Patient‐reported convenience of once‐daily versus three‐times‐daily dosing during long‐term studies of pramipexole in early and advanced Parkinson’s disease

Background and purpose: In chronic diseases including Parkinson’s disease (PD), complex pharmacotherapy dosing schedules are reported to reduce adherence, perhaps leading to less‐effective symptom control and, in PD, more erratic stimulation of dopamine receptors. However, blinded clinical‐trial designs preclude direct comparisons of adherence to various schedules. Methods: In two double‐blind (DB) studies of early PD and one of advanced PD, subjects received three‐times‐daily (t.i.d.) pramipexole or placebo. In open‐label (OL) extensions, subjects took extended‐release, once‐daily (q.d.) pramipexole. At 24 or 32 OL weeks, q.d. versus t.i.d. dosing preference was surveyed by questionnaire. Results: Of 590 DB‐trial completers with early PD, 511 entered the OL extension. Of 374 survey respondents, 94.4% preferred q.d. dosing (72.2% of them found it ‘very much more convenient’ and 27.8%‘more convenient’), 2.7% preferred t.i.d., and 2.9% chose ‘no difference’. Of 465 DB‐trial completers with advanced PD, 391 entered its OL extension. Of 334 survey respondents, 88.9% preferred q.d. dosing (59.9% of them found it ‘very much more convenient’ and 40.1%‘more convenient’), 5.7% preferred t.i.d., and 5.4% chose ‘no difference’. Results excluding DB‐placebo recipients were highly similar. Conclusions: In this first direct comparison of patient preference for q.d. versus t.i.d. dopamine‐agonist dosing, patients with early or advanced PD had a strong preference for q.d. rather than t.i.d. pramipexole. The high proportion of advanced‐PD patients declaring this preference indicates that it does not depend on whether a patient is taking concomitant PD medications dosed more frequently than q.d.     

Quantifying the Severity of a Delirium Episode Throughout Hospitalization: the Combined Importance of Intensity and Duration

Background

The ability to determine which episodes of delirium are likely to lead to poor clinical outcomes has remained a major area of challenge.

Objective

To quantify delirium severity and course over an entire hospitalization using several measures, and to evaluate their predictive validity for 30- and 90-day outcomes post-discharge.

Design

Two prospective cohort studies.

Participants

Analysis was conducted in two independent cohorts of adult patients aged ≥70.

Main Measures

Nine delirium episode severity measures were examined: (1) measures reflecting delirium intensity (peak Confusion Assessment Method-Severity [CAM-S] and mean CAM-S score), (2) a measure reflecting delirium intensity and duration (sum of all CAM-S scores, sum of all CAM-S scores on delirium days only, peak CAM-S score x days with delirium), (3) measures requiring information on delirium duration and delirium at discharge (total number of delirium days, percentage of delirium days, delirium at discharge), and (4) a measure of cognitive change. Associations of the delirium episode severity measures with 30- and 90-day post-hospital outcomes (death, nursing home placement, and readmission) relevant to delirium were examined.

Key Results

The delirium episode severity measure that required information on both delirium intensity and duration (sum of all CAM-S scores) was the most strongly associated with 30- and 90-day post-hospital outcomes. Using this measure, the relative risk [95 % confidence interval] for death at 30-days increased across levels of sum of all CAM-S scores from 1.0 (referent) to 2.1 [0.8, 5.4] for ‘low,’ to 2.9 [1.2, 7.1] for ‘moderate,’ to 6.4 [2.9, 14.0] for ‘high’ (p for trend <.01).

Conclusions

The delirium episode severity measure that included both intensity and duration had the strongest association with important post-hospital outcomes.

     

Comparison of the subacute toxicity and efficacy of 3-hydroxypyridin-4- one iron chelators in overloaded and nonoverloaded mice

Five orally effective iron chelators of the 3-hydroxypyridin-4-one series have been administered intraperitoneally to iron-overloaded and nonoverloaded male mice at a dose of 200 mg/kg/24 h for a total of 60 days to investigate the effect on iron loading and toxicity. There was a significant reduction in hepatic iron at the end of the study in the iron-overloaded mice with all compounds studied using chemical iron quantitation (P less than .001) and with Perls' stain (P less than .01). Liver iron removal with the hydroxypyridinones ranged from 37% with CP20 to 63% with CP51, compared with 46% removal for desferrioxamine (DFO). There was no significant reduction in splenic or cardiac iron with any chelator. There were no deaths in iron-overloaded animals receiving any of the hydroxypyridin-4-ones, but significantly more deaths in the nonoverloaded groups as a whole (P less than .03). No weight loss was observed with any chelator. Significant reductions in hemoglobin and white cell count were observed with CP20(L1). No histologic abnormalities of kidney, spleen, bone marrow, or stifle joints were observed. Intracytoplasmic inclusion bodies were observed in the centrilobular hepatocytes of animals administered each of the hydroxypyridin-4-ones, while the DFO-treated and control groups showed no such changes.     

Loading deproteinized bovine bone with strontium enhances bone regeneration in rat calvarial critical size defects

Clinical Oral Investigations - To evaluate the effect of grafting with strontium (Sr)-loaded deproteinized bovine bone (DBB) on bone healing in calvarial critical size defects (CSD) in rats. Two...     

Regional neurovascular coupling and cognitive performance in those with low blood pressure secondary to high-level spinal cord injury: improved by alpha-1 agonist midodrine hydrochloride

Individuals with high-level spinal cord injury (SCI) experience low blood pressure (BP) and cognitive impairments. Such dysfunction may be mediated in part by impaired neurovascular coupling (NVC) (i.e., cerebral blood flow responses to neurologic demand). Ten individuals with SCI >T6 spinal segment, and 10 age- and sex-matched controls were assessed for beat-by-beat BP, as well as middle and posterior cerebral artery blood flow velocity (MCAv, PCAv) in response to a NVC test. Tests were repeated in SCI after 10 mg midodrine (alpha₁-agonist). Verbal fluency was measured before and after midodrine in SCI, and in the control group as an index of cognitive function. At rest, mean BP was lower in SCI (70±10 versus 92±14 mm Hg; P<0.05); however, PCAv conductance was higher (0.56±0.13 versus 0.39±0.15 cm/second/mm Hg; P<0.05). Controls exhibited a 20% increase in PCAv during cognition; however, the response in SCI was completely absent (P<0.01). When BP was increased with midodrine, NVC was improved 70% in SCI, which was reflected by a 13% improved cognitive function (P<0.05). Improvements in BP were related to improved cognitive function in those with SCI (r²=0.52; P<0.05). Impaired NVC, secondary to low BP, may partially mediate reduced cognitive function in individuals with high-level SCI.