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R J Levy

Publications and source records attributed to R J Levy.

At least 73 records · Page 4Linked to original sources
PubMed1993

Synergistic inhibition of the calcification of glutaraldehyde pretreated bovine pericardium in a rat subdermal model by FeCl3 and ethanehydroxydiphosphonate: preincubation and polymeric controlled release studies.

Calcification is a frequent cause of the clinical failure of bioprosthetic heart valves fabricated from glutaraldehyde-pretreated porcine aortic valves or glutaraldehyde-pretreated bovine pericardium (GPBP). We investigated the hypothesis that ferric chloride (FeCl3) and sodium-ethanehydroxydiphosphonate (EHDP) may act synergistically to prevent bioprosthetic tissue calcification. Pre-incubations and controlled release systems were studied individually. FeCl3-EHDP polymeric controlled release matrices were formulated using silicone rubber and evaluated for in vitro release kinetics at pH 7.4 and 37 degrees C. The effects of Fe-EHDP synergism on GPBP calcification were investigated with 21 d subdermal implants in 3 wk-old male rats. Results demonstrated that levels of Fe3+ and EHDP uptake, measured in GPBP tissues pre-incubated first in an FeCl3 solution (10(-5) M) followed by an EHDP solution (0.1 M), were higher than in the reverse order of incubation. In the first series of rat implants, GPBP was pre-incubated in either FeCl3 or Na2EHDP solutions, or sequential pre-incubations of first FeCl3 and then Na2EHDP solutions, or the reverse. The inhibition of calcification was greatest when FeCl3 (first pre-incubation, 10(-5) M) was combined with Na2EHDP (second pre-incubation, 0.1 M) (1.78 +/- 0.2 micrograms of Ca2+/mg of dried tissue) compared with the other pre-incubation groups: EHDP (first pre-incubation) combined with FeCl3 (second pre-incubation) (21.7 +/- 6.4), FeCl3 solution alone at 10(-5) M (27.9 +/- 10.7), Na2EHDP solution alone at 0.1 M (52.3 +/- 11.9) and the control group (72.3 +/- 10.2). In a second series of implants, GPBP specimens were co-implanted with individual controlled release systems containing one of the following formulations (weight percentage in silicone rubber): 1% FeCl3, 20% CaEHDP, 20% protamine sulphate, 1% FeCl3-20% CaEHDP, and 1% FeCl3-20% protamine sulphate. The 1% FeCl3-20% CaEHDP silicone-rubber matrices were the most effective for inhibiting GPBP mineralization (13.7 +/- 3.0 micrograms Ca2+/mg of dried tissue) compared with non-drug silicone co-implant controls (74.7 +/- 5.58 micrograms Ca2+/mg of dried tissue) and other polymeric treatment groups (32.3 +/- 2.3-80.0 +/- 19.7). No adverse effects on bone or overall growth of any treatment protocols were noted. Thus, combinations of FeCl3 and EHDP, using either pre-incubations or polymeric controlled release, were synergistic for inhibiting GPBP calcification.

Animals↗
PubMed1992

Epicardial propranolol administration for ventricular arrhythmias in dogs: matrix formulation and characterization.

The effect of propranolol on the prevention of ventricular tachycardia/fibrillation (VT/VF) due to acute coronary ischaemia was studied in dogs. A series of propranolol-polymer controlled release matrices in slab configuration using various polyurethanes and a polyurethane-silicone rubber copolymer were formulated and characterized. In general, drug release in vitro occurred with an initial burst phase followed by an exponentially declining delivery rate; the silicone rubber containing copolymer preparation had more sustained release properties than did pure polyurethane matrices. In the animal studies, dogs underwent 5-hourly 10 min complete occlusions of the left anterior descending coronary artery (LAD), followed by 50 min normal perfusion. During non-drug occlusions VT occurred at a frequency of 1.22 +/- 0.12 episodes/min. A propranolol-polyurethane matrix (30% w/w, 28-42 mg) was placed on the ischaemic zone of the left ventricular epicardium immediately after the fifth occlusion. After an hour of drug delivery a sixth occlusion took place. The number of arrhythmia episodes both before and after drug were quantified and compared. The time to ventricular fibrillation (when present) and the mean blood pressure were also assessed. The drug patch delivered propranolol at a dose of 140 +/- 45 micrograms/kg by the conclusion of the 1 h study period. Therapeutic drug levels were achieved in the peripheral blood samples (8.7-43.7 ng/ml) and were enhanced in coronary venous samples (360.9-556.2 ng/ml). Reduction of blood pressure and proarrhythmic events following epicardial controlled release propranolol administration were noted but were not statistically significant. Arrhythmia episodes before and after propranolol were not found to be significantly different (VT/min 1.02 +/- 0.31 and 1.22 +/- 0.12).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Epicardial controlled-release verapamil prevents ventricular tachycardia episodes induced by acute ischemia in a canine model.

Sustained-release preparations composed of verapamil-polymeric controlled-release matrices were characterized in vitro and utilized as epicardial implants in dogs with ischemic ventricular arrhythmias. Anesthetized open-chest dogs were subjected to 5 hourly, 10-min complete occlusions of the left anterior descending coronary artery followed by reperfusion. A controlled-release matrix preparation (20% verapamil, 80% polyurethane), placed on the left ventricular epicardium prior to the third occlusion, resulted in successful inhibition of ventricular tachycardia (VT) during acute ischemia in a dose-dependent manner. The largest matrix size used, 300 mg (20% verapamil), provided a net systemic dose of 0.52 +/- 0.18 mg/kg over 140 min and significantly reduced VT episodes during acute ischemia (fifth occlusion) compared to untreated controls (0.16 +/- 0.04 vs. 1.01 +/- 0.35 episodes/min, respectively; t = 2.62, p = 0.01). In controls, by the fifth occlusion ventricular fibrillation (VF) occurred after 5.41 +/- 0.78 min in 89% of animals. However, after a 300-mg verapamil matrix was placed on the left ventricular ischemic zone, VF occurred in only 45% (chi-squared = 4.1, p = 0.04, vs. controls) of the animals after 7.87 +/- 0.92 min (fifth occlusion). Systemic venous plasma verapamil levels during the 2 h following the 300-mg matrix ischemic zone implantation ranged from 8.4-22.0 ng/ml, while simultaneous regional coronary venous levels were 125.0-387.0 ng/ml. Sonomicrometry studies of left ventricular wall thickening carried out with a series of 300-mg verapamil matrix cardiac implants did not demonstrate any significant myocardial dysfunction. It is concluded that controlled-release verapamil, administered directly to the heart, was effective for preventing VT and VF associated with acute coronary ischemia, and that this route of administration was not associated with any significant deterioration of cardiac function.

Animals↗
PubMed1992

Heart valve bioprostheses: antimineralization.

Clinical and experimental studies indicate that calcification of bioprosthetic valves depends on host, implant, and biomechanical factors. The earliest mineral deposits in both clinical and experimental bioprosthetic tissue are localize to transplanted connective tissue cells; collagen involvement occurs later. Passive calcium entry occurs unimpeded in cells modified by aldehyde cross-linking, but the mechanisms for calcium removal are dysfunctional; calcium influx contributes to apatite formation by reacting with compartmentalized, bound phosphorus. Specific strategies for prevention of bioprosthetic tissue mineralization involve modification of either valve preparation details or the local implant environment. Efficacy, mechanisms and safety must be demonstrated for any antimineralization strategy.

Bioprosthesis↗
PubMed1992

Antimineralization treatments for bioprosthetic heart valves. Assessment of efficacy and safety.

Since calcification limits the durability of contemporary bioprosthetic heart valves, antimineralization treatments are being widely investigated. Potential antimineralization treatments must have sustained prevention of mineralization without adverse effects. The preclinical investigation of efficacy and safety of antimineralization treatments comprises four essential steps: (1) subcutaneous implantation in small animals, (2) in vitro biomechanical studies of hemodynamics and durability, (3) morphology of unimplanted valves, and (4) circulatory implants in large animals.

Animals↗
PubMed1992

Calcification of allograft aortic wall in a rat subdermal model. Pathophysiology and inhibition by Al3+ and aminodiphosphonate preincubations.

Aortic allograft conduits and valves frequently undergo calcific degeneration. To study this problem, a rat subdermal model of nonvalved aortic wall allograft calcification was characterized, and experimental studies were carried out to test the hypothesis that aortic allograft preincubation in either amino-propanehydroxydiphosphonate (APDP) or AlCl3 would inhibit calcification in a rat subdermal model. Fresh thoracic aortas were harvested under sterile conditions from male Sprague-Dawley rats (350-400 g). APDP aortas were preincubated immediately in either 4 x 10(-3) mol/l, 4 x 10(-4) mol/l, or 4 x 10(-5) mol/l [14C] APDP (37 degrees C, pH 7.4) and controls were incubated in 0.05 mol/l HEPES buffer (pH 7.4, 37 degrees C, 30 min). Al3+ aortas were preincubated in either 10(-1) mol/l, 10(-2) mol/l, or 10(-3) mol/l AlCl3. Pretreated aortas were next implanted subdermally in weanling rats (3-week-old, male, Sprague-Dawley, 50-60 g) and retrieved after 21 days. Control explants retrieved at intervals up to 21 days demonstrated progressive calcification with bulk aortic allograft Ca2+ levels increasing from a preimplant value of 0.8 +/- 0.1 micrograms/mg to 129.8 +/- 12.9 micrograms/mg by 21 days. Light microscopy revealed that much of the calcium deposition was associated with elastin. Calcification was significantly inhibited in the 4 x 10(-3) mol/l and 4 x 10(-4) mol/l APDP preincubated groups was observed (Ca2+ = 0.70 +/- 0.15 micrograms/mg, 36.6 +/- 19.8 micrograms/mg, respectively versus 117.2 +/- 24.3 micrograms/mg, control). Inhibition of calcification in the groups preincubated in the two most concentrated AlCl3 solutions (Ca2+ = 13.9 +/- 4.9 micrograms/mg [10(-2) mol/l AlCl3], 36.6 +/- 7.1 micrograms/mg [10(-3) mol/l AlCl3], 171.0 +/- 13.2 micrograms/mg [control]) was also demonstrated. No adverse effects of either pretreatment, APDP, or AlCl3 were noted on bone or overall somatic growth.

Aluminum↗
PubMed1991

Initiation of mineralization in bioprosthetic heart valves: studies of alkaline phosphatase activity and its inhibition by AlCl3 or FeCl3 preincubations.

The principal cause of the clinical failure of bioprosthetic heart valves fabricated from glutaraldehyde-pretreated porcine aortic valves is calcification. Other prostheses composed of tissue-derived and polymeric biomaterials also are complicated by deposition of mineral. We have previously demonstrated that: (a) Failure due to calcification of clinical bioprosthetic valves can be simulated by either a large animal circulatory model or subdermal implants in rodents. (b) Calcification of bioprosthetic tissue has complex host, implant, and mechanical determinants. (c) The initial calcification event in the rat subdermal model is the mineral deposition in devitalized cells intrinsic to the bioprosthetic tissue within 48 to 72 h, followed later by collagen mineralization. (d) Initiation of bioprosthetic tissue mineralization, like that of physiological bone formation, has "matrix vesicles" as early nucleation sites. (e) Alkaline phosphatase (AP), an enzyme also associated with matrix vesicles involved in bone mineral nucleation, is present in both fresh and fixed bioprosthetic tissue at sites of initial mineralization. (f) Certain inhibitors of bioprosthetic tissue calcification (e.g., Al3+, Fe3+) are localized to the sites at which alkaline phosphatase is present. On the basis of these results, we hypothesize that alkaline phosphatase is a key element in the pathogenesis of mineralization of bioprosthetic tissue. In the present studies, we focused on the relationship of AP to early events in calcification, and the inhibition of both calcification and AP activity by FeCl3 and AlCl3 preincubations. Subdermal implants of glutaraldehyde pretreated bovine pericardium (GPBP) were done in 3-week-old rats. AP was characterized by enzymatic hydrolysis of paranitrophenyl phosphate (pnpp), and by histochemical studies. Calcification was evaluated chemically (by atomic adsorption spectroscopy) and morphologically (by light microscopy). The results of these studies are as follows: (a) Extractable AP activity is present in fresh but not glutaraldehyde-pretreated bovine pericardial tissue. However, histochemical studies reveal active AP within the intrinsic devitalized cells of GPBP, despite extended glutaraldehyde incubation. (b) Extrinsic AP is rapidly adsorbed following implantation, with peak activity at 72 h (424 +/- 67.2 nm pnpp/mg protein/min enzyme activity [units]), but markedly lesser amounts at 21 days (96.8 +/- 3.9 units). (c) Simultaneously to the AP activity maximum, bulk calcification is initiated, with GPBP calcium levels rising from 1.2 +/- 0.1 (unimplanted) to 2.4 +/- 0.2 micrograms/mg at 72 h, to 55.6 +/- 3.1 micrograms/mg at 21 days, despite a marked decline in AP activity at this later time.(ABSTRACT TRUNCATED AT 400 WORDS)

Alkaline Phosphatase↗
PubMed1991

Cardiovascular implant calcification: a survey and update.

Calcification of cardiovascular prosthetic implants is a common and important problem. This review provides an update based upon the Conference on Cardiovascular Implant Calcification held as part of the 13th World Congress of the International Society for Heart Research, 1989. A variety of cardiovascular prostheses are affected clinically by calcification, including bioprosthetic heart valves, aortic homografts and trileaflet polymeric valve prostheses. In addition, experimental studies have demonstrated calcification of artificial heart devices in ventricular assist systems in long-term calf studies. The pathophysiology of this disease process is incompletely understood. A common element between the various types of cardiovascular implant calcification is the localization of calcific deposits to devitalized cells and membranous debris. Prevention of cardiovascular implant calcification by either biomaterial modifications or regional drug therapy (controlled release) is being investigated.

Animals↗
PubMed1991

Inhibition of mineralization of glutaraldehyde-pretreated bovine pericardium by AlCl3. Mechanisms and comparisons with FeCl3, LaCl3, and Ga(NO3)3 in rat subdermal model studies.

In the present study, the authors investigated the mechanism by which Al3+ preincubations inhibited the pathologic calcification of glutaraldehyde-pretreated bovine pericardium (GPBP) implanted subdermally in rats. The concentration dependency of the Al3+ anticalcification effect was compared with that of other trivalent metal ions (Fe3+, Ga3+, La3+) known to interact with calcium phosphates. In vitro incubations of GPBP were carried out in AlCl3 (10(-3) mol/l [molar] to 10(-1) mol/l) to ascertain both the optimal conditions for uptake of Al3+ and the time course of Al3+ dissociation. Al3+ uptake by GPBP was concentration dependent and occurred rapidly, with tissue levels after 1 hour not differing significantly from those after 72 hours of incubation. Analyses of GPBP samples preincubated in AlCl3 (0.1 mol/l, 24 hours) showed that more than 75% of the Al3+ remained tightly bound after 60 days' in vitro release at 37 degrees C, pH 7.4. Preincubations of GPBP in AlCl3 significantly inhibited calcification after subdermal implantation in rats for 60 days (Ca++ = 5.1 +/- 0.9 microgram/mg, 11.5 +/- 4.6 micrograms/mg, 70.3 +/- 23.0 micrograms/mg, mean +/- standard error [SE], for 10(-1) mol/l, 10(-2) mol/l, 10(-3) mol/l AlCl3, respectively), compared with controls (Ca++ = 110.0 +/- 9.3 micrograms/mg). All animals were free of Al3(+)-mediated adverse effects on bone, as determined by light microscopic evaluation of femoral epiphyseal growth plates. Transmission electron microscopy coupled with electron energy loss spectroscopy (EELS) of GPBP incubated in 10(-1) mol l AlCl3 for 24 hours demonstrated discrete Al3+ localization in the sarcolemma and cytoplasmic and nuclear membranes of devitalized pericardial connective tissue cells at intracellular sites coincident with phosphorus loci. Similar intracellular localization remained prominent in explants removed after 60 days; no calcific deposits were noted in these specimens. Preincubations in Fe3+ but not Ga3+ and La3+ solutions yielded significant inhibition of GPBP calcification, which did not differ significantly from that provided by Al3- and had a comparable concentration dependency. Light microscopic examination (Prussian blue staining) and EELS of FeCl3-preincubated explants demonstrated Fe3+ localization within devitalized GPBP connective tissue cells. The authors conclude that Al3+ and Fe3+ significantly inhibit the pathologic mineralization of glutaraldehyde-pretreated bovine pericardium by mechanisms that are likely related to the high affinity of these cations for membrane associated and other intracellular phosphorus loci.

Aluminum↗
PubMed1990

Sustained behavioral recovery from unilateral nigrostriatal damage produced by the controlled release of dopamine from a silicone polymer pellet placed into the denervated striatum.

This study was conducted to determine if the behavioral asymmetry associated with unilateral nigrostriatal dopamine (DA) depletion could be alleviated by placing a small DA-releasing silicone polymer matrix pellet into the denervated striatum of rats. Animals that received DA-releasing pellets showed a 50% reduction in apomorphine-induced rotational behavior, and this effect persisted for the 2-month duration of the experiment. The results suggest that the controlled release of DA from an intrastriatal polymer matrix can produce a long-lasting reduction in some of the symptoms associated with DA depletion.

Animals↗
PubMed1990

Prevention of calcification of glutaraldehyde pretreated bovine pericardium through controlled release polymeric implants: studies of Fe3+, Al3+, protamine sulphate and levamisole.

Calcification is the principal cause of the clinical failure of bioprosthetic heart valves fabricated from glutaraldehyde pretreated porcine aortic valves or bovine pericardium. The present study investigated controlled-release implants for prevention of the calcification of glutaraldehyde pretreated bovine pericardium in a rat subdermal model. Either Al3+ and Fe3+ (inhibitors of the growth and dissolution rate of hydroxyapatite crystals), levamisole (alkaline phosphatase inhibitor) or protamine sulphate (charge modifier) were individually incorporated into various polymeric carriers (either silicone rubber, polyurethane or silicone rubber-polyurethane copolymer). Polymeric implants were evaluated for in vitro release kinetics, which revealed that sustained drug release was obtained from 21 d to more than 90 d from various drug matrices. In vivo efficacy was studied by co-implanting the polymeric delivery systems with glutaraldehyde pretreated bovine pericardium for 21 d using a subdermal rat model; glutaraldehyde pretreated bovine pericardium calcium levels were quantitated by atomic absorption spectroscopy in the explanted tissues. Fe3+ and Al3+ polymeric implants were the most effective for inhibiting deposition of calcium mineral. Al3+ demonstrated 82% inhibition of calcification compared to controls and Fe3+ resulted in 80% inhibition of calcification. Specific histologic staining methods showed that Fe3+ and Al3+ were localized within the devitalized cells of the explanted glutaraldehyde pretreated bovine pericardium. No adverse effects on somatic growth or recipient bone morphology were noted following controlled-release drug administration. Controlled release of protamine sulphate or levamisole did not significantly inhibit glutaraldehyde pretreated bovine pericardium calcification. It is concluded that regional controlled release of Fe3+ or Al3+ inhibits glutaraldehyde pretreated bovine pericardium calcification in the rat subdermal model without adverse effects.

Aluminum↗
PubMed1990

Conversion of ouabain-induced ventricular tachycardia in dogs with epicardial lidocaine: pharmacodynamics and functional effects.

Epicardial antiarrhythmic drug administration was studied as a therapeutic approach for experimental ventricular tachycardia (VT) in an open-chest dog model. Lidocaine-polyurethane matrices (28%, w/w) were formulated as a model system. Matrices were placed on the left ventricular epicardium in each of 23 anesthetized open-chest dogs with ouabain-induced VT, to evaluate effectiveness in restoring sinus rhythm. Conversion occurred in all animals treated with matrices containing 300 mg or more of lidocaine after 1.5 to 7.0 min. The matrix lidocaine content correlated linearly with the time required for conversion to sinus rhythm (r = 0.75, P = 0.0002); irrespective of matrix size the myocardial/plasma lidocaine ratio was 20.1 +/- 4.2 (mean +/- SD) at the time of conversion. In a separate series of five dogs without ventricular tachycardia, systolic wall thickening measured with sonomicrometers after 5 min of controlled-release lidocaine administration (500- to 1000-mg matrix lidocaine content, 7.48 +/- 3.49-mg/kg dose) was only minimally diminished (-14.1%) and this effect was observed only at the site of matrix placement on the anterior-apical epicardium. In contrast, intracoronary injection of 0.3 or 1.0 mg/kg of lidocaine-HCl resulted in complete elimination of wall thickening or replacement by systolic thinning. Thus epicardial administration of lidocaine from polyurethane matrices was an effective means of treating ouabain-induced ventricular tachycardia. Regional myocardial function in the vicinity of the matrices was modified to a very limited degree, supporting the view that the matrices can be used safely, without serious risk to ventricular contractile performance.

Animals↗
PubMed1990

Efficacy of epicardial controlled-release lidocaine for ventricular tachycardia induced by rapid ventricular pacing in dogs.

The effects of epicardial lidocaine on ventricular tachycardia (VT) induced by rapid ventricular pacing (50 Hz) were studied in dogs. Lidocaine-polyurethane (28% wt/wt) matrixes (40-50 mg, 5 x 5 mm) were placed proximal to bipolar left ventricular epicardial electrodes in open-chest anesthetized dogs (n = 9) after VT was established by rapid ventricular pacing. In the first set of experiments, matrices were removed immediately after VT had converted to sinus rhythm. Control animals underwent VT induction protocol with a nondrug-containing matrix positioned next to the epicardial electrode. In the lidocaine-treated animals, VT conversion was noted in all animals and occurred after 51.7 +/- 8.9 s (mean +/- SE), with a VT threshold current elevation of 73.5 +/- 11.2% above baseline at the time of conversion which progressed to 259 +/- 44% of the initial value by 5.4 +/- 0.5 min post-matrix placement. Lidocaine 1.4 +/- 0.1 mg was delivered to the myocardium at the time of VT conversion (0.11 +/- 0.01 mg/kg). In comparison, accelerated VT persisted for 5 min in three of five control animals, and progressed to ventricular fibrillation (VF) in the other two animals. In a separate series of eight dogs, the lidocaine-polyurethane matrixes were left in palce for 4 h so that we could study the sustained antiarrhythmic action of controlled-release lidocaine on VT induction. The results of these experiments demonstrated a maintenance of the VT threshold elevation at a level of 53.9 +/- 10.8% after 4 h, with a net lidocaine dose of 0.52 +/- 0.06 mg/kg after 4 h of controlled release.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Sensitive high-performance liquid chromatographic assay using 9-fluorenylmethylchloroformate for monitoring controlled-release lidocaine in plasma.

A sensitive high-performance liquid chromatographic (HPLC) assay using fluorescence detection for quantifying lidocaine levels in plasma (in the ng/ml range) was developed. This novel HPLC assay has made possible the simultaneous monitoring of lidocaine levels in coronary and peripheral plasma obtained after myocardial controlled-release matrix administration (0.92 mg/kg during 4 h) in the arrhythmic dog. The method employed extracts the drug from plasma using 1-chlorobutane and a subsequent derivatization with 9-fluorenylmethylchloroformate in acetonitrile at 110 degrees C. The derivative was chromatographed on a C18 reversed-phase column and measured with fluorescence detection (excitation 254 nm, emission 313 nm). N-Methylephedrine was found to be suitable as an internal standard, post-derivatization. The derivatization product of lidocaine was identified and characterized by mass spectral analysis. It was found to have a unique and reproducible dicarbamate structure, which was stable for at least three days at room temperature. The method was tested with human plasma as well as on dog plasma. Analytical recoveries were 88.6 +/- 3.6 and 77.4 +/- 3.0% (mean +/- S.E.), respectively, at levels ranging from 25 to 200 ng/ml. The lower detection limit was 1 ng/ml lidocaine. In conclusion, this rapid and convenient analysis was found to be suitable for the bioavailability pharmacokinetic assessment of lidocaine following low-dose regional drug administration.

Animals↗