Phase 0 Study of Vandetanib-Eluting Radiopaque Embolics as a Preoperative Embolization Treatment in Patients with Resectable Liver Malignancies.

Purpose: To assess the safety and tolerability of a vandetanib-eluting radiopaque embolic (BTG-002814) for transarterial chemoembolization (TACE) in patients with resectable liver malignancies.

Materials And Methods: The VEROnA clinical trial was a first-in-human, phase 0, single-arm, window-of-opportunity study. Eligible patients were aged ≥18 years and had resectable hepatocellular carcinoma (HCC) (Child-Pugh A) or metastatic colorectal cancer (mCRC).

Radiopaque drug-eluting embolisation beads as fiducial markers for stereotactic liver radiotherapy.

Objective: To determine the feasibility of using radiopaque (RO) beads as direct tumour surrogates for image-guided radiotherapy (IGRT) in patients with liver tumours after transarterial chemoembolisation (TACE).

Methods: A novel vandetanib-eluting RO bead was delivered via TACE as part of a first-in-human clinical trial in patients with either hepatocellular carcinoma or liver metastases from colorectal cancer. Following TACE, patients underwent simulated radiotherapy imaging with four-dimensional computed tomography (4D-CT) and cone-beam CT (CBCT) imaging.

Radiosensitisation of Hepatocellular Carcinoma Cells by Vandetanib.

Unlabelled: Hepatocellular Carcinoma (HCC) is increasing in incidence worldwide and requires new approaches to therapy. The combination of anti-angiogenic drug therapy and radiotherapy is one promising new approach. The anti-angiogenic drug vandetanib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and RET proto-oncogene with radio-enhancement potential.

Handling and performance characteristics of a new small caliber radiopaque embolic microsphere.

The in vitro and in vivo handling and performance characteristics of a small caliber radiopaque embolic microsphere, 40-90 μm DC Bead LUMI™ (LUMI40-90), were studied. Microsphere drug loading and elution and effects on size, suspension, and microcatheter delivery were evaluated using established in vitro methodologies. In vivo evaluations of vascular penetration (rabbit renal artery embolization), long-term biocompatibility and X-ray imaging properties, pharmacokinetics and local tissue effects of both doxorubicin (Dox) and irinotecan (Iri) loaded microspheres (swine hepatic artery embolization) were conducted.

Vandetanib-eluting Radiopaque Beads: Pharmacokinetics, Safety, and Efficacy in a Rabbit Model of Liver Cancer.

Background Transarterial chemoembolization with cytotoxic drugs is standard treatment for unresectable intermediate-stage hepatocellular carcinoma but achieves suboptimal outcomes because of hypoxic stress and the production of detrimental proangiogenic factors. An alternative approach using radiopaque embolization beads loaded with the antiangiogenic drug vandetanib may provide improved anticancer efficacy. Purpose To evaluate the pharmacokinetics, safety, and efficacy of vandetanib-eluting radiopaque bead (VERB) chemoembolization of rabbit liver tumors.

Evaluation of novel formulations for transarterial chemoembolization: combining elements of Lipiodol emulsions with Drug-eluting Beads.

Unlabelled: There are currently two methods widely used in clinical practice to perform transarterial chemoembolization (TACE). One is based on mixing an aqueous drug with an iodized oil (Lipiodol) and creating an emulsion that is delivered intraarterially, followed by embolization with a particulate agent. The other is based on a one-step TACE using Drug-eluting Beads (DEBs) loaded with drug.

Predicting pharmacokinetic behaviour of drug release from drug-eluting embolization beads using in vitro elution methods.

Drug-eluting Embolic Bead - Transarterial Chemoembolisation (DEB-TACE) is a minimally invasive embolising treatment for liver tumours that allows local release of chemotherapeutic drugs via ion exchange, following delivery into hepatic arterial vasculature. Thus far, no single in vitro model has been able to accurately predict the complete kinetics of drug release from DEB, due to heterogeneity of rate-controlling mechanisms throughout the process of DEB delivery. In this study, we describe two in vitro models capable of distinguishing between early phase and late phase drug release by mimicking in vivo features of each phase.

Comparison of microsphere penetration with LC Bead LUMI™ versus other commercial microspheres.

The purpose of this study was to evaluate LC Bead LUMI™ (40-90µm and 70-150µm) in order to determine if their increased resistance to compression influences microsphere penetration and distribution compared to more compressible commercial microspheres. LC Bead LUMI™ 40-90µm and 70-150µm, LC BeadM1 70-150µm, Embozene™ 40µm and Embozene™ 100µm size and distributions were measured using optical microscopy. Penetration in vitro was evaluated using an established 'plate model', consisting of a calibrated tapered gap between a glass plate and plastic housing to allow visual observation of microsphere penetration depth.

Vandetanib-eluting Radiopaque Beads: Pharmacokinetics, Safety and Toxicity Evaluation following Swine Liver Embolization.

Purpose: To evaluate the plasma and tissue pharmacokinetics, safety and toxicity following intra-arterial hepatic artery administration of Vandetanib (VTB)-eluting Radiopaque Beads (VERB) in healthy swine.

Materials And Methods: In a first phase, healthy swine were treated with hepatic intra-arterial administration of VERB at target dose loading strengths of 36 mg/mL (VERB36), 72 mg/mL (VERB72) and 120 mg/mL (VERB120). Blood and tissue samples were taken and analysed for VTB and metabolites to determine pharmacokinetic parameters for the different dose forms over 30 days.

Long-term biocompatibility, imaging appearance and tissue effects associated with delivery of a novel radiopaque embolization bead for image-guided therapy.

The objective of this study was to undertake a comprehensive long-term biocompatibility and imaging assessment of a new intrinsically radiopaque bead (LC Bead LUMI™) for use in transarterial embolization. The sterilized device and its extracts were subjected to the raft of ISO10993 biocompatibility tests that demonstrated safety with respect to cytotoxicity, mutagenicity, blood contact, irritation, sensitization, systemic toxicity and tissue reaction. Intra-arterial administration was performed in a swine model of hepatic arterial embolization in which 0.

Pregnane X receptor activators inhibit human hepatic stellate cell transdifferentiation in vitro.

Background & Aims: The activated pregnane X receptor is antifibrogenic in rodent chronic liver injury in vivo models. The aim of this study was to determine the effects of human pregnane X receptor activators on human hepatic stellate cell transdifferentiation to a profibrogenic phenotype in vitro.

Methods: Hepatic stellate cells were isolated from resected human liver and cultured under conditions in which they trans-differentiate into profibrogenic myofibroblasts.

Characterization of a putative nitric oxide synthase in the neuromuscular system of the parasitic nematode, Ascaris suum.

In this paper we report on the biochemical presence of nitric oxide synthase (NOS)-like activity in Ascaris suum tissue and examine the pharmacological effect of NO donors on A. suum muscle strip preparation. NOS activity was determined by monitoring the formation of [3H]citrulline from [3H]L-arginine and NO formation via the oxyhaemoglobin assay.

Immunocytochemical localization of a putative inhibitory amino acid receptor subunit in the parasitic nematodes Haemonchus contortus and Ascaris suum.

A rabbit antiserum was raised against a synthetic peptide corresponding to a region near the N-terminus of the Haemonchus contortus inhibitory amino acid receptor subunit, HG1. The antiserum recognized a recombinant form of the N-terminal domain of the subunit on Western blots and reacted with the ventral nerve cord of H. contortus in immunofluorescence experiments.

Novel azole derivatives are antagonists at the inhibitory GABA receptor on the somatic muscle cells of the parasitic nematode Ascaris suum.

The somatic muscle cells of the parasitic nematode Ascaris suum possess GABA receptors that gate chloride conductances in a similar fashion to the mammalian GABAA receptor subtype. These receptors mediate muscle relaxation and are the site of action of the anthelmintic piperazine. The properties of this receptor differ from the properties of the GABA-gated chloride receptors in the mammalian host, in particular they are not as sensitive to mammalian GABA receptor antagonists such as bicuculline and picrotoxin.

NADPH diaphorase activity in peptidergic neurones of the parasitic nematode, Ascaris suum.

The histochemical marker for nitric oxide synthase, NADPH diaphorase, is known to co-localize in mammalian neurones with various classical neurotransmitters and neuropeptides. The nervous system of the parasitic nematode Ascaris suum has previously been shown to contain both NADPH diaphorase activity and neuropeptide immunoreactivity. This study examined the possibility that NADPH diaphorase and neuropeptide immunoreactivity may co-exist in the same neurones.

Histochemical mapping of NADPH diaphorase in the nervous system of the parasitic nematode Ascaris suum.

NADPH diaphorase has recently been discovered to be responsible for neuronal nitric oxide (NO) synthase activity in mammals. It thus serves as a histochemical marker for the localization of NO synthase in the nervous system. The histochemical technique was used to map out potential NO-producing neurones in the nervous system of the parasitic nematode, Ascaris suum.

Estimation of intracellular calcium activity in confluent monolayers of primary cultures of quail medullary bone osteoclasts.

The present study was concerned with an investigation of the relative utilities of the fluorescent indicators fura-2 and fluo-3 for spectrofluorimetric estimation of the intracellular calcium concentration ([Ca2+]i) in confluent osteoclast monolayers that had been isolated from medullary bone of quail hens and maintained in tissue culture for 6-8 days. Additionally, we have determined the effects of raised extracellular calcium ([Ca2+]o) and chicken calcitonin (CT) on [Ca2+]i in this preparation. Relative to fura-2, fluo-3 was poorly incorporated into the osteoclasts and had a high apparent equilibrium binding constant (Kd) for Ca2+ binding (809 nM).

Quantitative studies on the effect of prostacyclin on freshly isolated rat osteoclasts in culture.

Prostaglandins exert marked but transient inhibitory effects on bone resorption. The present study examines the effects of prostacyclin (0.15 to 25 microM) on the morphology of freshly disaggregated rat osteoclasts.

Effect of raised extracellular calcium on cell spread area in quail medullary bone osteoclasts.

The present study reports on the effects of extracellular calcium ([Ca2+]o) elevation and ionomycin on cell spread area of medullary bone osteoclasts freshly isolated from egg-laying Japanese quail. The responses were compared with those demonstrated in osteoclasts cultured for periods of 5-8 days and also to those previously demonstrated in neonatal rat osteoclasts. Freshly isolated medullary bone osteoclasts, unlike rat osteoclasts, were refractory to 20 mM [Ca2+]o, in that they showed no change in cell spread area.

Osteoclasts from medullary bone of egg-laying Japanese quail do not express the putative calcium 'receptor'.

The present study reports the contrasting effects of extracellular calcium ([Ca2+]e) elevation on cytosolic free calcium levels ([Ca2+]i) of osteoclasts, freshly isolated either from medullary bone of the egg-laying Japanese quail or from rat cortical bone. [Ca2+]i was measured in single osteoclasts using the Ca(2+)-sensitive fluorochrome, Indo-1. We found that elevation of [Ca2+]e failed to induce a rise of [Ca2+]i in quail osteoclasts, whilst causing an elevation of [Ca2+]i in rat osteoclasts.

Calcitonin gene-related peptide promotes transient radiocalcium uptake into chick bone in vivo.

We have examined the in vivo effects in chicks of intravenously injected chicken (c-) and rat (r-) calcitonin gene-related peptides (CGRP) on uptake into bone of a simultaneously administered 45Ca label. Both peptides caused transient (10 min) increases in 45Ca uptake into a variety of bone types. In dose-response experiments at 10 min, CGRP doses of 0.

Abnormal redox status without increased lipid peroxidation in sugar cataract.

In conflict with a previous report, we find that phenolic inhibitors of lipid peroxidation (butylated hydroxytoluene [BHT] and butylated hydroxyanisole [BHA]) do not have significant inhibitory effect on galactosemic cataract formation. This is consistent with the lack of enhancement of stable products of lipid peroxidation (measured by the thiobarbituric acid assay) in the lenses of galactosemic rats. This does not imply that oxidative stress plays no role in galactosemic cataract formation (indeed, we find that galactosemic lens homogenates contain increased amounts of an Fe2+ oxidant, possibly a peroxide), but rather that BHT- and BHA-inhibitable lipid peroxidation specifically has no role to play.

Effects of rat and chicken calcitonin gene-related peptides (CGRP) upon calcium metabolism in chicks.

In vivo effects of intravenously injected chicken(c-) and rat(r-) calcitonin gene related peptide (CGRP) upon plasma total (Cat), ionized (Cai) calcium, inorganic phosphate (Pi) and clearance of an acutely administered 45Ca label have been examined in chicks. Both peptides were hypercalcaemic in fasted chicks, unlike previously reported hypocalcaemic response in mammals. r-CGRP was hypercalcaemic at doses of both 0.