Complementary versus companion diagnostics: apples and oranges?

There have been several major problems that have plagued biopharmaceutical development since the end of the 1990s, but two in particular have reached the point where they are impacting the economic viability of the industry: the lack of efficacy of new drugs and increasing competition among therapeutics that broadly attack certain common diseases and disease areas. The US FDA has noted that the era of one-size-fits-all treatment may well be reaching its end days as companies increasingly adopt approaches that involve biomarkers (there are now commercial databases that purport to track over 11,000 of them). Pharmacogenomic biomarkers in particular are used to create diagnostics that help to differentiate or stratify the likely outcomes a patient will experience with a drug, which can now be said to be targeted or tailored to patients with particular traits (i.e., personalized), leading to an era of so-called precision medicine. As more is understood about diseases and the why and how of their effects on people through advances in biomarkers and genomics, personalized medicine is becoming a natural result of biomedical science and a natural trajectory for the innovation-based biopharmaceutical industry. The focus of this article is to examine an apparent divergence in that trajectory engendered by a growing differentiation in the approaches to personalized medicines in terms of their accompanying diagnostics: companion diagnostics are typically linked to a specific drug within its approved label, while complementary diagnostics are associated more broadly, usually not with a specific drug but with a class of drugs, and not confined to specific uses by labeling, with consequent ramifications for economic, regulatory and strategic considerations.

Can salivary activity predict periodontal breakdown in A. actinomycetemcomitans infected adolescents?

OBJECTIVE: While Aggregatibacter actinomycetemcomitans (Aa) is highly associated with localised aggressive periodontitis (LAP) many Aa-carriers do not develop LAP. This study was designed to determine whether specific salivary factors could distinguish between subjects who have Aa initially and remain healthy (H/AA) as compared to those who develop LAP (LAP/AA). DESIGN: H/AA subjects and healthy controls with no Aa (H) were enrolled in a longitudinal cohort study to investigate initiation of bone loss (LAP) over 3 years. After detection of LAP, stored saliva from 10 H, 10 H/AA, and 10 LAP/AA subjects was thawed, processed, and tested for (1) lactoferrin (Lf) concentration and iron levels; (2) agglutination of Aa; (3) killing of Gram-positive bacteria. RESULTS: LAP/AA saliva levels of Lf iron were low prior to and after bone loss (3.6+1.7ngFe/µg) (LAP/AA vs. H and H/AA p≤0.01). Saliva from H/AA subjects caused Aa to agglutinate significantly more than H or LAP/AA saliva (p≤0.01). LAP/AA saliva killed Streptococcus mutans, Streptococcus sanguis and Lactobacillus in vitro by >83%. Saliva from H individuals killed these bacteria by <3.3% (LAP/AA vs. H; p≤0.01). H/AA killing was intermediate. CONCLUSION: LAP/AA saliva showed: low levels of Lf iron, minimal Aa agglutinating activity, and high killing activity against Gram-positive bacteria. Aa-positive healthy saliva (H/AA) showed: higher levels of Lf iron, maximal Aa agglutinating activity, and moderate killing of Gram-positive bacteria. A salivary activity profile can distinguish between subjects who are Aa-positive and remain healthy from those who develop LAP.

Whole mouth antimicrobial effects after oral hygiene: comparison of three dentifrice formulations.

AIMS: This study compared the antimicrobial effects of three commercial dentifrice formulations: sodium fluoride/triclosan/copolymer (TCN/C), stannous fluoride/sodium hexametaphosphate/zinc lactate (SnF(2)/SHMP) and sodium fluoride (NaF). MATERIALS AND METHODS: Thirty-five adults (15 men and 20 women; average age 33 years and pockets <5 mm) completed this double-blind, triple-crossover study. After washout, baseline samples from four sites, plaque, saliva, tongue and buccal mucosa, were collected and evaluated for six microbial types, anaerobes, Streptococci, Actinomyces, hydrogen-sulphide (H(2) S)-producing bacteria, Fusobacteria and Veillonella. A specific dentifrice was randomly assigned for twice-daily use for 13 days. On day 14, 12 h after brushing, samples were collected for microbiological evaluations. Alternate dentifrices followed this identical protocol. RESULTS: For all four oral sites and six organisms evaluated in each site, the TCN/C demonstrated significant reductions (49-83%) as compared with the other treatments (p < 0.01). The SnF(2)/SHMP group showed significant reductions of 14-43% for 14 of 24 outcomes as compared with the NaF group (p < 0.01), with no differences in 10 outcomes. CONCLUSIONS: The TCN/C dentifrice formulation consistently demonstrated significant reductions for a range of microorganisms in diverse oral sites in comparison with the NaF, or the SnF(2)/SHMP dentifrice formulations as seen 12 h after brushing.

An investigation of the effect of an essential oil mouthrinse on induced bacteraemia: a pilot study.

AIM: This pilot study was designed to assess the effect of an essential oil antiseptic mouthrinse (EOM) in reducing bloodstream bacteria after chewing an apple. MATERIAL AND METHODS: From a panel of 200, we screened 62 individuals with mild-to-moderate gingivitis. Twenty-two individuals who showed a bacteraemia after chewing an apple were enrolled. Subjects were recalled, instructed to chew an apple, had blood drawn (first baseline), and were randomly assigned EOM or a control (C) treatment for 2 weeks. Subjects were recalled, given an apple, and had blood taken for bacterial counts. Following a 1-week fluoride dentifrice wash-out, subjects were recalled, given the apple challenge, had blood drawn (second baseline), assigned the alternate treatment, and recalled for testing. Differences between baseline and 2-week post-treatment (EOM versus C) in blood-borne bacteria were assessed by analysis of covariance. RESULTS: Mean aerobic blood-borne bacteria decreased by 68.5% (17.7 viable counts from baseline; p<0.001), while anaerobic counts decreased by 70.7% (14.5 mean viable counts from baseline; p<0.001) for the EOM treatment. No reduction was seen for the C treatment. CONCLUSIONS: This double-blind, placebo-controlled, randomized, 2-week cross-over study showed that rinsing with essential oils reduced the level of bloodstream bacteria in subjects with mild-to-moderate gingivitis.

Macrophage inflammatory protein-1alpha: a salivary biomarker of bone loss in a longitudinal cohort study of children at risk for aggressive periodontal disease?

BACKGROUND: Periodontitis develops in a time-dependent manner. Cross-sectional studies document one moment in time but fail to capture the progressive nature of disease. Radiographic measures of bone loss are relatively insensitive but are reliable markers of irreversible disease. Longitudinal studies are needed to identify biomarkers that can precede radiographic evidence of bone loss and, thus, mark the period prior to clinical evidence of irreversible disease. A longitudinal study of students susceptible to localized aggressive periodontitis (LAgP) was conducted to evaluate chemokines/cytokines found in saliva derived from periodontally healthy children who subsequently developed alveolar bone loss. METHODS: Students were screened, sampled for Aggregatibacter actinomycetemcomitans (previously Actinobacillus actinomycetemcomitans [Aa]), and divided into a cohort of Aa+ and Aa- students. Ninety-six periodontally healthy Aa+ and Aa- students were recalled every 6 to 9 months following screening. Examinations, saliva collections, and radiographs were performed. After seven students developed bone loss, the levels of 21 cytokines were assessed and matched to saliva from seven Aa+ and seven Aa- students who remained healthy for > or =1 year. Subsequently, saliva from an additional 27 students who remained healthy was analyzed. RESULTS: Nineteen cytokines were not detected or were detected at low levels. Macrophage inflammatory protein (MIP)-1alpha was elevated 50-fold in seven Aa+ students who developed disease 6 to 9 months prior to radiographic detection of bone loss compared to levels in 21 Aa+ and 20 Aa- students who remained healthy (P <0.001). Interleukin (IL)-1beta was also elevated (P = 0.01). MIP-1alpha had a specificity of 96.8% and a sensitivity of 100%, whereas IL-1beta showed 90.3% specificity and 85.7% sensitivity relative to bone loss. MIP-1alpha levels were also related to increasing probing depth and the number of pockets >6 mm. CONCLUSION: The superior sensitivity and specificity of MIP-1alpha, which correlated well with probing depths and the onset of bone loss, suggested that it could be used as an early biomarker for LAgP.

Aggregatibacter actinomycetemcomitans and its relationship to initiation of localized aggressive periodontitis: longitudinal cohort study of initially healthy adolescents.

Aggregatibacter actinomycetemcomitans is frequently associated with localized aggressive periodontitis (LAP); however, longitudinal cohort studies relating A. actinomycetemcomitans to initiation of LAP have not been reported. A periodontal assessment was performed on 1,075 primarily African-American and Hispanic schoolchildren, ages 11 to 17 years. Samples were taken from each child for A. actinomycetemcomitans. A cohort of 96 students was established that included a test group of 38 A. actinomycetemcomitans-positive students (36 periodontally healthy and 2 with periodontal pockets) and 58 healthy A. actinomycetemcomitans-negative controls. All clinical and microbiological procedures were repeated at 6-month intervals. Bitewing radiographs were taken annually for definitive diagnosis of LAP. At the initial examination, clinical probing attachment measurements indicated that 1.2% of students had LAP, while 13.7% carried A. actinomycetemcomitans, including 16.7% of African-American and 11% of Hispanic students (P = 0.001, chi-square test). A. actinomycetemcomitans serotypes a, b, and c were equally distributed among African-Americans; Hispanic students harbored predominantly serotype c (P = 0.05, chi-square test). In the longitudinal phase, survival analysis was performed to determine whether A. actinomycetemcomitans-positive as compared to A. actinomycetemcomitans-negative students remained healthy ("survived") or progressed to disease with attachment loss of >2 mm or bone loss (failed to "survive"). Students without A. actinomycetemcomitans at baseline had a significantly greater chance to remain healthy (survive) compared to the A. actinomycetemcomitans-positive test group (P = 0.0001). Eight of 38 A. actinomycetemcomitans-positive and none of 58 A. actinomycetemcomitans-negative students showed bone loss (P = 0.01). A. actinomycetemcomitans serotype did not appear to influence survival. These findings suggest that detection of A. actinomycetemcomitans in periodontally healthy children can serve as a risk marker for initiation of LAP.