Differential dose adjustments of immunosuppressants after resuming boosted versus unboosted HIV-protease inhibitors postliver transplant.

Pharmacokinetic (PK) interactions between protease inhibitors (PI(s)) and immunosuppressive agents (IS) are critical elements in the management of HIV-infected patients who undergo liver transplantation (LT(x)). The primary objective of this study was to evaluate the decreases in IS dosages necessary to maintain an appropriate therapeutic window (TW) after initiating PI-based antiretroviral therapy regimens post-LT(x). Single-center, PK cross-sectional study of consecutive HIV-infected adult patients who underwent LT(x) was done. Blood trough concentrations (C(t)) of IS were obtained using a commercial MEIA test; plasma C(t) of PI(s) were measured using HPLC. Twelve consecutive HIV-infected adult patients (11 males, 1 female) were enrolled. More rapid increases in IS plasma C(t) were observed 48 h after initiating ritonavir (RTV)-boosted PI therapy post-LT(x) than when using unboosted PI(s). Seven patients developed acute renal failure. The median fold decrease in IS dosages required to regain IS concentrations that were in the TW was 7.5 (range 6-14) after resuming boosted PI(s) and 2.9 (range 2-4) after unboosted PI(s). The overall median time necessary to reach IS TW after dose adjustment was 3.5 days (range 0-15). Unboosted PI(s) exhibited lesser PK interactions with IS than did RTV-boosted PI(s) and were thus more amenable to use in the post-LT(x) setting.

Efficacy and safety of atazanavir in patients with end-stage liver disease.

BACKGROUND: No data are available on the use of atazanavir (ATV) in patients with end-stage liver disease (ESLD), and guidelines discourage its use in this setting. The objective of our study was to evaluate the efficacy and safety of unboosted ATV in patients infected with HIV and suffering from ESLD who had been screened for orthotopic liver transplantation (OLT(x)). PATIENTS AND METHODS: This was a single-arm, 24-week pilot study. Atazanavir-naïve patients undergoing a highly active antiretroviral therapy were switched to ATV 400 mg daily plus two non-thymidine nucleoside reverse transcriptase inhibitors. RESULTS: Fifteen patients (ten males and five females, age range 36-59 years) were enrolled in the study. Of these, 11 (73%) had a baseline CD4 cell count > 200 microl(-1), and 12 had undetectable plasma HIV-RNA. 12 subjects (80%) were able to remain on ATV until week 24 (n = 10) or transplantation (n = 2). At the end of the study, the median CD4 cell count was 340 microl(-1) , and nine of the ten patients had undetectable RNA. During the study period, two patients received a transplant, two died of intracerebral hemorrhage and lactic acidosis, respectively, and one discontinued ATV. Among the ten patients completing the 24-week study, no significant changes from baseline were observed for most of the liver function markers, with the exception of unconjugated bilirubin (from 1.15 mg/dl to 1.32 mg/dl, p = 0.047). CONCLUSIONS: Unboosted ATV treatment did not worsen liver disease and was able to maintain or gain immunovirological eligibility for OLT(x) in all patients, with a limited effect on unconjugated bilirubin. These results suggest that ATV is an easy-to-use drug in patients with ESLD.

Effective prophylactic treatments of migraine lower plasma glutamate levels.

The role of glutamate in migraine treatment has not been much studied, even if this amino acid seems to be crucial in the pathogenesis of migraine. Our aim was to determine if there were differences in the plasma levels of glutamate between migraine patients and control subjects and if plasma levels of glutamate in migraine patients modified after 8 weeks of prophylactic treatment. We studied 24 patients with diagnosis of migraine without aura according to International Classification of Headache Disorders, 2nd edn criteria, and 24 age- and sex-matched healthy subjects, as controls. In migraineurs the level of glutamate was measured before and after 8 weeks of prophylactic treatment (topiramate 50 mg/day, five patients; amitriptyline 20 mg/day, seven patients; flunarizine 5 mg/day, seven patients; propranolol 80 mg/day, five patients). Venous blood samples were taken in the morning, after overnight fasting, and at least 3 days after the last migraine day. Glutamate levels were measured by means of a fluorimetric detector high-pressure liquid chromatographic method. Plasma levels of glutamate were significantly higher in migraine patients-either before (61.79 +/- 18.75 micromol/l) or after prophylactic treatment (17.64 +/- 5.08 micromol/l)-than in controls (9.36 +/- 2.1 micromol/l) (P < 0.05, anova followed by Newman-Keuls' test). After prophylactic treatment, with headache frequency reduced, plasma glutamate levels were significantly lower in the same patient with respect to the prior baseline level (P < 0.0001, Student's t-test for paired data), without any differences depending on the kind of prophylactic drug. Effective prophylactic treatments reducing high glutamate plasma levels found in migraine patients could act on the underlying mechanism that contributes to cause migraine. Plasma glutamate level monitoring in migraine patients might serve as a biomarker of response to treatments and as an objective measure of disease status.

Pharmacokinetics of a new extended-release nifedipine formulation following a single oral dose, in human volunteers.

This study aimed to define the pharmacokinetics of nifedipine following oral administration of a new extended-release formulation. Twelve healthy volunteers of both sexes, aged 39 +/- 4 years, were treated with a single oral tablet of a new extended-release formulation containing 40 mg of nifedipine. Samples of venous blood were taken before dosing, after 30 min and at 1, 2, 4, 8, 12, 16, 20 and 24 h after administration. Nifedipine concentration was measured by means of a high-performance liquid chromatography method. Noncompartmental pharmacokinetics parameters were then calculated. The plasma concentration of nifedipine increased slowly and in seven subjects biphasic peaks occurred. The mean values were as follows: t(max): 8.5 +/- 1.2 h; C(max): 36.55 +/- 6.76 ng/ml; AUC: 347.06 +/- 51.61 ng/h/ml; AUC 409.99 +/- 61.08 ng/h/ml; A(half-life): 2.26 +/- 0.36 h; D(half-life): 2.43 +/- 0.44 h; E(half-life): 4.62 +/- 0.79 h. Twenty-four hours after administration nifedipine was still detectable (3.17 +/- 0.67 ng/ml). Arterial blood pressure decreased and heart rate increased concurrently and proportionally to the increase in nifedipine concentration. Extended-release nifedipine formulations have better tolerability profiles than immediate-release formulations, which are at present not recommended in the treatment of hypertension, hypertensive crises or myocardial infarction. This new extended-release formulation has interesting pharmacokinetic parameters and may be effective in conditions in which dihydropyridine calcium channel blockers are indicated.