Christian Vlachojannis

Effectiveness and Safety of a Mouthwash Containing Essential Oil Ingredients

The mouthwash, Listerine®, was compounded in 1879 from four essential oils. Later, the oils were replaced by one ingredient per oil with approximately 25% ethanol as a vehicle to keep them in solution. From then on, Listerine® was no longer a medicinal plant product. In 2003, a review by the FDA Subcommittee on Oral Health Care Drug Products for Over‐the‐Counter Human Use concluded that the product is effective and safe, and a review of studies published in the meantime showed that Listerine® fulfils the consensus criteria for an effective antigingivitis/antiplaque product. However, concerns have been raised about the long‐term safety of some of the ingredients, particularly the ethanol content, and in the light of these concerns, the evidence has been re‐examined for both the efficacy and safety of Listerine®. In summary, the studies support the claim that Listerine® shows benefit for oral health, but the concerns over its safety remain to be clarified. Until these have been addressed, high risk populations (children, alcohol addicts, patients with genetic deficiencies in ethanol metabolism) should use alcohol‐free mouthwashes for the maintenance of oral health. Copyright

Rise and Fall of Oral Health Products with Canadian Bloodroot Extract

The rhizome of Sanguinaria canadensis (SC, bloodroot) contains an active principle with antimicrobial, antiinflammatory, antioxidative and immunomodulatory effects. For this reason SC extract has been added to toothpastes and mouthwashes in various concentrations. When tested separately, neither the toothpastes nor the mouthwashes with SC extract had any demonstrable clinical effectiveness against dental plaque and gingivitis. Although using them together twice a day seemed more effective than using placebo, more recent studies have shown conflicting results. Preclinical safety studies up to 2000, which did not include studies longer than 6 months, were thought not to indicate any appreciable potential for harm – to the oral mucosa in particular. In 2003, the FDA Subcommittee on Oral Health Care Drug Products for Over‐the‐Counter Human Use concluded from a review that using SC‐containing products is safe. However, for reasons unknown, the review failed to consider publications between 1999 and 2001 that suggested a possible link between the use of SC‐containing products and the pre‐neoplastic lesion, leukoplakia. As it happened, bloodroot had already been removed (in 2001) from the formula of one of the most widely used products in question and the brand has since then disappeared altogether from the worldwide market. Copyright

Efficacy and Safety of Pomegranate Medicinal Products for Cancer

Preclinical in vitro and in vivo studies demonstrate potent effects of pomegranate preparations in cancer cell lines and animal models with chemically induced cancers. We have carried out one systematic review of the effectiveness of pomegranate products in the treatment of cancer and another on their safety. The PubMed search provided 162 references for pomegranate and cancer and 122 references for pomegranate and safety/toxicity. We identified 4 clinical studies investigating 3 pomegranate products, of which one was inappropriate because of the low polyphenol content. The evidence of clinical effectiveness was poor because the quality of the studies was poor. Although there is no concern over safety with the doses used in the clinical studies, pomegranate preparations may be harmful by inducing synthetic drug metabolism through activation of liver enzymes. We have analysed various pomegranate products for their content of anthocyanins, punicalagin, and ellagic acid in order to compare them with the benchmark doses from published data. If the amount of coactive constituents is not declared, patients risk not benefiting from the putative pomegranate effects. Moreover, pomegranate end products are affected by many determinants. Their declaration should be incorporated into the regulatory guidance and controlled before pomegranate products enter the market.

Paramedian vertical palatal bone height for mini-implant insertion: a systematic review

Paramedian insertion of orthodontic mini-implants is increasingly used to anchor molar distalizers. The aim of this review was to systematically examine the available measurements of vertical palatal bone height (VBH). PUBMED, MEDLINE and the Cochrane Controlled Trials Register were searched using specific search terms. Hand searches of bibliographies of articles were also performed to identify studies measuring VBH or bone thickness in the human palate. Sixteen studies were included, arising from 19 published articles. Repeat presentations were excluded. Ten of the 11 computed tomogram (CT)-based studies presented data from 956 orthodontic patients on average VBH and its variation at a range of palatal sites. Individual data were not available, and pooling of data was not feasible because of heterogeneity of subjects, different measurement sites, different CT methods and their associated software. The compilation of data did indicate that the region 3-4mm behind the incisive foramen and 3-9mm lateral to the midpalatal suture should normally provide sufficient VBH to anchor molar distalizers. The risks of unwanted effects during distalization should be small, but the limitations listed above and the small numbers of studies available impair the precision of the estimates and do not allow the results to be generalized. Paramedian anchorage in the anterior palate can be recommended for molar distalization but, given the great inter-individual variability of the palatal bone height, it must be preceded by reliable CT-based imaging in patients identified by routine investigations as being at risk.

Pomegranate Juice and Prostate Cancer: Importance of the Characterisation of the Active Principle.

Two exploratory clinical studies investigating proprietary pomegranate products showed a trend of effectiveness in increasing prostate‐specific antigen doubling time in patients with prostate cancer. A recent clinical study did not support these results. We therefore analysed a lot of the marketed pomegranate blend for co‐active pomegranate compounds. The high‐performance liquid chromatography method was used to detect punicalagin, ellagic acid and anthocyanins. Total polyphenoles were determined by the Folin–Ciocalteu method using gallic acid as reference. The results show that the co‐active compounds in the daily dose of the pomegranate blend were far below those previously tested and that the photometric assessment is not reliable for the standardisation of study medications. Not pomegranate but the low amount of co‐active compounds in the proprietary pomegranate blend was responsible for its clinical ineffectiveness. Copyright

Quantification of anthocyanins in elderberry and chokeberry dietary supplements.

Elderberry and chokeberry food supplements may be ‘functional food’ in patients with metabolic syndrome or influenza but, for this, adequate amounts of co‐active ingredients must be consumed in the daily dose. This study aimed to quantify the anthocyanin content in three elderberry and six chokeberry products to assess their usefulness as functional food. Analyses were carried out using an established HPLC procedure. The minimum anthocyanin doses for the treatment of metabolic syndrome disorders were estimated as 110 mg per day and 3.5 g per day for influenza. Three products were inappropriate for clinical use. The lowest liquid supplies were achieved with a proprietary elderberry concentrate (11 mL) and a proprietary chokeberry mother juice (100 mL). Clinical studies are now required to prove the effectiveness and adapt the doses according to the clinical symptoms. Copyright

A Critical Evaluation of the Clinical Evidence for Pomegranate Preparations in the Prevention and Treatment of Cardiovascular Diseases

This study attempts a critical evaluation of the clinical evidence behind the use of dietary pomegranate preparations in the prevention and treatment of cardiovascular diseases. A search of PubMed on August 10, 2014 identified 228 references, which yielded extractable data from 24 clinical studies of pomegranate preparations. Hand searching identified two further studies. The quality of the studies and evidence of effectiveness of pomegranate were assessed by an established set of conventional criteria. Overall, the study quality was poor. Even in the best studies, indications of benefit did not reach the conventional levels of statistical significance. The only study with a definitive design had a biochemical rather than a clinical endpoint: it showed the expected difference in blood concentrations of myeloperoxidase after a single dose of either pomegranate or placebo. Only 10 of the 26 studies provided HPLC data on the amounts of co‐active ingredients in the preparations that were consumed by the subjects. If pomegranate has a role in the prevention and treatment of cardiovascular diseases, there is a pressing need for dose‐finding and long‐term confirmatory studies. The ultimate endpoint for definitive studies would be mortality, but reductions in blood pressure or demonstrable decreases in atherosclerotic plaques would be useful surrogates. Sample sizes for various assumptions are provided. Future studies need to prove the clinical benefit. Copyright

A Preliminary Investigation on the Antimicrobial Activity of Listerine®, Its Components, and of Mixtures Thereof

Listerine® is one of the most popular mouthwashes worldwide and claims to combat harmful bacteria. In the past century, its recipe was changed from an essential oil mouthwash to a five‐component mixture (thymol, menthol, eucalyptol, and methyl salicylate dissolved in 27% ethanol). The aim of this study was to get preliminary information about the antimicrobial activities of individual Listerine® components and their mixtures. We tested the bacterial strains Streptococcus mutans, Enterococcus faecalis, and Eikenella corrodens and the yeast Candida albicans. The established minimum inhibitory concentration (MIC) assay and the minimum bactericidal/fungicidal concentration (MBC/MFC) assay were applied. None of the combinations of two phenols at the concentrations contained within Listerine® were associated with either an additive or synergistic effect. Thymol had lower MIC and MBC/MFC values than the other Listerine® components and Listerine® against E. corrodens and C. albicans. The mixtures consisting of eucalyptol, methyl salicylate, and thymol were the most effective against S. mutans and E. faecalis and more effective than Listerine®. Our results demonstrate that the phenols and their concentrations as contained within Listerine® could be further optimized in terms of selecting those which increase their general effectiveness, at concentrations that do not induce harm. Copyright

Listerine® Products: An Update on the Efficacy and Safety

In the 19th century, the mouthwash Listerine® was formulated from four essential oils. Later, the oils were replaced by their marker substances. To keep them in solution, 24–27% ethanol was added as a vehicle. This is an update of our previous review on the efficacy and safety of Listerine®. Method: PubMed was searched for clinical studies on the therapeutic benefits and safety of Listerine® from the end of 2011 to the end of October 2015. Results: Sixteen studies were found and extracted. Three of the four 6‐month studies were of sound confirmatory design. Two of these investigated Listerine® and one Listerine Zero®. The evidence of effectiveness for Listerine®, based on the bulk of three confirmatory studies and numerous exploratory studies carried out so far, is strong, but only moderate for Listerine® Zero and poor for Listerine® Cool Blue. In the three safety studies identified, we found methodological flaws that biased the results. Conclusions: Evidence is accumulating that Listerine® is effective in improving oral health, but the absence of systematic toxicological studies means that an accurate safety assessment cannot be made. Copyright

Pro and Contra Duration Restriction of Treatment with Willow Bark Extract

The European Medicines Agency (EMA, Website, 2013) serves as a guidance for application dossiers to obtain marketing authorizations by the regulatory authorities of the individual countries in the European Union. The EMA assessment report on salicis cortex (willow bark) as well as on other herbal preparations thereof restricts treatment duration with this PhytoAnti-Inflammatory Drug (PAID) to 4 weeks (EMA, 2009a). The medical publications related to the risk of adverse events and toxicity occurring during prolonged periods of treatment with this PAID do not seem to endorse the 4 weeks treatment restriction demanded by the EMA. It must be noted that none of the EMA monographs have used an evidence-based approach similar to the Cochrane group. In this letter, the beneficial and adverse effects of prolonged treatment with willow bark extract and NSAIDs are compared in order to find an explanation for the duration of treatment restriction in terms of risk of adverse events and toxicity. Osteoarthritis is a chronic condition that requires long-term treatment. Because of the high risk of adverse events, especially in the elderly, it was suggested that NSAIDs should be limited to shortterm use only because of the high risk of adverse events (O’Neil et al., 2012). Such serious adverse events have not been observed during treatment with willow bark extract. The latter has no major impact on blood coagulation (Krivoy et al., 2001) and does not damage the gastrointestinal mucosa. Willow bark extract even contains gastroprotective compounds (Pobłocka-Olech and Krauze-Baranowska, 2008, 2010). Whereas 9 of 10 aspirin-treated rats (100 mg/kg) showed stomach lesions, ethanolic willow bark extract (12% salicin) in a dose of up to 120 mg/kg did not exert any negative effects on the stomach. (Glinko, 1998). Severe adverse events were also not observed in patients treated with willow bark extract, neither in 5 clinical studies over up to 6 weeks (Vlachojannis et al., 2009), nor in 3 surveys over 8 weeks including a total of 5871 patients (Werner and Scheithe, 2004, Zenner-Weber, 2004, Müller-Faßbender et al., 2007)