scholarly journals Pharmacokinetics and Pharmacodynamics Modeling and Simulation Systems to Support the Development and Regulation of Liposomal Drugs

Pharmaceutics ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 110 ◽  
Author(s):  
Hua He ◽  
Dongfen Yuan ◽  
Yun Wu ◽  
Yanguang Cao
Keyword(s):  
Modeling And Simulation ◽  
Targeted Delivery ◽  
Therapeutic Efficacy ◽  
Therapeutic Index ◽  
Physiological Factors ◽  
Multiple Components ◽  
Sites Of Action ◽  
The Impact ◽  
Simulation Systems ◽  
Liposomal Drugs

Liposomal formulations have been developed to improve the therapeutic index of encapsulated drugs by altering the balance of on- and off-targeted distribution. The improved therapeutic efficacy of liposomal drugs is primarily attributed to enhanced distribution at the sites of action. The targeted distribution of liposomal drugs depends not only on the physicochemical properties of the liposomes, but also on multiple components of the biological system. Pharmacokinetic–pharmacodynamic (PK–PD) modeling has recently emerged as a useful tool with which to assess the impact of formulation- and system-specific factors on the targeted disposition and therapeutic efficacy of liposomal drugs. The use of PK–PD modeling to facilitate the development and regulatory reviews of generic versions of liposomal drugs recently drew the attention of the U.S. Food and Drug Administration. The present review summarizes the physiological factors that affect the targeted delivery of liposomal drugs, challenges that influence the development and regulation of liposomal drugs, and the application of PK–PD modeling and simulation systems to address these challenges.

Improved Therapeutic Efficacy of Topotecan Against A549 Lung Cancer Cells with Folate-targeted Topotecan Liposomes

2020 ◽  
Vol 21 (11) ◽  
pp. 902-909
Author(s):  
Jingxin Zhang ◽  
Weiyue Shi ◽  
Gangqiang Xue ◽  
Qiang Ma ◽  
Haixin Cui ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Delivery ◽  
Cancer Cells ◽  
Targeted Delivery ◽  
Therapeutic Efficacy ◽  
Drug Delivery Systems ◽  
Lung Tumor ◽  
A549 Cells ◽  
Delivery Systems ◽  
Lung Cancer Cells

Background: Among all cancers, lung cancer has high mortality among patients in most of the countries in the world. Targeted delivery of anticancer drugs can significantly reduce the side effects and dramatically improve the effects of the treatment. Folate, a suitable ligand, can be modified to the surface of tumor-selective drug delivery systems because it can selectively bind to the folate receptor, which is highly expressed on the surface of lung tumor cells. Objective: This study aimed to construct a kind of folate-targeted topotecan liposomes for investigating their efficacy and mechanism of action in the treatment of lung cancer in preclinical models. Methods: We conjugated topotecan liposomes with folate, and the liposomes were characterized by particle size, entrapment efficiency, cytotoxicity to A549 cells and in vitro release profile. Technical evaluations were performed on lung cancer A549 cells and xenografted A549 cancer cells in female nude mice, and the pharmacokinetics of the drug were evaluated in female SD rats. Results: The folate-targeted topotecan liposomes were proven to show effectiveness in targeting lung tumors. The anti-tumor effects of these liposomes were demonstrated by the decreased tumor volume and improved therapeutic efficacy. The folate-targeted topotecan liposomes also lengthened the topotecan blood circulation time. Conclusion: The folate-targeted topotecan liposomes are effective drug delivery systems and can be easily modified with folate, enabling the targeted liposomes to deliver topotecan to lung cancer cells and kill them, which could be used as potential carriers for lung chemotherapy.

scholarly journals Modified Gold Nanoparticles for Efficient Delivery of Betulinic Acid to Cancer Cell Mitochondria

2021 ◽  
Vol 22 (10) ◽  
pp. 5072
Author(s):  
Olakunle Oladimeji ◽  
Jude Akinyelu ◽  
Aliscia Daniels ◽  
Moganavelli Singh
Keyword(s):  
Polyethylene Glycol ◽  
Cancer Cell ◽  
Betulinic Acid ◽  
Targeted Delivery ◽  
Epigallocatechin Gallate ◽  
High Amplitude ◽  
Significant Inhibition ◽  
Mitochondrial Targeting ◽  
The Impact

Advances in nanomedicine have seen the adaptation of nanoparticles (NPs) for subcellular delivery for enhanced therapeutic impact and reduced side effects. The pivotal role of the mitochondria in apoptosis and their potential as a target in cancers enables selective induction of cancer cell death. In this study, we examined the mitochondrial targeted delivery of betulinic acid (BA) by the mitochondriotropic TPP+-functionalized epigallocatechin gallate (EGCG)-capped gold NPs (AuNPs), comparing the impact of polyethylene glycol (PEG) and poly-L-lysine-graft-polyethylene glycol (PLL-g-PEG) copolymer on delivery efficacy. This included the assessment of their cellular uptake, mitochondrial localization and efficacy as therapeutic delivery platforms for BA in the human Caco-2, HeLa and MCF-7 cancer cell lines. These mitochondrial-targeted nanocomplexes demonstrated significant inhibition of cancer cell growth, with targeted nanocomplexes recording IC50 values in the range of 3.12–13.2 µM compared to that of the free BA (9.74–36.31 µM) in vitro, demonstrating the merit of mitochondrial targeting. Their mechanisms of action implicated high amplitude mitochondrial depolarization, caspases 3/7 activation, with an associated arrest at the G0/G1 phase of the cell cycle. This nano-delivery system is a potentially viable platform for mitochondrial-targeted delivery of BA and highlights mitochondrial targeting as an option in cancer therapy.

scholarly journals Petasin and isopetasin reduce CGRP release from trigeminal afferents indicating an inhibitory effect on TRPA1 and TRPV1 receptor channels

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Johanna Kleeberg-Hartmann ◽  
Birgit Vogler ◽  
Karl Messlinger
Keyword(s):  
Inhibitory Effect ◽  
Transient Receptor Potential Channels ◽  
Mustard Oil ◽  
Root Extract ◽  
Dependent Manner ◽  
Trpv1 Receptor ◽  
Cgrp Release ◽  
Ganglion Neurons ◽  
Sites Of Action ◽  
The Impact

Abstract Background Butterbur root extract with its active ingredients petasin and isopetasin has been used in the prophylactic treatment of migraine for years, while its sites of action are not completely clear. Calcitonin gene-related peptide (CGRP) is known as a biomarker and promoting factor of migraine. We set out to investigate the impact of petasins on the CGRP release from trigeminal afferents induced by activation of the calcium conducting transient receptor potential channels (TRPs) of the subtypes TRPA1 and TRPV1. Methods We used well-established in vitro preparations, the hemisected rodent skull and dissected trigeminal ganglia, to examine the CGRP release from rat and mouse cranial dura mater and trigeminal ganglion neurons, respectively, after pre-incubation with petasin and isopetasin. Mustard oil and capsaicin were used to stimulate TRPA1 and TRPV1 receptor channels. CGRP concentrations were measured with a CGRP enzyme immunoassay. Results Pre-incubation with either petasin or isopetasin reduced mustard oil- and capsaicin-evoked CGRP release compared to vehicle in an approximately dose-dependent manner. These results were validated by additional experiments with mice expressing functionally deleted TRPA1 or TRPV1 receptor channels. Conclusions Earlier findings of TRPA1 receptor channels being involved in the site of action of petasin and isopetasin are confirmed. Furthermore, we suggest an important inhibitory effect on TRPV1 receptor channels and assume a cooperative action between the two TRP receptors. These mechanisms may contribute to the migraine prophylactic effect of petasins.

scholarly journals Standards of laboratory practice: cardiac drug monitoring

1998 ◽  
Vol 44 (5) ◽  
pp. 1096-1109 ◽  
Author(s):  
Roland Valdes ◽  
Saeed A Jortani ◽  
Mihai Gheorghiade
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Drug Monitoring ◽  
Free Fraction ◽  
Therapeutic Index ◽  
Therapeutic Monitoring ◽  
Therapeutic Drug ◽  
Laboratory Practice ◽  
Clinical Complications ◽  
The Impact

Abstract In this Standard of Laboratory Practice we recommend guidelines for therapeutic monitoring of cardiac drugs. Cardiac drugs are primarily used for treatment of angina, arrhythmias, and congestive heart failure. Digoxin, used in congestive heart failure, is widely prescribed and therapeutically monitored. Monitoring and use of antiarrhythmics such as disopyramide and lidocaine have been steadily declining. Immunoassay techniques are currently the most popular methods for measuring cardiac drugs. Several reasons make measurement of cardiac drugs in serum important: their narrow therapeutic index, similarity in clinical complications and presentation of under- and overmedicated patients, need for dosage adjustments, and confirmation of patient compliance. Monitoring may also be necessary in other circumstances, such as assessment of acetylator phenotypes. We present recommendations for measuring digoxin, quinidine, procainamide (and N-acetylprocainamide), lidocaine, and flecainide. We discuss guidelines for measuring unbound digoxin in the presence of an antidote (Fab fragments), for characterizing the impact of digoxin-like immunoreactive factor (DLIF) and other cross-reactants on immunoassays, and for monitoring the unbound (free fraction) of drugs that bind to α1-acid glycoprotein. We also discuss logistic, clinical, hospital, and laboratory practice guidelines needed for implementation of a successful therapeutic drug monitoring service for cardiac drugs.

scholarly journals Repeated Intraperitoneal -Radioimmunotherapy of Ovarian Cancer in Mice

2010 ◽  
Vol 2010 ◽  
pp. 1-5 ◽  
Author(s):  
Jörgen Elgqvist ◽  
Håkan Andersson ◽  
Holger Jensen ◽  
Helena Kahu ◽  
Sture Lindegren ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Monoclonal Antibody ◽  
Cell Line ◽  
Nude Mice ◽  
Therapeutic Efficacy ◽  
Therapeutic Index ◽  
Repeated Treatment ◽  
Treatment Regimens ◽  
Potential Increase

The aim of this study was to investigate the therapeutic efficacy of -radioimmunotherapy of ovarian cancer in mice using different fractionated treatment regimens. The study was performed using the monoclonal antibody MX35 F labeled with the -particle emitter .Methods. Nude mice were intraperitoneally inoculated with ~ cells of the cell line NIH:OVCAR-3. Four weeks later 6 groups of animals were given F as a single or as a repeated treatment of up to 6 times ( in each group). The fractionated treatments were given every seventh day. Control animals were treated with unlabeled F (). Eight weeks posttreatment the animals were sacrificed and the presence of macro- and microscopic tumors and ascites was determined.Results. The tumor-free fractions (TFFs) of the animals, defined as the fraction of animals with no macro- and microtumors and no ascites, were 0.17, 0.11, 0.39, 0.44, 0.44, and 0.67 when treated with F once or 2, 3, 4, 5, or 6 times, respectively. Repeated treatment 3 times or more resulted in a significantly higher () TFF than compared to treatment once or twice. The presence of ascites decreased from 15 out of 18 animals in the group given only one treatment to zero for the 2 groups given 5 or 6 fractions. Treatment with unlabeled F resulted in a TFF of zero.Conclusion. Weekly repeated intraperitoneal injections of tolerable amounts of activity of F of up to 6 times produced increased therapeutic efficacy without observed toxicity, indicating a potential increase of the therapeutic index.

scholarly journals Lipophilicity and Click Reactivity Determine the Performance of Bioorthogonal Tetrazine Tools in Pretargeted in Vivo Chemistry

2020 ◽  
Author(s):  
Johanna Stéen ◽  
Jesper Tranekjær Jørgensen ◽  
Denk Christoph ◽  
Umberto Maria Battisti ◽  
Kamilla Nørregaard ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Rational Design ◽  
Structural Parameters ◽  
Early Time ◽  
High Rate ◽  
Drug Conjugates ◽  
Compound Libraries ◽  
Drug Concentrations ◽  
The Impact

<p>The development of highly selective and fast biocompatible reactions for ligation and cleavage has paved the way for new diagnostic and therapeutic applications of <i>in vivo</i> chemistry. The concept of bioorthogonal pretargeting has attracted considerable interest, in particular for the targeted delivery of radionuclides and drugs. In nuclear medicine, pretargeting can provide increased target-to-background ratios at early time-points compared to traditional approaches. This reduces the radiation burden to healthy tissue and, depending on the selected radionuclide, enables better imaging contrast or higher therapeutic efficiency. Moreover, bioorthogonally triggered cleavage of pretargeted antibody-drug conjugates represents an emerging strategy to achieve controlled release and locally increased drug concentrations. The toolbox of bioorthogonal reactions has significantly expanded in the past decade, with the tetrazine ligation being the fastest and one of the most versatile <i>in vivo</i> chemistries. Progress in the field, however, relies heavily on the development and evaluation of (radio)labeled compounds, preventing the use of compound libraries for systematic studies. The rational design of tetrazine probes and triggers has thus been impeded by the limited understanding of the impact of structural parameters on the <i>in vivo</i> ligation performance. In this work, we describe the development of a pretargeted blocking assay that allows for the investigation of the <i>in vivo</i> fate of a structurally diverse library of 45 unlabeled tetrazines and their capability to reach and react with pretargeted <i>trans</i>-cyclooctene (TCO)-tagged antibodies in tumor-bearing mice. This study enabled us to assess the correlation of click reactivity and lipophilicity of tetrazines with their <i>in vivo</i> performance. In particular, high rate constants (>50,000 M<sup>-1</sup>s<sup>-1</sup>) for the reaction with TCO and low calculated log<i>D</i><sub>7.4</sub> values (below -3) of the tetrazine were identified as strong indicators for successful pretargeted <i>in vivo</i> click chemistry. Click-radiolabeling gave access to a set of selected <sup>18</sup>F-labeled tetrazines, including highly reactive scaffolds, which were used in pretargeted PET imaging studies to confirm the results from the blocking study. These insights thus enable the rational design of tetrazine probes for <i>in vivo</i> application and will thereby assist the clinical translation of bioorthogonal pretargeting.</p>

scholarly journals Explicit and implicit markers of fairness preeminence in criminal judges

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hernando Santamaría-García ◽  
Jorge Martínez Cotrina ◽  
Nicolas Florez Torres ◽  
Carlos Buitrago ◽  
Diego Mauricio Aponte-Canencio ◽  
...  
Keyword(s):  
Decision Making ◽  
Ultimatum Game ◽  
Reaction Times ◽  
Control Group ◽  
Physiological Factors ◽  
Social Decision ◽  
Implicit Measurement ◽  
New Research ◽  
Social Decision Making ◽  
The Impact

AbstractAchieving justice could be considered a complex social decision-making scenario. Despite the relevance of social decisions for legal contexts, these processes have still not been explored for individuals who work as criminal judges dispensing justice. To bridge the gap, we used a complex social decision-making task (Ultimatum game) and tracked a heart rate variability measurement: the square root of the mean squared differences of successive NN intervals (RMSSD) at their baseline (as an implicit measurement that tracks emotion regulation behavior) for criminal judges (n = 24) and a control group (n = 27). Our results revealed that, compared to controls, judges were slower and rejected a bigger proportion of unfair offers. Moreover, the rate of rejections and the reaction times were predicted by higher RMSSD scores for the judges. This study provides evidence about the impact of legal background and expertise in complex social decision-making. Our results contribute to understanding how expertise can shape criminal judges’ social behaviors and pave the way for promising new research into the cognitive and physiological factors associated with social decision-making.

scholarly journals Update on the drug-food interactions

2014 ◽  
Vol 1 (2) ◽  
pp. 100-106
Author(s):  
Hafid Bahri ◽  
◽  
Abdelkader Douaoui ◽  
Moufida Gharbi ◽  
Djamila Amroun
Keyword(s):  
Drug Interactions ◽  
Renal Clearance ◽  
Enzyme Inhibitor ◽  
Plasma Concentrations ◽  
Public Health Problem ◽  
Therapeutic Index ◽  
Major Public Health Problem ◽  
Urine Ph ◽  
Pharmacodynamic Interaction ◽  
The Impact

Drug interactions are a major public health problem, which partly attributed to some 10,000 deaths/year in Canada. Besides the interactions between two drugs, drug interactions are also due to the effect of other substances such as foods or nutrients. The drug-food interaction will be pharmacokinetic (affecting the absorption, distribution, metabolism, and elimination) or pharmacodynamic interaction. It is in the intestine that food may have the greatest impact with mainly a change in the amount of drugs absorbed that may be clinically significant for some drugs with narrow therapeutic index (cyclosporine, phenytoin, theophylline, etc.). The absorption of the drug in the presence of food will be determined by the particular physicochemical properties of the drug but also by the impact of food on one of the parameters determining the absorption such as: modified gastric acidity and emptying, the fat content of the food, the use of common transport between the drug and nutrients, chemical reactions between elements and drugs. Fasting situations or malnutrition can affect the distribution of drugs by increasing the free drug fraction, involving sometimes the risk of overdose. Diet affects drug metabolism by changing the activity of cytochrome P450. Most often is described the increase by grapefruit juice (enzyme inhibitor) of plasma concentrations of some drugs (cyclosporine, some statins, and calcium antagonists). Other foods (garlic, smoked meats and fish, caffeine) may increase metabolism. Diet can influence two stages of renal clearance (glomerular filtration - tubular reabsorption) by modifying urine pH or renal clearance. Pharmacodynamic interactions are also monitored, especially foods rich in vitamin k or tyramine with antivitamins K or MAOIs. Finally, health professionals must mobilize against these interactions, including through patient information.

Sign in / Sign up

Export Citation Format

Share Document