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R J Levy

Publications and source records attributed to R J Levy.

At least 55 records · Page 3Linked to original sources
PubMed1995

Calcification of valved aortic allografts in rats: effects of age, crosslinking, and inhibitors.

Experiments were carried out to investigate rat aortic allograft calcification using valved abdominal aortic allografts. Results indicated that this was a potentially useful model for investigating fresh allograft calcification, as well as mineralization of glutaraldehyde-crosslinked valved allografts. Valve cusp results, however, were not comparable to those noted in large animal or human studies, while aortic wall calcification was more comparable. Calcification inhibitor investigations demonstrated that nearly complete inhibition of the calcification of the aortic wall of glutaraldehyde-crosslinked allografts was achieved using a number of individual inhibitors, including controlled release diphosphonates, and pretreatment with either ferric chloride or aluminum chloride. However, aminopropanehydroxydiphosphonate pretreatment was not efficacious, and sodium dodecyl sulfate pretreatment was only partially effective for inhibiting the aortic wall calcification in the glutaraldehyde-crosslinked allografts. It is concluded that valved aortic allografts in rats provide a useful model for investigating aortic wall (but not valve cusp) calcification and its inhibition.

Aging↗
PubMed1995

Rhabdomyolysis: an unusual complication of cytotoxic chemotherapy.

Acute rhabdomyolysis has rarely been reported after cytotoxic chemotherapy, including cytarabine and 5-azacytidine. We observed a case of acute rhabdomyolysis and renal failure after treatment with mitoxantrone and cyclophosphamide. No other cause of muscle injury could be identified, although biochemical analysis of a muscle biopsy specimen revealed a deficiency of muscle phosphorylase activity. Retreatment with doxorubicin and paclitaxel was not associated with recurrent rhabdomyolysis.

Adult↗
PubMed1995

Effects of antisense c-myb oligonucleotides on vascular smooth muscle cell proliferation and response to vessel wall injury.

The process of restenosis after arterial balloon dilatation has been demonstrated to involve smooth muscle cell hyperplasia. Initial reports with antisense oligonucleotides directed against the proto-oncogene c-myb suggest marked in vitro specificity and in vivo efficacy. In the present study, we sought to confirm and extend the hypothesis that antisense to c-myb results in a specific antiproliferative effect with a comprehensive assessment by using different oligonucleotide preparations, different species, and tissue and cellular uptake experiments. Phosphorothioate-protected oligonucleotides representing the appropriate sequence for antisense to c-myb and multiple controls were used to inhibit proliferation of platelet-derived growth factor- and fetal bovine serum-stimulated rat, dog, and human aortic smooth muscle cells in vitro and neointimal proliferation in the rat carotid injury model. In vitro experiments using identical culture conditions in rat, dog, and human aortic smooth muscle cells failed to show specificity as well as consistency in growth inhibitory effects that could be attributed to an antisense mechanism. Proliferation of smooth muscle cell growth in culture was consistently inhibited with oligomers containing a contiguous 4-guanosine residue motif. In vivo, the rat carotid injury neointimal hyperplasia was similar for antisense c-myb (0.095 +/- 0.009 mm2) and sense c-myb (0.090 +/- 0.009 mm2). Fluorescent-labeled oligonucleotides were present in tissue after local delivery via pluronic gel, and their activity rapidly declined over a 72-hour period. Our findings point to the potential nonspecificity and lack of consistency of the antisense oligonucleotide to c-myb in vitro and in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Angioplasty, Balloon↗
PubMed1995

Novel delivery of antiarrhythmic agents.

Conventional antiarrhythmia therapy by oral or intravenous routes of administration is often ineffective and results in drug-associated complications and toxicity. In addition, poor bioavailability and a high first-pass effect limit therapeutic applications of several investigational antiarrhythmic compounds, which are otherwise more potent and less toxic than available agents. The regional nature of the several cardiac diseases, such as ischaemia, restenosis or heart valve calcification, may require a high concentration of drug at the location of the disease, which by conventional routes may not be attainable due to systemic toxicity of the drug. Localised cardiac delivery of antiarrhythmic agents, based on drug-polymer implants, may have several advantages, including enhanced drug effects and reduced systemic drug toxicity. Computer-assisted automated feedback systems may further enhance the usefulness of this therapy in the clinical setting. Before clinical application of this method of drug delivery further study will be required, but it is hypothesised that pharmacokinetic variability for drugs delivered in this manner will be reduced and therefore efficacy and toxicity will be more predictable.

Anti-Arrhythmia Agents↗
PubMed1994

Phosphonated polyurethanes that resist calcification.

Cardiovascular implant mineralization involving bioprosthetic materials, such as glutaraldehyde cross linked porcine aortic valves or synthetic materials such as polyurethanes, is an important problem that frequently leads to clinical failure of bioprosthetic heart valves, and complicates long-term experimental artificial heart device implants. Novel, proprietary, calcification resistant polyetherurethanes (PEU) as an alternative to bioprosthetic materials were the subject of these investigations. A series of PEU was derivatized through a proprietary reaction mechanism to achieve covalent binding of 100 to 500 nM/mg of bisphosphonate (2-hydroxyethane bisphosphonic acid, HEBP). The stability of HEBP (physically dispersed or covalently bound) verified by studying the release kinetics in physiological buffer (pH 7.4) at 37 degrees C, demonstrated the covalent binding reaction to be stable, efficient, and permanent. Surface (FTIR-ATR, ESCA, SEM/EDX) and bulk (solubility, GPC) properties demonstrated that the covalent binding of HEBP occurs in the soft segment of the PEU, reduces surface degradation, and does not affect the original material properties of the PEU (prior to derivatization). In vitro calcium diffusion of the derivatized PEU showed a decrease in calcium permeation as the concentration of HEBP covalent binding was increased. In vivo properties of underivatized and derivatized PEU (containing 100 nM of covalently bound HEBP) were studied with rat subdermal implants for 60 days. Explants demonstrated calcification resistance due to the covalently bound HEBP without any side effects. It is concluded that a PEU containing HEBP might serve as a calcification resistant candidate material for the fabrication of a heart valve prosthesis and other implantable devices.

Animals↗
PubMed1994

Effect of 2-amino oleic acid exposure conditions on the inhibition of calcification of glutaraldehyde cross-linked porcine aortic valves.

Postimplant calcific degeneration is a frequent cause of clinical failures of glutaraldehyde cross-linked porcine bioprosthetic heart valves (BPHV). It was demonstrated previously that 2-amino oleic acid (AOA) used as a bioprosthesis treatment was highly effective in mitigating aortic valve cusp but not aortic wall calcification. Our main objective was to study the efficacy of various AOA exposure conditions for inhibiting calcification of both cusps and aortic wall tissues using rat subdermal implants. BPHV tissues were treated with a saturated AOA solution for different time intervals before experimental. Aortic wall AOA levels were consistently lower than that of the cusps after the same exposure times. The diffusion of calcium ion across both cusp and aortic wall tissues was evaluated, and the results demonstrated that there was an AOA exposure time-dependent retardation of calcium ion penetration for cusp but not aortic wall. An 8-month extraction study was performed to determine the stability of AOA binding. When Tween 80 was used as an extraction medium, cusp and aortic wall retained 12.9 and 48.7%, respectively, of their initial AOA levels. AOA inhibition of calcification in rat subdermal implants (60 days) was found to be exposure time-dependent with maximum treatment time (120 h), resulting in the lowest calcium levels (20.1 +/- 10.3 and 71.4 +/- 5.4 micrograms/mg of cusp and aortic wall, respectively) as compared with controls (219.1 +/- 6.8 and 104.9 +/- 8.5 micrograms/mg of cusp and aortic wall, respectively). The significance of AOA binding on BPHV tissue was determined by either blocking or reducing BPHV's (cusp and aortic wall) free aldehyde residues with lysine or NaBH4, respectively, before AOA treatment. For aortic cusps, the AOA contents after 72 h were 98.3 +/- 2.7, 34.2 +/- 3.6, and 54.1 +/- 3.0 nM/mg of tissue for AOA (control), lysine-pretreated (plus AOA) and NaBH4-pretreated (plus AOA) tissues, respectively. However, their calcium levels after 60 days of rat subdermal implant were all comparable (i.e., 48.1 +/- 6.2, 38.2 +/- 9.1, and 47.0 +/- 15.0 micrograms calcium per mg of tissue). Similar results were observed on BPHV aortic wall. It can thus be concluded that AOA inhibition of BPHV calcification is exposure time-dependent, but the efficacy of AOA for aortic wall is less than that noted for aortic cusps, perhaps because of lower AOA binding and differences in calcium diffusion kinetics.

Animals↗
PubMed1994

Sotalol controlled-release systems for arrhythmias: in vitro characterization, in vivo drug disposition, and electrophysiologic effects.

An array of controlled-release formulations of sotalol were investigated for epicardial drug delivery in short-term and chronic long-term treatment models with dogs. A nondegradable matrix formulation of sotalol made with polyurethane was studied by use of short-term treatment model with dogs, and the electrophysiologic effects were compared with those resulting from an intravenous dose of 2 mg/kg of body weight. Epicardial sotalol-polyurethane matrices were also used in 7-day canine implant studies. A sotalol-silicone rubber matrix was used in 60-day epicardial canine implant studies. A biodegradable poly(dl-lactide-co-glycolide) (PLGA) microsphere formulation of sotalol was also studied as a pericardial injection in another series involving 30-day dog experiments. The short-term treatment electrophysiologic effects observed with the epicardial (left ventricular) implantation of a sotalol-polyurethane matrix formulation were comparable to those observed with intravenous sotalol. However, the total dose delivered by the matrix over a 2-h experimental period was 25 times smaller than the intravenous dose (0.077 versus 2 mg/kg). Furthermore, coronary venous sotalol levels after sotalol-polyurethane matrix implantation were in the therapeutic range (1812.4 +/- 415.1 ng/mL), whereas simultaneous peripheral venous levels were more than 1 order of magnitude lower (149.8 +/- 14.1 ng/mL). An intravenous bolus administration of sotalol (2 mg/kg) resulted in coronary venous levels (1537.1 +/- 44.6 ng/mL) that were very close to simultaneous peripheral venous levels (1428.6 +/- 63.9 ng/mL).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Modulated drug release using iontophoresis through heterogeneous cation-exchange membranes. 2. Influence of cation-exchanger content on membrane resistance and characteristic times.

An implantable drug delivery method using iontophoresis through cation-selective membranes was further developed. Heterogeneous cation-exchange membranes (HCMs) were prepared by mixing conductive sulfonated polystyrene beads into a nonconductive silicone rubber matrix. The membrane resistivity and lag time to steady-state transport of two salts, (+/-)-phenylpropanolamine hydrochloride (PPA) and NaCl, were evaluated during constant current iontophoresis at 37 degrees C as a function of the resin content in the HCMs. A continuous decline in membrane resistivity was observed as fractional resin content (l) was increased over the entire usable region (l = 0.29-0.52), a characteristic that could be described by a percolation scaling law (for an infinite lattice, 3-D geometry). Morphological analysis of the membranes before and after swelling strongly suggested that the conducting clusters of resin beads form during the swelling period prior to use. The response time to steady-state transport of PPA into NaCl during a 40 microA constant current (0.27 cm2) was found to increase with increasing l, but not without decreasing the permselectivity of the HCMs for the drug cation. The lag time effect could be explained in terms of an increasing number of fixed charge groups in the membrane available for transport (mfcA), which was derived from a macroscopic mass balance model. The values of mfcA were also found to be related to the characteristic time of diffusion in a homogeneous transport projection of the HCM (or an effective medium), an essential parameter for future non-steady-state simulations. The characteristic time of diffusion was found to be invariant with changing resin content, suggesting that the membranes are fairly nontortuous (ca. seven beads thick). By assuming that the thickness of the HCM approaches the thickness of its homogeneous projection, an expression was derived to predict lag time to steady-state PPA transport requiring resistance measurements only (provided that the resin capacity is known). There was excellent agreement between the theoretical and experimental lag time to steady-state transport of PPA (r = 0.96, p < 0.001), further implicating the role of membrane resistance in the bi-ionic system. These modeling approaches have already found utility in iontophoretic implant design for prevention of cardiac arrhythmias and may be valuable in future non-steady-state analysis to further develop on-line detection-implant response technology.

Cations↗
PubMed1994

Epicardial administration of ibutilide from polyurethane matrices: effects on defibrillation threshold and electrophysiologic parameters.

Polymer-drug composites known as controlled-release systems have been used effectively to prevent and treat ventricular arrhythmias in experimental studies. We wished to determine if such systems could be useful in reducing ventricular defibrillation energy requirements in an acute canine model without producing undesirable electrophysiologic effects. Ibutilide-polyurethane monolithic controlled-release matrices were formulated with ibutilide fumarate and a polyether polyurethane. In vitro drug-release characteristics of the drug matrices were determined. Two formulations were investigated: (a) 20% ibutilide by weight in polyether polyurethane, and (b) 4% ibutilide/16% dimethyl tartrate in polyurethane. Based on in vitro release studies, 20% ibutilide matrices (25 mg) would provide a 25-kg dog with a dose of 25 micrograms/kg ibutilide in a 2-h acute experimental period, and 4% ibutilide matrices were estimated to provide 3.5 micrograms/kg. We used each of these types of matrices in acute open-chest dog studies to assess electrophysiologic effects and the influence of epicardial controlled-release ibutilide, as compared with intravenous (i.v.) administration, on defibrillation energy thresholds (DFTs), using epicardial defibrillation electrodes. In monophasic defibrillation waveform studies, 20% matrices significantly decreased DFT as compared with a predrug control period [2.54 +/- 0.59 (mean +/- SEM) vs. 7.23 +/- 1.73 J, respectively, p = 0.038]. Administration of the same dose i.v. did not cause significant reduction in energy requirement. With a biphasic defibrillation waveform, 4% ibutilide matrices significantly decreased DFT as compared with control (2.53 +/- 0.34 vs. 3.42 +/- 0.46 J, respectively, p = 0.003). Administration of an equivalent i.v. dose did not cause a significant reduction in biphasic energy requirement. Both types of controlled-release systems significantly prolonged refractoriness and conduction times of ventricular extrastimuli as compared with vehicle. No proarrhythmia events were observed. Epicardial polymeric controlled-release ibutilide significantly prolonged ventricular refractoriness and conduction and thus may enhance antiarrhythmia activity. In addition, controlled-release ibutilide formulations significantly decreased DFT requirements. Thus, ibutilide-polymeric controlled-release matrix systems may be useful in conjunction with implantable defibrillators in preventing ventricular arrhythmias and reducing defibrillation energy requirements.

Animals↗
PubMed1994

Site-specific dexamethasone delivery for the prevention of neointimal thickening after vascular stent implantation.

BACKGROUND: Site-directed pharmacologic therapy using drug-impregnated polymers may achieve high local tissue levels at sites of arterial injury without systemic side effects. The aim of this study was to determine whether sustained, local administration of the synthetic glucocorticoid dexamethasone reduces the severity of intimal hyperplasia induced by arterial stenting in a porcine model of restenosis. METHODS: Dexamethasone-impregnated silicone polymers (20% loading by weight) were formulated and tested in vitro to determine the time course of drug release. Oversized metallic stents were implanted in both carotid arteries of 14 juvenile Yorkshire farm pigs. A dexamethasone-impregnated polymer matrix was then placed around the external surface of the stented artery on one side, and a control polymer was placed contralaterally in an identical manner. Two animals were killed 5 days after stent implantation and the remainder after 35 +/- 1 days. RESULTS: Ex-vivo dexamethasone release from the silicone polymers was estimated to be 5 mg/day for the first 3 days and 0.3 mg/day thereafter. The arterial tissue dexamethasone levels after 5 days were 1307 +/- 498 ng/g of tissue on the treated side and 7.5 +/- 1.0 ng/g of tissue on the control side. The plasma dexamethasone level was 1.6 +/- 0.3 ng/ml, with no step-up in concentration across the segment surrounded by the drug-impregnated polymer. After 35 days, macroscopic examination and computerized morphometric analysis showed a substantial difference in the extent of polymer-induced adventitial and perivascular scarring but no difference in the extent of neointimal thickening. The adventitia:media ratio was 2.99 +/- 0.33 on the dexamethasone-treated side but 4.29 +/- 0.36 on the control side (P < 0.02). The intima:media ratios were 0.48 +/- 0.09 and 0.52 +/- 0.07, respectively. CONCLUSION: Sustained, local dexamethasone therapy has potent anti-inflammatory and anti-fibrotic effects but, with the dose and route of administration used in this study, does not reduce the intimal hyperplastic response to injury in this model.

Animals↗
PubMed1994

Pathology of substitute heart valves: new concepts and developments.

All types of contemporary cardiac valve substitutes suffer deficiencies and complications that limit their success. Mechanical and bioprosthetic valves are intrinsically obstructive, especially in small sizes. Mechanical valves are associated with thromboembolic problems; the chronic anticoagulation used in virtually all mechanical valve recipients causes hemorrhage in some. Calcification limits the success of porcine and pericardial bioprostheses, allograft valves, and the yet experimental trileaflet polymeric prostheses. The predominant mechanism of calcification in porcine, pericardial, and allograft valves is cell mediated, being nucleated at the membranes and in organelles of the transplanted cells. In polymeric leaflet valves, calcification is both extrinsic (in adherent thrombus) and intrinsic (subsurface and acellular in the solid elastomer). Nevertheless, except for a few notable exceptions, contemporary mechanical valves are durable. Other important potential complications of prosthetic and bioprosthetic valves include paravalvular leak, endocarditis, or extrinsic interference with function. Moreover, aortic valvular allografts undergo progressive noncalcific degeneration, tearing, sagging, and/or retraction. Studies of retrieved long-term cryopreserved allograft explants demonstrate severe degeneration, with distortion of normal architectural detail, loss of endothelial and deep connective tissue cells, and variable inflammatory cellularity. Thus, they are morphologically nonviable valves, whose structural basis for function seems primarily related to the largely preserved collagen, and they are unlikely to have the capacity to grow, remodel, or exhibit active metabolic functions. Since calcification intrinsic to the cusps is the major pathologic process necessitating bioprosthetic valve reoperations, efforts to prevent formation of mineral deposits are active.(ABSTRACT TRUNCATED AT 250 WORDS)

Bioprosthesis↗
PubMed1994

Mechanism of efficacy of 2-amino oleic acid for inhibition of calcification of glutaraldehyde-pretreated porcine bioprosthetic heart valves.

BACKGROUND: Calcification is a frequent cause of the clinical failures of glutaraldehyde-pretreated bioprosthetic heart valves (BPHV) fabricated from glutaraldehyde-cross-linked porcine aortic valves. 2-Amino oleic acid (AOA) has been shown in previous in vivo studies to be a promising anticalcification agent. Our objective was to investigate the mechanism of calcification inhibition mediated by AOA pretreatment of porcine aortic valve bioprostheses. METHODS AND RESULTS: BPHV tissues were treated with an AOA solution for 72 hours before experimentation. The diffusion of AOA across both cusp and aortic wall was evaluated. The lag time for AOA to diffuse across the aortic wall was prolonged compared with that of the cusp. An extraction study was performed to determine the stability of AOA binding; the results indicated that the binding was relatively stable regardless of solvent extraction conditions. The interaction between ionic calcium and AOA on treated tissue also was investigated by evaluating the patterns of calcium diffusion across both treated and untreated tissues. The results showed that AOA significantly reduced the diffusion of calcium. AOA inhibition of aortic valve calcification (calcium level, 5.5 +/- 3.0 mg/g of tissue compared with control; calcium level, 91.2 +/- 19.5 mg/g of tissue) but not aortic wall (calcium level, 158.7 +/- 10.3 mg/g of tissue compared with control; calcium level, 157.5 +/- 7.9 mg/g of tissue) was demonstrated on representative specimens from valves implanted in left ventricular apicoaortic shunts explanted after 150 days. CONCLUSIONS: AOA covalently binds to glutaraldehyde-pretreated bioprosthetic heart valve tissue, presumably as the result of an aldehyde-amino reaction. Covalently bound AOA diminishes Ca2+ diffusion compared with non-AOA-pretreated bioprosthetic tissues. This may explain in part the anticalcification mechanism of AOA. Furthermore, AOA inhibits calcification of porcine BPHV cusps in the circulation.

Animals↗
PubMed1994

Local delivery of dexamethasone for prevention of neointimal proliferation in a rat model of balloon angioplasty.

A periadventitial polymer system is an alternative local drug delivery technique to obtain and maintain high tissue levels of the drug at the site of vascular injury. To determine if local periadventitial delivery of dexamethasone decreases neointimal proliferation after balloon vascular injury, in three groups of Sprague-Dawley rats, 5% dexamethasone, 0.5% dexamethasone, and placebo silicone polymers were implanted around the left common carotid artery after balloon injury. In a fourth group, placebo polymers were implanted without balloon injury. Dexamethasone serum and tissue levels after polymer implantation were significantly higher in the 5% dexamethasone group compared with the 0.5% dexamethasone group. There was no neointima formation in any of the arterial segments covered with placebo polymers for 3 wk, but without balloon injury. In the arterial segments covered by the 5 and 0.5% dexamethasone polymers, there was a 76 and 75% reduction in intima/media ratios, respectively, compared with the placebo group (5% dexamethasone, 0.26 +/- 0.04; 0.5% dexamethasone, 0.27 +/- 0.03; placebo, 1.09 +/- 0.16, respectively; P < 0.0001). These results suggest that: (a) silicone polymers wrapped around the common carotid arteries for 3 wk did not, without balloon injury, stimulate neointimal proliferation in the rat model; (b) the activity of the drug-eluting polymer for suppressing intimal proliferation was chiefly, but not exclusively, site specific; and (c) transadventitial local delivery of dexamethasone at two different doses markedly inhibits neointimal proliferation after balloon vascular injury.

Administration, Topical↗
PubMed1994

Onset and progression of calcification in porcine aortic bioprosthetic valves implanted as orthotopic mitral valve replacements in juvenile sheep.

The purpose of this study was to characterize the onset and progression of mineralization in porcine bioprosthetic valves implanted in sheep and to test the hypothesis that such valves simulate calcification that is observed clinically and in other experimental models. Hancock I porcine aortic bioprosthetic valves (Medtronic Heart Valve Division, Irvine, Calif.) were implanted as orthotopic mitral valve replacements in juvenile sheep, retrieved after 1 to 124 days, and analyzed as follows: gross inspection, radiography, light, transmission, and surface scanning electron microscopy, and calcium analysis by absorption spectroscopy. Mineralization increased with increasing time after implantation in both valve cusps and adjacent aortic wall. Mean cuspal calcification was 80 micrograms/mg in valves removed after 3 to 4 months. Nevertheless, considerable variability among valves was apparent in the level of calcification noted at specific time intervals. Virtually all aspects of the morphologic characteristics were identical to those previously noted for clinical explants and experimental specimens, both subcutaneous and circulatory. In particular, ultrastructural examination revealed that the earliest calcific deposits were associated with devitalized cuspal connective tissue cells and their fragments. Collagen calcification was sparse. Both surface scanning and transmission electron microscopy indicated a lack of endothelial or blood-derived cells on the valves at all sampling times. We conclude that porcine bioprosthetic valves implanted as mitral valves in sheep provide a useful calcification model, simulating morphologic and pathobiologic events that occur clinically and in noncirculatory models. However, sufficient specimen replicates must be done to overcome variability in calcification among valves and sampling sites.

Animals↗
PubMed1993

Inhibition of calcification of glutaraldehyde pretreated porcine aortic valve cusps with sodium dodecyl sulfate: preincubation and controlled release studies.

Calcification of bioprosthetic heart valves fabricated from glutaraldehyde pretreated bovine pericardium or porcine aortic valves (PAV) is a frequent cause of the failure of these devices. Of all strategies considered thus far, only detergent preincubations using compounds such as sodium dodecyl sulfate (SDS) inhibited PAV bioprosthetic mineralization in circulatory sheep bioprosthetic valve replacements. The present study sought to characterize the mechanism of action of SDS preinicubation. Results of transport and material characterization studies showed that SDS had a relatively high affinity for PAV, with a maximum uptake of 167.1 +/- 6.8 micrograms SDS/mg tissue over 24 h at 37 degrees C with a partition coefficient of 19.3. The PAV diffusion of SDS was 1.95 +/- 0.35 10(-6) cm2/sec. The principal effect of SDS on PAV was phospholipid extraction. The residual organic phosphate in the SDS pretreated tissue was 2.22 +/- 0.72 nmol/mg tissue compared to the control untreated group with 18.52 +/- 2.1 nmol/mg tissue. Incubations of PAV specimens in a 1% SDS solution for 24 h significantly inhibited calcification after 21 days in subdermal implants in 3-week-old male rats (PAV Ca2+ = 18.0 +/- 11.8 micrograms/mg) compared to control (177.8 +/- 6.0 micrograms/mg). In contrast, coimplants of 30% SDS silicone rubber polymers, for regional sustained SDS administration, did not impede PAV calcification in 21 day implants Ca2+ = 166.0 +/- 14.0 micrograms/mg compared to the nondrug silicone matrix controls, Ca2+ = 173.0 +/- 6.6 micrograms/mg). Thus, we conclude that the mechanisms of SDS inhibition of PAV calcification is due to material effects which occur during preincubation, and is not facilitated by sustained SDS administration.

Animals↗
PubMed1993

Effects of metallic ions and diphosphonates on inhibition of pericardial bioprosthetic tissue calcification and associated alkaline phosphatase activity.

This study focused on the association of extrinsic alkaline phosphatase (AP) activity with both early and advanced calcification of glutaraldehyde-pretreated bovine pericardial bioprosthetic (GPBP) tissue, and the inhibition of both calcification and AP activity by pre-incubation in diphosphonates (sodium-ethanehydroxydiphosphonate [NaEHDP], aminopropanehydroxydiphosphonate [APD]) and metallic salts (FeCl3, Ga(NO3)3, AICI3). GPBP specimens were implanted subcutaneously in 3 wk old male rats after pre-incubation. Following explantation of the tissue at 72 h and 21 d, calcification was assessed morphologically by light microscopy and chemically by atomic adsorption spectroscopy for calcium content and by molybdate complexation for phosphorus. AP activity was characterized by enzymatic hydrolysis of paranitrophenyl phosphate and by histochemical studies. In both control and pretreated groups, AP levels were greater in 72 h explants than 21 d retrievals, which demonstrated extensive calcification in control explants. All pre-incubations that resulted in inhibition of calcification after 21 d, except for APD, were associated with 72 h AP content which was lower than control specimens. The typical time of initiation of calcification was 72 h, as determined by previous studies with this model system. Covalently bound APD inhibited calcification. Increased AP activity in the APD group may be due to the toxicity of this agent with resultant acute inflammation, or other incompletely understood effects of diphosphonates on calcification and AP. Furthermore, EHDP and Ga3+ incubations were also associated with decreased GPBP AP at 72 h compared to control, but were not effective for inhibiting calcification after 21 d. We concluded that inhibition of peak GPBP AP activity is not necessarily associated with the prevention of GPBP mineralization.

Alkaline Phosphatase↗