Development of Stealth Liposome Formulation of 2′-Deoxyinosine as 5-Fluorouracil Modulator: <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Study

Purpose The aims of this study were to develop a stealth, pegylated liposomal formulation of 2′-deoxyinosine (d-Ino), a 5-fluorouracil (5-FU) modulator, to evaluate its efficacy in vitro and in tumor-bearing mice, and to study its pharmacokinetics in rats. Method After designing a pegylated liposome encapsulating d-Ino (L-d-Ino), we evaluated its efficacy as 5-FU modulator in vitro. Antiproliferative assays, thymidylate synthase (TS) inhibition, and apoptosis studies were carried out to check whether an optimization of 5-FU action was achieved on the 5-FU-resistant SW620 cell line. Animal pharmacokinetic and ex vivo studies were next performed to confirm that L-d-Ino displayed a slower plasma elimination pattern than free d-Ino. Finally, effects on tumor growth of L-d-Ino + 5-FU combination was evaluated in xenografted mice. Results We developed a stable, sterile, and homogenous 100-nm population of pegylated liposomes encapsulating 30% of d-Ino. Liposomal d-Ino exhibited a strong potential as 5-FU modulator in vitro by enhancing TS inhibition and subsequent apoptosis induction, while displaying a better pharmacokinetic profile in animals, with a near seven times clearance reduction as compared with the free form. When used in tumor-bearing mice in combination with 5-FU, our results showed next that the association led to 70% of tumor reduction with a doubling median survival time as compared with untreated animals, whereas 5-FU alone was ineffective. Conclusion Our data show that liposomal d-Ino, through an optimized pharmacokinetic profile, displays apotenteffect as fluoropyrimidines modulator, both in vitro and in xenografted mice. Besides, we showed here that itispossible to reverse a resistant phenotype to 5-FU, a major drug extensively described in clinical oncology.     

The WHO age-friendly cities program raises the issue of strategic planning, coordination and local political structure

In 2005 the World Health Organization initiated the ?global age-friendly cities project? which encourages cities to be more inclusive of older people and to develop seniors' involvement by setting up a continuous cycle of assessment and improvement of urban living. The conclusions of the first french audit, which was made in Lyon in 2011, raise the issue of the capacity of cities to implement projects in all the areas fostering active aging. The question of strategic planning and of the level of intervention is relevant for the topics selected, and especially that of health. Is the present organization between the different actors satisfactory, or should large cities have more power? Co-ordination is necessary, and the creation of ?gerontopoles? could bring an answer.     

Determinants of adherence to non-occupational post HIV exposure prophylaxis

We conducted a study on 140 patients who sought advice at hospital after a non-occupational exposure. The full 28-day course of prophylactic antiretroviral therapy was completed by 109 patients. No HIV contamination was observed. Factors associated with suboptimal adherence were African ethnicity [odds ratio (OR) 13.3, 2.02-87.54] and oral sexual intercourse (OR 8.35, 1.66-41.99). Compliance with prophylactic antiretroviral therapy can be increased by addressing social and psychological barriers to adherence.     

Value of D-dimer testing for the exclusion of pulmonary embolism in patients with previous venous thromboembolism

BACKGROUND: D-dimer levels remain elevated in many patients after completion of a 6-month anticoagulant drug course for a first episode of venous thromboembolism (VTE), which may limit the clinical usefulness of D-dimer testing for ruling out a possible recurrence. METHODS: We assessed the safety and usefulness of D-dimer testing in patients with suspected pulmonary embolism (PE) who had experienced a previous VTE. We analyzed data from 2 outcome studies that enrolled 1721 consecutive emergency department patients with clinically suspected PE. Information on the existence of a previous episode of VTE was abstracted from the database. All the patients underwent a sequential diagnostic workup, including an enzyme-linked immunosorbent assay D-dimer test and a 3-month follow-up. RESULTS: The proportion of confirmed PE was 24.1% (415/1719); PE was ruled out by a negative D-dimer test result in 32.7% (462/1411) of the patients without previous VTE but in only 15.9% (49/308) of the patients with previous VTE (P<.001). The 3-month thromboembolic risk was 0% (95% confidence interval, 0.0%-7.9%) in patients with previous VTE and a negative D-dimer test result. The 2-fold lower chance of a negative D-dimer test result in patients with previous VTE was independent of older age, active malignancy, fever, and recent surgery. CONCLUSIONS: In patients with suspected PE and previous VTE, a negative D-dimer test result seems to allow safely ruling out a recurrent event. However, the proportion of negative results is lower in such patients, definitely reducing the clinical usefulness of the D-dimer test in that subgroup.     

Immunological efficacy of a three-dose schedule of hepatitis A vaccine in HIV-infected adults: HEPAVAC study

BACKGROUND: The immunogenicity of vaccines, including vaccine against hepatitis A virus (HAV), is impaired in patients with HIV infection, requiring revised immunization regimens. METHODS: We evaluated the immunological efficacy and safety of a 3-dose schedule of hepatitis A vaccine in HIV-infected adults. HAV-seronegative HIV-infected adults were randomized to receive either 3 doses of 1440 UI of hepatitis A vaccine (HAVRIX; GlaxoSmithKline, Marly le Roi, France) at weeks 0, 4, and 24 (46 patients) or 2 doses 24 weeks apart (49 patients). RESULTS: At week 28, seroconversion, defined as an anti-HAV antibody >or=20 mIU/mL, occurred in 82.6% and 69.4% of patients in the 3-dose and the 2-dose group, respectively (P = 0.13, intent-to-treat analysis, missing data = nonresponder), and in 88.4% and 72.3% of patients in the 3-dose and the 2-dose group, respectively (P = 0.06, observed analysis). Only 37.9% of patients experienced seroconversion after 1 vaccine dose (intent-to-treat analysis). Anti-HAV antibody geometric mean titers were 323 and 132 mIU/mL in the 3-dose group and 138 and 67 mIU/mL in the 2-dose group, respectively, 28 (P = 0.03) and 72 weeks (P = 0.05) after the first vaccine dose. There were no serious adverse events associated with the vaccine. Multivariate analysis showed no treatment group effect but indicated that absence of tobacco smoking (odds ratio = 2.92, 95% confidence interval: 1.07 to 7.97; P = 0.04) was an independent predictor of response to HAV vaccine. CONCLUSIONS: In HIV-infected adults, immunogenicity of hepatitis A vaccine is poor. Three doses of vaccine were safe and increased antibody titers.