Drug Extravasation Research Articles

Kejadian Ekstravasasi Obat Kemoterapi pada Pasien Kanker

Chemotherapy is a cancer management with drugs. The complication that can be occurred is extravasation. The objective of this study was to analyze factors such as vein conditions, type of medications/chemotherapeutic agents, volume of chemotherapeutic agents, and their correlation with chemotherapy drugs extravasation incidences. This study used cross-sectional observational analytic design, with purposive sampling. The sample of this study was 70 cancer patients undergoing chemotherapy in hospitals. Inclusive criteria were patients with ages 18-65 in their first to fifth cycle of chemotherapy. The observation form was used as research instrument. The study showed that there were no correlation between vein conditions, type of medications/chemotherapeutic agents, and volume of chemotherapeutic agents with extravasation. Most veins were still in good condition while undergoing chemotherapy. The length of time for administering chemotherapy were mostly <24 hours, which contributed for reducing risk for extravasation, although the type of medication used were irritants and vesicants, and with drugs volume of 100�1000 milliliter. The incidences of extravasation that were immediately can be observed during chemotherapy occurred 7.14% of the time. It was possibly occurred by medical devices used, such as infusion pump that was facilitated the nurses in early anticipate drugs leakage outside the veins tissue. Nurses� roles also contributed to reduced extravasation risks. As conclusion, the results shown there were no correlation statistically; however there might be other contributing factors that need to be explored furthermore.

Perspectives on cavitation enhanced endothelial layer permeability.

Traditional drug delivery systems, where pharmaceutical agents are conveyed to the target tissue through the blood circulation, suffer of poor therapeutic efficiency and limited selectivity largely due to the low permeability of the highly specialised biological interface represented by the endothelial layer. Examples concern cancer therapeutics or degenerative disorders where drug delivery is inhibited by the blood-brain barrier (BBB). Microbubbles injected into the bloodstream undergo volume oscillations under localised ultrasound irradiation and possibly collapse near the site of interest, with no effect on the rest of the endothelium. The resulting mechanical action induces a transient increase of the inter-cellular spaces and facilitates drug extravasation. This approach, already pursed in in vivo animal models, is extremely expensive and time-consuming. On the other hand in vitro studies using different kinds of microfluidic networks are firmly established in the pharmaceutical industry for drug delivery testing. The combination of the in vitro approach with ultrasound used to control microbubbles oscillations is expected to provide crucial information for developing cavitation enhanced drug delivery protocols and for screening the properties of the biological interface in presence of healthy or diseased tissues. Purpose of the present review is providing the state of the art in this rapidly growing field where cavitation is exploited as a viable technology to transiently modify the permeability of the biological interface. After describing current in vivo studies, particular emphasis will be placed on illustrating characteristics of micro-devices, biological functionalisation, properties of the artificial endothelium and ultrasound irradiation techniques.

A generic whole body physiologically based pharmacokinetic model for therapeutic proteins in PK-Sim

Proteins are an increasingly important class of drugs used as therapeutic as well as diagnostic agents. A generic physiologically based pharmacokinetic (PBPK) model was developed in order to represent at whole body level the fundamental mechanisms driving the distribution and clearance of large molecules like therapeutic proteins. The model was built as an extension of the PK-Sim model for small molecules incorporating (i) the two-pore formalism for drug extravasation from blood plasma to interstitial space, (ii) lymph flow, (iii) endosomal clearance and (iv) protection from endosomal clearance by neonatal Fc receptor (FcRn) mediated recycling as especially relevant for antibodies. For model development and evaluation, PK data was used for compounds with a wide range of solute radii. The model supports the integration of knowledge gained during all development phases of therapeutic proteins, enables translation from pre-clinical species to human and allows predictions of tissue concentration profiles which are of relevance for the analysis of on-target pharmacodynamic effects as well as off-target toxicity. The current implementation of the model replaces the generic protein PBPK model available in PK-Sim since version 4.2 and becomes part of the Open Systems Pharmacology Suite.

Evidence-based practice on the application of sanyrene in one case of sodium aescinate drug extravasation

Objective To explore sodium aescinate drug extravasation treatment method with method of evidence-based medicine. Methods According to the clinical symptoms of a patient who suffered the extravasation of sodium aescinate, electronic databases were searched to collect relevant materials of preventing extravasation of sodium aescinate. The evidence was applied to the patient after evaluating the reality, feasibility of these evidences mentioned in the literatures. Results Eventually, six random trials, five clinical experience, and two literature reviews were included. The collected evidences supported that sanyrene was safe and effective in treating the extravasation of sodium aescinate. The color and function the patient′s hand returned to normal after using sanyrene in three days, meanwhile, irreversible complication was avoided. Conclusions Sanyrene applied to sodium aescinate extravasation, easy to operate, the effect is obvious, it is worth promoting. Key words: Evidence-based nursing; Sanyrene; Sodium aescinate; Drug extravasation

Quantifying the effects of antiangiogenic and chemotherapy drug combinations on drug delivery and treatment efficacy.

Tumor-induced angiogenesis leads to the development of leaky tumor vessels devoid of structural and morphological integrity. Due to angiogenesis, elevated interstitial fluid pressure (IFP) and low blood perfusion emerge as common properties of the tumor microenvironment that act as barriers for drug delivery. In order to overcome these barriers, normalization of vasculature is considered to be a viable option. However, insight is needed into the phenomenon of normalization and in which conditions it can realize its promise. In order to explore the effect of microenvironmental conditions and drug scheduling on normalization benefit, we build a mathematical model that incorporates tumor growth, angiogenesis and IFP. We administer various theoretical combinations of antiangiogenic agents and cytotoxic nanoparticles through heterogeneous vasculature that displays a similar morphology to tumor vasculature. We observe differences in drug extravasation that depend on the scheduling of combined therapy; for concurrent therapy, total drug extravasation is increased but in adjuvant therapy, drugs can penetrate into deeper regions of tumor.

The effects of non-invasive radiofrequency electric field hyperthermia on biotransport and biodistribution of fluorescent [60]fullerene derivative in a murine orthotopic model of breast adenocarcinoma

The aim of this study is to understand the combined and differential biokinetic effects of radiofrequency (RF) electric-field hyperthermia as an adjunctive therapy to [60]fullerene nanoparticle-based drug delivery systems in targeting the micro-vasculature and micro-environments of breast cancer tumors. Intravital microscopy (IVM) is an ideal tool to provide the spatial and temporal resolution needed for quantification in this investigation. The water-soluble and fluorescent [60]fullerene derivative (C60-serPF) was designed to be an amphiphilic nanostructure, which is able to cross several biological membranes and accumulate in tumor tissues by passing through abnormally leaky tumor blood vessels. To elucidate the coupled effects of the highly permeable, but heterogeneous tumor vasculature, with the permeabilizing effects of mild (40–42°C) hyperthermia produced by a local RF field, we controlled variables across tumor and non-tumor mammary gland microvasculature with and without application of RF hyperthermia in each condition. We notice that tumor tissue is characterized by more intense drug extravasation than in contralateral mammary fat pad tissue, which is consistent with enhanced permeability and retention (EPR) effects. The analysis of a permeability parameter (Papp), C60-serPF velocity, and the time of compound influx into the intra- and extra-vascular space suggest that mild RF hyperthermia can improve nanoparticle delivery into tumor tissue.

PBCA-based polymeric microbubbles for molecular imaging and drug delivery

Microbubbles (MB) are routinely used as contrast agents for ultrasound (US) imaging. We describe different types of targeted and drug-loaded poly(n-butyl cyanoacrylate) (PBCA) MB, and demonstrate their suitability for multiple biomedical applications, including molecular US imaging and US-mediated drug delivery. Molecular imaging of angiogenic tumor blood vessels and inflamed atherosclerotic endothelium is performed by modifying the surface of PBCA MB with peptides and antibodies recognizing E-selectin and VCAM-1. Stable and inertial cavitation of PBCA MB enables sonoporation and permeabilization of blood vessels in tumors and in the brain, which can be employed for direct and indirect drug delivery. Direct drug delivery is based on US-induced release of (model) drug molecules from the MB shell. Indirect drug delivery refers to US- and MB-mediated enhancement of extravasation and penetration of co-administered drugs and drug delivery systems. These findings are in line with recently reported pioneering proof-of-principle studies showing the usefulness of (phospholipid) MB for molecular US imaging and sonoporation-enhanced drug delivery in patients. They aim to exemplify the potential and the broad applicability of combining MB with US to improve disease diagnosis and therapy.

Incidence, risk factors and treatment outcomes of drug extravasation in pediatric patients in China.

Yan YM, Gong M, Chen JL, Li D, Xu TT, Zou H, Li AQ, Fan QL, Lu QF. Incidence, risk factors and treatment outcomes of drug extravasation in pediatric patients in China. Turk J Pediatr 2017; 59: 162-168. Extravasation injury is a common phenomenon in hospitals. Failure to detect and treat extravasation injury can lead to irreversible local injuries, tissue necrosis and malfunction of the affected tissue. Until now, it is largely unknown about incidence, risk factors and treatment outcomes of extravasation in Chinese pediatric patients. The aim of this study is to explore the incidence, risk factors and summarize the characteristics and treatment outcomes of extravasation injuries resulting in drug extravasation among Chinese children in our hospital. The children undergoing infusion therapy (0-18 years) were enrolled in this study between December 2014 and June 2015 in Shanghai Children`s Hospital. The patients` information including age, gender, injection site, estimated volume of solution extravasated, patient symptoms, severity of extravasation injury, treatment methods, and outcomes was collected. Multivariate logistic regression was used to identify the independent risk factors for the development of extravasation. The incidence of extravasations in pediatric patients was 1.79% (18/1,004). The severity of extravasation was labeled with grade range from Grade 1 through Grade 4: 4 cases with Grade 1, 8 cases with Grade 2, 5 cases with Grade 3, and 1 case with Grade 4. The risk factors of extravasation include infused high volume/day (≥1000 ml), received operation, infused agents with high osmolarity and poor vein condition. The severity of extravasation was related to the large volumes of drug or special drugs (high-osmolarity, high-risk, low pH, etc). All extravasations were treated with physical, pharmacological and surgical intervention according to our standard operation protocols. Systematic implementation of intervention can alleviate the extravasation injuries and improve the patients` outcome.

Extravasation of Chemotherapy Drug

Extravasation of Chemotherapy Drug

Concurrent anti-vascular therapy and chemotherapy in solid tumors using drug-loaded acoustic nanodroplet vaporization.

Tumor vasculature plays an important role for tumor cell proliferation by transporting oxygen and nutrients. Previous studies combined anti-vascular therapy and drug release to inhibit tumor growth by ultrasound-stimulated microbubble destruction or acoustic droplet vaporization. Although the efficacy of combined therapy has been demonstrated; the relative spatial distribution of vascular disruption, drug delivery, and accompanied immune responses within solid tumors was not discussed clearly. Herein, our study used drug-loaded nanodroplets to combined physical anti-vascular and chemical therapy. The in vitro cytotoxicity, intravital imaging, and histological assessment were used to evaluate the temporal and spatial cooperation between physical and chemical effect. These results revealed some evidences for complementary action to explain the high efficacy of tumor inhibition by combined therapy.

Vascular permeability in the RG2 glioma model can be mediated by macropinocytosis and be independent of the opening of the tight junction

This study evaluates the extravasation pathways of circulating macromolecules in a rat glioma model (RG2) which was observed by both magnetic resonance imaging using ultrasmall superparamagnetic iron oxide and electron microscopy. Although magnetic resonance imaging signal enhancement was observed as soon as 10 min after injection (9.4% 2 h after injection), electron microscopy showed that endothelial cells were still tightly sealed. However, circulating immunoglobulin G and ultrasmall superparamagnetic iron oxide were found in large membrane compartments of endothelial cells, in the basal lamina (7.4 ± 1.2 gold particles/µm2 in the tumor versus 0.38 ± 0.17 in healthy tissue, p = 1.4.10−5) and between tumoral cells. Altogether, this strongly suggests an active transport mediated by macropinocytosis. To challenge this transport mechanism, additional rats were treated with amiloride, an inhibitor of macropinocytosis, leading to a reduction of membrane protrusions (66%) and of macropinosomes. Amiloride however also opened tumoral tight junctions allowing a larger extravasation of ultrasmall superparamagnetic iron oxide (magnetic resonance imaging signal enhancement of 35.7% 2 h after injection). Altogether, these results suggest that ultrasmall superparamagnetic iron oxide and immunoglobulin G in the RG2 glioma model follow an active extravasation pathway mediated by a macropinocytosis process. Amiloride also appears as a potential strategy to facilitate the extravasation of chemotherapeutic drugs in glioma.

Theragnostic ultrasound using microbubbles in the treatment of prostate cancer.

The use of gas-filled microbubbles in perfusion monitoring as intravascular ultrasound contrast agents has recently become more common. Additionally, microbubbles are employed as carriers of pharmaceutical substances or genes. Microbubbles have great potential to improve the delivery of therapeutic materials into cells and to modify vascular permeability, causing increased extravasation of drugs and drug carriers. Prostate cancer is the most common neoplasm in Europe and America, with an incidence twice to three times that of lung and colorectal cancer. Its incidence is still rising in Asian countries, including Japan and Korea. In this review, we present current strategies regarding the synthesis of microbubbles with targeted ligands on their surfaces, with a focus on prostate cancer.

Ultrasound-mediated drug targeting to tumors: Revision of paradigms through intravital imaging

In collaboration with Dr. Brian O’Neill (Houston Methodist Research Institute), the intravital fluorescence microscopy was performed using a customized Nikon A1R system to monitor the effect of ultrasound on the extravasation and tissue diffusion of various potential drug carriers including individual polymeric molecules, polymeric micelles, phase-shift nanoemulsions, and nanoemulsion-encapsulated drug. Carrier and drug extravasation and tissue accumulation was compared for the normal and tumor tissue upon intravenous injections to pancreatic tumor bearing mice. This approach allowed for the first time discriminating vascular and tissue compartments in the processes of the ultrasound-mediated drug delivery. Nanoemulsion accumulation in the tumor tissue was much faster than in the normal tissue. Without ultrasound, extravasation coefficient was threefold lower while tissue accumulation rate was two orders of magnitude lower for perfluorocarbon nanodroplets than for polymeric micelles. However, ultrasound a...

Iatrogenic Calcinosis Cutis of the Upper Limb Arising from the Extravasation of Intravenous Anticancer Drugs in a Patient with Acute Lymphoblastic Leukemia.

Iatrogenic Calcinosis Cutis of the Upper Limb Arising from the Extravasation of Intravenous Anticancer Drugs in a Patient with Acute Lymphoblastic Leukemia.

Are extravasation injuries “Negligence”?

Recent High Court and Supreme Court judgments have awarded large compensations for complications arising out of intravenous treatment. Extravasation of fluids and drugs is the most common complication of any medical procedure worldwide. Extravasation injury leading to gangrene occurs rarely and is due to factors related to patient characteristics, underlying disease, and the type of drug which is being injected. Human error rarely may be contributory to development of the extravasations and injury resultant thereof, but to label all of these complications as negligence by the application of “res ipsa loquitur” has serious consequences. High compensation risk for a complication which is faced universally by all doctors has the potential to raise the cost of this simple procedure.

Microbubble-liposome conjugate: Payload evaluation of potential theranostic vehicle.

Liposome–microbubble conjugates are considered as better targeted drug delivery vehicles compared to microbubbles alone. The microbubble in the integrated drug delivery system delivers the drug intracellularly on the target, whereas the liposome component allows loading of high drug dose and extravasation through leaky vasculature. In this work, a new high yielding microbubble production method was used to prepare microbubbles for formulation of the liposome-conjugated drug delivery system. In formulation process, the prepared liposome of 200 nm diameter was attached to the microbubble surface using the avidin–biotin interaction. The analysis of the confocal scanning laser microscope images showed that approximately 8 × 108 microbubbles per millilitre (range: 2–7 μm, mean size 5 ± 0.5 μm) can be efficiently conjugated to the liposomes. The method of conjugation was found to be effective in attaching liposome to microbubbles.

The management of cytotoxic chemotherapy extravasation: a systematic review of the literature to evaluate the evidence underpinning contemporary practice.

Management of cytotoxic drug extravasation remains contentious, with differing views on the most effective management strategy. With the increasing drive to provide effective, evidence-based healthcare, while ensuring the patient experience of the treatment provided plays a significant part in the development of clinical practice guidelines, the purpose of this literature review was to both critically analyse the quality of evidence that underpins contemporary practice and to determine if the patient experience is taken into account. A literature search was undertaken sourcing publications from the 1960s to July 2014 identifying all studies detailing strategies aimed at preventing the need for surgical debridement and all studies evaluating extravasation management from the patient's perspective. No conclusive evidence was found to suggest one clinical strategy as more effective than the other. No studies were identified that evaluated outcome from the patient's perspective. It is therefore suggested that outcomes-based research should underpin contemporary extravasation management guidelines to determine what the final outcome or 'end result' is and how this impacts on the patient and that the current lack of research into the patient experience of extravasation management is an area that needs to be addressed.

Sonochemotherapy: from bench to bedside.

The combination of microbubbles and ultrasound has emerged as a promising method for local drug delivery. Microbubbles can be locally activated by a targeted ultrasound beam, which can result in several bio-effects. For drug delivery, microbubble-assisted ultrasound is used to increase vascular- and plasma membrane permeability for facilitating drug extravasation and the cellular uptake of drugs in the treated region, respectively. In the case of drug-loaded microbubbles, these two mechanisms can be combined with local release of the drug following destruction of the microbubble. The use of microbubble-assisted ultrasound to deliver chemotherapeutic agents is also referred to as sonochemotherapy. In this review, the basic principles of sonochemotherapy are discussed, including aspects such as the type of (drug-loaded) microbubbles used, the routes of administration used in vivo, ultrasound devices and parameters, treatment schedules and safety issues. Finally, the clinical translation of sonochemotherapy is discussed, including the first clinical study using sonochemotherapy.

Extravasation of Cytostatic Drugs - Prevention and Best Practices

Extravasation is the leakage of a drug (intended primarily for intravenous administration) into tissues surrounding the vascular system. The damage to surrounding varies depending on the nature and volume of extravasation. Cytostatic extravasation is associated with poor outcomes for patients. This paper summarizes the types of risk associated with cytostatic extravasation, and the preventative measures that can be used when such an event occurs. We also provide information on potential treatments. However, justification for their use has only been substantiated in papers with different levels of significance and these papers are not available in all countries. We summarize current international recommendations for actions to be taken in the event of extravasation.

Influence of vascular normalization on interstitial flow and delivery of liposomes in tumors

Elevated interstitial fluid pressure is one of the barriers of drug delivery in solid tumors. Recent studies have shown that normalization of tumor vasculature by anti-angiogenic factors may improve the delivery of conventional cytotoxic drugs, possibly by increasing blood flow, decreasing interstitial fluid pressure, and enhancing the convective transvascular transport of drug molecules. Delivery of large therapeutic agents such as nanoparticles and liposomes might also benefit from normalization therapy since their transport depends primarily on convection. In this study, a mathematical model is presented to provide supporting evidence that normalization therapy may improve the delivery of 100 nm liposomes into solid tumors, by both increasing the total drug extravasation and providing a more homogeneous drug distribution within the tumor. However these beneficial effects largely depend on tumor size and are stronger for tumors within a certain size range. It is shown that this size effect may persist under different microenvironmental conditions and for tumors with irregular margins or heterogeneous blood supply.