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Related Concept Videos

Pharmacokinetic–Pharmacodynamic Relationship: Problems01:24

Pharmacokinetic–Pharmacodynamic Relationship: Problems

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The empirical approach to drug therapy optimization relies on correlating pharmacological response with administered dosage. Such an approach can be costly, time-consuming, and often yields poor correlation due to variables like formulation factors and drug elimination characteristics. A more precise approach correlates response with plasma drug concentration or the amount of drug in the body, rather than dosage. This is achieved through pharmacokinetic-pharmacodynamic (PK/PD) modeling, which...
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Pharmacodynamic Models: Overview01:27

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Pharmacodynamic (PD) responses describe the interaction between a drug and its biological target, culminating in a physiological effect. These responses can be classified into different types: continuous variables, such as blood glucose levels; categorical outcomes, like survival rates; and time-to-event metrics, such as disease progression. Understanding and modeling PD responses are critical for optimizing drug efficacy and safety.PD models describe the relationship between drug concentration...
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Treatment strategies for poisoning are a critical aspect of emergency medicine, focusing on preventing the absorption of toxins and enhancing their elimination. When a poisoning incident occurs, the first response is to halt exposure and decontaminate the patient, particularly through gastrointestinal (GI) methods if the poison was ingested.Gastrointestinal Decontamination Techniques:Activated charcoal is the cornerstone of GI decontamination. It works through adsorption, binding the toxin to...
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Impact of Pharmacokinetic–Pharmacodynamic Models: Regulatory Decisions01:15

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PK–PD modeling has significantly influenced FDA regulatory decisions, particularly drug approval, dosage optimization, and labeling. These models integrate pharmacokinetics (PK) and pharmacodynamics (PD) to predict drug behavior and effects, aiding in optimizing dosing regimens and enhancing the probability of clinical trial success.One notable example is Nesiritide (Natrecor®), a recombinant human brain natriuretic peptide for treating acute decompensated congestive heart failure...
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Bioavailability Enhancement: Determination and Conceptual Approaches in Overcoming Bioavailability Problems01:22

Bioavailability Enhancement: Determination and Conceptual Approaches in Overcoming Bioavailability Problems

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Bioavailability is a critical pharmacological concept that measures the extent and rate at which an active drug ingredient or therapeutic moiety enters the systemic circulation, remaining unchanged. It's a pivotal factor in determining a drug's efficacy and safety.The Biopharmaceutics Classification System (BCS) plays an essential role in drug development by categorizing drugs into four classes based on their solubility and permeability. This classification aids in understanding drug absorption...
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Pharmaceutical Poisoning: Potential Scenarios01:26

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Pharmaceutical poisoning can occur through various channels, impacting an estimated 2 million hospitalized patients in the U.S. annually with serious adverse drug responses. These scenarios encompass both therapeutic uses, such as drug toxicity, where even standard dosages can lead to severe central nervous system depression, and non-therapeutic exposures, including accidental ingestion by children, and environmental and occupational exposures.Unintentional poisonings often involve exploratory...
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High-throughput Identification of Synergistic Drug Combinations by the Overlap2 Method
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Match-making for posaconazole through systems thinking.

Matthias A Fügi1, Marcel Kaiser1, Marcel Tanner1

  • 1Swiss Tropical and Public Health Institute, CH-4051 Basel, Switzerland; University of Basel, CH-4000 Basel, Switzerland.

Trends in Parasitology
|December 10, 2014
PubMed
Summary
This summary is machine-generated.

New combination therapies show promise for treating chronic Chagas' disease. Combining posaconazole with sphingolipid biosynthesis inhibitors could overcome current treatment limitations and improve efficacy against Trypanosoma cruzi.

Keywords:
Chagas’ diseasecombination therapysphingolipidssterolssystems biology

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Area of Science:

  • * Infectious Diseases
  • * Drug Discovery and Development
  • * Parasitology

Background:

  • * Current Chagas' disease treatments exhibit significant toxicity and limited efficacy, particularly in chronic infections.
  • * Posaconazole, a promising anti-chagasic drug candidate, showed potential but did not fully meet expectations in Phase II clinical trials.
  • * Posaconazole demonstrates high in vitro activity against Trypanosoma cruzi and good tolerability in clinical settings.

Purpose of the Study:

  • * To explore combination therapy strategies to enhance the efficacy of posaconazole for Chagas' disease.
  • * To identify a synergistic partner for posaconazole by investigating functional interactions between sterol and sphingolipid pathways.
  • * To advance drug development for chronic Chagas' disease through systems-scale approaches.

Main Methods:

  • * Investigated the interplay between sterol biosynthesis (posaconazole's target) and sphingolipid biosynthesis.
  • * Utilized systems-scale approaches to identify potential drug combination partners.
  • * Focused on inhibitors targeting both sterol and sphingolipid pathways.

Main Results:

  • * Evidence suggests critical functional interactions between sterols and sphingolipids in vivo.
  • * Combination therapy targeting both pathways presents a promising strategy.
  • * Posaconazole's established safety profile makes it a viable candidate for combination treatment.

Conclusions:

  • * Abandoning posaconazole for Chagas' disease is premature due to its in vitro activity and safety.
  • * Combining posaconazole with sphingolipid biosynthesis inhibitors offers a highly promising therapeutic approach.
  • * This combination strategy holds significant potential for improving treatment outcomes in chronic Chagas' disease.