HIV protease inhibitors do not cause the accumulation of prelamin A in PBMCs from patients receiving first line therapy: the ANRS EP45 "aging" study.

BACKGROUND: The ANRS EP45 "Aging" study investigates the cellular mechanisms involved in the accelerated aging of HIV-1 infected and treated patients. The present report focuses on lamin A processing, a pathway known to be altered in systemic genetic progeroid syndromes. METHODS: 35 HIV-1 infected patients being treated with first line antiretroviral therapy (ART, mean duration at inclusion: 2.7±1.3 years) containing boosted protease inhibitors (PI/r) (comprising lopinavir/ritonavir in 65% of patients) were recruited together with 49 seronegative age- and sex-matched control subjects (http://clinicaltrials.gov/, NCT01038999). In more than 88% of patients, the viral load was <40 copies/ml and the CD4+ cell count was >500/mm³. Prelamin A processing in peripheral blood mononuclear cells (PBMCs) from patients and controls was analysed by western blotting at inclusion. PBMCs from patients were also investigated at 12 and 24 months after enrolment in the study. PBMCs from healthy controls were also incubated with boosted lopinavir in culture medium containing various concentrations of proteins (4 to 80 g/L). RESULTS: Lamin A precursor was not observed in cohort patient PBMC regardless of the PI/r used, the dose and the plasma concentration. Prelamin A was detected in PBMC incubated in culture medium containing a low protein concentration (4 g/L) but not in plasma (60-80 g/L) or in medium supplemented with BSA (40 g/L), both of which contain a high protein concentration. CONCLUSIONS: Prelamin A processing abnormalities were not observed in PBMCs from patients under the PI/r first line regimen. Therefore, PI/r do not appear to contribute to lamin A-related aging in PBMCs. In cultured PBMCs from healthy donors, prelamin A processing abnormalities were only observed when the protein concentration in the culture medium was low, thus increasing the amount of PI available to enter cells. ClinicalTrials.gov NCT01038999 http://clinicaltrials.gov/ct2/show/NCT01038999.

Dosage of enoxaparin among obese and renal impairment patients.

BACKGROUND: Enoxaparin dosage for obese patients and patients with renal impairment remains controversial. OBJECTIVE: To compare anti-factor Xa activity (anti-Xa) among obese and renal impairment patients to patients with healthy weight and adequate renal function. DESIGN: Open, prospective, nonrandomized clinical trial. SETTING: A major community teaching hospital. PATIENTS: A total of 233 patients with prescription of enoxaparin. INTERVENTIONS: Enoxaparin 1.5 mg/kg once daily or 1 mg/kg twice daily except those on dialysis, who received 75% of the dose. MEASUREMENTS: Anti-Xa was measured 4 h post-injection on day 2 or 3. RESULTS: Mean (95% confidence interval (95% CI)) anti-Xa was equal to 1.14 IU/mL (1.07-1.21) and 1.14 IU/mL (1.08-1.20) among patients who received one (n=92) and two injections (n=122) per day, respectively. Anti-Xa increases with body mass index (BMI) (0.01 IU/mL for each kg/m2; 95% CI: 0.002-0.017), but the increase is insufficient to reach supratherapeutic anti-Xa. Anti-Xa decreases with higher creatinine clearance (CrCl) (-0.003 IU/mL for each mL/min; 95% CI: -0.006 to -0.001). On the twice-daily regimen, this is sufficient to reach supratherapeutic anti-Xa. The odd ratio (OR) (95% CI) of having a nontherapeutic anti-Xa is equal to 2.28 (1.25-4.16) when enoxaparin is administered twice daily and to 3.03 (1.16-7.86) among severe renal impairment patients (< or =30 mL/min). CONCLUSIONS: Based on Anti-Xa, no dosage adjustments are required in obese patients. In renally impaired patients, adjustments may be necessary when enoxaparin is administered twice daily.