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Related Concept Videos

RMS Value in AC Circuit01:13

RMS Value in AC Circuit

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The root mean square (RMS) value is a measure of the effective or average value of an alternating current (AC) waveform. In AC circuits, the voltage or current waveform constantly changes direction and magnitude, making it difficult to describe with a single value. The RMS value provides a convenient way to calculate the equivalent DC voltage or current that would produce the same heating effect in a resistor as the AC waveform.
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Pharmacokinetics in Pediatric Patients: Drug Excretion01:26

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In pediatric medicine, understanding the renal function and drug elimination nuances is crucial for administering safe and effective treatments. Newborns, in particular, display markedly slower renal functions than adults, profoundly affecting how drugs are cleared from their bodies. This slower drug clearance requires clinicians to extend the dosing intervals for many medications to prevent drug accumulation and toxicity while ensuring therapeutic efficacy.One key area where these adjustments...
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Pharmacokinetics in Pediatric Patients: Drug Distribution01:17

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Drug distribution in the pediatric population exhibits unique challenges and considerations due to the physiological differences between children, particularly neonates and infants, and adults. A crucial aspect of pediatric pharmacology is understanding how these differences impact the pharmacokinetics of various drugs, necessitating age-specific dosing strategies to ensure efficacy and safety.Neonates and infants have a higher total body water content, ~75%–90% of their body weight,...
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Pharmacokinetics in Pediatric Patients: Drug Metabolism01:24

Pharmacokinetics in Pediatric Patients: Drug Metabolism

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In pediatric care, understanding the nuances of hepatic drug metabolism is crucial, as it significantly differs from that of adults. This divergence is primarily due to the developmental stage of drug-metabolizing enzymes, which affects how medications are processed in the body. In neonates, for instance, the activity of Phase I enzymes—critical for the initial breakdown of drugs—is markedly reduced, functioning at just 20–40% of the levels seen in adults. This reduction poses...
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Pharmacokinetics in Pediatric Patients: Overview and Drug Absorption01:23

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Understanding the physiological differences in the pediatric population is crucial for effective pharmacotherapy. Neonates, infants, and children exhibit significant variations in gastric pH, gastric emptying time, intestinal transit time, and biliary function. These variations profoundly affect oral drug absorption, necessitating a nuanced approach to pediatric dosing.Neonates present with a unique physiological profile, having a gastric pH greater than 4 and faster and more irregular gastric...
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Most chemical reactions in cells require enzymes—biological catalysts that speed up the reaction without being consumed or permanently changed. They reduce the activation energy needed to convert the reactants into products. Enzymes are proteins, that usually work by binding to a substrate—a reactant molecule that they act upon.
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Targeting ALK in pediatric RMS does not induce antitumor activity in vivo.

Monika Wierdl1, Lyudmila Tsurkan1, Liying Chi1

  • 1Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105-2794, USA.

Cancer Chemotherapy and Pharmacology
|June 2, 2018
PubMed
Summary
This summary is machine-generated.

Anaplastic Lymphoma Kinase (ALK) inhibitors show promise against pediatric rhabdomyosarcoma (RMS) in lab tests. However, these ALK inhibitors failed to treat tumors in vivo and may even accelerate growth, cautioning against their use in patients.

Keywords:
ALKALK inhibitorsCrizotinibPatient-derived xenograftsRhabdomyosarcoma

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Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Anaplastic Lymphoma Kinase (ALK) is a validated target in certain cancers.
  • Recent findings suggest ALK overexpression in pediatric rhabdomyosarcoma (RMS).

Purpose of the Study:

  • To investigate ALK as a therapeutic target in pediatric RMS.
  • To evaluate the efficacy of ALK inhibitors in preclinical RMS models.

Main Methods:

  • Assessed ALK expression in RMS cell lines and patient-derived xenografts (PDX).
  • Tested sensitivity to ALK inhibitors (crizotinib, NVP-TAE684, LDK-378) in vitro and in vivo.
  • Evaluated combination therapy with standard-of-care agents.

Main Results:

  • RMS cell lines demonstrated in vitro sensitivity to ALK inhibitors.
  • siRNA-mediated ALK reduction inhibited RMS cell proliferation.
  • In vivo studies showed no antitumor activity of ALK inhibitors, alone or combined.
  • Crizotinib treatment accelerated tumor growth in vivo.

Conclusions:

  • While ALK is a relevant target in vitro for RMS, in vivo therapeutic efficacy is lacking.
  • Caution is advised regarding the use of ALK inhibitors in pediatric RMS patients due to observed in vivo effects.