General slowing in language impairment: methodological considerations in testing the hypothesis.

Although the general slowing hypothesis of language impairment (LI) is well established, the conventional method to test the hypothesis is controversial. This paper compares the usual method, ordinary least squares regression (OLS), with another method, hierarchical linear modeling with random coefficients (HLM). The analyses used available response time (RT) data from studies of perceptual-motor, cognitive, and language skills of LI and chronological-age-matched (CA) groups. The data set included RT measures from 25 studies investigating 20 different tasks (e.g., auditory detection, mental rotation, and word recognition tasks). OLS and HLM analyses of the RT data yielded very different results. OLS supported general slowing for the LI groups, and indicated that they were significantly slower than CA groups across studies by an overall estimate of 10%. HLM indicated a larger average extent of LI slowing (18%). However, the variability around this average was much greater than that yielded by OLS, and the extent of slowing was not statistically significant. Importantly, HLM showed a significant difference in the RT relation between LI and CA groups across studies, indicating that study-specific slowing, rather than general slowing across studies, was present. A separate HLM analysis of two types of language tasks, picture naming and word recognition, was performed. Although the extent of slowing was equivalent across these tasks, the slowing was minimal (2%) and not significant. Methodological limitations of each analysis to assess general slowing are highlighted.

Respiratory and laryngeal contributions to maximum phonation duration.

Maximum phonation duration (MPD) is a common assessment procedure in speech-language pathology. However, the specific contributions of the respiratory and phonatory components of the speech-production mechanism to this task are not typically assessed. Six women and 6 men with normal speech and voice were monitored for lung volume during a standard MPD task, and for laryngeal airway resistance (Rlaw) during a modified MPD (slow syllable-repetition) task. On average, subjects used 90% of their vital capacity (VC) for their best MPD trial. There was no systematic relation between MPD and VC for these subjects. Rlaw was strongly correlated with MPD for the men (r(s) = 0.886 for /a/; r(s) = 0.829 for /i/), but not for the women. Rlaw increased linearly as lung volume decreased (slope > 0.15) for a subset of trials (32%). This was a common pattern for four of the subjects. The clinical utility of MPD to assess breathing for speech is questioned because of the lack of association between MPD and VC, and some atypical laryngeal-valving strategies.

Pharmacokinetic and pharmacodynamic evaluation of warfarin and nefazodone coadministration in healthy subjects.

Nefazodone, an antidepressant with serotonin and norepinephrine receptor modulating activity, is highly protein bound and eliminated by oxidative metabolism. This study evaluated the potential for clinically significant drug interactions with warfarin and nefazodone coadministration. Eighteen subjects received warfarin daily for 14 days, achieving steady-state warfarin concentrations and a stable prothrombin ratio. Nefazodone 200 mg every 12 hours (n = 12) or placebo every 12 hours (n = 6) was then added to the daily warfarin dose for the next 7 days in a double-blind, randomized design. No serious or unexpected adverse events or events suggestive of abnormal bleeding occurred during coadministration. The addition of nefazodone had no effect on the unbound fraction of total warfarin in plasma or on the steady-state pharmacokinetics of R-warfarin based on within-subject or comparison to placebo-treated subjects. The steady-state AUCTAU over the dosing interval and Cmax of S-warfarin decreased by 12%; however, this change is clinically insignificant because the prothrombin ratio and bleeding time remained unchanged. The steady-state minimum concentrations for nefazodone and metabolites, achieved on coadministration day 3, were typical of healthy men treated with this nefazodone dosage. In conclusion, warfarin and nefazodone coadministration was safe and well-tolerated with no clinically significant interactions.

Effect of metoclopramide and loperamide on the pharmacokinetics of didanosine in HIV seropositive asymptomatic male and female patients.

The pharmacokinetics of orally-administered didanosine were evaluated in 6 male and 6 female HIV seropositive patients to determine the effect of pretreatment with metoclopramide, an inducer of gastrointestinal motility, and loperamide, which retards motility. Using a randomized, balanced, crossover design, each patient received the following three treatments under fasting conditions: didanosine as a single agent, didanosine 5 min after a single 10 mg intravenous dose of metoclopramide, and didanosine 1 h after the final of 4 doses, 4 mg each, of loperamide. Serial blood and urine samples were collected for up to 12 h after each dose. Plasma and urine aliquots were analysed for intact didanosine using HPLC with UV detection. Pharmacokinetic parameter values were calculated using noncompartmental methods. The mean Cmax values were significantly greater for the didanosine single agent (2.04 micrograms.ml-1) and didanosine with metoclopramide (2.30 micrograms.ml-1) treatments than for the combination of didanosine with loperamide (1.57 microgram.ml-1). The t1/2 in males was significantly greater than in females for the didanosine (1.75 vs 1.12 h, respectively) and didanosine with metoclopramide treatments (1.74 vs 1.20 h, respectively). No significant treatment or gender effects were observed for AUC or UR (urinary recovery). The pharmacokinetics of didanosine were not altered appreciably by dosing with metoclopramide. Administration with loperamide affected the rate but not the extent of absorption. There were no clinically relevant differences between males and females in the disposition of didanosine.