Effect of polyphenol-rich cranberry extracts on cariogenic biofilm properties and microbial composition of polymicrobial biofilms

To investigate the effect of cranberry extracts on saliva-derived polymicrobial biofilms with regards to biofilm biomass, acidogenicity, exopolysaccharide (EPS)/microbial biovolumes, colony forming unit (CFU) counts, and the relative abundance of specific caries- and health-associated bacteria.Saliva-derived polymicrobial biofilms were grown for 96 h in a cariogenic environment and treated for 2 min every 12 h over the entire biofilm growth period with 500 μg/mL cranberry extract or vehicle control. The effect of the cranberry extract on biofilm behaviour was evaluated using different assays and its influence on key cariogenic and health-associated bacterial populations was assessed with a microarray real-time quantitative PCR method.Cranberry-treated biofilms showed significant drops in biomass (38% reduction, P

Polyphenol-Rich Cranberry Extracts Modulate Virulence of Streptococcus mutans-Candida albicans Biofilms Implicated in the Pathogenesis of Early Childhood Caries

Purpose: The purpose of this study was to investigate the effects of polyphenol-rich cranberry extracts on dual-species Streptococcus mutans-Candida. albicans biofilms implicated in contributing to the severity of early childhood caries. Methods:S. mutans-C. albicans biofilms were grown on saliva-coated hydroxyapatite discs (s-HA) mounted on the high-throughput Amsterdam Active Attachment model. The s-HA discs were treated with the cranberry extracts/vehicle control for five minutes just before biofilm growth and subsequently, for similar exposure times, after 12 hours and 24 hours of biofilm growth. The treated 24-hour-old biofilms were then assessed for acidogenicity, metabolic activity, exopolysaccharide (EPS)/microbial biovolumes, structural organization, and colony forming unit (CFU) counts. Results: Treatment with 500 to 1,000 μg/mL of the cranberry extracts produced significant reductions in acidogenicity and metabolic activity (

Growth inhibitory effects of antimicrobial natural products against cariogenic and health-associated oral bacterial species

Purpose: This study investigated whether selected natural products could specifically target the growth of a caries-associated bacterial species (Streptococcus mutans) without affecting the viability of a health-associated oral commensal bacterial species (Streptococcus sanguinis).Materials and Methods: Agar diffusion assays were used to screen the natural products for bacterial-growth inhibitory effects and the diameters of the inhibitory zones for the two bacterial species compared. The minimum inhibitory concentrations (MIC) of the natural products that showed growth inhibitory effects were determined using the broth microdilution method.Results: Except for the berry extracts (cranberry, wild blueberry, and strawberry), all the other selected natural products (peppermint, ginger, cinnamon, rosemary, liquorice, xanthorrrhizol, tt-farnesol, guaijaverin, and macelignan) exhibited varying degrees of bacterial growth inhibition. The MIC values ranged from as low as 4 mu g/ml for xanthorrrhizol to 1000 mu g/ml for guaijaverin. All the growth inhibitory natural agents tested showed similar inhibition for both S. mutans and S. sanguinis.Conclusions: Although several natural products exerted significant antibacterial effects, none had selective inhibitory action on the growth of S. mutans

A Randomized, Open-Label, Multicenter, Dose Escalation Study of HQK-1001 (2,2-Dimethylbutyrate, Sodium Salt) in Sickle Cell Disease

Abstract Abstract 998 Fetal hemoglobin (Hb F) induction is an effective therapeutic strategy in SCD. Widespread use of hydroxyurea (HU), the only approved anti-switching agent, has been limited by patient concerns about tolerability, patient compliance, and long-term use of a cytotoxic agent. There is a need for alternative anti-switching agents that are not cytotoxic and with different mechanisms of action. HQK-1001, an orally bioavailable short-chain fatty acid, promotes Hb F synthesis and prolongs erythroid survival and proliferation in pre-clinical models. In an earlier placebo-controlled Phase I/II study in SCD, HQK-1001 at 10, 20, and 30 mg/kg/day for 12 weeks was well tolerated and resulted in dose-dependent increase in Hb F. This randomized, open-label, dose escalation study evaluated the safety, pharmacodynamics (PD) and pharmacokinetics (PK) of HQK-1001 given at higher doses and for longer duration (NCT01322269). Patients with SCD ≥ 12 years of age were randomized to receive HQK-1001 at 30, 40, or 50 mg/kg daily for 26 weeks. Enrollment at 50 mg/kg was opened after an interim review of safety data at the 2 lower doses. Patients were stratified by HU at enrollment, and those on HU had to be on a stable dose for ≥ 6 months. HQK-1001 was discontinued if the patient was transfused. Oral iron was given daily if baseline plasma ferritin was < 700 ng/mL. Week 4 PK was evaluated in 4 patients at each dose. Pre-dose plasma concentrations were measured at each 4-weekly visits in all patients to verify compliance with dosing. Between April and September 2011, 52 patients were randomized to HQK-1001 at 30 mg/kg (n = 15), 40 mg/kg (n = 18), and 50 mg/kg (n = 19). There were 28 males and 24 females with a median age of 21 years (range, 12–46). The phenotype was Hb S-S in 45 and Hb S-β-thal-0 in 7, and 31 patients (60%) were on HU. The median duration on study drug was 114 days (range, 8–192), with 27 patients (52%) having discontinued HQK-1001 prior to completing the planned 26 weeks of dosing, 12 due to a transfusion and 15 for other reasons including withdrawal of consent and adverse events (AEs). The most common drug-related AEs, nausea (44%), vomiting (29%), somnolence (25%), headache (17%) and upper abdominal pain (17%), were usually graded as mild or moderate. Oral iron may have exacerbated upper gastrointestinal (GI) AEs. Dose limiting toxicities identified at 40 and 50 mg/kg doses consisted of gastritis (n = 3), somnolence (n = 2), pancreatitis (n = 1) and increased AST (n = 1). The maximum tolerated dose was established as 30 mg/kg/day and the protocol was amended to dose all patients at 30 mg/kg/day and discontinue oral iron. To further improve GI tolerability, the protocol was then amended to switch all patients to 15 mg/kg twice a day. No new drug-related severe toxicities were reported after stopping oral iron and dosing all patients at 30 mg/kg/day. Peak plasma concentrations were dose proportional. Average half-lives ranged from 9.8 to 11.7 hours and were dose independent. Plasma concentrations at 30 mg/kg were in the range shown to induce Hb F and erythropoiesis in pre-clinical models. Plasma concentrations were < 99% of the lower limit of confidence intervals in 16% of pre-dose samples collected at the scheduled times, suggesting non-compliance with HQK-1001 dosing in some patients. Of the 21 patients receiving HQK-1001 alone, Hb F increased in 18 patients (86%), with a mean increase of 2% (range, −2% to +10%), total Hb increased by a mean of 0.5 g/dL (range, −0.7 to 2.4 g/dL), and reticulocytes increased by a mean of 4.1% (range, to −4% to +15%). In 31 patients receiving HQK-1001 + HU, Hb F increased in 25 patients (80%), with a mean increase of 2.7% (range, −3% to + 10%), total Hb increased by a mean of 0.75 g/dL (range, −1.2 to + 1.8 g/dL), and reticulocytes increased by a mean of 1.4% (range, −6% to +15%). Covariate analysis showed significant correlation between change in Hb F at peak value and baseline ferritin (positive correlation, p = 0.008) and TIBC (negative correlation, p < 0.0001). This study demonstrated that HQK-1001 is well tolerated at 30 mg/kg/day. Plasma concentrations at this dose were in the range shown to induce Hb F and erythropoiesis in pre-clinical models. Hb F increased in most patients, both in HU and non-HU groups. HQK-1001 also increased erythropoiesis. Based on these positive results, a placebo-controlled Phase 2 study was launched to evaluate the PD, efficacy and safety of HQK-1001 at 15 mg/kg BID in SCD patients not currently treated with HU. Disclosures: Kutlar: HemaQuest Pharmaceuticals, Inc.: Research Funding. Reid:Haemaquest: Honoraria. Taher:Novartis: Research Funding, Speakers Bureau. Abboud:Novartis: Speakers Bureau; Pfizer: Research Funding; Sangart: Membership on an entity's Board of Directors or advisory committees. Buchanan:HemaQuest Pharmacuetical, Inc.: Research Funding. Ataga:HemaQuest Pharmaceuticals, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. White:HemaQuest: Consultancy. Johnson:HemaQuest Pharmaceuticals: Employment, Equity Ownership. Ghalie:HemaQuest Pharmaceuticals: Employment, Equity Ownership