Tacrolimus Pharmacokinetics and Dose Monitoring After Lung Transplantation for Cystic Fibrosis and Other Conditions

In cystic fibrosis (CF), absorption of tacrolimus through the gastrointestinal tract may be impaired due to fat malabsorption. The aim of this pilot study was to compare tacrolimus pharmacokinetics and inter- and intrasubject variability of exposure in stable lung transplant recipients with and without CF, and to determine the best single-time predictors of exposure. The study included 11 lung transplant recipients with CF and 11 without CF who received tacrolimus twice daily. Blood samples were obtained predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 h postdose on 3 separate days within 1 week. Tacrolimus pharmacokinetics and inter- and intrasubject variability of exposure were similar in the two groups, though exposure-per-milligram-dose was approximately 50% lower in CF patients. Tacrolimus trough concentration did not accurately predict the area under the concentration curve (AUC(0-12)), but the concentration measured 3 h postdose (C(3)) was tightly correlated with the AUC(0-12) in both CF (r(2)= 0.86) and non-CF (r(2)= 0.92) patients. In summary, patients with CF have a higher tacrolimus oral clearance, but nonsignificant differences in short-term inter- and intrasubject variability of exposure compared to patients without CF. C(3) is tightly correlated with AUC(0-12) in lung transplant recipients with and without CF.     

Publication bias in the medical literature: A review by a Canadian research ethics board

BACKGROUND: We reviewed the publication record of all protocols submitted to the Capital District Health Authority Research Ethics Board (REB) in Halifax, Nova Scotia, for the period 1995-1996. Because of a heightened awareness of the issue, we hypothesized that there would be less publication bias (a failure to report negative results) and a higher publication rate from completed studies, than previously reported. METHODS: Closed studies were identified from the REB database. Publications were identified by the investigators, requests from sponsors, and a literature review. For each publication, we identified authors, title, journal, number of subjects enrolled, and whether or not the publication was a report of a randomized clinical trial. Comparisons were done using a Student's t test, the Chi-square statistic, or Fisher's exact test as appropriate. RESULTS: From the database of closed studies, 106 remained unpublished, while completed investigations resulted in 84 publications (44% publication rate). The median time to publication was 32.5 months. Publication of statistically significant results occurred in 71/84 trials. Publication of protocols submitted by departments ranged from 91% (anesthesia; 10/11) to 25% [nursing; 2/8 (P<0.05)]. Trials investigating new drugs in Phase 3 or 4 studies were more likely to be published than trials investigating agents in Phase 1 or 2 (P<0.05), and were less likely to be published if sponsored by a pharmaceutical company (P<0.05). CONCLUSIONS: Publication bias continues to be a problem, particularly for early phase investigative studies. Our results suggest that a different approach is required to reduce publication bias. The role that REBs and peer-reviewed journals might play requires further exploration.     

Reciprocal relationships between general (Propofol) anesthesia and circadian time in rats.

Several common postdischarge symptoms, such as sleep disorders, headache, drowsiness or general malaise, evoke disturbances of circadian rhythms due to jet lag (ie crossing time zones) or shift work rotation. Considering that general anesthesia is associated with numerous effects on the central nervous system, we hypothesized that it may also act on the circadian timing system. We first determined the effects of the circadian timing on general anesthesia. We observed that identical doses of propofol showed marked circadian fluctuations in duration of effects, with a peak at the middle of the resting period (ie 7 h after lights on). Then, we examined the effects of general anesthesia on circadian timing, by analysing stable free-running circadian rhythms (ie in constant environmental conditions), an experimental approach used widely in circadian biology. Free-running rats were housed in constant darkness and temperature to assess possible phase-shifting effects of propofol anesthesia according to the time of the day. When administered around (+/-2 h) the daily rest/activity transition point, a 30-min propofol anesthesia induced a 1-h phase advance in the free-running rest-activity rhythm, while anesthesia had no significant resetting effect at other times of the day. Anesthesia-induced hypothermia was not correlated with the phase-shifting effects of propofol anesthesia. From our results, anesthesia itself can reset circadian timing, and acts as a synchronizing cue for the circadian clock.     

Single-Blind, Randomized Study Comparing Chromated Glycerin, Polidocanol Solution, and Polidocanol Foam for Treatment of Telangiectatic Leg Veins

BACKGROUND: A single-blind, randomized, comparative study was performed to evaluate the efficacy of pure chromated glycerin (CG), polidocanol (POL) 0.25% solution, and POL 0.25% foam (Monfreux technique) for treatment of telangiectasias and reticular leg veins. OBJECTIVE: To determine the relative efficacy and safety of two sclerosing agents and foam. METHOD: Of 150 randomized patients presenting comparable areas (lateral face of thigh) of telangiectasias and reticular leg veins, 147 could be evaluated by photographic assessment, patients' satisfaction score, and pain at injection sites. Internal and external agreement for the photographic assessment was good for two independent blinded experts. RESULTS: CG cleared vessels significantly better than POL solution or foam (p<0.002). The patients' satisfaction score was also higher in the CG group, although the difference did not reach statistical significance. CG was significantly more painful at injection sites. Other side effects were very few, precluding any statistical comparison. Foam was associated with more side effects (microthrombi, matting) than CG or POL solution. Three patients treated with POL foam experienced a transient visual disturbance. CONCLUSION: This study shows that CG is superior to POL solution and foam for sclerotherapy of leg telangiectasias.     

Influenza A pneumonia presenting as progressive focal infiltrates in a stem cell transplant recipient.

BACKGROUND: Stem cell transplant recipients are susceptible to pulmonary infections, including influenza A. Typically, isolated influenza pneumonia has a diffuse, interstitial infiltrate pattern. OBJECTIVES: To describe the unusual clinical and radiographic course of influenza A pneumonia in a stem cell transplant recipient. STUDY DESIGN: Case report in which microbiologic assays, bronchoscopic and pathologic specimens are obtained. RESULTS: We describe a patient with influenza A pneumonia 8 months following a peripheral blood stem cell transplant who presented with minimal respiratory symptoms and rapidly progressing, focal pulmonary infiltrates. The large size and appearance of the masses have not been reported before in a patient with isolated influenza. CONCLUSION: This case highlights the differences of presentation and importance of early diagnosis and treatment of immunocompromised patients infected with influenza.