Dose-dependent hyperlipidemia in rabbits following administration of poloxamer 407 gel.

Poloxamer 407 (P-407) is a tri-block polymer that exhibits concentration-dependent reverse thermal gelation, a characteristic potentially useful for developing sustained release injectable drugs. While some reports suggest that P-407 is 'non-toxic', rodent studies demonstrate that P-407 induces hyperlipidemia, an action that makes this polymer a questionable drug delivery vehicle. Unfortunately, the majority of earlier studies employed supra-physiologic doses of P-407. The present study examined if lower, clinically useful, doses of gel-forming concentrations of P-407 induced hyperlipidemia in rabbits. Male and female rabbits were injected with 5.5 mg/kg (0.025 mL/kg), 27.5 mg/kg (0.125 mL/kg), or 137.5 mg/kg (0.625 mL/kg) of 22% P-407 and the actions of this polymer on blood chemistry were assessed at 6 h, 1 d, 2 d, 7 d, and 14 d following injection. Control rabbits received no injection. The highest dose of P-407 (137.5 mg/kg) significantly increased serum triglycerides and cholesterol in both male and female rabbits with the maximum increase observed at 2 d after injection. Male rabbits were more sensitive to P-407 than females following injection of 137.5 mg/kg P-407. The lower doses of P-407 did not alter serum triglycerides or cholesterol. In all groups, serum triglycerides and cholesterol were at baseline levels by 14 d. P-407 did not affect other blood chemistry parameters. Although P-407 induces a dose-dependent hyperlipidemia in rabbits, low doses of this polymer may be used in controlled release drug delivery applications without the untoward hyperlipidemic effect.

Periodontal pocket treatment in beagle dogs using subgingival doxycycline from a biodegradable system. I. Initial clinical responses.

The present study evaluated the clinical response of periodontal pockets in beagle dogs after treatment with a biodegradable delivery system containing 10% doxycycline hyclate (ABDS-D). Eight adult, female beagle dogs had generalized, severe periodontitis with plaque and calculus-laden pockets. In each animal, 3 teeth with multiple pocket sites > or = 4 mm (mean depth = 6.0 mm) associated with attachment loss (mean = 5.4 mm) and which bled on probing (mean score = 2.5) were treated with a single application of either ABDS-D (experimental group) or the delivery system alone without the doxycycline (control group). Residual polymer was removed at day 7. Bioassay of doxycycline in gingival crevicular fluid associated with presence of ABDS-D gave mean levels of bioactivity of approximately 250 micrograms/ml. Levels of bioactive doxycycline were detected for approximately 7 days after ABDS-D removal. Periodontal maintenance consisted of thrice-weekly toothbrushing the treated sites. Clinical responses were evaluated at 2 weeks, and at bi-weekly intervals thereafter for 4 months. Analyses of the data from the control group showed that there was only slight clinical improvement. In contrast, in the experimental group, bleeding on probing and probing depths were significantly reduced from baseline at all post-treatment time points. At 1 month, mean probing depth reduction was 2.4 mm and this was maintained at 4 months (mean reduction = 2.5 mm). These probing depth reductions occurred primarily through gain of clinical attachment which was 2.0 mm at 4 months. Bleeding had been virtually eliminated (mean = 0.2). It was concluded that, for the beagle dogs with severely infected periodontal pockets in this study, treatment with subgingival doxycycline using the delivery system resulted in substantial improvement in periodontal health.

Periodontal regeneration in naturally occurring Class II furcation defects in beagle dogs after guided tissue regeneration with bioabsorbable barriers.

THE EFFICACY OF A BIOABSORBABLE polylactic acid based barrier was evaluated using naturally occurring buccal Class II furcation defects in beagle dogs. Sixteen furcation sites (8 control and 8 experimental) were treated in 6 adult animals. After full thickness flap reflection, exposed furcations and root surfaces were thoroughly root planed. In experimental sites a customized barrier was formed and fitted to cover the defect. Surgical flaps were replaced slightly coronal to the cemento-enamel junction. Animals were sacrificed at 6 months and specimens processed for histologic evaluation. Histologic and histometric analyses were done using 6 micrograms step serial sections in the buccal-lingual plane, corresponding to the buccal-lingual extent of the furcation. Results were: mean total defect experimental sites 1.92 mm; control sites 1.47 mm. Mean new cementum formation experimental sites 1.36 mm (71% of initial defect); control sites 0.25 mm (17% of initial defect). Mean new bone formation experimental sites 1.42 mm (74% of initial defect); control sites 0.20 mm (14% of initial defect). Mean junctional epithelium formation experimental sites 0.42 mm (22% of initial defect); control sites 1.21 mm (82% of initial defect). Statistical analysis demonstrated significant differences in all healing parameters favoring experimental (barrier-treated) sites. In this model, regeneration (new bone, cementum, and periodontal ligament) of 71% of the original defect in experimental sites and only 14% in control sites demonstrated a response that highly favored use of the barrier.

Periodontal healing after guided tissue regeneration with Atrisorb barriers in beagle dogs.

Periodontal healing after use of Atrisorb barrier material (polylactic acid) for guided tissue regeneration was studied in the premolar and molar teeth of six beagle dogs. Defects studied were surgically induced or were caused by naturally occurring periodontitis. Barriers fragmented and became displaced in 2 to 5 weeks after application. Granulation tissue was sometimes present between the barrier and root surface at 10 days to 4 weeks. Several sites were surgically reentered at 4 months, and new bone covered 60% to 100% of the formerly exposed furcations and root surfaces. Sites obtained for histologic evaluation 9 to 12 months after the baseline surgery showed new connective tissue attachment, cementum, and alveolar bone. Histomorphometric analyses quantitated these tissue changes, and new connective tissue attachment covered 72% of surgically exposed root surfaces and 77% of periodontitis-exposed root surfaces. It was concluded that new periodontal supporting tissues became reconstituted on root and furcation surfaces after use of the Atrisorb barrier material for GTR.

Biodegradation and biocompatibility of a guided tissue regeneration barrier membrane formed from a liquid polymer material.

Biodegradable barrier films were made by coagulating a solution of poly(DL-lactide) in N-methyl-2-pyrrolidone on porous polyethylene pads wetted with saline solution. The semisolid films were cut into 10 x 10 mm barriers and implanted subcutaneously in rabbits. At monthly intervals, the polymer implant sites were compared histologically to those implanted with USP negative control plastic. The polymer films were retrieved from the surrounding tissue, dried, weighed, and the changes in molecular weight determined using gel permeation chromatography. The molecular weight of the polymer decreased at a relatively constant rate over 5 months; however, no significant mass loss occurred until 5 months postimplantation. Also, no distinct histological differences were noted between the polymer barrier and the control plastic sites until 6 months when histiocytes and multinucleated giant cells showed a modest increase around fragmented polymer films. Similar barrier films also were fitted over naturally occurring buccal dehiscence defects in beagle dogs and the tissue sites compared histologically at 6 months to sham-operated control sites. New bone and dense connective tissues closely approximated segments of the remaining polymer and demonstrated the biocompatibility of the biodegradable films. Histomorphometric analyses of treated sites compared to sham controls showed that the polymer barrier is effective in promoting bone and cementum regeneration in periodontal defects in dogs.