Lack of effect of ketoconazole on the pharmacokinetics of rosuvastatin in healthy subjects

AIMS: To examine in vivo the effect of ketoconazole on the pharmacokinetics of rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. METHODS: This was a randomized, double-blind, two-way crossover, placebo-controlled trial. Healthy male volunteers (n = 14) received ketoconazole 200 mg or placebo twice daily for 7 days, and rosuvastatin 80 mg was coadministered on day 4 of dosing. Plasma concentrations of rosuvastatin, and active and total HMG-CoA reductase inhibitors were measured up to 96 h postdose. RESULTS: Following coadministration with ketoconazole, rosuvastatin geometric least square mean AUC(0,t) and Cmax were unchanged compared with placebo (treatment ratios (90% confidence intervals): 1.016 (0.839, 1.230), 0.954 (0.722, 1.260), respectively). Rosuvastatin accounted for essentially all of the circulating active HMG-CoA reductase inhibitors and most (> 85%) of the total inhibitors. Ketoconazole did not affect the proportion of circulating active or total inhibitors accounted for by circulating rosuvastatin. CONCLUSIONS: Ketoconazole did not produce any change in rosuvastatin pharmacokinetics in healthy subjects. The data suggest that neither cytochrome P450 3A4 nor P-gp-mediated transport contributes to the elimination of rosuvastatin.     

Conventional dose fludarabine-based regimens are effective but have excessive toxicity in elderly patients with refractory chronic lymphocytic leukemia

The best approach to elderly patients with relapsing chronic lymphocytic leukemia (CLL) or disease refractory to conventional therapy with alkylating agents has not yet been established. Fludarabine and its combination with mitoxantrone and/or cyclophosphamide, which is the most effective treatment in younger patients, has not been extensively utilized in the elderly CLL. Here we report our results with fludarabine-based chemotherapy in 32 previously treated patients over the age of 65 years. The overall response rate was 59% with no complete remission, 3 nodular partial remissions and 16 partial remissions. The median time to progression of disease was 7 months. Only 10 patients completed the entire treatment program, because of poor compliance due to toxicity. Eight patients developed neutropenic fever, 14 severe bacterial infections and 2 patients showed progressive encephalopathy. For comparison, in a younger group of patients with refractory CLL (< 65 years), 38 of 50 patients completed the treatment plan, and the ORR was 80% (10 CR, 11 PR-nodular, 19 PR) with a median response of 12 months. Neutropenic fever was diagnosed in 10 and severe bacterial infection in 4 patients. In conclusion, fludarabine-based chemotherapy is effective for refractory CLL, however, excessive toxicity such as severe infections and neurological complications, do not allow completion of treatment in the majority of the elderly patients. Because maintenance of a good quality of life should be the main goal in the elderly CLL population, dose reduction of fludarabine and the appropriate use of myeloid growth factors and prophylactic antibiotics appear mandatory in this group of patients.     

Trochanteric osteotomy and fixation during total hip arthroplasty

Once used routinely, trochanteric osteotomy in total hip arthroplasty now is usually limited to difficult primary and revision cases. There are three types: the standard trochanteric osteotomy and its variations, the trochanteric slide, and the extended trochanteric osteotomy. Each has unique indications, fixation techniques, and complications. Primary total hip arthroplasty procedures requiring the enhanced exposure provided by trochanteric osteotomy may be needed in patients with hip ankylosis or fusion, protrusio acetabuli, proximal femoral deformities, developmental dysplasia, or abductor muscle laxity. Trochanteric osteotomies in revision arthroplasties, primarily the extended trochanteric osteotomy, facilitate the removal of well-fixed femoral components, provide direct access to the diaphysis for distal fixation, and enhance acetabular exposure.     

The Intubating Dose of Succinylcholine: The Effect of Decreasing Doses on Recovery Time

Background: The usually cited "intubation dose" of succinylcholine is 1.0 mg/kg. In the majority of patients, this dose will produce apnea of sufficient duration that significant hemoglobin desaturation may occur before neuromuscular recovery takes place in those whose ventilation is not assisted. This study was undertaken to examine the extent to which reducing this dose would decrease the duration of action of succinylcholine.

Methods: During stable desflurane/oxygen/opioid anesthesia and after adequate twitch stabilization, neuromuscular function was recorded with an acceleromyographic monitor. Supramaximal stimuli were delivered at 0.10 Hz. Patients received 0.40, 0.60, or 1.0 mg/kg succinylcholine, and twitch height was monitored for at least 20 min thereafter.

Results: The onset times to maximal effect were 105 +/- 23 s, 81 +/- 19 s, and 71 +/- 22 s, respectively. The lowest dose (0.40 mg/kg) did not reliably produce 100% twitch depression. The times to 90% twitch recovery at the adductor pollicis in the three groups were 6.6 +/- 1.5 min, 7.6 +/- 1.6 min, and 9.3 +/- 1.2 min, respectively.     

Effects of perioperative administration of a selective cyclooxygenase 2 inhibitor on pain management and recovery of function after knee replacement: a randomized controlled trial

Context  Controlling postoperative pain after knee replacement while reducing opiod-induced adverse effects and improving outcomes remains an important challenge. Objective  To assess the effect of combined preoperative and postoperative administration of a selective inhibitor of cyclooxygenase 2 on opioid consumption and outcomes after total knee arthroplasty (TKA). Design, Setting, and Patients  Randomized, placebo-controlled, double-blind trial conducted June 2001 through September 2002, enrolling 70 patients aged 40 to 77 years and undergoing TKA at a university hospital in the United States. Interventions  Patients were randomly assigned to receive 50 mg of oral rofecoxib at 24 hours and at 1 to 2 hours before TKA, 50 mg daily for 5 days postoperatively, and 25 mg daily for another 8 days, or matching placebo at the same times. Main Outcome Measures  Postoperative outcomes including postsurgical analgesic consumption and pain scores achieved, nausea and vomiting, joint range of motion, sleep disturbance, patient satisfaction with analgesia, and hematologic and coagulation parameters. Results  Total epidural analgesic consumption and in-hospital opioid consumption were less in the group receiving rofecoxib compared with the group receiving placebo (P<.05). Median pain score (visual analog scale [VAS], 0-10) achieved for the knee was lower in the rofecoxib group compared with the placebo group during hospital stay (2.2 [interquartile range {IQR}, 1.4-3.2] vs 3.5 [IQR, 2.7-4.3], P<.001) and 1 week after discharge (2.6 [IQR, 1.4-3.5] vs 3.7 [IQR, 2.9-4.7], P = .03). There was less postoperative vomiting in the rofecoxib group (6%) compared with the placebo group (26%) (P = .047), as well as a decrease in sleep disturbance compared with the placebo group on the night of surgery (P = .006) and on the first (P = .047) and second (P<.001) days postoperatively. Knee flexion was increased in the rofecoxib group compared with the placebo group at discharge (active flexion: mean [SD], 84.2° [11.1°] vs 73.2° [13.6°], P = .03; passive flexion: 90.5° [6.8°] vs 81.8° [13.4°], P = .05) and at 1 month postoperatively (109.3° [8.5°] vs 100.8° [11.8°], P = .01), with shorter time in physical therapy to achieve effective joint range of motion. The rofecoxib group was more satisfied with analgesia and anesthesia at discharge compared with the placebo group (median satisfaction score, 4.3 [IQR, 3.0-4.7] vs 3.3 [IQR, 2.3-4.3], respectively; P = .03), and the differences persisted at 2-week and at 1-month follow-up. There was no intergroup difference in surgical blood loss (P>.05 for both intraoperative and postoperative blood loss). Conclusion  Perioperative use of an inhibitor of cyclooxygenase 2 is an effective component of multimodal analgesia that reduces opioid consumption, pain, vomiting, and sleep disturbance, with improved knee range of motion after TKA.      

Effects of attentional load on auditory scene analysis

The effects of attention on the neural processes underlying auditory scene analysis were investigated through the manipulation of auditory task load. Participants were asked to focus their attention on tuned and mistuned stimuli presented to one ear and to ignore similar stimuli presented to the other ear. For both tuned and mistuned sounds, long (standard) and shorter (deviant) duration stimuli were presented in both ears. Auditory task load was manipulated by varying task instructions. In the easier condition, participants were asked to press a button for deviant sounds (target) at the attended location, irrespective of tuning. In the harder condition, participants were further asked to identify whether the targets were tuned or mistuned. Participants were faster in detecting targets defined by duration only than by both duration and tuning. At the unattended location, deviant stimuli generated a mismatch negativity wave at frontocentral sites whose amplitude decreased with increasing task demand. In comparison, standard mistuned stimuli generated an object-related negativity at central sites whose amplitude was not affected by task difficulty. These results show that the processing of sound sequences is differentially affected by attentional load than is the processing of sounds that occur simultaneously (i.e., sequential vs. simultaneous grouping processes), and that they each recruit distinct neural networks.