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Clinical Pharmacokinetics 2001Labradimil (Cereport; also formerly referred to as RMP-7) is a 9-amino-acid peptide designed for selectivity for the bradykinin B2 receptor and a longer plasma half-life... (Review)
Review
Labradimil (Cereport; also formerly referred to as RMP-7) is a 9-amino-acid peptide designed for selectivity for the bradykinin B2 receptor and a longer plasma half-life than bradykinin. It has been developed to increase the permeability of the blood-brain barrier (BBB) and is the first compound with selective bradykinin B2 receptor agonist properties to progress from concept design through to tests of efficacy in patients. In vitro studies demonstrate that labradimil has a longer half-life than bradykinin and selectively binds to bradykinin B2 receptors, initiating typical bradykinin-like second messenger systems, including increases in intracellular calcium and phosphatidylinositol turnover. Initial proof of principle studies using electron microscopy demonstrated that intravenous labradimil increases the permeability of the BBB by disengaging the tight junctions of the endothelial cells that comprise the BBB. Autoradiographic studies in rat models further demonstrated that labradimil increases the permeability of the BBB in gliomas. Intravenous or intra-arterial labradimil increases the uptake of many different radiolabelled tracers and chemotherapeutic agents into the tumour in a dose-related fashion. These effects are selective for the tumour and for the brain surrounding the tumour, and are particularly robust in tumour areas that are normally relatively impermeable. The increased chemotherapeutic concentrations are maintained for at least 90 minutes, well beyond the transient effects on the BBB. The increase in permeability with labradimil occurs rapidly but is transient, in that restoration of the BBB occurs very rapidly (2 to 5 minutes) following cessation of infusion. Even with continuous infusion of labradimil, spontaneous restoration of the barrier begins to occur within 10 to 20 minutes. Collectively, these data demonstrate that the B2 receptor system that modulates permeability of the BBB is highly sensitive and autoregulated and that careful attention to the timing of labradimil and the chemotherapeutic agent is important to achieve maximal effects. Survival studies in rodent models of both gliomas and metastatic tumours in the brain demonstrate that the enhanced uptake observed with the combination of labradimil and water-soluble chemotherapeutics enhances survival to a greater extent than achieved with chemotherapy alone. Finally, preliminary clinical trials in patients with gliomas provide confirmatory evidence that labradimil permeabilises the blood-brain tumour barrier and might, therefore, be used to increase delivery of agents such as carboplatin to tumours without the toxicity typically associated with dose escalation.
Topics: Animals; Blood-Brain Barrier; Bradykinin; Capillary Permeability; Central Nervous System Neoplasms; Dose-Response Relationship, Drug; Glioma; Half-Life; Humans; Rats; Receptor, Bradykinin B2; Receptors, Bradykinin
PubMed: 11286321
DOI: 10.2165/00003088-200140020-00003 -
Expert Opinion on Drug Discovery Apr 2014Currently, there are many novel drugs that belong to class III or IV of the Biopharmaceutics Classification System, showing low bioavailability. Tight junction (TJ)... (Review)
Review
INTRODUCTION
Currently, there are many novel drugs that belong to class III or IV of the Biopharmaceutics Classification System, showing low bioavailability. Tight junction (TJ) modulation offers an approach to increase bioavailability of pharmaceutical compounds. Furthermore, some diseases are accompanied by disturbed barrier function or TJ dysregulation and thus represent a second application for TJ modulators.
AREAS COVERED
This review contains a summary of three different TJ modulators: AT1002, PN159 and labradimil. Within this summary, the authors provide a description of their effects on TJs, their adverse effects and their success in clinical trials. Furthermore, the authors present the current understanding of TJ regulation and highlight opportunities to develop new TJ modulators; they also review the problems that might occur.
EXPERT OPINION
The development of new mechanism-based (MB) TJ modulators is a very promising field of research. MB approaches are expected to have the best future prospects. Further elucidation of signaling pathways and TJ regulation will be necessary for advancing MB TJ modulator research.
Topics: Animals; Antimicrobial Cationic Peptides; Biological Availability; Bradykinin; Humans; Oligopeptides; Tight Junctions
PubMed: 24558958
DOI: 10.1517/17460441.2014.892070 -
Methods and Findings in Experimental... 2007Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data the following tables have been retrieved from...
Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issues focuses on the following selection of drugs: 4'-Thio-ara-C, 5-methyltetrahydrofolate; ABT-089, AD-237, AF-37702, alvocidib hydrochloride, apricitabine, armodafinil, atrasentan, AVE-5883, avian influenza vaccine, azimilide hydrochloride; Banoxantrone, BIBF-1120; CD34+ cells, certolizumab pegol, CHIR-258, cilansetron, CoFactor, CX-3543, cystemustine; D-003, dexloxiglumide, DMXB-anabaseine; Ecogramostim, elcometrine, elcometrine/ethinylestradiol, etravirine; Fenretinide, fingolimod hydrochloride, fospropofol disodium; Gaboxadol, gestodene, glutamine; Human insulin, hyaluronic acid; Incyclinide, indacaterol, ispronicline, istradefylline; Labradimil, lamifiban, lapatinib, L-arginine hydrochloride, liposomal cisplatin, liposome encapsulated paclitaxel, LY-517717; Manidipine hydrochloride/delapril hydrochloride, maraviroc, MBP(82-98), MD-0727, MDX-214, melanotan I, MMR vaccine; Nacystelyn, nalfurafine hydrochloride, nibentan, nilotinib, NK-105; OBI-1, oblimersen sodium, olmesartan medoxomil, olmesartan medoxomil/hydrochlorothiazide, oregovomab; Pexelizumab, PG-116800, PG-CPT, PHA-794428, prasugrel; RC-3095, rDNA insulin, RFB4(dsFv)-PE38, rhEndostatin, rhenium Re-186 etidronate, rhGM-CSF, roflumilast, romidepsin; Sarcosine, SGLU1, SGN-40, succinobucol; TAU, teduglutide, telatinib, tesofensine, tipifarnib, tirapazamine, TKA-731, tolvaptan, trabectedin; Vaccimel, vatalanib succinate, velafermin, vildagliptin, vinflunine; XP-19986; YM-155.
Topics: Clinical Trials as Topic; Humans
PubMed: 17344945
DOI: No ID Found -
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 -
Reviews on Recent Clinical Trials Jan 2009Primary central nervous system neoplasms are the second malignancy in children following leukemia. Despite developments in neurosurgery and new drugs in chemotherapy,... (Review)
Review
Primary central nervous system neoplasms are the second malignancy in children following leukemia. Despite developments in neurosurgery and new drugs in chemotherapy, irradiation is an essential part of the management in most of pediatric brain tumors. A good treatment strategy should consider not only survival but also the quality of life. The new approach of radiotherapy and importance of new drugs in combined treatment are recently considered. This article summarizes the recent clinical trials conducted in pediatric brain tumors management. Results of randomized study of pre-irradiation chemotherapy versus radiotherapy alone for medulloblastoma were presented by SIOP/UKCCSG PNET-3. The French M-SFOP 98 protocol considered hyper-fractionated radiotherapy with reduced boost volume, without chemotherapy and estimated impact on early relapses and intellectual function. The influence of radiotherapy quality on survival in high-risk medulloblastoma patients was evaluated in POG Trial 9031. In the treatment of low-grade glioma in children the effectiveness of novel combination chemotherapy was considered. Role of new drugs as temozolamid, topotecan and RMP-7 was investigated in pediatric high grade glioma and brain stem tumors. Impact of combined treatment on outcome of intracranial germ-cell tumors was investigated as well.
Topics: Brain Neoplasms; Brain Stem Neoplasms; Child; Clinical Trials as Topic; Combined Modality Therapy; Craniopharyngioma; Disease Progression; Dose Fractionation, Radiation; Glioma; Humans; Medulloblastoma; Neoadjuvant Therapy; Neoplasms, Germ Cell and Embryonal; Neuroectodermal Tumors, Primitive; Radiotherapy, Conformal; Treatment Outcome
PubMed: 19149762
DOI: 10.2174/157488709787047567 -
European Journal of Pharmaceutics and... Sep 2019Tight junction (TJ) modulation is a promising approach for improving drug bioavailability by enhancing the absorption of active pharmaceutical ingredients. However, the...
Tight junction (TJ) modulation is a promising approach for improving drug bioavailability by enhancing the absorption of active pharmaceutical ingredients. However, the application of many different test methods to determine the efficacy of new TJ modulators (TJMs) or to assess different compounds is accompanied by a lack of comparable results, reducing the rational evaluation and commercial marketing of these pharmaceutical excipients. The establishment of unified testing methods can fill this gap and offers the opportunity to compare results from different laboratories. Furthermore, the calculation of a TJ modulation score allows the objective comparison of TJ modulators and facilitates the selection of appropriate candidates. In this study, eight well-known TJ modulators were tested with a focus on four different in vitro bioassays carried out with MDCK cells. The extent of TJ modulation was determined by transepithelial electric resistance (TEER) measurements and permeability studies with mannitol. To evaluate tolerability, cell viability (MTT) and cytotoxicity (CellTox Green) assays were performed, and TEER regeneration was monitored for 24 h after exposure. With the exception of labradimil, seven TJ modulators caused significant TEER reduction of up to 100 %. For five compounds, an enhancement of mannitol permeation was observed. As expected, first-generation enhancers exhibited lower cell compatibility than mechanism-based modulators. Based on the experimental results of this study, for the first time, an evaluation system (tight junction modulator scoring system, TJMSS) is presented that provides a ranking of the tested modulators depending on weighted parameters. Such a system offers the possibility of rational formulation development for drugs requiring improved absorption.
Topics: Animals; Biological Availability; Cell Line; Cell Survival; Dogs; Excipients; Madin Darby Canine Kidney Cells; Mannitol; Permeability; Pharmaceutical Preparations; Tight Junctions
PubMed: 31278992
DOI: 10.1016/j.ejpb.2019.07.004 -
Expert Opinion on Investigational Drugs May 2003The nonapeptide bradykinin (BK) is a Janus-faced hormone, which exerts pathophysiological as well as pronounced beneficial physiological effects, mainly by stimulation... (Review)
Review
The nonapeptide bradykinin (BK) is a Janus-faced hormone, which exerts pathophysiological as well as pronounced beneficial physiological effects, mainly by stimulation of BK B(2) receptors. In various animal models and in humans it has been shown that the stimulation of BK B(2) receptors is not only implicated in the pathogenesis of inflammation, pain and tissue injury but also in powerful cardioprotective mechanisms. Either exogenous administration of BK or locally increased BK concentrations as a consequence of the inhibition of its metabolic breakdown by angiotensin-converting enzyme inhibitors, reveal the significant contribution of BK in powerful cardioprotective mechanisms. These are mainly triggered by the synthesis and release of the vasorelaxant, anti-hypertrophic and anti-atherosclerotic endothelial mediators nitric oxide, prostaglandins and tissue-type plasminogen activator, by ischaemic preconditioning and by an increase in insulin sensitivity. Consequently, BK B(2) receptor agonists may have important clinical value in the treatment and prevention of various cardiovascular disorders such as hypertension, ischaemic heart disease, left ventricular hypertrophy, ventricular remodelling and congestive heart failure as well as diabetic disorders by mimicking the reported beneficial effects of BK. However, none of the currently known potent and selective peptide and non-peptide agonists of BK B(2) receptors--RMP-7 (lobradamil, Cereport; Alkermes), JMV-1116 (Fournier), FR-190997 (Fujisawa) and FR-191413 (Fujisawa)--have been selected for a clinical assessment in cardiovascular indications. One major challenge of this approach is the still unanswered question of whether there is a sufficient safe therapeutic window between potential cardioprotective and pro-inflammatory effects following BK B(2) receptor agonism.
Topics: Animals; Cardiomyopathy, Dilated; Cardiovascular Diseases; Clinical Trials as Topic; Heart Failure; Humans; Hypertension; Kinins; Myocardial Ischemia; Receptor, Bradykinin B2; Receptors, Bradykinin; Ventricular Remodeling
PubMed: 12720488
DOI: 10.1517/13543784.12.5.759 -
Brain Research Bulletin May 2003One novel approach of transporting drugs into the central nervous system (CNS) involves the activation of receptors on the endothelial cells comprising the blood brain... (Review)
Review
Facilitation of drug entry into the CNS via transient permeation of blood brain barrier: laboratory and preliminary clinical evidence from bradykinin receptor agonist, Cereport.
One novel approach of transporting drugs into the central nervous system (CNS) involves the activation of receptors on the endothelial cells comprising the blood brain barrier (BBB). Recently the selective B(2) bradykinin receptor agonist, Cereport (also called RMP-7), has been shown to transiently increase permeability of the BBB. Although initially developed to increase the permeability of the vasculature feeding glioma, recent studies have demonstrated that Cereport also increases the delivery of pharmacological agents across the normal (i.e. nontumor) BBB. In this review paper, we discuss evidence of enhanced CNS delivery of carboplatin, loperamide, and cyclosporin-A, which are accompanied by enhanced chemotherapeutic, analgesic and neuroprotective effects, respectively. These observations suggest feasibility of Cereport as an adjunct therapy to pharmacological treatments that require drug availability in the CNS to exert therapeutic efficacy. Because many potential drugs for CNS disorders normally do not cross the BBB, Cereport-induced transient permeation of BBB stands as an efficacious strategy for enhancing pharmacotherapy.
Topics: Animals; Blood-Brain Barrier; Bradykinin; Capillary Permeability; Central Nervous System; Drug Combinations; Drug Delivery Systems; Humans; Receptors, Bradykinin
PubMed: 12754091
DOI: 10.1016/s0361-9230(03)00043-1