ulcerative colitis who was unresponsive to therapy with thiopurines and had both a high TPMT activity and an unfavorable ratio of thiopurine metabolites, i.e., a high concentration of methylmercaptopurine nucleotides (MMPNs)2 relative to thioguanine nucleotides (TGNs). Higher MMPN and lower TGN concentrations are associated with a reduced thiopurine response; a high TPMT activity may be involved in determining this unfavorable metabolic ratio (1). Recent evidence has provided additional promising genetic determinants for a high TPMT activity and a lack of thiopurine response; however, these molecular features still need further validation before their clinical use. Polymorphisms in the TPMT3 (thiopurine S-methyltransferase) promoter have been associated with increased TPMT activity. Moreover, trans effects of single-nucleotide polymorphisms that affect TPMT activity and mercaptopurine sensitivity have recently been discovered in the PACSIN2 (protein kinase C and casein kinase substrate in neurons 2) gene. These molecular factors influencing TPMT activity may identify patients with high TPMT activity. For azathioprine, deletion of the GSTM1 (glutathione S-transferase mu 1) gene, which encodes an enzyme involved in the conversion of azathioprine to 6-mercaptopurine, has been associated with reduced drug activation, a lower TGN concentration, and a reduced response to therapy. An increased understanding of the molecular features that lead to an unfavorable response to thiopurines may provide useful tools, via a multilocus genotype approach, for identifying patients with a lower probability of responding to thiopurine therapy. Clinical implementation of this multifactorial assessment may be possible via the use of computerized decision-support tools in combination with electronic medical records (2), which would improve patients' pharmacological treatment
Immunomodulatori
No full textGli immunomodulatori, intesi come farmaci in grado di modulare (e più
precisamente di ridurre) la risposta immune, trovano ampio spazio di utilizzo
in gastroenterologia pediatrica, principalmente nel trattamento delle
malattie infiammatorie croniche intestinali e nella prevenzione del rigetto
nel trapianto di organo.
Conoscere il loro meccanismo d’azione, gli effetti avversi, i corretti dosaggi
e le indicazioni è indispensabile per il pediatra gastroenterologo (ma anche
per il pediatra generalista), sia ospedaliero che di libera scelta, per l’elevato
numero di bambini che ne fanno utilizzo e per prevenire o trattare gli effetti
avversi, primo fra tutti l’aumentato rischio di infezioni, con una corretta
prevenzione vaccinale
Pharmacogenetics, cost of genotyping, and guidelines for individualizing therapy with mercaptopurine in pediatric acute lymphoblastic leukemia.
No full textWe read with interest the article by Donnan
et al. [1], reporting that screening for thiopurine-S-methyl-transferase
(TPMT) status prior to the administration of mercaptopurine
for the treatment of pediatric acute lymphoblastic leukemia
(ALL) is not cost-effective.
We feel that for TPMT status and its clinical relation to
mercaptopurine administration, the measure of effectiveness
should not be limited to prolonged survival, but rather to reduction
in toxicity without altering efficacy. As mentioned by
Donnan et al., there are previous studies showing that TPMT
genotyping is cost-effective, even when considering only
patients with TPMT homozygous variant genotypes as those
who benefit from the genotyping assay and survival as the endpoint
[2,3].
We understand the interest in applying economical models
to evaluate and choose the optimal therapy for patients. However,
in reference to evaluating the cost of acquiring genetic
information, with the dawn of high-throughput genotyping
approaches for clinical use, the cost of obtaining robust and
reliable genotypes has been decreasing and it is now possible to
obtain high-throughput genotyping of multiple genes for $1/
gene [4]. One would think that the potentially severe nature of
mercaptopurine toxicity (which can be fatal [5]) and the risk of
sub-therapeutic treatment (e.g., leukemia relapse) would make
the consequences of inadequate dosing too compelling to ignore
established pharmacogenetic data when treating a child
with ALL. Moreover, it should not be forgotten that genotyping
results are permanent for a patient and need be acquired only
once in a lifetime. Any potential risks to the patient of including
genetic test results in the medical record have been minimized
by the adoption of genetic nondiscrimination laws [6].
The real issue then will be how to translate useful pharmacogenetic
information to the clinical setting and how to encourage
and educate clinicians to do so [7,8]. This will require
overcoming some of the barriers to implementing individualized
medicine such as fragmentation of health-care systems,
low use of electronic medical records, and health care systems
that do not reward prevention of a disease or adverse events and
therefore lack of interest in preemptive approaches [9]. In this
perspective, for the clinical implementation of pharmacogenetics,
the development of solid and accepted guidelines seems
to be of key relevance [9]. For mercaptopurine in leukemia
these guidelines are currently available and comprise for
patients with a variant TPMT allele starting with reduced doses
(30–70% of full dose given daily for patients heterozygous for
TPMT, or 10% of full dose given three times a week for
patients homozygous for TPMT) and increased monitoring of
hematologic efficacy and toxicity [10,11]. These robust molecular
diagnostics should be embraced by clinicians in order to
reduce toxicity and provide better treatment with mercaptopurine
for their patients. The methods are at hand to move medicine
closer to science than art
Emerging molecular mechanisms underlying cancer metastasis: the rising role of the long non-coding RNA GAS5
No full textMetastasis is a multistep process, wherein cells in a primary tumor acquire invasive properties and disseminate throughout the body to establish secondary tumors at distant organs. During the metastatic cascade a complex interaction of signals are involved and identification of novel players in this process is crucial for cancer prognosis and for the development of agents effective on late stage malignancies. Although most of the studies in the literature focus on protein modulators of metastasis, the relevance of non-coding RNAs is now being appreciated. Long non-coding RNAs (lncRNAs) are commonly referred to as non-protein-coding RNA transcripts longer than 200 nucleotides. Emerging evidence has shown that lncRNAs are dysregulated in multiple cancer types and have a critical role in the process of metastasis (1). Of particular interest in this regard is the lncRNA GAS5 (growth arrest- speci c transcript 5) which is down-regulated and inversely correlates with clinicopathological characteristics such as tumor size and metastasis progression in various human cancers, such as renal clear cells and bladder cancer (2,3). However, studies on melanoma are still scarce
ITPA genetic polymorphism is possibly associated with survival rate in Korean children with acute lymphoblastic leukemia.
No full textComment on "Pharmacogenetic analysis of pediatric patients with acute lymphoblastic leukemia: a possible association between survival rate and ITPA polymorphism."
Kim H, Kang HJ, Kim HJ, Jang MK, Kim NH, Oh Y, Han BD, Choi JY, Kim CW, Lee JW, et al.
PLoS One. 2012; 7(9):e45558. Epub 2012 Sep 24
Challenges in Therapeutic Drug Monitoring: Optimizing Biological Treatments in Patients With Inflammatory Bowel Disease and Other Immune-Mediated Inflammatory Diseases
Full text linkBackground: Therapeutic drug monitoring (TDM) is a decision-making tool for optimizing the use of certain therapies. In this article, the authors review the role of proactive TDM of biological agents in patients with inflammatory bowel disease (IBD) and other immune-mediated inflammatory diseases (IMID). They also discuss the future of TDM as a component of personalized medicine from the clinical laboratory perspective. Methods: This narrative review originated from proceedings of the fifth biannual Challenges in Therapeutic Drug Monitoring seminar and was supplemented by additional literature identified at various stages of critical review. Results: Proactive TDM aims to achieve adequate concentrations of biological drugs, such that patients attain and maintain an optimal treatment response. Proactive TDM may also have a role in de-escalating anti-tumor necrosis factor therapy in patients in clinical remission and in optimizing infliximab monotherapy as an alternative to combination therapy with an immunomodulator. A major proactive TDM application is in pediatric patients with IBD. Achieving mucosal healing in children with IBD requires that infliximab or adalimumab concentrations are monitored early during induction therapy, with dose modifications guided by the timing (week) of measurement. Recent innovations in biological therapy include international standards for infliximab and adalimumab for the global harmonization of bioactivity and monotest devices with an accuracy equivalent to that of conventional enzyme-linked immunosorbent assays and quicker turnaround times. Conclusions: Despite several knowledge gaps regarding proactive TDM of anti-tumor necrosis factor therapy in patients with IMID, growing evidence suggests that it is associated with better outcomes than empiric optimization and/or reactive TDM in IBD. Enhanced pharmacokinetic modeling to predict drug exposure and patient genotyping for the precise application of proactive TDM are considered key elements to optimize biological therapy in the future
DMETTM Plus array delivers results in good concordance with those of several lower-throughput genotyping methods in patient samples.
No full textComment on "Concordance of DMET plus genotyping results with those of orthogonal genotyping methods"
Fernandez CA, Smith C, Yang W, Lorier R, Crews KR, Kornegay N, Hicks JK, Stewart CF, Kawedia JD, Ramsey LB, et al.
Clin Pharmacol Ther. 2012 Sep; 92(3):360-5. Epub 2012 Aug 8
Processes for incorporation of pharmacogenetic tests and interpretations in medical records for clinical practice.
No full textComment on "A clinician-driven automated system for integration of pharmacogenetic interpretations into an electronic medical record."
Hicks JK, Crews KR, Hoffman JM, Kornegay NM, Wilkinson MR, Lorier R, Stoddard A, Yang W, Smith C, Fernandez CA, et al.
Clin Pharmacol Ther. 2012 Nov; 92(5):563-6. Epub 2012 Sep 19
Thiopurine-S-methyltransferase genotype and the response to azathioprine in inflammatory bowel disease.
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