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Rabbit Model of Intra-Arterial Chemotherapy Toxicity Demonstrates Retinopathy and Vasculopathy Related to Drug and Dose, Not Procedure or Approach.
Daniels AB, Froehler MT, Nunnally AH, Pierce JM, Bozic I, Stone CA, Santapuram PR, Tao YK, Boyd KL, Himmel LE, Chen SC, Du L, Friedman DL, Richmond A
(2019) Invest Ophthalmol Vis Sci 60: 954-964
MeSH Terms: Animals, Antineoplastic Agents, Antineoplastic Agents, Alkylating, Carboplatin, Dose-Response Relationship, Drug, Electroretinography, Female, Fluorescein Angiography, Humans, Infant, Infusions, Intra-Arterial, Male, Melphalan, Models, Animal, Ophthalmic Artery, Rabbits, Retina, Retinal Diseases, Retinal Neoplasms, Retinal Vessels, Retinoblastoma, Retrospective Studies, Tomography, Optical Coherence
Show Abstract · Added July 29, 2019
Purpose - To use our intra-arterial chemotherapy (IAC) rabbit model to assess the impact of IAC procedure, drug, dose, and choice of technique on ocular structure and function, to study the nature and etiology of IAC toxicity, and to compare to observations in patients.
Methods - Rabbits received IAC melphalan (0.4-0.8 mg/kg), carboplatin (25-50 mg), or saline, either by direct ophthalmic artery cannulation, or with a technique emulating nonocclusion. Ocular structure/function were assessed with examination, electroretinography (ERG), fundus photography, fluorescein angiography, optical coherence tomography (OCT), and OCT angiography, prior to and 5 to 6 weeks after IAC. Blood counts were obtained weekly. We reviewed our last 50 IAC treatments in patients for evidence of ocular or systemic complications.
Results - No toxicity was seen in the saline control group. With standard (0.4 mg/kg) melphalan, no vascular/microvascular abnormalities were seen with either technique. However, severe microvascular pruning and arteriolar occlusions were seen occasionally at 0.8 mg/kg doses. ERG reductions were dose-dependent. Histology showed melphalan dose-dependent degeneration in all retinal layers, restricted geographically to areas of greatest vascular density. Carboplatin caused massive edema of ocular/periocular structures. IAC patients experienced occasional periocular swelling/rash, and only rarely experienced retinopathy or vascular events/hemorrhage in eyes treated multiple times with triple (melphalan/carboplatin/topotecan) therapy. Transient neutropenia occurred after 46% of IAC procedures, generally after triple therapy.
Conclusions - IAC toxicity appears to be related to the specific drug being used and is dose-dependent, rather than related to the IAC procedure itself or the specific technique selected. These rabbit findings are corroborated by our clinical findings in patients.
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23 MeSH Terms
Pharmacokinetics, Tissue Localization, Toxicity, and Treatment Efficacy in the First Small Animal (Rabbit) Model of Intra-Arterial Chemotherapy for Retinoblastoma.
Daniels AB, Froehler MT, Pierce JM, Nunnally AH, Calcutt MW, Bridges TM, LaNeve DC, Williams PE, Boyd KL, Reyzer ML, Lindsley CW, Friedman DL, Richmond A
(2018) Invest Ophthalmol Vis Sci 59: 446-454
MeSH Terms: Animals, Antineoplastic Agents, Alkylating, Disease Models, Animal, Electroretinography, Fluorescein Angiography, Infusions, Intra-Arterial, Melphalan, Ophthalmic Artery, Rabbits, Retina, Retinal Neoplasms, Retinoblastoma, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Tissue Distribution, Treatment Outcome, Vitreous Body
Show Abstract · Added April 5, 2018
Purpose - Current intra-arterial chemotherapy (IAC) drug regimens for retinoblastoma have ocular and vascular toxicities. No small-animal model of IAC exists to test drug efficacy and toxicity in vivo for IAC drug discovery. The purpose of this study was to develop a small-animal model of IAC and to analyze the ocular tissue penetration, distribution, pharmacokinetics, and treatment efficacy.
Methods - Following selective ophthalmic artery (OA) catheterization, melphalan (0.4 to 1.2 mg/kg) was injected. For pharmacokinetic studies, rabbits were euthanized at 0.5, 1, 2, 4, or 6 hours following intra-OA infusion. Drug levels were determined in vitreous, retina, and blood by liquid chromatography tandem mass spectrometry. To assess toxicity, angiograms, photography, fluorescein angiography, and histopathology were performed. For in situ tissue drug distribution, matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) was performed. The tumor model was created by combined subretinal/intravitreal injection of human WERI-Rb1 retinoblastoma cells; the tumor was treated in vivo with intra-arterial melphalan or saline; and induction of tumor death was measured by cleaved caspase-3 activity.
Results - OA was selectively catheterized for 79 of 79 (100%) eyes in 47 of 47 (100%) rabbits, and melphalan was delivered successfully in 31 of 31 (100%) eyes, without evidence of vascular occlusion or retinal damage. For treated eyes, maximum concentration (Cmax) in the retina was 4.95 μM and area under the curve (AUC0→∞) was 5.26 μM·h. Treated eye vitreous Cmax was 2.24 μM and AUC0→∞ was 4.19 μM·h. Vitreous Cmax for the treated eye was >100-fold higher than for the untreated eye (P = 0.01), and AUC0→∞ was ∼50-fold higher (P = 0.01). Histology-directed MALDI-IMS revealed highest drug localization within the retina. Peripheral blood Cmax was 1.04 μM and AUC0→∞ was 2.07 μM·h. Combined subretinal/intravitreal injection of human retinoblastoma cells led to intra-retinal tumors and subretinal/vitreous seeds, which could be effectively killed in vivo with intra-arterial melphalan.
Conclusions - This first small-animal model of IAC has excellent vitreous and retinal tissue drug penetration, achieving levels sufficient to kill human retinoblastoma cells, facilitating future IAC drug discovery.
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16 MeSH Terms
Early arterial stasis during resin-based yttrium-90 radioembolization: incidence and preliminary outcomes.
Piana PM, Bar V, Doyle L, Anne R, Sato T, Eschelman DJ, McCann JW, Gonsalves CF, Brown DB
(2014) HPB (Oxford) 16: 336-41
MeSH Terms: Aged, Brachytherapy, Embolization, Therapeutic, Female, Humans, Infusions, Intra-Arterial, Liver Neoplasms, Male, Microspheres, Middle Aged, Radiopharmaceuticals, Regional Blood Flow, Retrospective Studies, Risk Factors, Time Factors, Treatment Outcome, Yttrium Radioisotopes
Show Abstract · Added March 5, 2014
OBJECTIVES - This study was conducted to determine the incidence of early stasis in radioembolization using resin yttrium-90 (Y-90) microspheres, to evaluate potential contributing factors, and to review initial imaging outcomes.
METHODS - Patients in whom early stasis occurred were compared with those in whom complete delivery was achieved for tumour type and vascularity, tumour : normal liver ratio (T : N ratio) at technetium-99m-macroaggregated albumin (Tc-99m-MAA) angiography, previous intra-arterial therapy, and infusion site (left, right or whole liver). Tumour response was evaluated at 3 months and defined according to whether a partial response and stable disease versus progressive disease were demonstrated.
RESULTS - A total of 71 patients underwent 128 Y-90 infusions in which 26 (20.3%) stasis events occurred. Hypervascular and hypovascular tumours had similar rates of stasis (17.4% versus 27.8%; P = NS). The mean ± standard deviation T : N ratio was 3.03 ± 1.54 and 3.66 ± 2.79 in patients with and without stasis, respectively (P = NS). Stasis occurred in 14 of 81 (17.3%) and 12 of 47 (25.5%) infusions following previous intra-arterial therapy and in therapy-naïve territories, respectively (P = NS). Early stasis occurred in 15 of 41 (36.6%) left, 10 of 65 (15.4%) right and one of 22 (4.5%) whole liver infusions (P < 0.001). Rates of partial response and stable disease were similar in the stasis (88.3%) and non-stasis (76.0%) groups (P = NS).
CONCLUSIONS - Early stasis occurred in approximately 20% of infusions with similar incidences in hyper- and hypovascular tumours. Whole-liver therapy reduced the incidence of stasis. Stasis did not appear to affect initial imaging outcomes.
© 2013 International Hepato-Pancreato-Biliary Association.
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17 MeSH Terms
Quality improvement guidelines for transhepatic arterial chemoembolization, embolization, and chemotherapeutic infusion for hepatic malignancy.
Brown DB, Nikolic B, Covey AM, Nutting CW, Saad WE, Salem R, Sofocleous CT, Sze DY, Society of Interventional Radiology Standards of Practice Committee
(2012) J Vasc Interv Radiol 23: 287-94
MeSH Terms: Antineoplastic Agents, Chemoembolization, Therapeutic, Embolization, Therapeutic, Evidence-Based Medicine, Hepatic Artery, Humans, Infusions, Intra-Arterial, Injections, Intra-Arterial, Liver Neoplasms, Patient Selection, Quality Improvement, Risk Assessment
Added March 5, 2014
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12 MeSH Terms
The bradykinin type 2 receptor BE1 polymorphism and ethnicity influence systolic blood pressure and vascular resistance.
Pretorius MM, Gainer JV, Van Guilder GP, Coelho EB, Luther JM, Fong P, Rosenbaum DD, Malave HA, Yu C, Ritchie MD, Vaughan DE, Brown NJ
(2008) Clin Pharmacol Ther 83: 122-9
MeSH Terms: Adult, African Americans, Blood Flow Velocity, Blood Pressure, Bradykinin, Dose-Response Relationship, Drug, European Continental Ancestry Group, Female, Forearm, Gene Frequency, Genotype, Humans, Infusions, Intra-Arterial, Male, Nitroprusside, Phenotype, Polymorphism, Genetic, Receptor, Bradykinin B2, Regional Blood Flow, Vascular Resistance, Vasodilator Agents
Show Abstract · Added December 10, 2013
We examined the effect of -58 C/T and BE1 +9/-9 polymorphisms in the bradykinin B2 receptor gene on forearm vascular resistance (FVR) before and during intrabrachial artery infusion of the B2 receptor-, endothelium-dependent agonist bradykinin and the endothelium-independent agonist sodium nitroprusside in 228 normotensive subjects. In 166 white Americans, systolic blood pressure (SBP) and pulse pressure were highest in the BE1 +9/+9 group (118+/-2 and 51+/-2 mm Hg, respectively; P<0.05 versus -9/-9 for either), intermediate in the +9/-9 group (114+/-1 and 49+/-1 mm Hg, P<0.05 versus -9/-9 for pulse pressure), and lowest in the -9/-9 group (110+/-2 and 44+/-2 mm Hg). In 62 black Americans, FVR was 25% higher in the BE1 +9/+9 group compared with the BE1 +9/-9 and -9/-9 groups at baseline (P=0.038) or during bradykinin (P=0.03). Increased SBP or vascular resistance may contribute to increased left ventricular mass reported previously in individuals with the BE1+9/+9 genotype.
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21 MeSH Terms
Chemotherapy and regional therapy of hepatic colorectal metastases: expert consensus statement.
Bartlett DL, Berlin J, Lauwers GY, Messersmith WA, Petrelli NJ, Venook AP
(2006) Ann Surg Oncol 13: 1284-92
MeSH Terms: Antineoplastic Agents, Antineoplastic Agents, Phytogenic, Antineoplastic Combined Chemotherapy Protocols, Camptothecin, Chemotherapy, Adjuvant, Colorectal Neoplasms, Hepatectomy, Hepatic Artery, Humans, Infusions, Intra-Arterial, Irinotecan, Liver Neoplasms, Organoplatinum Compounds, Oxaliplatin
Added March 20, 2014
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14 MeSH Terms
Quality improvement guidelines for transhepatic arterial chemoembolization, embolization, and chemotherapeutic infusion for hepatic malignancy.
Brown DB, Cardella JF, Sacks D, Goldberg SN, Gervais DA, Rajan D, Vedantham S, Miller DL, Brountzos EN, Grassi CJ, Towbin RB
(2006) J Vasc Interv Radiol 17: 225-32
MeSH Terms: Antineoplastic Agents, Carcinoma, Hepatocellular, Chemoembolization, Therapeutic, Embolization, Therapeutic, Hepatic Artery, Humans, Infusions, Intra-Arterial, Iodized Oil, Liver Neoplasms, Quality Assurance, Health Care, Radiography, Interventional, Societies, Medical
Added March 5, 2014
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12 MeSH Terms
Endovascular lung perfusion using high-dose cisplatin: uptake and DNA adduct formation in an animal model.
Brown DB, Ma MK, Battafarano RJ, Naidu S, Pluim D, Zamboni WC, McLeod HL
(2004) Oncol Rep 11: 237-43
MeSH Terms: Animals, Antineoplastic Agents, Chemotherapy, Cancer, Regional Perfusion, Cisplatin, DNA Adducts, Infusions, Intra-Arterial, Kidney, Lung, Models, Animal, Pulmonary Artery, Sus scrofa, Thiosulfates
Show Abstract · Added March 5, 2014
Mean survival after diagnosis of unresectable pulmonary metastases is less than one year. Isolated lung perfusion (ILP) is a technique that delivers chemotherapy into the pulmonary artery via a thoracotomy. Human trials are limited. We report an animal model for endovascular lung perfusion (ELP). Twelve swine were used. Treatment swine (N=6) received 150-mg of cisplatin (CDDP) into the pulmonary artery via a balloon occlusion catheter while nine grams of thiosulfate was given IV. Control swine (N=6) received 50-mg CDDP IV with sham pulmonary artery perfusion. Animals were sacrificed immediately (0 h), 4 or 24 h after infusion. Pulmonary and renal platinum/DNA adducts and serum CDDP levels were measured at all time points. Area under the adduct-time curve (AUA) was determined as a measure of systemic exposure. Pathologic study of the lungs was performed. At 0 h, ELP elevated pulmonary adduct levels by 17.38 times while thiosulfate led to reduction in renal DNA adducts despite the elevated CDDP dose. At all time points, pulmonary adducts were at least 6.9 times higher for ELP compared to IV administration. The AUA was 7 times greater for the ELP group. Serum CDDP levels were significantly higher after ELP (p<0.05). There was no evidence of toxic pulmonary injury from ELP. Direct pulmonary artery infusion of CDDP results in greater DNA adduct formation than would be expected from simple dose escalation. Further study of ELP evaluating the acute and chronic effects of repeated treatment administration is warranted.
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12 MeSH Terms
Blockade of nucleoside transport is required for delivery of intraarterial adenosine into the interstitium: relevance to therapeutic preconditioning in humans.
Gamboa A, Ertl AC, Costa F, Farley G, Manier ML, Hachey DL, Diedrich A, Biaggioni I
(2003) Circulation 108: 2631-5
MeSH Terms: Adenosine, Adult, Biological Transport, Blood Flow Velocity, Blood Pressure, Brachial Artery, Dipyridamole, Dose-Response Relationship, Drug, Extracellular Fluid, Forearm, Heart Rate, Humans, Infusions, Intra-Arterial, Injections, Intravenous, Ischemic Preconditioning, Myocardial, Microdialysis, Muscle, Skeletal, Nucleoside Transport Proteins, Nucleosides, Reference Values
Show Abstract · Added December 10, 2013
BACKGROUND - Adenosine, a known mediator of preconditioning, has been infused into the coronary circulation to induce therapeutic preconditioning, eg, in preparation for angioplasty. However, results have been disappointing. We tested the hypothesis that endothelial nucleoside transporter acts as a barrier impeding the delivery of intravascular adenosine into the underlying myocardium and that this can be overcome with dipyridamole, a nucleoside transporter blocker.
METHODS AND RESULTS - We infused saline or adenosine (0.125 and 0.5 mg/min) into the brachial artery while monitoring forearm blood flow (FBF) and interstitial adenosine levels with microdialysis probes implanted in the flexor digitorum superficialis of the forearm in 7 healthy volunteers during intravenous administration of saline or dipyridamole (loading dose, 0.142 mg/kg per min for 5 minutes followed by 0.004 mg/kg per min). Adenosine produced near maximal forearm vasodilation, increasing FBF from 4.0+/-0.7 to 10.4+/-1.9 and 13.1+/-1.6 mL/100 mL per min for the low and high doses, respectively, but did not increase muscle dialysate adenosine concentration (from 88+/-21 to 65+/-23 and 85+/-26 nmol/L). Intravenous dipyridamole enhanced resting muscle dialysate adenosine (from 77+/-25 to 147+/-50 nmol/L), adenosine-induced increase in FBF (from 4.1+/-0.8 to 12.6+/-3 and 15.1+/-3 mL/100 mL per min for the low and high dose, respectively), and the delivery of adenosine into the interstitium (to 290+/-80 and 299+/-143 nmol/L for the low and high dose, respectively, P=0.04).
CONCLUSIONS - Intravascular adenosine is likely ineffective in inducing myocardial preconditioning because of poor interstitial delivery. This can be overcome by blocking the nucleoside transporter with dipyridamole.
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Angiotensin-converting enzyme inhibition increases human vascular tissue-type plasminogen activator release through endogenous bradykinin.
Pretorius M, Rosenbaum D, Vaughan DE, Brown NJ
(2003) Circulation 107: 579-85
MeSH Terms: Adult, Angiotensin-Converting Enzyme Inhibitors, Blood Flow Velocity, Bradykinin, Bradykinin Receptor Antagonists, Dose-Response Relationship, Drug, Enalaprilat, Endothelium, Vascular, Female, Fibrinolysis, Forearm, Humans, Infusions, Intra-Arterial, Male, Methacholine Chloride, Muscarinic Agonists, Regional Blood Flow, Smoking, Tissue Plasminogen Activator, Vascular Resistance
Show Abstract · Added December 10, 2013
BACKGROUND - Angiotensin-converting enzyme (ACE) inhibition potentiates the tissue-type plasminogen activator (t-PA) response to exogenous bradykinin. This study tested the hypothesis that ACE inhibition increases endothelial t-PA release through endogenous bradykinin.
METHODS AND RESULTS - We measured the effect of intra-arterial enalaprilat (5 micro g/min) on forearm blood flow (FBF) and net t-PA release before and during intra-arterial infusion of bradykinin (25 to 400 ng/min) and methacholine (3.2 to 12.8 microg/min) in 24 smokers pretreated with bradykinin receptor antagonist HOE 140 (100 microg/kg intravenously) or vehicle. There was no specific effect of HOE 140 on FBF or forearm vascular resistance (FVR, 29.9+/-3.6 versus 29.7+/-3.6 mm Hg x mL(-1) x min(-1) x 100 mL(-1) after vehicle and HOE 140, respectively, P=0.956 between groups). Resting FVR decreased during enalaprilat compared with vehicle or HOE 140, but not compared with baseline, and the effect was similar in the 2 groups (22.0+/-2.7 and 24.1+/-2.9 mm Hg x mL(-1) x min(-1) x 100 mL(-1), respectively, P=0.610). In contrast, enalaprilat significantly increased resting net t-PA release (from 0.6+/-0.4 to 1.7+/-0.6 ng. min(-1) x 100 mL(-1), P=0.002); this effect was abolished by HOE 140 (0.1+/-0.3 ng x min(-1) x 100 mL(-1), P=0.036 versus enalaprilat alone). Enalaprilat increased the effect of exogenous bradykinin on FBF 60% (from 17.5+/-2.5 to 28.1+/-4.0 mL. min(-1) x 100 mL(-1) during 100 ng/min bradykinin, P=0.001) and on t-PA release 14-fold (from 21.2+/-7.9 to 317.4+/-118.9 ng x min(-1) x 100 mL(-1), P=0.024). Enalaprilat increased the t-PA response to bradykinin to a greater extent than the FBF response, shifting the relationship between net t-PA release and FBF (P=0.005). HOE 140 blocked these effects. There was no effect of enalaprilat or HOE 140 on the FBF or t-PA response to methacholine.
CONCLUSION - ACE inhibition increases constitutive endothelial t-PA release through endogenous bradykinin.
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20 MeSH Terms