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Biomedicine & Pharmacotherapy =... Mar 2020Non-allergic angioedema is largely driven by increased plasma levels of bradykinin and over-activation of bradykinin receptor type II (B2), but the specific downstream...
BACKGROUND
Non-allergic angioedema is largely driven by increased plasma levels of bradykinin and over-activation of bradykinin receptor type II (B2), but the specific downstream signalling pathways remain unclear. The aim of this study was to identify signal transduction events involved in bradykinin-induced dermal extravasation.
METHODS
Quantification of dermal extravasation was accomplished following intradermal (i.d.) injection of bradykinin or the B2 agonist labradimil in mice with endothelial NO-synthase (eNOS) deficiency and in C57BL/6J mice pre-treated with vehicle, NO-synthase or cyclooxygenase (COX) inhibitors. In the multicentre clinical study ABRASE, 38 healthy volunteers received i.d. bradykinin injections into the ventral forearm before and after oral treatment with the COX inhibitor ibuprofen (600 mg). The primary endpoint of ABRASE was the mean time to complete resolution of wheals (TTCR) and the secondary endpoint was the change of maximal wheal size.
RESULTS
Neither NOS inhibitors nor eNOS deficiency altered bradykinin-induced extravasation. In striking contrast, the COX inhibitors ibuprofen, diclofenac, SC560 and celecoxib significantly diminished this extravasation when given before injection. As for diclofenac, a similar but significantly lower effect was observed when given after i.d. injection of bradykinin. Similar results were obtained when bradykinin was replaced by labradimil. In volunteers, ibuprofen significantly reduced TTCR (P < 0.001) and maximal wheal size (P = 0.0044).
CONCLUSION
These data suggest that COX activity contributes to bradykinin-induced dermal extravasation in mice and humans. In addition, our findings may open new treatment options and point to a potential activity of drugs interfering with the release of the COX substrate arachidonic acid, e.g. glucocorticoids.
Topics: Animals; Bradykinin; Cyclooxygenase Inhibitors; Dermis; Extravasation of Diagnostic and Therapeutic Materials; Humans; Mice, Inbred C57BL; Prostaglandin-Endoperoxide Synthases
PubMed: 31874445
DOI: 10.1016/j.biopha.2019.109797 -
Journal of Translational Medicine May 2009The intravenous co-infusion of labradimil, a metabolically stable bradykinin B2 receptor agonist, has been shown to temporarily enhance the transvascular delivery of...
BACKGROUND
The intravenous co-infusion of labradimil, a metabolically stable bradykinin B2 receptor agonist, has been shown to temporarily enhance the transvascular delivery of small chemotherapy drugs, such as carboplatin, across the blood-brain tumor barrier. It has been thought that the primary mechanism by which labradimil does so is by acting selectively on tumor microvasculature to increase the local transvascular flow rate across the blood-brain tumor barrier. This mechanism of action does not explain why, in the clinical setting, carboplatin dosing based on patient renal function over-estimates the carboplatin dose required for target carboplatin exposure. In this study we investigated the systemic actions of labradimil, as well as other bradykinin B2 receptor agonists with a range of metabolic stabilities, in context of the local actions of the respective B2 receptor agonists on the blood-brain tumor barrier of rodent malignant gliomas.
METHODS
Using dynamic contrast-enhanced MRI, the pharmacokinetics of gadolinium-diethyltriaminepentaacetic acid (Gd-DTPA), a small MRI contrast agent, were imaged in rodents bearing orthotopic RG-2 malignant gliomas. Baseline blood and brain tumor tissue pharmacokinetics were imaged with the 1st bolus of Gd-DTPA over the first hour, and then re-imaged with a 2nd bolus of Gd-DTPA over the second hour, during which normal saline or a bradykinin B2 receptor agonist was infused intravenously for 15 minutes. Changes in mean arterial blood pressure were recorded. Imaging data was analyzed using both qualitative and quantitative methods.
RESULTS
The decrease in systemic blood pressure correlated with the known metabolic stability of the bradykinin B2 receptor agonist infused. Metabolically stable bradykinin B2 agonists, methionine-lysine-bradykinin and labradimil, had differential effects on the transvascular flow rate of Gd-DTPA across the blood-brain tumor barrier. Both methionine-lysine-bradykinin and labradimil increased the blood half-life of Gd-DTPA sufficiently enough to increase significantly the tumor tissue Gd-DTPA area under the time-concentration curve.
CONCLUSION
Metabolically stable bradykinin B2 receptor agonists, methionine-lysine-bradykinin and labradimil, enhance the transvascular delivery of small chemotherapy drugs across the BBTB of malignant gliomas by increasing the blood half-life of the co-infused drug. The selectivity of the increase in drug delivery into the malignant glioma tissue, but not into normal brain tissue or skeletal muscle tissue, is due to the inherent porous nature of the BBTB of malignant glioma microvasculature.
Topics: Animals; Antineoplastic Agents; Blood Pressure; Blood-Brain Barrier; Brain Neoplasms; Dose-Response Relationship, Drug; Drug Delivery Systems; Drug Stability; Gadolinium DTPA; Glioma; Half-Life; Infusions, Intravenous; Muscle, Skeletal; Rats; Rats, Inbred F344; Receptor, Bradykinin B2; Time Factors
PubMed: 19439100
DOI: 10.1186/1479-5876-7-33 -
Frontiers in Oncology 2020The blood-brain barrier (BBB) presents a formidable challenge in the development of effective therapeutics in neuro-oncology. This has fueled several decades of efforts... (Review)
Review
The blood-brain barrier (BBB) presents a formidable challenge in the development of effective therapeutics in neuro-oncology. This has fueled several decades of efforts to develop strategies for disrupting the BBB, but progress has not been satisfactory. As such, numerous drug- and device-based methods are currently being investigated in humans. Through a focused assessment of completed, active, and pending clinical trials, our first aim in this review is to outline the scientific foundation, successes, and limitations of the BBBD strategies developed to date. Among 35 registered trials relevant to BBBD in neuro-oncology in the ClinicalTrials.gov database, mannitol was the most common drug-based method, followed by RMP-7 and regadenoson. MR-guided focused ultrasound was the most common device-based method, followed by MR-guided laser ablation, ultrasound, and transcranial magnetic stimulation. While most early-phase studies focusing on safety and tolerability have met stated objectives, advanced-phase studies focusing on survival differences and objective tumor response have been limited by heterogeneous populations and tumors, along with a lack of control arms. Based on shared challenges among all methods, our second objective is to discuss strategies for confirmation of BBBD, choice of systemic agent and drug design, alignment of BBBD method with real-world clinical workflow, and consideration of inadvertent toxicity associated with disrupting an evolutionarily-refined barrier. Finally, we conclude with a strategic proposal to approach future studies assessing BBBD.
PubMed: 33072591
DOI: 10.3389/fonc.2020.563840 -
Journal of Visualized Experiments : JoVE Nov 2012Endothelial cells with tight junctions along with the basement membrane and astrocyte end feet surround cerebral blood vessels to form the blood-brain barrier(1). The...
Endothelial cells with tight junctions along with the basement membrane and astrocyte end feet surround cerebral blood vessels to form the blood-brain barrier(1). The barrier selectively excludes molecules from crossing between the blood and the brain based upon their size and charge. This function can impede the delivery of therapeutics for neurological disorders. A number of chemotherapeutic drugs, for example, will not effectively cross the blood-brain barrier to reach tumor cells(2). Thus, improving the delivery of drugs across the blood-brain barrier is an area of interest. The most prevalent methods for enhancing the delivery of drugs to the brain are direct cerebral infusion and blood-brain barrier disruption(3). Direct intracerebral infusion guarantees that therapies reach the brain; however, this method has a limited ability to disperse the drug(4). Blood-brain barrier disruption (BBBD) allows drugs to flow directly from the circulatory system into the brain and thus more effectively reach dispersed tumor cells. Three methods of barrier disruption include osmotic barrier disruption, pharmacological barrier disruption, and focused ultrasound with microbubbles. Osmotic disruption, pioneered by Neuwelt, uses a hypertonic solution of 25% mannitol that dehydrates the cells of the blood-brain barrier causing them to shrink and disrupt their tight junctions. Barrier disruption can also be accomplished pharmacologically with vasoactive compounds such as histamine(5) and bradykinin(6). This method, however, is selective primarily for the brain-tumor barrier(7). Additionally, RMP-7, an analog of the peptide bradykinin, was found to be inferior when compared head-to-head with osmotic BBBD with 25% mannitol(8). Another method, focused ultrasound (FUS) in conjunction with microbubble ultrasound contrast agents, has also been shown to reversibly open the blood-brain barrier(9). In comparison to FUS, though, 25% mannitol has a longer history of safety in human patients that makes it a proven tool for translational research(10-12). In order to accomplish BBBD, mannitol must be delivered at a high rate directly into the brain's arterial circulation. In humans, an endovascular catheter is guided to the brain where rapid, direct flow can be accomplished. This protocol models human BBBD as closely as possible. Following a cut-down to the bifurcation of the common carotid artery, a catheter is inserted retrograde into the ECA and used to deliver mannitol directly into the internal carotid artery (ICA) circulation. Propofol and N2O anesthesia are used for their ability to maximize the effectiveness of barrier disruption(13). If executed properly, this procedure has the ability to safely, effectively, and reversibly open the blood-brain barrier and improve the delivery of drugs that do not ordinarily reach the brain (8,13,14).
Topics: Animals; Blood-Brain Barrier; Brain; Carotid Artery, Internal; Catheters; Drug Delivery Systems; Endovascular Procedures; Male; Mannitol; Nitrous Oxide; Propofol; Rats; Rats, Long-Evans
PubMed: 23222697
DOI: 10.3791/50019 -
International Journal of Nanomedicine 2017A drug delivery system of quercetin (QU)-encapsulated liposomes (LS) grafted with RMP-7, a bradykinin analog, and lactoferrin (Lf) was developed to permeate the...
A drug delivery system of quercetin (QU)-encapsulated liposomes (LS) grafted with RMP-7, a bradykinin analog, and lactoferrin (Lf) was developed to permeate the blood-brain barrier (BBB) and rescue degenerated neurons, acting as an Alzheimer's disease (AD) pharmacotherapy. This colloidal formulation of QU-encapsulated LS grafted with RMP-7 and Lf (RMP-7-Lf-QU-LS) was used to traverse human brain microvascular endothelial cells (HBMECs) regulated by human astrocytes (HAs) and to treat SK-N-MC cells after an insult with cytotoxic β-amyloid (Aβ) fibrils. We found that surface RMP-7 and Lf enhanced the ability of QU to cross the BBB without inducing strong toxicity and damaging the tight junction. In addition, RMP-7-Lf-QU-LS significantly reduced Aβ-induced neurotoxicity and improved the viability of SK-N-MC cells. Compared with free QU, RMP-7-Lf-QU-LS could also significantly inhibit the expression of phosphorylated c-Jun N terminal kinase, phosphorylated p38, and phosphorylated tau protein at serine 202 by SK-N-MC cells, indicating an important role of RMP-7, Lf, and LS in protecting neurons against apoptosis. RMP-7-Lf-QU-LS is a promising carrier targeting the BBB to prevent Aβ-insulted neurodegeneration and may have potential in managing AD in future clinical applications.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Apoptosis; Astrocytes; Blood-Brain Barrier; Bradykinin; Brain; Cell Line, Tumor; Cells, Cultured; Drug Delivery Systems; Endothelial Cells; Endothelium, Vascular; Humans; Lactoferrin; Liposomes; Neuroprotective Agents; Peptide Fragments; Quercetin
PubMed: 28435263
DOI: 10.2147/IJN.S132472 -
Beijing Da Xue Xue Bao. Yi Xue Ban =... Aug 2004To establish an in vitro model of brain-blood barrier (BBB) using cultured mouse brain microvascular endothelial cells (BMVEC).
OBJECTIVE
To establish an in vitro model of brain-blood barrier (BBB) using cultured mouse brain microvascular endothelial cells (BMVEC).
METHODS
Mouse BMVEC were seeded on micro-pore membrane of gelatin-coated cell culture insert and cultured to confluence. The establishment of BBB was preliminary judged by a 4 h water-leaking test. The tight junctions between BMVEC were demonstrated by scanning and transmission electron microscope. The transendothelial electrical resistance(TEER) over BMVEC was measured. The permeability of Horseradish peroxidase (HRP) through the BBB was analyzed and the effect of RMP-7 on permeability of the BBB was investigated.
RESULTS
The 4 h water-leaking test became positive when BMVEC were cultured to confluence. By scanning and transmission electron microscope, the tight junctions were demonstrated on confluent BMVEC. The TEER over BMVEC monolayer increased 3.2 and 7.68 times and the permeability rates for HRP were 13.4% and 6.7% respectively, as compared with sub-confluent BMVEC and human umbilical vein endothelial cell monolayer(HUVEC). The HRP permeability rate in the model of BBB increased 2.7 times after treatment with RMP-7.
CONCLUSION
The established in vitro model of BBB has basic characteristics of BBB in vivo, and is suitable for central nervous system (CNS) drug research over BBB.
Topics: Animals; Blood-Brain Barrier; Brain; Capillaries; Cells, Cultured; Endothelial Cells; Mice; Mice, Inbred CBA; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission
PubMed: 15303143
DOI: No ID Found -
The Journal of Physiology Nov 2012The hippocampus has a central role in learning and memory. Although once considered a relatively homogenous structure along the longitudinal axis, it has become clear...
The hippocampus has a central role in learning and memory. Although once considered a relatively homogenous structure along the longitudinal axis, it has become clear that the rodent hippocampus can be anatomically and functionally divided into a dorsal component generally associated with spatial navigation, and a ventral component primarily associated with non-spatial functions that involve an emotional component. The ventral hippocampus (VHC) is also more sensitive to epileptogenic stimuli than the dorsal hippocampus (DHC), and seizures tend to originate in the VHC before spreading to other brain regions. Although synaptic and biochemical differences in DHC and VHC have been investigated, the intrinsic excitability of individual neurones from the DHC and VHC has received surprisingly little attention. In this study, we have characterized the intrinsic electrophysiological properties of CA1 pyramidal neurones from the DHC and the VHC using the whole-cell current-clamp method. Our results demonstrate that somatic current injections of equal magnitude elicit significantly more action potentials in VHC neurones than DHC neurones, and that this difference stems from the more depolarized resting membrane potential (RMP; 7 mV) and higher input resistance (R(in); 46 M measured from RMP) observed in VHC neurones. These differences in RMP and R(in) were also observed in dendritic whole-cell current-clamp recordings. Furthermore, morphological reconstructions of individual neurones revealed significant differences in the dendritic branching pattern between DHC and VHC neurones that could, in principle, contribute to the lower somatic R(in) of DHC neurones. Together, our results highlight significant differences in the intrinsic electrophysiological properties of CA1 pyramidal neurones across the longitudinal hippocampal axis, and suggest that VHC neurones are intrinsically more excitable than DHC neurones. This difference is likely to predispose the VHC to hyperexcitability.
Topics: Action Potentials; Animals; CA1 Region, Hippocampal; Dendrites; Male; Pyramidal Cells; Rats; Rats, Sprague-Dawley
PubMed: 22988138
DOI: 10.1113/jphysiol.2012.242693 -
AJNR. American Journal of Neuroradiology Mar 2000Factors predictive of primary brain tumor outcome have been studied extensively, although the prognostic value of radiologic data, such as MR imaging and angiographic... (Clinical Trial)
Clinical Trial
BACKGROUND AND PURPOSE
Factors predictive of primary brain tumor outcome have been studied extensively, although the prognostic value of radiologic data, such as MR imaging and angiographic characteristics, has not been studied in depth. The purpose of this study was to determine whether radiologic data were prognostic factors among patients with recurrent glioblastoma multiforme and anaplastic astrocytoma treated with selective intra-arterial chemotherapy.
METHODS
Forty-six patients were enrolled in a Phase II study of intra-arterial chemotherapy with carboplatin and Cereport (Alkermes Inc.; Cambridge, MA), a bradykinin analog that selectively increases permeability of the blood-tumor barrier. MR imaging volumes of enhancing tumor, resection cavity, and T2 signal abnormality were measured with T1-weighted and T2-weighted sequences. Volumes were analyzed individually and in various combinations. Tumor vascularity was graded on angiograms. Outcome was measured by time to tumor progression and survival.
RESULTS
Of 46 patients included in this study, 41 underwent evaluation. Thirty were male and 11 were female; mean age was 48.5 years. Karnofsky scores ranged from 70 to 100. Thirty-two patients had glioblastoma multiforme, whereas nine had anaplastic astrocytoma. Twenty-eight patients had tumor progression and 13 had stable disease. Twenty-three patients died after an average of 205 days; 18 were surviving at an average of 324 days from the start of intra-arterial chemotherapy. In multivariate analysis, time from diagnosis to intra-arterial chemotherapy was predictive both of time to tumor progression and survival. Net tumor volume and vascularity also were significant for survival. Age, Karnofsky performance status, histologic findings, gender, MR imaging area, resection cavity volume, T2 signal abnormality volume, and various combined volumes were not significant.
CONCLUSION
If confirmed by further studies, radiologic factors such as tumor volume and angiographic vascularity should be considered in design and stratification of future chemotherapy trials.
Topics: Adult; Aged; Antineoplastic Agents; Bradykinin; Brain; Brain Neoplasms; Carboplatin; Cerebral Angiography; Disease Progression; Female; Glioblastoma; Humans; Infusions, Intra-Arterial; Magnetic Resonance Imaging; Male; Middle Aged; Multivariate Analysis; Neoplasm Recurrence, Local; Prognosis; Retrospective Studies; Survival Rate
PubMed: 10730637
DOI: No ID Found -
Molecular Vision 2013To examine the bradykinin (BK) B₂-receptor system in human and monkey ciliary muscle (CM) using immunohistochemical techniques, and to pharmacologically characterize...
PURPOSE
To examine the bradykinin (BK) B₂-receptor system in human and monkey ciliary muscle (CM) using immunohistochemical techniques, and to pharmacologically characterize the associated biochemical signal transduction systems in human CM (h-CM) cells. BK-induced modulation of intraocular pressure (IOP) in pigmented Dutch-Belt rabbits and cynomolgus monkeys was also studied.
METHODS
Previously published procedures were used throughout these studies.
RESULTS
The human and monkey ciliary bodies expressed high levels of B₂-receptor protein immunoreactivity. Various kinins differentially stimulated [Ca²⁺](i) mobilization in primary h-CM cells (BK EC₅₀=2.4±0.2 nM > Hyp³,β-(2-thienyl)-Ala⁵,Tyr(Me)⁸-(®)-Arg⁹-BK (RMP-7) > Des-Arg⁹-BK EC₅₀=4.2 µM [n=3-6]), and this was blocked by B₂-selective antagonists, HOE-140 (IC₅₀=1.4±0.1 nM) and WIN-63448 (IC₅₀=174 nM). A phospholipase C inhibitor (U73122; 10-30 µM) and ethylene glycol tetraacetic acid (1-2 mM) abolished the BK-induced [Ca²⁺](i) mobilization. Total prostaglandin (primarily PGE₂) secretion stimulated by BK and other kinins in h-CM cells was attenuated by the cyclooxygenase inhibitors bromfenac and flurbiprofen, and by the B₂-antagonists. BK and RMP-7 (100 nM) induced a twofold increase in extracellular signal-regulated kinase-1/2 phosphorylation, and BK (0.1-1 µM; at 24 h) caused a 1.4-3.1-fold increase in promatrix metalloproteinases-1-3 release. Topical ocular BK (100 µg) failed to alter IOP in cynomolgus monkeys. However, intravitreal injection of 50 µg of BK, but not Des-Arg⁹-BK, lowered IOP in rabbit eyes (22.9±7.3% and 37.0±5.6% at 5 h and 8 h post-injection; n=7-10).
CONCLUSIONS
These studies have provided evidence of a functional endogenously expressed B₂-receptor system in the CM that appears to be involved in modulating IOP.
Topics: Amino Acid Sequence; Animals; Bradykinin; Bradykinin B2 Receptor Antagonists; CHO Cells; Calcium Signaling; Ciliary Body; Cricetinae; Cricetulus; Cyclooxygenase Inhibitors; Extracellular Signal-Regulated MAP Kinases; Humans; Immunohistochemistry; Intraocular Pressure; Macaca fascicularis; Matrix Metalloproteinases; Molecular Sequence Data; Muscle, Smooth; Nitric Oxide; Peptides; Phosphorylation; Prostaglandins; Rabbits; Receptor, Bradykinin B2; Signal Transduction; Time Factors
PubMed: 23805043
DOI: No ID Found -
Neuro-oncology Apr 2003RMP-7, a bradykinin analog, temporarily increases the permeability of the blood-brain tumor barrier to chemotherapy drugs like carboplatin. We conducted a randomized,... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
A randomized, double-blind, placebo-controlled, phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma.
RMP-7, a bradykinin analog, temporarily increases the permeability of the blood-brain tumor barrier to chemotherapy drugs like carboplatin. We conducted a randomized, controlled trial of carboplatin and RMP-7 versus carboplatin and placebo in patients with recurrent malignant glioma. The primary outcome measure was time to tumor progression (TTP). Adults with recurrent glioblastoma multiforme or anaplastic glioma were randomized in a 1:1 ratio to receive carboplatin and either RMP-7 or placebo. Radiation therapy had failed in all patients, and they may have received prior chemotherapy. Carboplatin (dosed to achieve an area under the curve of 5 mg/ml x time for patients who had received prior chemotherapy, or 7 mg/ml x time for those who had not) was given intravenously every 4 weeks, followed by intravenous infusion of either RMP-7 or placebo (300 ng/kg). TTP, tumor response, neuropsychological assessments, functional independence, and quality of life assessments were analyzed every 4 weeks. There were 122 patients enrolled, 62 in the RMP-7 and carboplatin group and 60 in the placebo and carboplatin group. Median TTP was 9.7 weeks (95% CI, 8.3-12.6 weeks) for the RMP-7 and carboplatin group and 8.0 weeks (95% CI, 7.4-12.6 weeks) for the placebo and carboplatin group. Median survival times were 26.9 weeks (95% CI, 21.3-37.6 weeks) for the RMP-7 group and 19.9 weeks (95% CI, 15.0-31.3 weeks) for the placebo group. No differences were noted for time to worsening of neuropsychological assessments, functional independence, or quality of life assessments. The use of RMP-7 had no effect on the pharmacokinetics or toxicity of carboplatin. At the dose and schedule used in this trial, RMP-7 did not improve the efficacy of carboplatin. Recent preclinical pharmacokinetic modeling of RMP-7 suggests that higher doses of RMP-7 may be required to increase carboplatin delivery to tumor.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Bradykinin; Carboplatin; Confidence Intervals; Double-Blind Method; Female; Glioblastoma; Glioma; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasm Recurrence, Local; Proportional Hazards Models; Survival Rate
PubMed: 12672281
DOI: 10.1093/neuonc/5.2.96