A randomized, double-blind, phase 2b study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single-dose regimen of ferroquine with artefenomel in adults and children with uncomplicated Plasmodium falciparum malaria.

BACKGROUND: For uncomplicated Plasmodium falciparum malaria, highly efficacious single-dose treatments are expected to increase compliance and improve treatment outcomes, and thereby may slow the development of resistance. The efficacy and safety of a single-dose combination of artefenomel (800 mg) plus ferroquine (400/600/900/1200 mg doses) for the treatment of uncomplicated P. falciparum malaria were evaluated in Africa (focusing on children ≤ 5 years) and Asia. METHODS: The study was a randomized, double-blind, single-dose, multi-arm clinical trial in patients aged > 6 months to < 70 years, from six African countries and Vietnam. Patients were followed up for 63 days to assess treatment efficacy, safety and pharmacokinetics. The primary efficacy endpoint was the polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) at Day 28 in the Per-Protocol [PP] Set comprising only African patients ≤ 5 years. The exposure-response relationship for PCR-adjusted ACPR at Day 28 and prevalence of kelch-13 mutations were explored. RESULTS: A total of 373 patients were treated: 289 African patients ≤ 5 years (77.5%), 64 African patients > 5 years and 20 Asian patients. None of the treatment arms met the target efficacy criterion for PCR-adjusted ACPR at Day 28 (lower limit of 95% confidence interval [CI] > 90%). PCR-adjusted ACPR at Day 28 [95% CI] in the PP Set ranged from 78.4% [64.7; 88.7%] to 91.7% [81.6; 97.2%] for the 400 mg to 1200 mg ferroquine dose. Efficacy rates were low in Vietnamese patients, ranging from 20 to 40%. A clear relationship was found between drug exposure (artefenomel and ferroquine concentrations at Day 7) and efficacy (primary endpoint), with higher concentrations of both drugs resulting in higher efficacy. Six distinct kelch-13 mutations were detected in parasite isolates from 10/272 African patients (with 2 mutations known to be associated with artemisinin resistance) and 18/20 Asian patients (all C580Y mutation). Vomiting within 6 h of initial artefenomel administration was common (24.6%) and associated with lower drug exposures. CONCLUSION: The efficacy of artefenomel/ferroquine combination was suboptimal in African children aged ≤ 5 years, the population of interest, and vomiting most likely had a negative impact on efficacy. Trial registration ClinicalTrials.gov, NCT02497612. Registered 14 Jul 2015, https://clinicaltrials.gov/ct2/show/NCT02497612?term=NCT02497612&draw=2&rank=1.

The Formation, Persistence, and Resistance to Disinfectant of the Erysipelothrix piscisicarius Biofilm.

Erysipelothrix piscisicarius is an emergent pathogen in fish aquaculture, particularly in the ornamental fish trade. Very little is known on the biology of this pathogen; however, the recurrence of infection and disease outbreaks after removing the fish from a system and disinfecting the tank suggest its environmental persistence. Moreover, biofilm lifestyle in E. piscisicarius has been suspected but not previously shown. The purpose of this study was to investigate the formation of biofilms on an abiotic surface in Erysipelothrix spp. We used hydroxyapatite-coated plastic pegs to demonstrate the attachment, growth, and persistence of E. piscisicarius on abiotic surfaces in both fresh and marine environments and to investigate the susceptibility of this pathogen to different disinfectants that are used in the aquaculture industry. E. piscisicarius formed biofilms that persisted significantly longer than planktonic cells did in both freshwater and saltwater over a period of 120 h (P = 0.004). The biofilms were also more resistant to disinfectants than the planktonic cells were. Hydrogen peroxide was the most effective disinfectant against E. piscisicarius, and it eradicated the biofilms and planktonic cells at the recommended concentrations. In contrast, Virkon and bleach were able to eradicate only the planktonic cells. This information should be taken into consideration when developing biosecurity protocols in aquaculture systems, aquariums, and private collections.

A Single-Dose Combination Study with the Experimental Antimalarials Artefenomel and DSM265 To Determine Safety and Antimalarial Activity against Blood-Stage Plasmodium falciparum in Healthy Volunteers.

Artefenomel and DSM265 are two new compounds that have been shown to be well tolerated and effective when administered as monotherapy malaria treatment. This study aimed to determine the safety, pharmacokinetics, and pharmacodynamics of artefenomel and DSM265 administered in combination to healthy subjects in a volunteer infection study using the Plasmodium falciparum-induced blood-stage malaria model. Thirteen subjects were inoculated with parasite-infected erythrocytes on day 0 and received a single oral dose of artefenomel and DSM265 on day 7. Cohort 1 (n = 8) received 200 mg artefenomel plus 100 mg DSM265, and cohort 2 (n = 5) received 200 mg artefenomel plus 50 mg DSM265. Blood samples were collected to measure parasitemia, gametocytemia, and artefenomel-DSM265 plasma concentrations. There were no treatment-related adverse events. The pharmacokinetic profiles of artefenomel and DSM265 were similar to those of the compounds when administered as monotherapy, suggesting no pharmacokinetic interactions. A reduction in parasitemia occurred in all subjects following treatment (log10 parasite reduction ratios over 48 h [PRR48] of 2.80 for cohort 1 and 2.71 for cohort 2; parasite clearance half-lives of 5.17 h for cohort 1 and 5.33 h for cohort 2). Recrudescence occurred in 5/8 subjects in cohort 1 between days 19 and 28 and in 5/5 subjects in cohort 2 between days 15 and 22. Low-level gametocytemia (1 to 330 female gametocytes/ml) was detected in all subjects from day 14. The results of this single-dosing combination study support the further clinical development of the use of artefenomel and DSM265 in combination as a treatment for falciparum malaria. (This study has been registered at ClinicalTrials.gov under identifier NCT02389348.).

Spray drying OZ439 nanoparticles to form stable, water-dispersible powders for oral malaria therapy.

BACKGROUND: OZ439 is a new chemical entity which is active against drug-resistant malaria and shows potential as a single-dose cure. However, development of an oral formulation with desired exposure has proved problematic, as OZ439 is poorly soluble (BCS Class II drug). In order to be feasible for low and middle income countries (LMICs), any process to create or formulate such a therapeutic must be inexpensive at scale, and the resulting formulation must survive without refrigeration even in hot, humid climates. We here demonstrate the scalability and stability of a nanoparticle (NP) formulation of OZ439. Previously, we applied a combination of hydrophobic ion pairing and Flash NanoPrecipitation (FNP) to formulate OZ439 NPs 150 nm in diameter using the inexpensive stabilizer hydroxypropyl methylcellulose acetate succinate (HPMCAS). Lyophilization was used to process the NPs into a dry form, and the powder's in vitro solubilization was over tenfold higher than unprocessed OZ439. METHODS: In this study, we optimize our previous formulation using a large-scale multi-inlet vortex mixer (MIVM). Spray drying is a more scalable and less expensive operation than lyophilization and is, therefore, optimized to produce dry powders. The spray dried powders are then subjected to a series of accelerated aging stability trials at high temperature and humidity conditions. RESULTS: The spray dried OZ439 powder's dissolution kinetics are superior to those of lyophilized NPs. The powder's OZ439 solubilization profile remains constant after 1 month in uncapped vials in an oven at 50 °C and 75% RH, and for 6 months in capped vials at 40 °C and 75% RH. In fasted-state intestinal fluid, spray dried NPs achieved 80-85% OZ439 dissolution, to a concentration of 430 µg/mL, within 3 h. In fed-state intestinal fluid, 95-100% OZ439 dissolution is achieved within 1 h, to a concentration of 535 µg/mL. X-ray powder diffraction and differential scanning calorimetry profiles similarly remain constant over these periods. CONCLUSIONS: The combined nanofabrication and drying process described herein, which utilizes two continuous unit operations that can be operated at scale, is an important step toward an industrially-relevant method of formulating the antimalarial OZ439 into a single-dose oral form with good stability against humidity and temperature.

Impact of Ferroquine on the Solubilization of Artefenomel (OZ439) during in Vitro Lipolysis in Milk and Implications for Oral Combination Therapy for Malaria.

Milk is an attractive lipid-based formulation for the delivery of poorly water-soluble drugs to pediatric populations. We recently observed that solubilization of artefenomel (OZ439) during in vitro intestinal lipolysis was driven by digestion of triglycerides in full-cream bovine milk, reflecting the ability of milk to act as an enabling formulation in the clinic. However, when OZ439 was co-administered with a second antimalarial drug, ferroquine (FQ) the exposure of OZ439 was reduced. The current study therefore aimed to understand the impact of the presence of FQ on the solubilization of OZ439 in milk during in vitro intestinal digestion. Synchrotron small-angle X-ray scattering was used for in situ monitoring of drug solubilization (inferred via decreases in the intensity of drug diffraction peaks) and polymorphic transformations that occurred during the course of digestion. Quantification of the amount of each drug solubilized over time and analysis of their distributions across the separated phases of digested milk were determined using high-performance liquid chromatography. The results show that FQ reduced the solubilization of OZ439 during milk digestion, which may be due to competitive binding of FQ to the digested milk products. Interactions between the protonated FQ-H+ and ionized liberated free fatty acids resulted in the formation of amorphous salts, which removes the low-energy crystalline state as a barrier to dissolution of FQ, while inhibiting the solubilization of OZ439. We conclude that although milk could enhance the solubilization of poorly water-soluble OZ439 during in vitro digestion principally due to the formation of fatty acids, the solubilization efficiency was reduced by the presence of FQ by competition for the available fatty acids. Assessment of the solubilization of both drugs during digestion of fixed-dose combination lipid formulations (such as milk) is important and may rationalize changes in bioavailability when compared to that of the individual drugs in the same formulation.

Understanding the skin sensitization capacity of ascaridole: a combined study of chemical reactivity and activation of the innate immune system (dendritic cells) in the epidermal environment.

To improve the prediction of the possible allergenicity of chemicals in contact with the skin, investigations of upstream events are required to better understand the molecular mechanisms involved in the initiation of allergic reactions. Ascaridole, one of the compounds responsible for skin sensitization to aged tea tree oil, degrades into intermediates that evolve via different mechanisms involving radical species. We aimed at broadening the knowledge about the contribution of radical intermediates derived from ascaridole to the skin sensitization process by assessing the reactivity profile towards amino acids, identifying whether free radicals are formed in a reconstructed human epidermis (RHE) model and their biological properties to activate the immune system, namely dendritic cells in their natural context of human HaCaT keratinocytes and RHE. Electron paramagnetic resonance combined to spin-trapping in EpiSkin™ RHE confirmed the formation of C-radicals in the epidermal tissue from 10 mM ascaridole concentration, while reactivity studies toward amino acids showed electrophilic intermediates issued from radical rearrangements of ascaridole as the main reactive species. Activation of THP-1 cells, as surrogate for dendritic cells, that were cocultured with HaCaT was significantly upregulated after treatment with low micromolar concentrations based on cell surface expression of the co-stimulatory molecule CD86 and the adhesion molecule CD54. Placing THP-1 cells underneath the RHE allowed us to monitor which of the concentrations that produce radical(s) and/or protein antigens in the epidermal skin environment promote the activation of dendritic cells. We detected no significant upregulation of CD86/CD54 after topical RHE application of concentrations up to 30 mM ascaridole (t = 24 h) but clear upregulation after 60 mM.

Effectiveness and effect of non-vital bleaching on the quality of life of patients up to 6 months post-treatment: a randomized clinical trial.

OBJECTIVES: The aim of this study was to evaluate the esthetic perception of patients at 6 months after bleaching of non-vital teeth with 35% of hydrogen peroxide and 37% of carbamide peroxide using a walking bleach technique. We also assessed psychosocial impacts as well as the clinical effectiveness and stability of the color change. MATERIALS AND METHODS: The teeth bleaching treatment was randomly assigned to two groups according to the bleaching agent used: G1 HP = 35% of hydrogen peroxide (n = 25) and G2 CP = 37% of carbamide peroxide (n = 25). The non-vital bleaching was performed in four sessions using the walking bleach technique. The color was objectively (ΔE) and subjectively (ΔSGU) evaluated. The esthetic perception and psychosocial factors were evaluated before treatment as well as one and 6 months post-treatment using Oral Health Impact Profile (OHIP) esthetics and Psychosocial Impact of Dental Esthetics Questionnaire (PIDAQ). RESULTS: The color change (ΔE) at 6 months (G1 = 14.53 ± 5.07 and G2 = 14.09 ± 6.61) for both color groups remained stable until the 6-month post-treatment (p > 0.05). There was a decrease in the values of OHIP esthetics and PIDAQ after treatment compared to the baseline (p < 0.05), and this effect was maintained 6 months post-treatment. CONCLUSIONS: Both agents were highly effective and maintained the color stability at 6 months; this positively affected the esthetic perception and psychosocial impact of patients who also remained stable over time. CLINICAL RELEVANCE: Non-vital bleaching produces a positive and stable impact on the esthetic perception and psychosocial factors at medium-term follow-ups.

Randomized clinical trial of 2 nonvital tooth bleaching techniques: A 1-year follow-up.

STATEMENT OF PROBLEM: Controlled clinical trials comparing the effectiveness of the walking bleaching (WB) technique and the inside-outside (I-O) technique used in a short daily regimen are lacking. PURPOSE: The purpose of this randomized clinical trial was to investigate the effectiveness of WB with that of the I-O technique conducted over 4 weeks and to compare color changes after 1 year. MATERIAL AND METHODS: Discolored and endodontically treated anterior teeth received a cervical seal and were randomly divided into groups according to the technique. In the WB group (n=9), a mixture of sodium perborate and 20% hydrogen peroxide was applied in the pulp chambers and replaced weekly up to 4 weeks. For the I-O group (n=8), participants applied 10% carbamide peroxide in the pulp chambers and wore custom-fitted trays for 1 hour per day over 4 weeks. CIELab parameters were obtained using a spectrophotometer at baseline, during bleaching (1, 2, 3, and 4 weeks) and after 1 year. Changes in color (ΔE), lightness (ΔL*), green-red axis (Δa*), blue-yellow axis (Δb*), and absolute color parameters (L*, b*, and a*) for each evaluation time were calculated and analyzed by repeated measures analysis of variance (ANOVA) and post hoc Bonferroni test (α=.05). RESULTS: No significant differences between WB and I-O techniques were observed for ΔE, ΔL*, Δa*, Δb*, L*, a*, or b* values (P>.05); however, significant differences were observed among the evaluation times (P<.05). Color changes observed after 2 weeks were stable after 1 year; ΔL* and Δa* values after 1 year were not significantly different from the 1-week evaluation, and significant changes in Δb* after 3 weeks were maintained at the 1-year follow-up. The same trend was observed for the absolute CIELab color parameters. CONCLUSIONS: Both WB and I-O regimens were similarly effective as shown by significant ΔE after 2 weeks and no color regression after 1 year.

A Phase 3, Double-Blind, Randomized Study of Arterolane Maleate-Piperaquine Phosphate vs Artemether-Lumefantrine for Falciparum Malaria in Adolescent and Adult Patients in Asia and Africa.

BACKGROUND: Artemisinins, which are derived from plants, are subject to risk of supply interruption due to climatic changes. Consequently, an effort to identify a new synthetic antimalarial was initiated. A fixed-dose combination of arterolane maleate (AM), a new synthetic trioxolane, with piperaquine phosphate (PQP), a long half-life bisquinoline, was evaluated in patients with uncomplicatedPlasmodium falciparummalaria. METHODS: In this multicenter, randomized, double-blind, comparative, parallel-group trial, 1072 patients aged 12-65 years withP. falciparummonoinfection received either AM-PQP (714 patients) once daily or artemether-lumefantrine (A-L; 358 patients) twice daily for 3 days. All patients were followed up until day 42. RESULTS: Of the 714 patients in the AM-PQP group, 638 (89.4%) completed the study; of the 358 patients in the A-L group, 301(84.1%) completed the study. In both groups, the polymerase chain reaction corrected adequate clinical and parasitological response (PCR-corrected ACPR) on day 28 in intent-to-treat (ITT) and per-protocol (PP) populations was 92.86% and 92.46% and 99.25% and 99.07%, respectively. The corresponding figures on day 42 in the ITT and PP populations were 90.48% and 91.34%, respectively. After adjusting for survival ITT, the PCR-corrected ACPR on day 42 was >98% in both groups. The overall incidence of adverse events was comparable. CONCLUSIONS: AM-PQP showed comparable efficacy and safety to A-L in the treatment of uncomplicatedP. falciparummalaria in adolescent and adult patients. AM-PQP demonstrated high clinical and parasitological response rates as well as rapid parasite clearance. CLINICAL TRIALS REGISTRATION: India. CTRI/2009/091/000101.

Endoperoxide Drug Cross-Resistance Patterns for Plasmodium falciparum Exhibiting an Artemisinin Delayed-Clearance Phenotype.

The ring-stage susceptibility assay was modified to quantify the susceptibilities of multiple strains of control and delayed-clearance phenotype (DCP) Plasmodium falciparum strains to seven endoperoxide antimalarial drugs. The susceptibility of all of the DCP lines to six of the drugs was lower than that of the controls. In contrast, DCP parasites did not show reduced susceptibility to the synthetic endoperoxide drug OZ439. These data show that it is possible to circumvent emerging artemisinin resistance with a modified endoperoxide drug.

Efficacy of OZ439 (artefenomel) against early Plasmodium falciparum blood-stage malaria infection in healthy volunteers.

OBJECTIVES: OZ439, or artefenomel, is an investigational synthetic ozonide antimalarial with similar potency, but a significantly improved pharmacokinetic profile, compared with artemisinins. We wished to measure key pharmacokinetic and pharmacodynamic parameters and the pharmacokinetic/pharmacodynamic relationship of artefenomel in humans to guide the drug's further development as combination therapy in patients. PATIENTS AND METHODS: We tested artefenomel in the human induced blood-stage malaria (IBSM) model. Plasmodium infection was monitored by quantitative PCR (qPCR) and upon reaching 1000 parasites/mL single doses of 100, 200 and 500 mg of artefenomel were administered orally with evaluation of drug exposure and parasitaemia until rescue treatment after 16 days or earlier, if required. RESULTS: A single 100 mg dose had only a transient effect, while the 200 mg dose resulted in a significant reduction in parasitaemia before early recrudescence. At the highest (500 mg) dose, initial clearance of parasites below the limit of detection of qPCR was observed, with a 48 h parasite reduction ratio (PRR48) >10 000 and a parasite clearance half-life of 3.6 h (95% CI 3.4-3.8 h). However, at this dose, recrudescence was seen in four of eight subjects 6-10 days after treatment. Pharmacokinetic/pharmacodynamic modelling predicted an MIC of 4.1 ng/mL. CONCLUSIONS: These results confirm the antimalarial potential of artefenomel for use in a single-exposure combination therapy. The observations from this study support and will assist further clinical development of artefenomel.

Efficacy and safety of over-the-counter whitening strips as compared to home-whitening with 10 % carbamide peroxide gel--systematic review of RCTs and metanalysis.

OBJECTIVES: The study aims to compare the efficacy and safety of over-the-counter whitestrips with the American Dental Association (ADA)-recommended home-whitening using the 10 % carbamide peroxide gel. MATERIALS AND METHODS: Randomized controlled trials (RCTs) comparing the clinical efficacy and safety of the whitestrips with the 10 % carbamide peroxide (10 % CP) gel applied on tray for tooth whitening in adults were searched at PubMed and Cochrane Central Register of Controlled Trials databases and selected up to October 2014. Efficacy of the whitening techniques was assessed through ∆E, ∆L, and ∆b parameters, while side effects were analyzed as dichotomous variables. Data was extracted independently by two reviewers. Metanalysis was performed using random- and fixed-effect models (RevMan 5.3). RESULTS: Eight studies were included in the metanalysis. The metanalysis revealed no significant difference between the intervention groups for tooth-whitening efficacy measured as ΔE (mean difference [MD]-0.53; 95 % CI [-1.72;0.66]; Z = 0.88; p = 0.38) and ΔL (MD-0.22; 95 % CI [-0.81;0.36]; z = 0.75; p = 0.45); reduction of yellowing was higher with the whitestrips (MD-0.47; 95 % CI [-0.89; -0.06]; Z = 2.25; p = 0.02). Tooth sensitivity (risk ratio [RR] 1.17; 95 % CI [0.81-1.69]; Z = 0.81; p = 0.42) and gingival sensitivity (RR 0.76; 95 % CI [0.53-1.10]; Z = 1.44; p = 0.15) were similar, regardless of the whitening method used. The observed gingival irritation was higher when the 10 % CP gel was applied on tray (RR 0.43; 95 % CI [0.20-0.93]; Z = 2.14; p = 0.03). The quality of evidence generated was rated very low for all outcomes. CONCLUSIONS: There is no sound evidence to support the use of the whitening strips in detriment of the ADA-recommended technique based on the 10 % carbamide peroxide gel applied on tray. CLINICAL RELEVANCE: To the moment, there is no sound evidence in dental literature to suggest that the ADA-recommended whitening technique based on 10 % carbamide peroxide gel could be substituted by the whitening strips. The existing studies, with their limitations, revealed similar tooth whitening and tooth and gingival sensitivity for both whitening techniques.

Effect of Short-Duration, Localized Carbamide Peroxide Application to Remove Enamel Staining on Bond Strength of Resin Cement to Enamel.

UNLABELLED: Objective Peripheral enamel staining is often noticed after removal of long-term veneer or crown provisional restorations. Application of carbamide peroxide (CP) easily removes the stain, but the potential for immediate bonding with a resin-based cement is questionable. This project tested the short-term, shear bond strength of a commercial, photo-curable, resin cement to bovine enamel after application of a 10% concentration of CP placed for different exposure times. MATERIALS AND METHODS: Bovine enamel was flattened and polished. Surfaces had either no CP application (control), or 10% CP applied for 10, 20, or 30 seconds. Teeth were acid-etched, rinsed, dried, and controlled sized stubs of a commercial resin cement were photocured onto the treated surfaces. The shear bond strength of each specimen was determined using a universal testing machine, and results were compared using an analysis of variance at a preset alpha of 0.5 (n = 10/group). RESULTS: No significant differences (p = 0.819) in shear bond strength were found among any CP cleaning treatments or the experimental (nontreated) control. CONCLUSIONS: Short-term application of 10% carbamide peroxide prior to acid etching, to remove enamel stains in teeth prepared to receive ceramic veneers or crowns, does not reduce immediate shear bond strength of resin-based cement to enamel. CLINICAL SIGNIFICANCE: Clinicians can confidently apply 10% CP for short-term, localized stain removal on enamel and not be concerned about affecting subsequent bond strength of a resin-based cement to enamel. (J Esthet Restor Dent, 2016).

Evaluation of the QT effect of a combination of piperaquine and a novel anti-malarial drug candidate OZ439, for the treatment of uncomplicated malaria.

AIMS: The aim was to investigate the QT effect of a single dose combination regimen of piperaquine phosphate (PQP) and a novel aromatic trioxolane, OZ439, for malaria treatment. METHODS: Exposure-response (ER) analysis was performed on data from a placebo-controlled, single dose, study with OZ439 and PQP. Fifty-nine healthy subjects aged 18 to 55 years received OZ439 alone or placebo in a first period, followed by OZ439 plus PQP or matching placebos in period 2. OZ439 and PQP doses ranged from 100-800 mg and 160-1440 mg, respectively. Twelve-lead ECG tracings and PK samples were collected serially pre- and post-dosing. RESULTS: A significant relation between plasma concentrations and placebo-corrected change from baseline QTc F (ΔΔQTc F) was demonstrated for piperaquine, but not for OZ439, with a mean slope of 0.047 ms per ng ml(-1) (90% CI 0.038, 0.057). Using an ER model that accounts for plasma concentrations of both piperaquine and OZ439, a largest mean QTc F effect of 14 ms (90% CI 10, 18 ms) and 18 ms (90% CI 14, 22 ms) was predicted at expected plasma concentrations of a single dose 800 mg OZ439 combined with PQP 960 mg (188 ng ml(-1) ) and 1440 mg (281 ng ml(-1) ), respectively, administered in the fasted state. CONCLUSIONS: Piperaquine prolongs the QTc interval in a concentration-dependent way. A single dose regimen combining 800 mg OZ439 with 960 mg or 1440 mg PQP is expected to result in lower peak piperaquine plasma concentrations compared with available 3 day PQP-artemisinin combinations and can therefore be predicted to cause less QTc prolongation.

From hybrid compounds to targeted drug delivery in antimalarial therapy.

The discovery of new drugs to treat malaria is a continuous effort for medicinal chemists due to the emergence and spread of resistant strains of Plasmodium falciparum to nearly all used antimalarials. The rapid adaptation of the malaria parasite remains a major limitation to disease control. Development of hybrid antimalarial agents has been actively pursued as a promising strategy to overcome the emergence of resistant parasite strains. This review presents the journey that started with simple combinations of two active moieties into one chemical entity and progressed into a delivery/targeted system based on major antimalarial classes of drugs. The rationale for providing different mechanisms of action against a single or additional targets involved in the multiple stages of the parasite's life-cycle is highlighted. Finally, a perspective for this polypharmacologic approach is presented.

Antimicrobial effects of carbamide peroxide against a polymicrobial biofilm model.

PURPOSE: To investigate the in vitro antimicrobial effects of carbamide peroxide (CP) and CP-based home bleaching agents against polymicrobial (PM) biofilms. METHODS: Using a high-throughput active attachment model, PM biofilms were cultured on glass coverslips by diluting the stimulated saliva of one healthy adult. All experiments were performed anaerobically in McBain medium, which was refreshed twice daily. After biofilm formation for 24 or 72 hours, the biofilms were treated with 0.5%, 2.5%, 5%, or 10% CP, 20-fold dilutions of HiLite Shade Up (HS) or Opalescence Regular (OR), 0.2% chlorhexidine digluconate (CHX), 0.2% NaF, or deionized water (n = 10 each). Biofilms were dispersed and the number of colony forming units (CFU) was measured on tryptic soy agar blood plates. Coverslips containing 72-hour biofilms treated with 0.5% and 10% CP and deionized water were stained and scanned by confocal laser scanning microscopy (CLSM). RESULTS: Treatment of 24- and 72-hour biofilms with HS, OR and CH yielded significantly fewer colonies than treatment with water or 0.2% NaF. No growing colonies were observed after treatment with 10% CP. CLSM showed that the percentage of dead bacteria increased as the concentration of CP increased.

Employment of Reservoirs in At-Home Whitening Trays: Efficacy and Efficiency in Tooth Whitening.

AIM: This study aimed to determine the efficacy of trays made with and without reservoirs, in conjunction with time and cost evaluations, by measuring color change with home whitening procedures. MATERIALS AND METHODS: Extracted human maxillary teeth (central incisors n = 20; canines n = 20; molars n = 20) and 60 artificial teeth (lateral n = 20; premolar n = 40) were mounted into ten typodonts. Tray fabrication was completed such that a block-out resin reservoir was placed on half of the buccal surface of the tray, while the other half remained without a reservoir. Whitening with custom fabricated trays was performed based on two different whitening regimens, where each regimen was assigned to five typodonts: Night-time: Opalescence PF 10% carbamide peroxide for 8 hours daily and Day-time: Philips DayWhite 9.5% hydrogen peroxide for 30 minutes, twice daily. Both systems were applied for 1 week. To evaluate tooth shade, the VITA Easyshade® Advance 4.0 spectrophotometer was used. Color measurements were obtained at baseline (T1), 1-day post-whitening (T2), and 1 month post-whitening (T3). One-way ANOVA, followed by post-hoc Tukey's HSD test, was used to detect significant difference in the overall color change (ΔE*) among the four groups at T2 and T3. Additionally, paired-sample t-test was used to assess difference in ΔE* between T2 and T3 treatment within each of four techniques of tray fabrication. RESULTS: No significant difference in ΔE* was found among the four groups at T2 and T3 (p > 0.05 in each instance). There were significant differences in mean ΔE* between T2 and T3 treatment for the day white treatment groups without reservoir (6.96 vs 10.19 respectively; p = 0.0026) and with reservoirs (6.23 vs 9.79 respectively; p = 0.0031). CONCLUSION: The use of reservoirs does not have a significant effect on whitening efficacy, regardless of type of whitening material and regimen. CLINICAL SIGNIFICANCE: The use of custom fabricated trays with or without reservoirs were equally effective in whitening teeth.

An overview on the Effects of 10% and 15% Carbamide Peroxide and its Relationship to Dentine Sensitivity.

The purpose of this overview was to review the available literature to determine if there was any evidence that the application of 10% and 15% carbamide peroxide in tooth whitening procedures resulted in tooth (dentine) sensitivity. The conclusions from the review would indicate that tooth whitening with either 10% or 15% carbamide peroxide is an effective and safe treatment when under a dental professionals' supervision. Reported side-effects were considered mild to moderate in nature and were transient in duration. Reported incidences of dentine sensitivity range from 15-65% of patients using 10% carbamide peroxide.

The optimal patch test concentration for ascaridole as a sensitizing component of tea tree oil.

BACKGROUND: Tea tree oil is used as a natural remedy, but is also a popular ingredient in household and cosmetic products. Oxidation of tea tree oil results in degradation products, such as ascaridole, which may cause allergic contact dermatitis. OBJECTIVES: To identify the optimal patch test concentration for ascaridole, and to investigate the relationship between a positive reaction to ascaridole and a positive reaction to oxidized tea tree oil. PATIENTS/MATERIALS/METHODS: Three hundred and nineteen patients with eczema were patch tested with ascaridole 1%, 2%, and 5%, and 250 patients were patch tested with oxidized tea tree oil 5%. Readings were performed on D3 and D7 according to a patch test calibration protocol. RESULTS: With an increasing ascaridole test concentration, the frequency of positive reactions increased: ascaridole 1%, 1.4%; ascaridole 2%, 5.5%; and ascaridole 5%, 7.2%. However, the frequencies of irritant and doubtful reactions also increased, especially for ascaridole 5%. A positive reaction to ascaridole was related to a positive reaction to tea tree oil. CONCLUSIONS: This study is in support of ascaridole being a sensitizer. We recommend patch testing with ascaridole at 2%. The finding that every positive reaction to oxidized tea tree oil is accompanied by a positive reaction to ascaridole suggests that ascaridole might be a contact allergen in oxidized tea tree oil.

Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria.

Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. OZ439 has successfully completed Phase I clinical trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing Phase IIa trials in malaria patients. Herein, we describe the discovery of OZ439 and the exceptional antimalarial and pharmacokinetic properties that led to its selection as a clinical drug development candidate. In vitro, OZ439 is fast-acting against all asexual erythrocytic Plasmodium falciparum stages with IC(50) values comparable to those for the clinically used artemisinin derivatives. Unlike all other synthetic peroxides and semisynthetic artemisinin derivatives, OZ439 completely cures Plasmodium berghei-infected mice with a single oral dose of 20 mg/kg and exhibits prophylactic activity superior to that of the benchmark chemoprophylactic agent, mefloquine. Compared with other peroxide-containing antimalarial agents, such as the artemisinin derivatives and the first-generation ozonide OZ277, OZ439 exhibits a substantial increase in the pharmacokinetic half-life and blood concentration versus time profile in three preclinical species. The outstanding efficacy and prolonged blood concentrations of OZ439 are the result of a design strategy that stabilizes the intrinsically unstable pharmacophoric peroxide bond, thereby reducing clearance yet maintaining the necessary Fe(II)-reactivity to elicit parasite death.