Two multi-center studies evaluating locally delivered doxycycline hyclate, placebo control, oral hygiene, and scaling and root planing in the treatment of periodontitis.

BACKGROUND: The clinical efficacy and safety of doxycycline hyclate (8.5% w/w) delivered subgingivally in a biodegradable polymer (DH) was compared to placebo control (VC), oral hygiene (OH), and scaling and root planing (SRP) in 2 multi-center studies. METHODS: Each study entered 411 patients who demonstrated moderate to severe periodontitis. Patients had 2 or more quadrants each with a minimum of 4 qualifying pockets > or =5 mm that bled on probing. At least 2 of the pockets were > or =7 mm. Treatment with DH, VC, OH, or SRP was provided at baseline and again at month 4. Clinical parameters were recorded monthly. RESULTS: DH and SRP resulted in nearly identical clinical changes over time in both studies. Mean 9 month clinical attachment level gain (ALG) was 0.8 mm for the DH group and 0.7 mm for the SRP group in Study 1, and 0.8 mm (DH) and 0.9 mm (SRP) in Study 2. Mean probing depth (PD) reduction was 1.1 mm for the DH group and 0.9 mm for the SRP group in Study 1 and 1.3 mm for both groups in Study 2. Frequency distributions showed an ALG > or =2 mm in 29% of DH sites versus 27% of SRP sites in Study 1 and 31% of DH sites versus 34% of SRP sites in Study 2. PD reductions > or =2 mm were seen in 32% of DH sites versus 31% of SRP sites in Study 1 and 41% of DH sites versus 43% of SRP sites in Study 2. Comparisons between DH, VC, and OH treatment groups showed DH treatment to be statistically superior to VC and OH. Safety data demonstrated a benign safety profile with use of the DH product. CONCLUSIONS: Results of this trial demonstrate that treatment of periodontitis with subgingivally delivered doxycycline in a biodegradable polymer is equally effective as scaling and root planing and superior in effect to placebo control and oral hygiene in reducing the clinical signs of adult periodontitis over a 9-month period. This represents positive changes resulting from the use of subgingivally applied doxycycline as scaling and root planing was not limited regarding time of the procedure or use of local anesthesia.

Apparent interaction of dimethyl sulfoxide with cisplatin released from polymer delivery devices injected subcutaneously in dogs.

Local tissue toxicity, systemic toxicity and platinum pharmacokinetics were evaluated in 6 normal healthy beagle dogs injected subcutaneously with two formulations of a polylactide biodegradable polymer (Atrigel) system containing cisplatin. Dogs were injected 4 times at 30 day intervals at platinum dosages of 70, 105 and 157.5 mg/m2 (dose escalation). Once pharmacokinetics were established, 29 dogs with spontaneous stage IIb appendicular osteosarcoma were treated with 4 injections of the same polymer system containing cisplatin at 70 mg/m2 (20 dogs) and 100 mg/m2 (9 dogs) to establish efficacy against micrometastatic disease. Local tissue toxicity was variable. Systemic toxicity, as judged by clinicopathologic evaluation was not noted at any dose level or injection number. Interim (6 month) survival analysis revealed a median disease-free interval of 180 days. Consistent platinum release characteristics were found, however, the lack of toxicity and decreased disease-free-interval raised concerns over the biologic activity of the cisplatin. Prior to completion of the study, it was discovered that dimethyl sulfoxide, the solvent used in the co-polymer system, may be responsible for biologic inactivation of cisplatin. This was subsequently demonstrated in tissue culture assays. The clinical trial was suspended and dogs were treated with traditional chemotherapy.

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.

Subgingival controlled release of antimicrobial agents in the treatment of periodontal disease.

Local drug delivery of antimicrobics by sustained release delivery systems can be used to treat periodontal disease. Advantages of these systems may include biodegradation of the system, maintaining high levels of antibiotic in the gingival crevicular fluid (GCF) for a sustained period of time and ease of use with high patient acceptance. This review will identify human in vivo clinical and microbiological studies. Sustained release formulations, application methods, clinical results and microbiological effects are discussed.

The drug delivery and biomaterial attributes of the ATRIGEL technology in the treatment of periodontal disease.

Two new products, ATRIDOX Periodontal Treatment and ATRISORB Guided Tissue Regeneration (GTR) Barrier have been evaluated as therapies for periodontal disease. Both products are based on the unique ATRIGEL technology. The system consists of a solution of a resorbable polymer in a biocompatible carrier. On in vivo administration, the polymer undergoes a phase change from a liquid to an in situ formed implant. Being in liquid form, it initially provides the advantage of in vivo placement by simple means, such as syringes to form implants at the site of use. The system is biocompatible and has the capability of serving as a biomaterial and a drug delivery system. The bioabsorption rates of various polymers and the release rates for a wide variety of drugs ranging from simple organics to proteins and peptides are tailored to the desired indication. Release periods ranging from one week to four months have been achieved with one month being the most often desired. For these reasons the ATRIGEL system is being applied to a number of medical applications ranging from site and systemic oncology to post-operative pain control and bone regeneration using growth factors. However, its most visible application to date has been in the development of a pipeline of products for the treatment of periodontal disease, which is the focus of this paper.

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.

Effects of sanguinarium, chlorhexidine and tetracycline on neutrophil viability and functions in vitro.

The effectiveness of an ideal antimicrobial agent depends on its ability to kill microbes with minimal toxicity to host cells. Depending on the treatment regimen, antimicrobial agents come into contact with host cells for various intervals of time. Sanguinarium (SANG), chlorhexidine (CHX) and tetracycline (TET) are 3 antimicrobial agents frequently used in the management of periodontal infections. However, their effects on host immune cells during different treatment regimens are not known. Due to their ability to serve as the first line of host defense against microbial infections, we have compared the effects of these antimicrobial agents on human neutrophil functions and viability. The results show that SANG is not lytic to neutrophils from peripheral blood or crevicular fluid, at all concentrations tested. However, exposures of neutrophils to very low concentrations of SANG (0.001%) inhibits neutrophil chemotaxis, oxidative metabolism and degranulation within 5 min. Increasing the exposure time results in a similar inhibition of neutrophil functions, albeit at 50-100 fold lower concentrations of SANG. CHX rapidly disrupts the cell membrane of both crevicular and peripheral blood neutrophils at concentrations above 0.005% within 5 min, and inhibition of all neutrophil functions is due to its lytic properties. While TET is least toxic to neutrophils, a dose dependent inhibition of neutrophil functions is dependent on the calcium concentrations of the cellular environment, and is observed only above 0.04% or higher concentrations in the absence of calcium. The data suggest that a critical cumulative concentration of these drugs is essential for their toxicity and inhibition of neutrophil functions. Therefore, both the length of exposure and the dose of the drug both are critical while considering the effectiveness of SANG, CHX or TET in the treatment of infections. Furthermore, due to differences in their mechanisms of action, the consequences of their effects on neutrophils may have significant bearing on tissue pathology as well as on their therapeutic efficacy.

Multi-center comparative evaluation of subgingivally delivered sanguinarine and doxycycline in the treatment of periodontitis. I. Study design, procedures, and management.

The design and conduct of a 9-month multi-center clinical trial to evaluate the safety and efficacy of subgingivally delivered 5% sanguinarium chloride (SC) and 10% doxycycline hyclate (DH) from a biodegradable drug delivery system in the treatment of adult periodontitis is described. The 3-group randomized study of 180 adults with moderate to severe periodontitis was a modified double-blind parallel design. One group received DH, one group received SC, and the other group received the vehicle control (VC). Patients selected had two quadrants with a minimum of four periodontal pockets > or = 5 mm in depth with two sites > or = 7 mm. All qualifying sites exhibited bleeding on gentle probing. Qualifying sites were treated at baseline and again at 4 months. Clinical response was assessed by measuring attachment level, probing depth, and bleeding on probing at monthly examinations at qualifying sites and the entire dentition. The plaque index was measured monthly to verify oral hygiene status. The parallel design afforded the opportunity to distinguish between treatment effectiveness of SC, DH, and VC independent of possible crossover effects. Also the effectiveness of oral hygiene in untreated sites of the mouth could be evaluated. Finally, treatment effects in moderate (5 to 6 mm) and deep (> or = 7 mm) pockets in both treated and untreated sites could be compared. The design was capable of simulating a periodontal practice maintenance program and assessing the response according to maintenance and treatment history. Study management procedures that emphasized center examiner and therapist training and adherence to protocol and procedures to reduce variability are described.

Multi-center comparative evaluation of subgingivally delivered sanguinarine and doxycycline in the treatment of periodontitis. II. Clinical results.

The clinical safety and effectiveness of a subgingivally delivered biodegradable drug delivery system containing either 10% doxycycline hyclate (DH), 5% sanguinarium chloride (SC) or no agent (VC) was evaluated in a 9-month multi-center trial. The study was a randomized parallel design with 180 patients who demonstrated moderate to severe periodontitis. All patients had at least two quadrants with a minimum of four qualifying pockets > or = 5 mm that bled on probing. Two of the qualifying pockets were required to be > or = 7 mm. At baseline and at 4 months all qualified sites were treated with the test article administered via syringe. Probing depth reduction (PDR), attachment level gain (ALG), bleeding on probing reduction (BOP), and plaque index were determined monthly. Analysis of efficacy data from the 173 efficacy-evaluable patients indicated that all treatments gave significant positive clinical changes from baseline at all subsequent timepoints. DH was superior to SC and VC in PDR at all timepoints (P < or = 0.01 to 0.001) with a maximum reduction of 2.0 mm at 5 months. For ALG, DH was superior to VC at months 2, 3, 4, 5, 6, 8, and 9 (P < or = 0.04 to 0.002) and superior to SC at months 5, 6, 7, 8, and 9 (P < or = 0.01 to 0.001) with a maximum ALG of 1.2 mm at 6 months. For BOP reduction, DH was superior to VC at all time points (P < or = 0.05) and to SC at months 3, 5, 6, 8, and 9 (P < or = 0.03). For DH, the maximum ALG in deep (> or = 7 mm) pockets was 1.7 mm and PDR 2.9 mm compared to 0.8 mm and 1.6 mm, respectively for moderate (5 to 6 mm) pockets. Test articles were applied without anesthesia and no serious adverse events occurred in the trial. The results of this study indicate that 10% doxycycline hyclate delivered in a biodegradable delivery system is an effective means of reducing the clinical signs of adult periodontitis and exhibits a benign safety profile.

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.

2 multi-center trials assessing the clinical efficacy of 5% sanguinarine in a biodegradable drug delivery system.

A biodegradable drug delivery system containing 5% sanguinarium (Sa) was compared to vehicle control (VC), scaling and root planing (SRP), and supragingival plaque control (SPC) in the treatment of adult periodontitis in 2 well-controlled clinical trials. Studies were 4-quadrant (split mouth) designs at 2 centers each, having 94 (Study A) and 107 (Study B) patients. All patients had at least 3 pockets between 5 and 9 mm that bled on probing, in each quadrant. Probing pocket depth (PD), clinical attachment level (AL), bleeding on probing (BOP), and plaque index were recorded at baseline, 14, 30, 60, and 90 days. All treatments gave statistically significant reductions from baseline for PD and BOP, and significant gains for AL. For PD reduction, SRP was superior to all test groups at all time points in both studies (p < 0.001). Sa was superior to VC in Study A at 14 and 30 days and to SPC at all time points. For AL gain at 90 days, in both studies, SRP gave gains of 0.42 and 0.78 mm respectively with superiority seen over the SPC group at 90 days (p < 0.001) in study A only, For BOP reduction, in Study A SRP was superior to Sa, VC, and SPC at 60 and 90 days (p < 0.005) and in Study B superiority to Sa and VC was at 90 days and to SPC at 60 days (p < 0.05). Sa was superior to VC for pocket depth in deep pockets only. Sa failed to demonstrate superiority over VC on a consistent basis. Analysis of residual Sa indicates that Sa potency was insufficient to show an advantage beyond clinical effects inherent in treatments with VC and SPC.

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.

Whole mouth microbiota effects following subgingival delivery of sanguinarium.

An increased incidence of antibiotic-resistant bacteria and yeast overgrowth has been reported following various periodontal treatments. The objective of this study was to detect possible overgrowth of opportunistic bacteria and fungi as well as changes in normal microbiota after application of a biodegradable delivery system containing 5% sanguinarium (ABDS-S) to one quadrant in a split-mouth study. An oral hygiene quadrant served as a control. The ABDS-S treated and control periodontal sites as well as the saliva of 17 subjects were sampled prior to treatment, immediately after ABDS-S removal at 7 days, and again at 30 and 60 days. At Day 7 sanguinarium-resistant bacteria increased in both control and ABDS-S periodontal sites as well as in the saliva. Enteric Gram-negative bacilli in both control and ABDS-S periodontal sites were 2.2 to 3.4 log colony forming units higher at Day 7 compared to baseline. This overgrowth was transient in that levels became undetectable at Days 30 and 60. No such overgrowth was observed for C. albicans or other fungi, or for S. aureus or other staphylococci in any periodontal sites. Levels of Actinomyces increased at Days 30 and 60 in both control and ABDS-S sites as well as saliva. These changes strongly suggest that a 7 day ABDS-S treatment in one quadrant of the mouth led to significant microbiota changes in the treated and control quadrants as well as in the saliva. Future microbial studies involving antimicrobials delivered by local delivery systems must consider the crossover effects of treatment inherent in the split-mouth design.

Initial study of guided tissue regeneration in Class II furcation defects after use of a biodegradable barrier.

This study evaluated guided tissue regeneration in Class II furcation defects after use of a polylactic acid biodegradable barrier in nine patients with mandibular molar defects. Following an initial hygienic phase, surgical flaps were elevated, and the sites were scaled and root planed. Defect perimeter was measured, and a customized barrier (600 to 750 mm thick) that adhered directly to tooth and bone was applied. At baseline, sites were measured for probing depth (6.2 +/- 0.5 mm), gingival margin location (-0.6 +/- 0.6 mm), and attachment level both vertically (6.9 +/- 0.7 mm) and horizontally (5.3 +/- 0.5 mm). Clinically, barriers fragmented and became displaced in 3 to 6 weeks. Substantial granulation tissue was sometimes present between barrier and root surfaces. Six months postsurgery, gingival margin location was close to the presurgical level (-0.4 +/- 0.8 mm). There was clinically and statistically significant improvement in all other parameters: a mean reduction of 3.1 mm in probing depth, a gain of 3.3 mm in vertical attachment level, and a gain of 3.0 mm in horizontal attachment level. These results suggested favorable regenerative outcomes.

Healing patterns associated with an Atrisorb barrier in guided tissue regeneration.

The current guided tissue regeneration clinical technique uses synthetic membranes at the time of the surgical procedure to separate the gingival and periodontal tissue components. These membranes are tied to the tooth surface and have to be ++removed during a second surgical procedure. The material Atrisorb is currently under development as a guided tissue regeneration barrier in Class II furcation defects. This material is applied directly over the furcation defect and is not tied to the tooth surface. Because of its biodegradability, Atrisorb does not have to be removed. A case study is presented.

Effect of sanguinaria extract on development of plaque and gingivitis when supragingivally delivered as a manual rinse or under pressure in an oral irrigator.

The effects on developing plaque and gingivitis following rinsing with a placebo oral rinse or an oral rinse containing 300 micrograms/ml sanguinaria extract (sanguinaria) were compared to effects produced by supragingival irrigation with dilute solutions of the rinse corresponding to 22.5 micrograms/ml sanguinaria and 90 micrograms/ml sanguinaria. The study design was a repeated measures, single-blind crossover with no oral hygiene over 2 weeks duration. After 7 and 14 [corrected] days, significantly lower plaque and gingivitis scores were obtained with use of the sanguinaria-containing rinse and irrigating solutions compared with the placebo rinse. There were no significant differences in plaque and gingivitis scores between the groups using the sanguinaria rinse and the sanguinaria irrigating solutions. A comparison [corrected] of % distribution of 0, 1 and 2+ scores also indicated that rinsing and supragingival irrigation with sanguinaria was more effective in plaque and gingivitis control than rinsing with the placebo. The results suggest that sanguinaria oral rinse may be effective in controlling plaque and gingivitis when delivered by manual rinsing or supragingival irrigation.

Effect of sanguinaria extract on established plaque and gingivitis when supragingivally delivered as a manual rinse or under pressure in an oral irrigator.

Sanguinaria extract (sanguinaria) solutions were evaluated in 44 subjects in a 2-week, no oral hygiene study as a 300 micrograms/ml manual rinse, and the results compared to supragingival irrigation with 22.5 micrograms/ml sanguinaria concentration and supragingival irrigation with water. Both the manual use of sanguinaria and supragingival irrigation of dilute sanguinaria produced significantly less plaque growth than supragingival irrigation with deionized water. In terms of % changes from baseline, manual rinsing and supragingival irrigation with sanguinaria limited plaque growth to 17.7% and 24.2%, respectively, while irrigation with water had a 51.5% growth. For gingivitis, control supragingival irrigation with sanguinarine and with water were statistically different from manual rinsing with sanguinaria. Compared to baseline, the groups irrigating with sanguinaria and with water had gingivitis reductions of 68.7% and 73.3%, respectively, while manual rinsing with sanguinaria had a 29.6% reduction. The results suggest that dilute solutions of sanguinaria delivered via rinsing or supragingival irrigation are effective in controlling plaque as an additional benefit to the use of supragingival irrigation to control gingivitis. Supragingival irrigation with sanguinaria as part of a home care routine for patients with plaque and gingivitis is suggested.

The relationship of sanguinaria extract concentration and zinc ion to plaque and gingivitis.

The effects of sanguinaria extract and zinc chloride on plaque growth and gingivitis inhibition were assessed on subjects with initially plaque-free tooth surfaces using a series of oral rinses in a single-blind, crossover, no-oral-hygiene study lasting 2 weeks. A placebo oral rinse containing no sanguinaria or zinc chloride (A), and test rinses containing 150 micrograms/ml sanguinaria and 0.2% zinc chloride (B), 300 micrograms/ml sanguinaria and no zinc chloride (C), and 300 micrograms/ml sanguinaria and 0.2% zinc chloride (D) were evaluated. Subjects using the higher concentration rinses C and D had significantly lower plaque scores than rinse A at 7 and 14 days (p less than 0.05 for C, p less than 0.01 for D). However, groups C and D were not significantly different from each other. Group D had significantly lower plaque (p less than 0.05) and gingivitis (p less than 0.01) scores than group B. Subjects who used rinse B and placebo rinse A had the highest plaque and gingivitis scores and comparison of these two groups revealed no significant difference. At the end of 14 days, the % distribution of 0 plaque and gingivitis scores was greatest among subjects using rinses C and D. Subjects in these 2 groups also had the lowest incidence of plaque and gingivitis scores of 2+. It is concluded that the effects of sanguinaria rinses on developing plaque and gingivitis are influenced more by sanguinaria concentrations than the presence or absence of zinc ion, but that zinc ion may provide a mild enhancement of sanguinaria effectiveness against gingivitis.

Short-term toxicity studies of sanguinarine and of two alkaloid extracts of Sanguinaria canadensis L.

The short-term toxicity of sanguinarine, a benzophenanthridine alkaloid, and of two alkaloid extracts of Sanguinaria canadensis L. are presented. The acute oral LD50 in rats of sanguinarine was calculated to be 1658 mg/kg, and of the two alkaloid extracts, 1440 and 1250 mg/kg. The acute iv LD50 in rats of sanguinarine was found to be 29 mg/kg. No toxic effects were observed in rats fed up to 150 ppm sanguinarine in the diet for 14 d and in rats treated by gavage with up to 0.6 mg/kg body weight for 30 d. The acute dermal LD50 in rabbits was found to be greater than 200 mg/kg.