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Biomedical subjects

J J Barry

Publications and source records attributed to J J Barry.

32 records · Page 2Linked to original sources
PubMed1994

Decreased platelet deposition and smooth muscle cell proliferation after intramural heparin delivery with hydrogel-coated balloons.

BACKGROUND: In vitro and in vivo studies have demonstrated both anticoagulant and antiproliferative effects of heparin. The purpose of this study was to assess the effect of local intramural delivery of heparin, using heparin-coated hydrogel balloons, on platelet deposition and early smooth muscle cell proliferation after in vivo balloon angioplasty. METHODS AND RESULTS: The effects of local heparin delivery were assessed during balloon angioplasty of porcine peripheral arteries. All balloon dilatations were performed with oversized hydrogel balloons coated with a known quantity of heparin. Balloon dilatations in contralateral vessels with uncoated hydrogel balloons served as study controls. The pharmacokinetics of heparin delivery were assessed using 3H-heparin to quantitate heparin wash-off from the balloon surface, heparin delivery to the arterial wall, and intramural persistence of drug. Platelet deposition at 1 hour after balloon injury was quantified using 111In-labeled platelets. Smooth muscle cell proliferation was assessed 6 to 7 days after angioplasty with immunohistochemical staining for proliferating cell nuclear antigen. 3H-heparin wash-off from the hydrogel balloon surface occurred rapidly, with approximately 95% of the heparin coating disappearing within 10 seconds in the intact circulation. Approximately 2% of heparin on the balloon surface was delivered intramurally at the time of angioplasty. Intramural heparin dissipated rapidly, although small amounts of intramural heparin could still be detected for at least 48 hours. In comparison to control vessels, there was less 111In-platelet deposition (P = .002) and less medial smooth muscle cell proliferation (P = .03) in heparin-treated vessels. CONCLUSIONS: Local intraluminal delivery of heparin at the time of balloon angioplasty with heparin-coated hydrogel balloons results in intramural deposition of drug that persists for at least 48 hours. This in vivo technique significantly decreases platelet deposition and early smooth muscle cell proliferation after angioplasty injury.

Angioplasty, Balloon↗
PubMed1994

Arterial gene transfer to rabbit endothelial and smooth muscle cells using percutaneous delivery of an adenoviral vector.

BACKGROUND: Previous investigations in live animals convincingly established that arterial gene transfer, while feasible, was compromised by a low transfection efficiency. More recent studies have shown that transfection efficiency may be substantially augmented by the use of recombinant adenoviral vectors. Most in vivo transfections reported to date, however, have used direct (operative) administration of the adenoviral vector. Clinical applications of arterial gene transfer (such as prevention of restenosis), however, would require local percutaneous delivery of the transgene. The present study was designed to extend in vivo intraoperative findings to percutaneous delivery system and to assess whether gene transfer remains site specific. METHODS AND RESULTS: A recombinant, replication-defective adenovirus modified to include an expression cassette for nucleus-targeted beta-galactosidase was introduced into rabbit iliac arteries in vivo using either a double-balloon catheter (DBC, n = 27) or a hydrogel-coated balloon catheter (HBC, n = 27). Contralateral arteries-normal, endothelium-denuded, or sham-transfected with a control adenoviral vector-served as controls. beta-Galactosidase expression was assessed by X-Gal staining. Cell-transduction efficiency was measured by morphometric analysis. Polymerase chain reaction (PCR) and histochemistry were used to detect the presence and/or expression of viral DNA in remote organs. Transgene expression was detected in all cases (46 of 46) between 3 and 14 days after transfection but was in no case detectable 28 days after transfection. In the DBC group, transgene expression was limited to endothelial cells when the endothelium was left intact and to rare medial cells (< 2.2%) when it had been removed. In contrast, HBC delivery resulted in transduction of up to 9.6% of medial smooth muscle cells (P = .0001). Optimized PCR and histochemistry failed to detect evidence of extra-arterial transfection except in a small number of cells (between 1 in 3 x 10(2) and 1 in 3 x 10(5) cells) in the livers of 2 animals in the DBC group. CONCLUSIONS: (1) Efficient, adenovirus-mediated, arterial gene transfer to endothelial and/or smooth muscle cells is feasible by percutaneous, clinically applicable techniques. (2) Consistent transfection of medial smooth muscle cells may be achieved when the endothelial layer is abraded. (3) Medial transfection is more efficient when an HBC, rather than a DBC, is used. (4) Percutaneous delivery of the adenoviral vector via HBC results in site-specific arterial gene transfer. Very-low-level extra-arterial transfection may occur, however, when the DBC is used.

Adenoviridae↗
PubMed1994

Inhibition of platelet deposition and lysis of intracoronary thrombus during balloon angioplasty using urokinase-coated hydrogel balloons.

BACKGROUND: Conventional balloon angioplasty of intracoronary thrombus is associated with a high incidence of abrupt closure, distal embolization, and no-reflow phenomenon. The purpose of this study was to assess a new technique for treating intracoronary thrombus consisting of the local delivery of urokinase directly to the angioplasty site with urokinase-coated hydrogel balloons. METHODS AND RESULTS: We assessed local urokinase delivery using hydrogel balloons in four protocols. First, we evaluated the pharmacokinetics of urokinase delivery in vitro using 125I-labeled urokinase to measure drug loading onto hydrogel balloons, drug retention by the hydrogel polymer during blood exposure, and drug transfer from the balloon surface to the arterial wall during balloon dilatation. Second, we measured 125I-urokinase washoff from the hydrogel balloon in the intact circulation and intramural drug delivery during in vivo balloon angioplasty in 10 anesthetized New Zealand rabbits. Third, we assessed the effect of local urokinase delivery on 111In-labeled platelet deposition after balloon angioplasty in vivo in 13 porcine carotid or iliac arteries dilated with urokinase-coated balloons and compared them with contralateral control arteries dilated with saline-coated balloons. Finally, we determined the clinical efficacy of urokinase-coated balloons in 15 patients with intracoronary thrombus, including 7 who demonstrated abrupt thrombotic closure after conventional angioplasty. Between 241 and 1509 U urokinase could be loaded onto hydrogel balloons ranging in size from 2 to 8 mm. In vitro and in vivo studies demonstrated that hydrogel balloons absorbed significantly more urokinase and demonstrated less drug wash-off than nonhydrogel balloons (P < .01). Similarly, both in vitro and in vivo studies demonstrated urokinase transfer from the hydrogel to the arterial wall during balloon angioplasty, with greater intramural drug deposition with larger balloons (P < .01). Local urokinase delivery after in vivo porcine angioplasty decreased 111In-labeled platelet deposition by 47% compared with contralateral control vessels (P = .03). Use of urokinase-coated balloons in patients with intracoronary thrombus resulted in thrombus dissolution and reversal of abrupt closure in all cases, without evidence of distal embolization. CONCLUSIONS: With the use of hydrogel-coated balloons, urokinase can be delivered locally to an angioplasty site. This technique decreases platelet deposition after in vivo balloon angioplasty and is efficacious in treating intracoronary thrombus in patients, including those with abrupt thrombotic closure.

Adult↗
PubMed1993

Arterial gene transfer using pure DNA applied directly to a hydrogel-coated angioplasty balloon.

Direct arterial gene transfer has been previously achieved using double-balloon catheters and perforated balloons, in most cases facilitated by the use of cationic liposomes or viral vectors. These gene delivery systems, however, have been compromised by issues relating to efficacy and/or safety, and furthermore require that angioplasty be performed independent of gene transfer. We investigated the possibility that arterial gene transfer might be performed during balloon angioplasty by delivery of naked genetic material from a thin coat of hydrogel polymer applied to a standard angioplasty balloon. Transfections with luciferase DNA applied to a hydrogel balloon were performed in rabbit arteries. Luciferase expression 3 days after transfection was tested in three different models: (i) an organ culture model (n = 10); (ii) surgically exposed carotid arteries (n = 14); and (iii) external iliac arteries using a percutaneous approach (n = 13). Supplementary transfections (n = 3), intended to identify the site of arterial transfection, were performed using the gene encoding for nuclear-specific beta-galactosidase (beta-gal). All rabbit arteries transfected with the luciferase gene (37/37; 100%) expressed luciferase activity. Gene expression achieved in vivo, either in the surgically exposed carotid arteries or in the external iliac arteries transfected percutaneously, was quantitatively similar to that achieved in the organ culture model. Reduction in the duration of inflation from 30 min to 1 min had no statistically significant impact on transfection efficiency. Gene expression was documented to persist up to 14 days post percutaneous transfection. Analysis of arteries transfected with nuclear-specific beta-gal showed the presence of the transgene in intimal and subintimal sites. These results demonstrate that vascular gene transfer can be performed successfully without liposomes or viral vectors using DNA applied to a standard angioplasty catheter balloon coated with hydrogel. Percutaneous transfection with a hydrogel-coated balloon permits gene transfer coincident with the angioplasty procedure itself, even with inflations as short as 1 min.

Angioplasty, Balloon↗
PubMed1993

Feasibility and drug delivery efficiency of a new balloon angioplasty catheter capable of performing simultaneous local drug delivery.

BACKGROUND: Local drug delivery at angioplasty treatment sites may improve acute and long-term results after angioplasty. A new dual-purpose balloon angioplasty catheter containing intramural channels and exterior pores ('channeled balloon') was designed to allow local drug delivery at low pressure without jet streams during simultaneous balloon angioplasty. METHODS: Acute feasibility studies were performed in normal ex-vivo and in-vivo arteries (three canine arteries and three rabbits with normal iliac arteries), in which 2 ml of marker agents were locally infused at 2 atm during simultaneous angioplasty at 6 atm with the channeled balloon. Histology, radioactive counting, and autoradiography were performed to determine the intramural localization of the delivered markers. The in-vitro efficiency of acute local drug delivery was estimated in seven normal canine arteries by infusing 3H-heparin and radioactive counting. RESULTS: Histology revealed the presence of markers in the inner third of the media in all ex-vivo samples, and markers in all in-vivo iliac arteries except for one, whereas control segments had no intramural staining. Autoradiography documented transmural radioactive granules. Radioactive counts were 40- to 263-fold higher in those locally treated with the radioactive marker agent. Efficiency of the acute local delivery was estimated by dividing the actual counts by the expected counts; it ranged from 24 to 48%. CONCLUSION: This study demonstrates that the channeled balloon is capable of delivering drugs locally at low pressure in adequate concentrations during simultaneous high-pressure balloon angioplasty in normal arteries.

Angioplasty, Balloon, Coronary↗
PubMed1992

Failure of countershock-type pulses in vitro to adversely alter mitochondrial oxidative phosphorylation.

STUDY OBJECTIVE: The aim of the study was to investigate a potential mechanism of myocardial injury after DC countershock. The effect of countershock-type electrical discharges on rabbit heart mitochondrial oxygen consumption was measured in vitro using a novel respiration cell. MEASUREMENTS AND MAIN RESULTS: Mitochondria were isolated from the hearts of adult Dutch and New Zealand White rabbits. Single rectangular shocks (voltage gradients 20 to 80 V/cm; 5 ms duration) caused no significant changes in state 3 oxygen consumption in standard incubation medium. Single and multiple defibrillator shocks (critically damped sine waveform; 5 ms duration) with peak voltage gradients of 242 to 659 V/cm similarly had no significant effect on state 3 oxygen consumption. CONCLUSION: At voltage gradients similar to and greater than those causing myocardial cell injury and necrosis, electrical discharges do not directly depress mitochondrial function. Therefore, the reduction in mitochondrial oxygen consumption observed following transthoracic shocks in vivo may invoke other mechanisms (eg, intracellular calcium influx, high circulating noradrenaline, or free radical formation in the intact heart).

Animals↗
PubMedDate not supplied

Local delivery of an antiproliferative drug with use of hydrogel-coated angioplasty balloons.

PURPOSE: To determine the feasibility of using hydrogel-coated angioplasty balloons to deliver drugs that inhibit vascular smooth muscle cell (VSMC) proliferation. MATERIALS AND METHODS: In initial experiments, the tyrphostin RG-50872 (1 mumol/L) completely inhibited VSMC proliferation induced by platelet-derived growth factor (PDGF) in vitro when RG-50872 treatment preceeded PDGF exposure by 15 minutes. This inhibition was reversible and was not due to cell toxicity. In further experiments, hydrogel-coated and silicone-coated angioplasty balloons (2.5 mm in diameter by 20 mm in length) were coated with either 10 microL of RG-50872 (40 mmol/L in dimethyl sulfoxide [DMSO]) or DMSO vehicle, or were left uncoated. Afterward, each angioplasty balloon was inflated, submerged in 50 mL of culture media, and agitated for 2 minutes to promote drug release. Dilutions of this media were tested for their ability to inhibit VSMC proliferation. RESULTS: All hydrogel-coated balloons (n = 5) released sufficient RG-50872 to inhibit PDGF-induced VSMC proliferation by 95% or more, whereas none of the silicone-coated balloons (n = 4) did. DMSO-treated and untreated balloons had no effect on proliferation. CONCLUSION: These findings demonstrate that the hydrogel-coating on angioplasty balloons can take up and release sufficient RG-50872 to significantly inhibit smooth muscle cell proliferation. Further in vivo experiments are needed to determine if hydrogel-coated balloons can deliver sufficient RG-50872 to the arterial wall to affect VSMC proliferation.

Angioplasty, Balloon↗
PubMedDate not supplied

Mural delivery of iloprost with use of hydrogel-coated balloon catheters suppresses local platelet aggregation.

PURPOSE: To develop reproducible and quantifiable methods for mural delivery of iloprost, a potent agent against platelet aggregation, with use of hydrogel-coated angioplasty balloons, and to determine the in vivo effect of direct iloprost delivery on platelet aggregation at the angioplasty site. MATERIALS AND METHODS: Drug loading of tritiated iloprost from an immersion solution onto hydrogel-coated balloons was evaluated as a function of balloon size (3 mm x 2 cm, 6 mm x 2 cm, 8 mm x 3 cm; n = 4 each), drug concentration (0.0715 mg/mL, 0.1072 mg/mL, 0.1430 mg/mL; n = 3 each), and duration of immersion (40 seconds, 60 seconds, 120 seconds; n = 3 each). In another set of experiments, optimal drying methods were tested to minimize drug loss within a protective delivery sheath (n = 3 each). Ex vivo angioplasty was performed on excised swine arteries to estimate how much of the drug present on the balloon could be delivered to the wall (n = 3 iliac segments). Finally, in vivo angioplasty was performed in three Yorkshire pigs (n = 6 iloprost-treated and 6 control arteries) and indium-111-labeled platelet aggregation was measured at these sites, which were harvested 1 hour after the procedure. RESULTS: In the initial set of experiments, the authors found that the volume of drug loaded is determined by the wet-volume of the hydrogel coating, that the majority of volume loading occurs within the first 2 minutes, and that the volume uptake is independent of the drug concentration. The optimal drying method resulting in the least loss of iloprost within the sheath (only 4%) was prolonged drying (5 hours) under ambient conditions. Ex vivo angioplasty experiments showed that approximately 33% of the drug present on the balloon can be delivered to the wall. Finally, in vivo experiments showed that platelet aggregation is significantly suppressed at treated sites (by approximately 33% compared to control sites; P = .03) by minuscule mural doses of iloprost (roughly estimated at under 1 microg). CONCLUSION: Quantifiable and reproducible methods for loading iloprost onto hydrogel-coated angioplasty balloons were developed. The best of these methods was able to deliver enough iloprost into the wall to significantly reduce local platelet aggregation.

Angioplasty, Balloon↗
PubMedDate not supplied

Site-specific delivery of iloprost during experimental angioplasty suppresses smooth muscle cell proliferation.

PURPOSE: The authors have previously reported that intramural delivery of iloprost during angioplasty suppresses local platelet aggregation at 1 hour in undiseased porcine arteries. In this study, the authors sought to quantify the effect of such treatment on medial vascular smooth muscle cell proliferation, an event implicated in the development of intimal hyperplasia. MATERIALS AND METHODS: Three Yorkshire pigs underwent percutaneous transluminal angioplasty with hydrogel-coated balloons for a total of 10 iloprost-treated (experimental) and 10 saline-treated (control) arterial sites. The balloons were prepared with previously reported techniques and loaded with 2.25 microg of iloprost for the experimental sites. On the eighth day after angioplasty, these sites were harvested and prepared for immunohistochemical staining. Thin (4 microm) sections of the specimens were stained with use of monoclonal antibody to proliferating cell nuclear antigen (PCNA). Appropriate positive and negative controls were used. Approximately 350-500 vascular smooth muscle cells were randomly counted under high power (100x) by an experienced physician who was blinded to the origin of the specimen. A PCNA index (%) was calculated as follows: [(#PCNA [+] cells)/(#PCNA [+] cells + #PCNA [-] cells)]x 100. A paired t test was used for statistical comparison. RESULTS: The PCNA indices for eight (n = 8) paired large vessels (iliac, carotid, subclavian) were 7.98 (+/- 1.8)%, for the iloprost-treated experimental sites, and 14.58 (+/- 3.8)% for the saline-treated control sites. This difference was statistically significant (P = .003). One large vessel pair was not available for analysis. When the pair of renal arteries of animal 3 were included (n = 9), the PCNA indices were 8.32 (+/- 2.3)% for the experimental sites, and 13.79 (+/- 4.2)% for the control sites. The differences were again significant (P = .01). CONCLUSION: Intraarterial site-specific delivery of iloprost during angioplasty with drug-loaded, hydrogel-coated balloons significantly suppresses medial smooth muscle cells in swine at the expected peak period of proliferation of 7 days after angioplasty.

Angioplasty, Balloon↗