Polyglactin 910 Meshes Coated with Sustained-Release Cannabigerol Varnish Inhibit Staphylococcus aureus Biofilm Formation and Macrophage Cytokine Secretion: An In Vitro Study.

Synthetic surgical meshes are commonly used in abdominal wall reconstruction surgeries to strengthen a weak abdominal wall. Common mesh-related complications include local infection and inflammatory processes. Because cannabigerol (CBG) has both antibacterial and anti-inflammatory properties, we proposed that coating VICRYL (polyglactin 910) mesh with a sustained-release varnish (SRV) containing CBG would prevent these complications. We used an in vitro infection model with Staphylococcus aureus and an in vitro inflammation model of lipopolysaccharide (LPS)-stimulated macrophages. Meshes coated with either SRV-placebo or SRV-CBG were exposed daily to S. aureus in tryptic soy medium (TSB) or macrophage Dulbecco's modified eagle medium (DMEM). Bacterial growth and biofilm formation in the environment and on the meshes were assessed by changes in optical density, bacterial ATP content, metabolic activity, crystal violet staining, spinning disk confocal microscopy (SDCM), and high-resolution scanning electron microscopy (HR-SEM). The anti-inflammatory effect of the culture medium that was exposed daily to the coated meshes was analyzed by measuring the release of the cytokines IL-6 and IL-10 from LPS-stimulated RAW 264.7 macrophages with appropriate ELISA kits. Additionally, a cytotoxicity assay was performed on Vero epithelial cell lines. We observed that compared with SRV-placebo, the segments coated with SRV-CBG inhibited the bacterial growth of S. aureus in the mesh environment for 9 days by 86 ± 4% and prevented biofilm formation and metabolic activity in the surroundings for 9 days, with respective 70 ± 2% and 95 ± 0.2% reductions. The culture medium that was incubated with the SRV-CBG-coated mesh inhibited LPS-induced secretion of IL-6 and IL-10 from the RAW 264.7 macrophages for up to 6 days without affecting macrophage viability. A partial anti-inflammatory effect was also observed with SRV-placebo. The conditioned culture medium was not toxic to Vero epithelial cells, which had an IC50 of 25 µg/mL for CBG. In conclusion, our data indicate a potential role of coating VICRYL mesh with SRV-CBG in preventing infection and inflammation in the initial period after surgery.

Sinonasal Stent Coated with Sustained-Release Varnish of Mometasone Furoate Inhibits Pro-Inflammatory Cytokine Release from Macrophages: An In Vitro Study.

The aim of the study was to develop a sustained-release varnish (SRV) containing mometasone furoate (MMF) for sinonasal stents (SNS) to reduce mucosa inflammation in the sinonasal cavity. The SNS' segments coated with SRV-MMF or an SRV-placebo were incubated daily in a fresh DMEM at 37 °C for 20 days. The immunosuppressive activity of the collected DMEM supernatants was tested on the ability of mouse RAW 264.7 macrophages to secrete the cytokines' tumor necrosis factor α (TNFα) and interleukin (IL)-10 and IL-6 in response to lipopolysaccharide (LPS). The cytokine levels were determined by respective Enzyme-Linked Immunosorbent Assays (ELISAs). We found that the daily amount of MMF released from the coated SNS was sufficient to significantly inhibit LPS-induced IL-6 and IL-10 secretion from the macrophages up to days 14 and 17, respectively. SRV-MMF had, however, only a mild inhibitory effect on LPS-induced TNFα secretion as compared to the SRV-placebo-coated SNS. In conclusion, the coating of SNS with SRV-MMF provides a sustained delivery of MMF for at least 2 weeks, maintaining a level sufficient for inhibiting pro-inflammatory cytokine release. This technological platform is, therefore, expected to provide anti-inflammatory benefits during the postoperative healing period and may play a significant role in the future treatment of chronic rhinosinusitis.

Prolonged Inhibition of Streptococcus mutans Growth and Biofilm Formation by Sustained Release of Chlorhexidine from Varnish Coated Dental Abutments: An in Vitro Study.

Background: It has been confirmed that bacterial biofilm covering dental implants is the main microbial source causing preimplant infectious and inflammatory diseases. The purpose of this study was to evaluate the antibacterial/antibiofilm effect of chlorhexidine, incorporated into a sustained-release varnish of chlorhexidine (SRV-CHX) coating, on dental abutments. Materials and Methods: Three kinds of dental abutments were used: a high-performance semi-crystalline engineering thermoplastic polyetheretherketone (PEAK) healing abutment, a titanium healing abutment, and a titanium permanent abutment. These abutments were coated with SRV-CHX or SRV-placebo and exposed daily to fresh cultures of Streptococcus mutans. The effect of SRV-CHX on S. mutans growth on agar plates was studied by measuring the zone of inhibition (ZOI) around each tested abutment every day for a period of 36 days. Biofilm formation on the SRV-CHX/placebo-coated abutments was detected using confocal laser scanning microscopy (CLSM) and high-resolution scanning electron microscopy (HR-SEM), energy dispersive X-ray analysis (EDX), and monitored by crystal violet (CV) staining. Results: SRV-CHX-coated abutments 2 and 3 were able to inhibit S. mutans growth for 34 days, while abutment 1 inhibited growth for 32 days. Abutment-associated biofilm formation was notably inhibited by SRV-CHX coating after 13 days of incubation with S. mutans. Finally, the biofilm formed around SRV-CHX-coated abutments was completely inhibited up to 12 days of abutment exposure to S. mutans. Conclusion: Coating of dental abutments with SRV-CHX demonstrated long-term effective inhibition of S. mutans growth and biofilm formation on the abutment surface.

Potential Combinatory Effect of Cannabidiol and Triclosan Incorporated into Sustained Release Delivery System against Oral Candidiasis.

Candida albicans is a common fungal pathogen. Biofilm formation on various surfaces is an important determinant of C. albicans pathogenicity. Our previous results demonstrated the high potential of cannabidiol (CBD) to affect C. albicans biofilms. Based on these data, we investigated the possibility of incorporating CBD and/or triclosan (an antimicrobial agent that is widely utilized in dentistry) in a sustained-release varnish (SRV) (SRV-CBD, SRV-triclosan) to increase their pharmaceutical potential against C. albicans biofilm, as well as that of the mixture of the agents into SRV (SRV-CBD/triclosan). The study was conducted in a plastic model, on agar, and in an ex vivo tooth model. Our results demonstrated strong antibiofilm activity of SRV-CBD and SRV-triclosan against C. albicans in all tested models. Both formulations were able to inhibit biofilm formation and to remove mature fungal biofilm. In addition, SRV-CBD and SRV-triclosan altered C. albicans morphology. Finally, we observed a dramatic enhancement of antibiofilm activity when combined SRV-CBD/triclosan was applied. In conclusion, we propose that incorporation of CBD or triclosan into SRV is an effective strategy to fight fungal biofilms. Importantly, the data demonstrate that our CBD/triclosan varnish is safe, and is not cytotoxic for normal mammalian cells. Furthermore, we propose that CBD and triclosan being in mixture in SRV exhibit complementary antibiofilm activity, and thus can be explored for further development as a potential treatment against fungal infections.

Sustained release varnish containing chlorhexidine for prevention of Streptococcus mutans biofilm formation on voice prosthesis surface: an in vitro study.

OBJECTIVES: In this study, we aimed to develop a novel, sustained release varnish (SRV) for voice prostheses (VP) releasing chlorhexidine (CHX), for the prevention of biofilm formation caused by the common oral bacteria Streptococcus mutans on VP surfaces. METHODS: This study was performed in an in vitro model as a step towards future in vivo trials. VPs were coated with a SRV containing CHX (SRV-CHX) or SRV alone (placebo-SRV) that were daily exposed to S. mutans. The polymeric materials of SRV were composed of ethylcellulose and PEG-400. Biofilm formation was assessed by DNA quantification (qPCR), crystal violet staining, confocal laser scanning microscopy (CLSM), scanning electron microscopy (SEM), and kinetics experiments. RESULTS: The amount of DNA in the biofilms formed by S. mutans on VP surfaces coated once with SRV-CHX (1.024 ± 0.218 ng DNA/piece) was 58.5 ± 8.8% lower than that of placebo-SRV-coated VPs (2.465 ± 0.198 ng DNA/piece) after a 48-h exposure to S. mutans (p = 0.038). Reduced biofilm mass on SRV-CHX-coated VPs was visually confirmed by CLSM and SEM. CV staining of SRV-CHX single-coated VPs that have been exposed to S. mutans nine times showed a 98.1 ± 0.2% reduction in biofilm mass compared to placebo-SRV-coated VPs (p = 0.003). Kinetic experiments revealed that SRV-CHX triple-coated VPs could delay bacterial growth for 23 days. CONCLUSIONS: Coating VPs with SRV-CHX has an inhibitory effect on biofilm formation and prevents bacterial growth in their vicinities. This study is a proof-of-principle that paves the way for developing new clinical means for reducing both VPs' bacterial biofilm formation and device failure.

Sinonasal Stent Coated with Slow-Release Varnish of Chlorhexidine Has Sustained Protection against Bacterial Biofilm Growth in the Sinonasal Cavity: An In Vitro Study.

The aim of the study was to develop a sustained-release varnish (SRV) containing chlorhexidine (CHX) for sinonasal stents (SNS) to reduce bacterial growth and biofilm formation in the sinonasal cavity. Segments of SNS were coated with SRV-CHX or SRV-placebo and exposed daily to bacterial cultures of Staphylococcus aureus subsp. aureus ATCC 25923 or Pseudomonas aeruginosa ATCC HER-1018 (PAO1). Anti-bacterial effects were assessed by disc diffusion assay and planktonic-based activity assay. Biofilm formation on the coated stents was visualized by confocal laser scanning microscopy (CLSM) and high-resolution scanning electron microscopy (HR-SEM). The metabolic activity of the biofilms was determined using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) method. Disc diffusion assay showed that SRV-CHX-coated SNS segments inhibited bacterial growth of S. aureussubsp. aureus ATCC 25923 for 26 days and P. aeruginosa ATCC HER-1018 for 19 days. CHX was released from coated SNS segments in a pH 6 medium up to 30 days, resulting in growth inhibition of S. aureussubsp. aureus ATCC 25923 for 22 days and P. aeruginosa ATCC HER-1018 for 24 days. The MTT assay showed a reduction of biofilm growth on the coated SNS by 69% for S. aureussubsp. aureus ATCC 25923 and 40% for P. aeruginosa ATCC HER-1018 compared to the placebo stent after repeated exposure to planktonic growing bacteria. CLSM and HR-SEM showed a significant reduction of biofilm formation on the SRV-CHX-coated SNS segments. Coating of SNS with SRV-CHX maintains a sustained delivery of CHX, providing an inhibitory effect on the bacterial growth of S. aureussubsp. aureus ATCC 25923 and P. aeruginosa ATCC HER-1018 for approximately 3 weeks.

Voice Prosthesis Coated with Sustained Release Varnish Containing Clotrimazole Shows Long-Term Protection against Candida albicans: An In Vitro Study.

Fungal biofilm formation on voice prosthesis (VP) is a major health problem that requires repeated replacement of the prosthesis. Candida albicans is one of the pathogens that frequently inhabits the VP. We proposed that coating VPs with sustained-release varnish (SRV) containing clotrimazole (CTZ) might prevent fungal biofilm formation. The long-term antifungal activities of SRV-CTZ- versus SRV-placebo-coated VPs was tested daily by measuring the inhibition zone of C. albicans seeded on agar plates or by measuring the fungal viability of C. albicans in suspension. The extent of biofilm formation on coated VPs was analyzed by confocal microscopy and scanning electron microscopy. We observed that SRV-CTZ-coated VPs formed a significant bacterial inhibition zone around the VPs and prevented the growth of C. albicans in suspension during the entire testing period of 60 days. Fungal biofilms were formed on placebo-coated VPs, while no significant biofilms were observed on SRV-CTZ-coated VPs. HPLC analysis shows that CTZ is continuously released during the whole test period of 60 days at a concentration above the minimal fungistatic concentration. In conclusion, coating VPs with an SRV-CTZ film is a potential effective method for prevention of fungal infections and biofilm formation on VPs.

Efficacy and potential use of novel sustained release fillers as intracanal medicaments against Enterococcus faecalis biofilm in vitro.

BACKGROUND: Enterococcus faecalis is a bacterium frequently isolated after failed root canal therapy. This study analyzed the antibacterial and antibiofilm effects in vitro of sustained-release fillers (SRF) containing cetylpyridinium chloride (CPC) against vancomycin resistant E. faecalis. METHODS: First, the solidification capability was tested by introducing liquid SRF into phosphate buffered saline, followed by 30 s of vortexing. The antimicrobial effects of SRF-CPC against static monospecies biofilms were analyzed with a metabolic assay. Inhibition of biofilm formation was tested by exposing daily refreshed E. faecalis suspensions to SRF-CPC for 9 weeks. To evaluate the effects of SRF-CPC against preformed biofilms, biofilms were grown for 1, 3 and 7 days, and then treated with SRF-CPC for 24 h. Biofilm kill time was tested by applying SRF-CPC to a 3-day-old biofilm and measuring its viability at different time points. All experiments were compared to Placebo SRFs and to untreated control biofilms. Data were analyzed with two-way ANOVA followed by Tukey's test. Results were considered significant at P < 0.05. RESULTS: The liquid SRF solidified within seconds and no structural changes were observed after 30 s of vortexing at maximum speed. SRF-CPC inhibited E. faecalis biofilm formation for 7 weeks and significantly reduced its viability in weeks 8 and 9. Mature biofilms grown for 1, 3 and 7 days were destructed by SRF-CPC in less than 24 h. Fifty percent of a 3-day-old biofilm was destructed in 2 h and complete destruction occurred in less than 12 h. (P < 0.05 in all cases, compared to SRII-Placebo). CONCLUSIONS: SRF-CPC's physical properties and long-lasting anti-biofilm effects make it a promising coadjuvant medication for endodontic therapy.

RETROSPECTIVE EVALUATION OF A NOVEL SUSTAINED-RELEASE IVERMECTIN VARNISH FOR TREATMENT OF WOUND MYIASIS IN ZOO-HOUSED ANIMALS.

Myiasis is a major disease condition in human and veterinary medicine. Domestic, free-ranging, and zoo-housed animals can be severely affected by myiasis. Depending on case severity, multiple treatment episodes may be indicated and can lead to recurrent capturing, handling stress, and anesthetics, all of which increase the risk of adverse responses (including death) individually and also in the herd. As an insecticide, ivermectin is often used for larval control. A total of 28 individual myiasis cases were retrospectively evaluated, out of which 11 cases were also treated using an ivermectin sustained-release varnish (SRV). The clinical outcome of all cases was assessed and the results suggest that the use of a topical ivermectin SRV (with or without concurrent injectable ivermectin) can reduce handling and treatments, has no adverse effects, and has minimal recurrence of the disease when compared with cases treated without it.

Comparison of the efficacy of a novel sustained release clotrimazole varnish and clotrimazole troches for the treatment of oral candidiasis.

OBJECTIVES: Candida albicans is a common fungal infection and is commensal in 40-65 % of healthy adults. The development and pharmacokinetics of a novel sustained release clotrimazole varnish (Clot-SRV) for topical oral use have been reported. The aim of this study was to compare the efficacy of this varnish with clotrimazole troche treatment of oral candidiasis. MATERIALS AND METHODS: Of the 12 patients with denture stomatitis treated for 14 days, six used Clot-SRV (study group) and six clotrimazole troches (control). The patients were instructed to use Clot-SRV (50 mg of clotrimazole) once a day, and the control group was instructed to use five troches of 10 mg clotrimazole/day. Microbiological samples were obtained from saliva, buccal mucosa, palate, and denture. The degree of erythema was recorded at three time points, and subjective opinions noted using a questionnaire. RESULTS: At the end of the study, the control group had relatively more cases of erythema on all examined surfaces; patients who applied the Clot-SRV had significantly lower levels of candida on the denture surfaces and in saliva, and had better compliance to the medication. CONCLUSIONS: The novel clotrimazole sustained release varnish may be an important part of a new protocol for oral candidiasis, with improved clinical outcomes.

Development and in vitro characterization of floating sustained-release drug delivery systems of polyphenols.

The aim of this study was to develop and characterize floating stomach-retentive matrix tablets that will deliver polyphenols in a controlled release manner. The tablets were prepared by direct compression. A number of polymers were examined and egg albumin was chosen in light of a better performance in terms of floating behavior and decomposition time. Dissolution studies for three representative polyphenols loaded into a number of formulations were performed using the "f2" factor in order to compare release profiles of different polyphenols and formulations. The release data showed a good fit into the power law equation and zero-order kinetics has been determined for some of the systems. Erosion and textural analysis studies revealed that higher concentration of egg albumin results in a higher gel strength that is less susceptible to erosion, potentially leading to a prolonged delivery time of drug. The ability of egg albumin-based tablets to resist high mechanical forces was also determined, while comparison to cellulose-derived polymers revealed that the latter have a much lower ability to resist the same forces. The developed delivery system has the potential to increase the efficacy of the therapy for various pathological stomach conditions and to improve patient compliance.

Use of a sustained release chlorhexidine varnish as treatment of oral necrobacillosis in Macropus spp.

Oral necrobacillosis or lumpy jaw is a common cause of morbidity and mortality affecting captive macropods. This article describes several cases of a new treatment regimen using a sustained release chlorhexidine varnish applied locally to the teeth and the gingivae of two Macropus species, eastern grey kangaroos (Macropus gigantus) from Gan-Garoo Australian Park and a red-necked wallaby (Macropus rufogriseus fruticus) from The Tisch Family Zoological Gardens in Jerusalem. The varnish was applied using a horsehair paint brush as three 1- to 2-mm thick layers. The active ingredient in the varnish was the disinfectant chlorhexidine. Results indicated that use of an intraoral sustained release varnish significantly shortens the treatment time and may prevent recurrence.

A novel sustained-release clotrimazole varnish for local treatment of oral candidiasis.

The use of dental varnish for therapeutic purposes has been reported for fluoride or antibacterial drugs. Our objectives were to develop a sustained-release varnish containing an antifungal drug (clotrimazole) for topical application and to evaluate the release rate of the drug in human saliva in comparison with an available commercial troche and their acceptance by healthy volunteers. Following in vitro optimization of the release rate from the varnish, we have embarked on a crossover comparative study assessing the oral sensations and pharmacokinetics of a 10-mg clotrimazole oral troche versus a 10-mg sustained-release clotrimazole varnish in 14 human volunteers over a period of 5 h. Saliva samples were assessed for clotrimazole concentration by high performance liquid chromatography analysis. The volunteers' evaluation of the varnish and troche (taste, other sensory changes, convenience, and oral suitability) were recorded. At all time points, salivary clotrimazole concentrations were higher, and the terminal half-life was significantly prolonged in the varnish group in comparison to the control group. This can be attributed to continuous release of clotrimazole from the varnish formulation. The duration of the drug over the minimal inhibitory concentration, following application of the varnish, was more than threefold longer than following administration of the troche. The developed sustained-release varnish can be applied in patients at a lower frequency than troches, thus, achieving higher patient compliance and efficacy. This novel varnish application can serve as the basis for a new treatment approach to oral candidiasis, a very common chronic opportunistic infection with improved clinical outcome.

Use of a sustained release preparation of clotrimazole to treat dermatophytosis in a siamang (Hylobates syndactylus).

In November 2004, an adult male siamang (Hylobates syndactylus) from The Tisch Family Zoological Gardens-Jerusalem Biblical Zoo (Israel) presented with skin lesions on various body parts. Lesions consisted of alopecia and dry, crusty areas of hyperkeratosis. A diagnosis of dermatophytosis due to Microsporum canis was determined by fungal culture of skin scraping taken from the edge of several lesions. Treatment with various oral and topical antifungal agents such as griseofluvin, itraconozole, and lufenuron resulted in the resolution of most lesions and a decrease in size of the single remaining lesion, which continued to be culture positive for M. canis. The animal was anesthetized and an experimental sustained-release clotrimazole varnish was painted directly on the lesion. Initially there was no change in the lesion, and 2 months later a slightly altered formula was applied under anesthesia. One month later, the lesion began to reduce in size; 3 months after the start of treatment, although 2 years after the onset of clinical signs, the lesion resolved. Minimizing the number of treatments is always an advantage when dealing with exotic animals or zoological collections.

Nanospheres of a bisphosphonate attenuate intimal hyperplasia.

The present study explored a novel strategy for attenuation of restenosis after arterial injury by a bisphosphonate encapsulated in polymeric nanoparticles (NP) for transient selective depletion of macrophages. A bisphosphonate (BP), 2-(2-Aminopyrimidino) ethyldiene-1,1-bisphosphonic acid betaine (ISA), was successfully formulated in 400 nm sized polylactide/glycolide-based NP with high yield (69%) and entrapment efficiency (60% w/w). ISA NP, but not blank NP or free ISA, exhibited specific and significant cytotoxic effect on macrophages-like RAW 264 cells, in a dose-dependent manner, with no inhibitory effect on the growth of smooth muscle cells (SMCs). Fluorescent pyrene-labeled NP were shown to be taken up by RAW 264 cells, but not by SMCs. Intravenously (i.v.) administered ISA NP (15 mg/kg, single dose on day-1) resulted in a significant attenuation of neointima to media area ratio (N/M) by 40% and stenosis by 45% 14 days after rat carotid injury, in comparison to animals treated with free ISA, buffer or blank NP. However, the effect was not preserved 30 days post injury, and an insignificant reduction of neointimal formation was observed. Neointimal hyperplasia was also significantly suppressed after subcutaneous (SC) injection of ISA NP (15 mg/kg, single dose on day-1), reducing both N/M and stenosis. Intraperitoneal (i.p.) injection of silica, a known selective toxin for macrophages, (1000 mg/kg), also resulted in a significant inhibition of N/M and stenosis, which further reinforces the cause-effect relationship of macrophage-inactivation and the prevention of neointima formation. Biocompatible and biodegradable NP loaded with ISA characterized by high colloidal stability, reproducible activity, and high drug entrapment warrant further consideration for restenosis therapy, and may be useful in other disease processes involving monocytes/macrophages.

Alendronate-loaded nanoparticles deplete monocytes and attenuate restenosis.

Systemic transient depletion of monocytes and macrophages by liposome-encapsulated bisphosphonates (BPs), reduces neointimal formation in experimental restenosis. The aim of this study was to examine the antirestenotic effect of a polymeric nanoparticulate formulation containing the BP alendronate (ALN). The BP was successfully formulated in polylactide-co-glycolide (PLGA) nanoparticles (NP). ALN NP with negative charge, size of 223+/-64 nm, and high entrapment efficiency (55.1%) have been formulated. ALN NP exhibited a significant cytotoxic effect, in a dose-response relationship, on macrophage-like RAW264 cells in cell culture. Subcutaneously (SC) administrated ALN NP (1.5 mg/kg on days -1 and +6) resulted in a significant attenuation of neointima to media ratio (N/M) by 52.7% and stenosis by 39.7% 28 days after balloon injury in the hypercholesterolemic rabbit model. Moreover, a good correlation was found between macrophage abundance in the injured arteries and the extent of stenosis. ALN NP treatment resulted in the reduction of both interleukin-1beta and matrix metalloproteinases (2 and 9). It is concluded that a particulated dosage form of polymeric NP loaded with ALN reduce neointimal formation in vivo by systemic transient depletion of monocytes.

Luminal delivery and dosing considerations of local celecoxib administration to colorectal cancer.

The purpose of this study was to develop a biodegradable drug platform composed of chitosan and guar gum and to explore the possibility of using it for local adjuvant or neoadjuvant therapy of colorectal cancer. Celecoxib (Cx), a chemopreventative drug for familial adenomatous polyposis (FAP) and under trial for reducing post surgical colorectal malignancies, was selected as a model drug for this topical system because of the contraindications that are associated with its systemic administration. Films made of chitosan (Ct) and guar gum (GG) were prepared, characterized for equilibrium swelling, mucoadhesion, in vitro and in vivo degradation and loaded with Cx. Short term dosing studies in vitro were performed in the HT-29 colon carcinoma cell line that was incubated with Cx using the MTT test to assess IC50. The impact of a single high dose was evaluated and compared with a repeating low-dose regimen. In vivo dosing experiments with Cx were performed in the perfused intestine of the anaesthetized rat. Measuring tissue LDH assessed epithelium injury. Mechanical, mucoadhesion and in vitro degradation of the polysaccharide films were dictated by manipulating the ratios of Ct and GG. The addition of rat cecal contents to the dissolution medium increased the total Cx released from those films containing high amounts of GG. MTT reduction, a measure of cell proliferation, diminished as a function of increasing drug concentration and exposure time in the HT-29 cell line studies. Local high concentrations of Cx were shown to impede the proliferation of cancer cells directly, while chemoprevention has been demonstrated with low Cx doses. Healthy cells were shown to be sensitive to high Cx doses. Maximum therapeutic efficiency in the context of minimal healthy tissue exposure would thus be predicted utilizing a local delivery system such as the proposed adhesive, biodegradable polysaccharide composites.

Changes in reducing power profile of gastric juice in patients with active duodenal ulcer.

Reactive oxygen species have been postulated to play a role in the pathogenesis of mucosal GI injury and in peptic ulcer disease (PUD). The low molecular weight antioxidants (LMWA) group plays an important role in the defense mechanism of the GI tract against oxidative damage, and is a major component of the reducing capacity of biological tissues and fluids. We hypothesized that altered gastric LMWA anti oxidative status might play a role in the pathogenesis of upper GI disorders such as PUD and could be evaluated by measuring gastric juice reducing power. The aim of the present study was to determine, by cyclic voltammetry, changes in the overall antioxidant activity of the gastric juice in active duodenal ulcer (DU) obtained during upper endoscopy from patients as compared with normal subjects. The results show that in 28/37 (76%) of the control subjects, gastric juice demonstrated a reducing power of at least two anodic waves indicating at least two different LMWA groups. Three or more anodic waves were recorded in 12 normal subject (32%). In contrast, 16/25 (64%) of gastric juice samples obtained from active DU patients exhibited only one anodic wave usually at a high potential (>900 mV). These results imply that gastric juice normally possesses a reducing power profile that can be determined by cyclic voltammetry. This profile is significantly changed in untreated DU disease. These changes in active DU may indicate decreased gastric antioxidant activity reflecting reduced mucosal protection that leading to increased susceptibility of the gastro-duodenum to injury.

Macrophage depletion by clodronate-containing liposomes reduces neointimal formation after balloon injury in rats and rabbits.

BACKGROUND: Inflammation is critical to vascular repair after mechanical injury. Excessive inflammation enhances neointimal formation and restenosis. We examined whether transient systemic inactivation of macrophages at the time of vascular intervention could attenuate the degree of expected restenosis. METHODS AND RESULTS: Liposomal clodronate (LC) inhibited the growth of cultured macrophages but had no effect on endothelial or smooth muscle cells and suppressed neointimal hyperplasia in hypercholesterolemic rabbits and rats after intravenous administration of LC, with no adverse effects. LC treatment reduced the number of blood monocytes and decreased macrophage infiltration in the injured arteries as well as smooth muscle cell proliferation, interleukin-1beta transcription, and production and matrix metalloproteinase-2 activity. CONCLUSIONS: Macrophages play a pivotal role in vascular repair after mechanical arterial injury. Systemic inactivation and depletion of monocytes and macrophages by LC reduce neointimal hyperplasia and restenosis.