Thomas Underwood

Arterial uptake of biodegradable nanoparticles for intravascular local drug delivery: Results with an acute dog model

Biodegradable nanoparticles (NP) with a spherical diameter ranging from 70 to 160 nm were investigated for potential usefulness for the local intraluminal therapy of restenosis, the disease process responsible for arterial reobstruction following angioplasty. NPs containing a water-insoluble anti-proliferative agent U-86983 (U-86, Pharmacia and Upjohn, Kalamazoo, MI) were formulated from oil-water emulsions using biodegradable polymers such as poly(lactic acid-co-glycolic acid) (PLGA), and specific additives after particle formation, to enhance arterial retention using either heparin, didodecylmethylammonium bromide (DMAB), or fibrinogen, or combinations. Femoral and carotid arteries of male mongrel dogs were isolated in situ, and were then subjected to a balloon angioplasty. A NP suspension of a predetermined concentration was then infused into the artery for various durations. This was followed by a 30 min restoration of blood flow through the vessel. The arterial segments were excised and analyzed for drug levels. From the drug loading the NP and the drug levels in the artery, the quantity of nanoparticles retained was calculated and expressed as microgram per 10 mg dry arteries. In general, repeated short infusions of nanoparticle suspension (15 s x 4) were two-fold more effective in terms of higher arterial U-86 levels than a single prolonged infusion (60 s). A single 15 s infusion was not significantly different than a 60 s compared to non-modified NPs (39.2 +/- 2.5 and 49.1 +/- 2.4 vs. 21.5 +/- 0.6 micrograms/10 mg mean +/- s.e., respectively). A comparably enhanced NP uptake was noted with a combined heparin/DMAB modification. Increasing the concentration of NP in infusate from 5 to 30 mg ml-1 significantly increased arterial NP uptake level (from 22.5 +/- 3.5 to 83.7 +/- 1.4 micrograms/10 mg). Thus, the results support the view that modified nanoparticles along with optimized infusion conditions could enhance arterial wall drug concentrations of agents to treat restenosis.

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.

Calcification of polyurethanes implanted subdermally in rats is enhanced by calciphylaxis

Calcification complicates the use of the polymer polyurethane in cardiovascular implants. To date only costly experimental circulatory animal models have been useful for investigating this disease process. In this paper we report that polyurethane calcification in rat subdermal implants is enhanced by overdosing with a vitamin-D analog. The calcification-prone state, known as calciphylaxis, was induced in 4-week old rats by oral administration of a vitamin-D analog, dihydrotachysterol. We studied two commercially available polyurethanes (Biomer and Mitrathane) and two proprietary polyurethanes (PEU-2000 and PEU-100). PEU-100 is unique because it is derivatized with ethanehydroxy-bisphosphonate (EHBP) for calcification resistance. Polyurethane calcium and phosphate levels and morphological changes due to calciphylaxis were compared with those of control rat subdermal explants in 60-day studies. Increased polyurethane mineralization was observed due to calciphylaxis with 60-day rat subdermal explants of Biomer, Mitrathane, and PEU-2000 (calcium levels, respectively, 4.13 +/- 0.56, 18.61 +/- 2.73, and 3.37 +/- 0.22 microgram/mg, mean +/- standard error) as compared to control explants (calcium levels, respectively, 1.22 +/- 0.1, 12.57 +/- 0.86, and 0.20 +/- 0.86 microgram/mg). The study also demonstrated that with 60-day implants calciphylaxis had no side effects on somatic growth and serum calcium levels. Explant surface morphology of these polyurethane explants examined by scanning electron microscopy, back scattering electron imaging coupled with energy dispersive X-ray spectroscopy, and light microscopy demonstrated the presence of predominantly surface-oriented calcification. PEU-100, derivatized with 100 n.moles/ mg of EHBP, resisted calcification with explant calcium levels 0.51 +/- 0.01 (calciphylaxis) and 0.38 +/- 0.01 (control) microgram/mg. It is concluded that calciphylaxis enhances superficial polyurethane calcification in rat subdermal implants and that an EHBP-modified polyurethane resists calcification despite calciphylaxis. Rat subdermal implants using calciphylaxis may be generally useful for evaluating the calcification potential of various biomedical polymers.

The efficacy of controlled release D-sotalol-polyurethane epicardial implants for ventricular arrhythmias due to acute ischemia in dogs

Epicardially implanted Dsotalol polyurethane composite matrices for preventing ischemic ventricular arrhythmias were studied in open chest dogs under general anesthesia. D-sotalol was combined with a polyureapolyurethane (3:7) in solvent-cast films, which were characterized in vitro for their drug release at 37°C at pH 7.4 (0.05 M K2HP04). D-sotalol in vitro release occurred rapidly in an initial burst phase, with roughly 20% released within the first five min, and 90% by 60 min. Thereafter, an exponentially decreasing release rate was observed with matrix depletion by live hours. In the animal studies, the left anterior descending coronary artery (LAD) was occluded for 10 min on an hourly basis for up to live occlusions. 10 min prior to the third LAD occlusion, either a D-sotalol matrix or a vehicle matrix (control) was placed on either the ischemic or nonischemic left ventricular epicardium. The study was then continued observing the effects of matrix placement on occlusions 3,4, and 5.200 mg D-SOtdO matrices, which delivered a net dose of 1.2 mg/kg, effectively inhibited ventricular arrhythmias only if placed on the left ventricular ischemic zone. Placement of 200 mg D-sotalol matrices in the nonischemic zone was ineffective for significantly reducing the occurrence of ventricular arrhythmias. Furthermore, D-sotalol controlled release matrices were ineffective for preventing ventricular fibrillation (VF) regardless of dose or placement site. 200 mg ischemic zone D-sotalol matrices resulted in plasma sotalol levels in regional coronary venous samples ranging from 3.5 pg/ml to 10.4 &ml. However, peripheral sotalol levels obtained simultaneously ranged from 0.23 pg/ml to 0.78 ,ug/ ml. It is concluded that epicardial D-sotalol controlled release matrices inhibited ischemic ventricular arrhythmias, but not VF, if placed in the left ventricular ischemic zone during repeated LAD occlusions.

Controlled release implant dosage forms for cardiac arrhythmias: Review and perspectives

Cardiac implants using drug-polymer systems for the release of anti-arrhythmic agents directly to the myocardium have been successfully utilized in experimental studies for preventing and treating arrhythmias. This approach is hypothesized to be optimal since anti-arrhythmic agents are provided directly to the heart, and therefore the possibility of systemic side effects is reduced. Furthermore, anti-arrhythmic agents with poor oral bioavailability or with first-pass clearance characteristics following intravenous administration, such as the class III agent ibutilide, are optimally used by the direct cardiac route of administration. Cardiac controlled release implants have been demonstrated to be effective for optimizing the therapy of ventricular tachycardia, ventricular fibrillation, and atrial flutter. Monolithic matrices have been used for fixed rate release kinetics, and modulation of release has been possible through the use of iontophoretic drug delivery systems. Future implants will interface with forefront strategies in tissue engineering and molecular genetics to provide optimal therapy of the diseased arrhythmogenic myocardium.

Prevention of acute inducible atrial flutter in dogs by using an ibutilide-polymer-coated pacing electrode.

Atrial arrhythmias (atrial fibrillation or atrial flutter) after coronary artery bypass graft surgery are difficult to prevent or treat and often result in significant morbidity. Prior experimental studies by our group showed improved therapeutic efficacy for antiarrhythmic drugs delivered via controlled-release polymeric matrices implanted on the epicardial surface. These experiments were conducted to test the hypothesis that direct atrial epicardial administration of ibutilide from a controlled-release system (compared with intravenous administration) can reduce the inducibility of atrial flutter in the acute postoperative atrial myocardium. Polymeric sustained-release preparations were formulated by solvent casting of an ibutilide and polyurethane (Pellathane) solution in tetrahydrofurane. Multilayer solvent-casted coatings on pacing electrode wires were carried out to fabricate a sustained-release electrode system. In animal model studies, each dog underwent a thoracotomy, followed by a right atriotomy that was repaired. Induction of atrial flutter was attempted by burst pacing with the bipolar pacing catheter. Sinus rhythm was restored with overdrive pacing. After determining the induction rate (percentage) of atrial flutter in the baseline state, a stainless-steel wire coated with the drug-delivery system, 10% ibutilide/90% polyurethane (n = 7), or without drug (polyurethane coating without ibutilide, n = 5; control) was sewn onto the right atrium. Systemic intravenous administration of ibutilide (1.2 microg/kg/h) also was carried out in a separate group of animals after atriotomy (n = 5). For ibutilide (at an estimated dose of 1.2 microg/kg/h), the atrial-flutter results were 41.85 +/- 2.21% induction for baseline compared with 12.42 +/- 5.26% (p = 0.02) after the ibutilide wire implant. In the control dogs, atrial flutter was induced 29.4 +/- 4.7% at baseline and 25.2 +/- 5.1% after implantation of the control wire (p = 0.4). Ibutilide coronary venous serum concentrations at the end of the ibutilide-polyurethane electrode experiments were 2.25 +/- 0.2 ng/ml (mean +/- SEM) versus systemic levels that were below the limits of detection. Systemic intravenous ibutilide infusions had no effect on the inducibility of atrial flutter. In conclusion, an epicardial implantable electrode coating with an ibutilide controlled drug-release system significantly reduced the inducibility of atrial flutter in an experimental atriotomy model. These results suggest that atrial arrhythmias occurring after coronary bypass surgery may be prevented by local atrial administration of ibutilide from a controlled-release pacing electrode.