Use of coumarins as complementary medicine with an integrative approach against cervical cancer: background and mechanisms of action.

Cervical cancer is characterized by the cellular transformation caused by Human Papillomavirus (HPV), favoring cell proliferation, migration, invasion, and metastasis. Cervical cancer is conventionally treated with radiation therapy, and chemotherapy focused on the destruction of tumor cells. However, chemoresistance and low selectivity between tumor and non-tumor cells have been reported, causing side effects in patients. Metabolites of natural origin have shown selectivity against tumor cells, suggesting their use for reducing the side effects caused by drugs used in conventional therapy. Among these compounds, several natural coumarins stand out, such as auraptene, scopoletin, osthole, and praeruptorin, of which antiproliferative, anti-migratory, and anti-invasive activity have been reported. Auraptene, scopoletin, osthole, and praeruptorin show a cytotoxic or antiproliferative effect on cervical tumor cells, arresting the cell cycle by inducing the overexpression of negative regulators of the cell cycle, or inducing cell death by increasing the expression of pro-apoptotic proteins and decreasing that of anti-apoptotic proteins. On the other hand, auraptene, scopoletin, and praeruptorin inhibit the capacity for migration, invasion, and metastasis of cervical tumor cells, mainly by inhibiting the expression and activity of matrix metalloproteinase-2 and -9. The PI3K/Akt signal pathway appears to be central to the anti-tumor activity of the coumarins analyzed in this review. In addition, auraptene, osthole, and praeruptorin are useful in sensitizing tumor cells to radiotherapy or chemotherapeutic molecules, such as FOLFOX, cisplatin, or DOX. Coumarins offer an excellent possibility for developing new drugs as complementary medicine with an integrative approach against cervical cancer.

Intraspecific and interspecific variation in thermotolerance and photoacclimation in Symbiodinium dinoflagellates.

Light and temperature are major drivers in the ecology and biogeography of symbiotic dinoflagellates living in corals and other cnidarians. We examined variations in physiology among 11 strains comprising five species of clade A Symbiodinium We grew cultures at 26°C (control) and 32°C (high temperature) over a duration of 18 days while measuring growth and photochemical efficiency (Fv /Fm ). Responses to thermal stress ranged from susceptible to tolerant across species and strains. Most strains exhibited a decrease in cell densities and Fv /Fm when grown at 32°C. Tolerance to high temperature (T32) was calculated for all strains, ranging from 0 (unable to survive at high temperature) to 1 (able survive at high temperature). There was substantial variation in thermotolerance across species and among strains. One strain had a T32 close to 1, indicating that growth was not reduced at 32°C for only this one strain. To evaluate the combined effect of temperature and light on physiological stress, we selected three strains with different levels of thermotolerance (tolerant, intermediate and susceptible) and grew them under five different light intensities (65, 80, 100, 240 and 443 µmol quanta m-2 s-1) at 26 and 32°C. High irradiance exacerbated the effect of high temperature, particularly in strains from thermally sensitive species. This work further supports the recognition that broad physiological differences exist not only among species within Symbiodinium clades, but also among strains within species demonstrating that thermotolerance varies widely between species and among strains within species.

The impact of publishing medical specialty society guidelines on subsequent adoption of best practices: a case study with type 2 diabetes.

AIMS: Our goal was to determine the effect of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) consensus algorithm for the initiation and adjustment of type 2 diabetes (T2D) therapy, published in 2006, on the incidence of early metformin monotherapy (EMM), defined as the prescription of metformin and no other antidiabetic medications within 30 days of initial T2D diagnosis. METHODS: The incidence of EMM in the United States (US) from January 2005 to December 2007 was estimated using data from the i3 InVision Data Mart, an integrated database of enrollment dates, inpatient and outpatient medical claims, pharmaceutical claims, and laboratory results from a diverse group of US health plans. The trend in the incidence of EMM was analysed using joinpoint regression modelling. RESULTS: A statistically significant joinpoint was found in July 2006 (p < 0.05). From January 2005 to July 2006, EMM increased at an annualised rate of 15.6%. From July 2006 to December 2007, EMM increased at an annualised rate of 66.0%. CONCLUSIONS: Our findings suggest that publication of the ADA/EASD algorithm caused a significant acceleration in the incidence of EMM.

An individual bioequivalence approach to compare the intrasubject variability of two ciclosporin formulations, SangCya and Neoral.

A novel bioequivalence testing approach was used to determine intrasubject variability and switchability of two ciclosporin formulations, SangCya (test) and Neoral (reference). Twenty healthy volunteers were enrolled into a single-dose, randomized, open-label, 4-period, 2-sequence study with a crossover replicate design. Subject-by-formulation interaction variances were compared using a mixed effects linear model. Intrasubject variability for ln AUC(0-infinity) and ln C(max) of SangCya and Neoral were not significantly different. The 95% confidence intervals of the intrasubject variability of AUC(0-infinity) (0.94) and C(max) (1.28) as determined using the bootstrap nonparametric percentile method (n = 2,000) were below the individual bioequivalence limit estimated at 2.25. We concluded equivalent intrasubject variability of ciclosporin pharmacokinetics and switchability between SangCya and Neoral.

Comparison of two cyclosporine formulations in healthy volunteers: bioequivalence of the new Sang-35 formulation and Neoral.

This study was conducted to establish bioequivalence between a newly developed oral cyclosporine formulation, Sang-35 (SangStat Medical Corp., Menlo Park, CA), and the microemulsion formulation Neoral (Novartis Pharmaceuticals, East Hanover, NJ). In a randomized, open-label, two-way crossover study, 36 fasted, healthy male volunteers received a single 500-mg cyclosporine dose formulated either as Sang-35 or Neoral. Mean are under the concentration-time curve to infinity (AUC0-infinity) for Sang-35 was 13,900 microg x hr/L compared with 14,000 microg x hr/L for Neoral, with a 90% confidence interval (CI) of 96% to 103% for the geometric mean ratio of the two formulations. Mean maximum concentration (Cmax) was 1,690 microg/L for Sang-35 and 1,700 microg/L for Neoral, with a 90% CI of 96% to 103%. Geometric mean ratios for both AUC0-infinity and Cmax were within the acceptance criteria for bioequivalence (80-125%). Additional studies showed no differences between Sang-35 and Neoral after high-fat meals (n = 19), in female volunteers (n = 25) and in black volunteers (n = 7). It is concluded that single doses of the oral cyclosporine formulations Sang-35 and Neoral are bioequivalent in healthy fasted subjects, after high-fat meals, in women, and in blacks.

Rheumatoid arthritis antirheumatic drug trials: effects of a standardized instructional videotape on the reliability of observer-dependent outcome measures.

AIMS: A study was designed to assess the effects of a standardized instructional videotape on reducing interobserver variability for several commonly used observer-dependent outcome measures. METHODS: During a single day, six rheumatologists independently examined six patients with rheumatoid arthritis (RA) in a predetermined order using a Latin square design, before and after viewing a standardized videotape demonstrating 13 examination techniques. Reliability coefficients were calculated based on the variance components of the analysis of variance (ANOVA) table. RESULTS: Prestandardization reliability coefficients were >0.80 for all measures and remained above 0.80 following standardization. CONCLUSIONS: It is usually assumed that serial measurement in clinical trials should be performed by the same assessor because of concern regarding interobserver variability. However, the high levels of prestandardization interobserver reliability observed in this study indicate that, for these variables, serial measurements in a clinical trial could be made by different assessors, assuming they were equally skilled. This observation has important implications for outcome measurement in RA clinical trials. Although high levels of prestandardization reliability precluded the demonstration of any significant effect, we speculate that the videotape might be effective in training less-experienced assessors. Reductions in observer variability have the potential to diminish sample size requirements for RA antirheumatic drug studies. The use of a videotape to achieve this goal offers cost and convenience advantages over one-on-one training procedures, and this method should be further assessed in less-experienced assessors.

Ankylosing spondylitis antirheumatic drug trials: Effects of a standardized instructional viddeotape on the reliability of observer-dependent outcome measures.

AIMS: A study was designed to assess the effects of a standardized instruction videotape on reducing interobserver variability for several commonly used observer-dependent outcome measures. METHODS: During a single day, six rheumatologists independently examined six patients with ankylosing spondylitis (AS) in a predetermined order using a Latin square design, before and after viewing a standardized videotape demonstrating 14 examination techniques. Reliability coefficients were calculated based on the variance components of the analysis of variance (ANOVA) table. RESULTS: Prestandardization reliability coefficients were <0.80 for three measures. Following standardization 12 reliability coefficients exceeded 0.80. For the majority of measures prestandardization reliability coefficients were high and no further improvement in reliability could be demonstrated. For one measure of cervical extension, but not another, an important and beneficial effect in reliability was noted. It was not possible to achieve adequate reliability in the performance of the chest excursion measurement. CONCLUSIONS: It is usually assumed that serial measurement in clinical trials should be performed by the same assessor because of concern regarding interobserver variability. However, the high levels of prestandardization interobserver reliability observed in this study indicate that for these variables serial measurements in a clinical trial could be made by different assessors, assuming they were equally skilled. This observation has important implications for outcome measurement in AS clinical trials. Although high levels of prestandardization reliability precluded the demonstration of any significant effect, we speculate that the videotape might be effective in training less experienced assessors. Nevertheless, an alternative approach to standardization may be required for the chest excursion measurement. Reductions in observer variability have the potential to diminish sample size requirements for AS antirheumatic drug studies. The use of a videotape to achieve this goal offers cost and convenience advantages over one-on-one training procedures, and this method should be further assessed in a group of less experienced assessors.