The effects of age and gender on the single dose pharmacokinetics of avitriptan administered to healthy volunteers

The effects of age and gender on the single dose pharmacokinetics of avitriptan and its three metabolites were assessed in 15 young men, 15 young women, 15 elderly men and 15 elderly women. Avitriptan was administered as a 150-mg capsule after a 10-hour fast and serial plasma and urine samples were collected up to 36 hours after the dose. Plasma samples were analyzed for avitriptan and its metabolites, N-desmethyl avitriptan (ND048), O-desmethyl avitriptan (OD048), and methoxypyrimidinyl piperazine (MPP). Urine samples were analyzed for only avitriptan and MPP. Avitriptan was well tolerated in all four groups. The drug was rapidly absorbed with a median time to maximum plasma concentration (tmax) between 0.5 and 1.5 hours. No significant gender-related differences were found in the maximum plasma concentration (Cmax) and area under the concentration-time curve extrapolated to infinity (AUC0-infinity) of avitriptan. Renal clearance of avitriptan was significantly smaller in young women compared with young men, but this is clinically not relevant because only 2% to 3% of the total dose is excreted unchanged. Compared with the young volunteers, mean Cmax was approximately 50% higher in the elderly but there was no difference in the AUC0-infinity between the 2 age groups. Plasma concentrations of ND048, OD048, and MPP were each 50 to 100 fold lower than those of avitriptan. Hence some age- and gender-related differences found in the pharmacokinetics of avitriptan metabolites are probably not relevant in the assessment of overall safety and efficacy of avitriptan. Based on the pharmacokinetics and tolerability, no age or gender-related dose adjustment is necessary for avitriptan.     

Prosthetic valve endocarditis: superiority of surgical valve replacement versus medical therapy only

The objective of our study was to assess the long-term outcome of patients with prosthetic valve endocarditis. We used a multicenter, prospective, observational study design. Six university teaching hospitals with high volume cardiothoracic surgery participated. Seventy-four patients with prosthetic valve endocarditis as defined by explicit, objective criteria were selected for participation. All patients were followed up prospectively for 1 year. Thirty-one percent and 69% had development of endocarditis within 60 days of valve insertion ("early") and after 60 days ("late"), respectively. The most common causes were Staphylococcus epidermidis (40%), Staphylococcus aureus (20%), streptococcal species (18%), and aerobic gram-negative bacilli (11%). Physical signs of endocarditis (new or changing murmur, stigmata, emboli) were seen in 58%. At 6 months and 12 months, mortality was 46% and 47%, respectively. Surgical replacement of the infected valve led to significantly lower mortality (23%) as compared with medical therapy alone (56%), as assessed by both univariate and multivariate analyses (p < 0.05). Improved outcome was seen for the surgical group even when controlling for severity of illness at time of diagnosis. From these findings we conclude that accurate assessment of outcome in prosthetic valve endocarditis requires long-term follow-up of at least 6 months following diagnosis. Surgical therapy warrants greater scrutiny; evaluation in controlled clinical trials is appropriate.     

Comparison of methods for identifying transcription units and transcription map of the Werner syndrome gene region

OBJECTIVE: The audiologic presentation of vestibular schwannoma (VS) associated with neurofibromatosis type 2 (NF2) has not been well characterized. The goal of this study was to investigate the audiologic features of NF2-associated VS and to determine their relationship to the size of the tumor. STUDY DESIGN: A retrospective case review. SETTING: Quaternary governmental medical research institute evaluating patients fitting specific criteria for ongoing clinical studies. PATIENTS: Audiologic and magnetic resonance imaging data were available for 40 patients (25 males, 15 females), with an average age of 32 years, who had been recruited for ongoing clinical and genetic studies of NF2. MAIN OUTCOME MEASURES: The audiologic profile and magnetic resonance imaging characteristic of tumor were retrospectively reviewed. RESULTS: The average size of the tumor at presentation was 7.26 +/- 16.58 cm3 and measured 1.2, 1.6, and 1.1 cm in the anterior/posterior, lateral/medial, and superior/inferior dimensions, respectively. An increase in lateral/medial size of the tumor most significantly correlated with deterioration in mid- (1,000-2,000 Hz) and high- (4,000-8,000 Hz) frequency hearing levels, elevated speech reception threshold, and prolonged auditory brain stem response waves III and V latency. CONCLUSIONS: Patients with NF2 demonstrate a more predictable audiologic profile for a given size tumor than has been previously described with spontaneous or sporadic VS.