Juan R. Castillo

Pharmacokinetics of zidovudine in end-stage renal disease: influence of haemodialysis.

Objective.To study the pharmacokinetics of zidovudine (ZDV) and its glucoronide metabolite (C-ZDV) in a patient with end-stage renal disease in haemodialysis. Design.Pharmacokinetics study performed during and between haemodialysis sessions. Methods.The patient was treated with oral ZDV (100 mg every 8 h). Concentrations of ZDV and G-ZDV were measured by radioimmunoassay. A monocompartmental model was used to calculate pharmacokinetic parameters. Results.The peak plasma concentrations of ZDV and C-ZDV after drug administration between haemodialysis sessions were 0.57 and 10.01 μg/ml, respectively. The half-lives of ZDV and C-ZDV rose to 3.2 and 14.2 h, respectively. The total body clearance for ZDV in the period between haemodialysis sessions (0.44 l/kg/h) was 66% lower than normal values. The ZDV half-life was normalized by haemodialysis, the total body clearance of ZDV increased (1.12 l/kg/h) and the C-ZDV half-life shortened (5.9–7.9 h). Neither C-ZDV accumulation nor derived ZDV toxicity occurred. Conclusions.Our data suggest that ZDV is safe and an efficient drug when administered at a dosage of 100 mg three times daily in patients with end-stage renal disease in haemodialysis sessions, and that ZDV and C-ZDV are cleared by haemodialysis.

Sirolimus-associated pneumonitis in heart transplant recipients.

TO THE EDITOR: In 2005, the registry report of the International Society for Heart and Lung Transplantation1 showed that 13% of heart transplant recipients were taking sirolimus, although, according to the summary of product characteristics,2 it is not indicated for heart transplants. There are few published studies about sirolimus-associated interstitial pneumonitis in heart transplant recipients; the incidence reported has ranged between 10%3 and 24%.4 Some authors think that it is a dose-dependent reaction, being more frequent in patients with sirolimus steady-state plasma concentrations higher than 15 ng/mL, although sirolimus levels are sometimes within the therapeutic range.4 Methods. We reviewed the charts of heart transplant recipients who had received sirolimus during admission at Hospital Universitario Virgen del Rocío between January 2001 and December 2006. Our objective was to assess the percentage of sirolimus-associated interstitial pneumonitis in this population. The causal relationship between sirolimus and pneumonitis was established according to specific criteria for drug-induced pneumonitis described by Morelon5 and the Naranjo probability scale.6 Morelon criteria are based on the following characteristics: (1) exposure to sirolimus preceding the onset of pulmonary symptoms; (2) exclusion of infection or alternative pulmonary disease, including toxicity due to other drugs, because clinical resolution is observed despite their continuation; (3) resolution after sirolimus discontinuation; and (4) the lymphocytic alveolar cellular profile, although nonspecific per se, is consistent with drug-induced lung toxicity. Authorization from the Research Ethics Committee was obtained. Results. We identified 43 patients who met the inclusion criteria; most (81.4%) of these patients were prescribed sirolimus off-label; the others participated in a clinical trial. Three patients (7%; CI 95% 1.5 to 19.1) developed sirolimus-associated interstitial pneumonitis; in these cases, the drug was considered very probably related to pneumonitis according to the Morelon criteria5 and probably related according to the Naranjo criteria.6 Table 1 summarizes the main characteristics of each case and compares our study with other published studies. This table shows the rapid clinical improvement in all 3 of our patients with sirolimus-associated interstitial pneumonitis following sirolimus discontinuation and initiation of corticosteroid treatment. The microbiological studies for habitual and opportunistic pulmonary pathogens in these patients were negative; chest radiographs and computed tomography showed interstitial infiltrates in one case and alveolar-interstitial infiltrates in the others. There was inflammatory cell infiltration, predominantly lymphocytes, in the bronchoalveolar lavage of the 2 patients in whom it was carried out. No patients were diagnosed with transplant rejection at the time of the reported pneumonitis. After sirolimus was withdrawn, steroids and tacrolimus were initiated and mycophenolate mofetil was continued in all patients. Respiratory symptoms had not reappeared one year after hospital discharge. The cases were reported to the Spanish Postmarketing Surveillance System. Discussion. Our results are similar to those of the largest report of a series of sirolimus-associated interstitial pneumonitis in renal transplant (11%)7 and the data shown by Delgado in heart transplant recipients (10%).3 Using the Morelon criteria, sirolimus was considered very probably associated with pneumonitis in all of the cases.5 Although our study was retrospective (which could affect data quality), sirolimus-associated interstitial pneumonitis is a serious adverse drug reaction that usually does not go unnoticed. Therefore, we believe that our data on its incidence are accurate. Sirolimus-associated interstitial pneumonitis is a serious adverse reaction that is usually reversible after the drug is withdrawn. It should be considered in heart transplant recipients who develop respiratory symptoms without response to antimicrobial therapy, even if sirolimus concentrations are within the therapeutic range. Although it is necessary to exclude other causes of pneumonitis, chest computed tomography, and especially the findings shown on bronchoalveolar lavage, can help to identify this severe adverse reaction.

THU0496 Combined Chondroitin Sulfate and Glucosamine is More Efficient than Celebrex in Reducing Serum Levels of COLL2-1, A Cartilage Degradation Biomarker, In Patients with Severe OA: Results from a Randomized, Double-Blind, Multicentric Clinical Trial

Background Coll2-1 is a peptide located in the triple helical part of type II collagen and Coll2-1NO2 is the nitrated form. Fib3-2 is a fragment of fibulin-3, an extracellular glycoprotein highly expressed in OA.The levels of these biomarkers have been found to be elevated in serum of OA patients and to vary with severity. Objectives To investigate soluble osteoarthritis (OA) biomarkers in the per-protocol (PP) population of the double-blind Multicentre Osteoarthritis interVEntion trial with Sysadoa (MOVES) comparing the efficacy and safety of Chondroitin Sulfate (CS) plus Glucosamine Hydrochloride (GH) versus CElecoxib (CE) in patients with knee OA. Methods Coll2-1, Coll2-1NO2 and Fib3-2 were directly measured by immunassays (ARTIALIS SA, Liège, Belgium) in the serum of the PP population of the MOVES trial including 606 patients with knee OA receiving 400 mg of CS+500 mg of GH three times daily or 200 mg of CE once daily for 6 months.This PP population included 418 subjects (215 receiving CS+GH and 203 receiving CE) with at least one biomarker value at three time points (D0, D120 and D180). Results Serum biomarkers values at baseline or at follow-up D120 and D180 were not associasted with age, sex, race, weight, height of BMI. In overall PP population, there were no statistically significant differences between CE and CS + GH groups for any of the three biomarkers at any time. However, there was a trend in favor of CS+GH in reducing Coll2-1 at D180 (p=0.069) and a trend in favor of CE to reduce Fib3-2 (p=0.055). When population was stratified according the radiological OA severity, the occurrence of synovitis, the WOMAC score or the sympromatic response to treatment some significant differences in biomarkers serum levels were observed between treatment groups. At D 180, CS +GH induced a significantly greater decrease of Coll2-1 in the subgroups of patients with the more severe radiographic disease (K&L III), with synovitis (at least one joint swelling or effusion event), in OMERACT-OARSI responders or in patients with WOMAC pain at baseline ≤369 compared to CE (p<0.05). For Coll2-1NO2, there was a trend in favor of CS + GH in the sub-population having at least one joint swelling event during the study period (p=0.077) at D180. CE was more effective than CS + GH in reducing Fib3-2 at D180 in patients with WOMAC pain at baseline >369 (p=0.042). Conclusions CS + GH was more efficient than CE in reducing serum Coll2-1 particularly in a subgroup of patients with severe OA. This data indicates that CS + GH may down-regulate cartilage catabolism and are in accordance with the symptomatic benefits observed in the clinical trials with these therapies. Disclosure of Interest None declared