Crystal L. Harris

Pallidal versus subthalamic deep-brain stimulation for Parkinson's disease

BACKGROUND Deep-brain stimulation is the surgical procedure of choice for patients with advanced Parkinsons disease. The globus pallidus interna and the subthalamic nucleus are accepted targets for this procedure. We compared 24-month outcomes for patients who had undergone bilateral stimulation of the globus pallidus interna (pallidal stimulation) or subthalamic nucleus (subthalamic stimulation). METHODS At seven Veterans Affairs and six university hospitals, we randomly assigned 299 patients with idiopathic Parkinsons disease to undergo either pallidal stimulation (152 patients) or subthalamic stimulation (147 patients). The primary outcome was the change in motor function, as blindly assessed on the Unified Parkinsons Disease Rating Scale, part III (UPDRS-III), while patients were receiving stimulation but not receiving antiparkinsonian medication. Secondary outcomes included self-reported function, quality of life, neurocognitive function, and adverse events. RESULTS Mean changes in the primary outcome did not differ significantly between the two study groups (P=0.50). There was also no significant difference in self-reported function. Patients undergoing subthalamic stimulation required a lower dose of dopaminergic agents than did those undergoing pallidal stimulation (P=0.02). One component of processing speed (visuomotor) declined more after subthalamic stimulation than after pallidal stimulation (P=0.03). The level of depression worsened after subthalamic stimulation and improved after pallidal stimulation (P=0.02). Serious adverse events occurred in 51% of patients undergoing pallidal stimulation and in 56% of those undergoing subthalamic stimulation, with no significant between-group differences at 24 months. CONCLUSIONS Patients with Parkinsons disease had similar improvement in motor function after either pallidal or subthalamic stimulation. Nonmotor factors may reasonably be included in the selection of surgical target for deep-brain stimulation. (ClinicalTrials.gov numbers, NCT00056563 and NCT01076452.)

The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: A report from the glucosamine/chondroitin arthritis intervention trial

OBJECTIVE Osteoarthritis (OA) of the knee causes significant morbidity and current medical treatment is limited to symptom relief, while therapies able to slow structural damage remain elusive. This study was undertaken to evaluate the effect of glucosamine and chondroitin sulfate (CS), alone or in combination, as well as celecoxib and placebo on progressive loss of joint space width (JSW) in patients with knee OA. METHODS A 24-month, double-blind, placebo-controlled study, conducted at 9 sites in the United States as part of the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), enrolled 572 patients with knee OA who satisfied radiographic criteria (Kellgren/Lawrence [K/L] grade 2 or grade 3 changes and JSW of at least 2 mm at baseline). Patients with primarily lateral compartment narrowing at any time point were excluded. Patients who had been randomized to 1 of the 5 groups in the GAIT continued to receive glucosamine 500 mg 3 times daily, CS 400 mg 3 times daily, the combination of glucosamine and CS, celecoxib 200 mg daily, or placebo over 24 months. The minimum medial tibiofemoral JSW was measured at baseline, 12 months, and 24 months. The primary outcome measure was the mean change in JSW from baseline. RESULTS The mean JSW loss at 2 years in knees with OA in the placebo group, adjusted for design and clinical factors, was 0.166 mm. No statistically significant difference in mean JSW loss was observed in any treatment group compared with the placebo group. Treatment effects on K/L grade 2 knees, but not on K/L grade 3 knees, showed a trend toward improvement relative to the placebo group. The power of the study was diminished by the limited sample size, variance of JSW measurement, and a smaller than expected loss in JSW. CONCLUSION At 2 years, no treatment achieved a predefined threshold of clinically important difference in JSW loss as compared with placebo. However, knees with K/L grade 2 radiographic OA appeared to have the greatest potential for modification by these treatments.

Randomized trial of deep brain stimulation for Parkinson disease: Thirty-six-month outcomes

Objectives: Our objective was to compare long-term outcomes of deep brain stimulation (DBS) of the globus pallidus interna (GPi) and subthalamic nucleus (STN) for patients with Parkinson disease (PD) in a multicenter randomized controlled trial. Methods: Patients randomly assigned to GPi (n = 89) or STN DBS (n = 70) were followed for 36 months. The primary outcome was motor function on stimulation/off medication using the Unified Parkinsons Disease Rating Scale motor subscale. Secondary outcomes included quality of life and neurocognitive function. Results: Motor function improved between baseline and 36 months for GPi (41.1 to 27.1; 95% confidence interval [CI] −16.4 to −10.8; p < 0.001) and STN (42.5 to 29.7; 95% CI −15.8 to −9.4; p < 0.001); improvements were similar between targets and stable over time (p = 0.59). Health-related quality of life improved at 6 months on all subscales (all p values significant), but improvement diminished over time. Mattis Dementia Rating Scale scores declined faster for STN than GPi patients (p = 0.01); other neurocognitive measures showed gradual decline overall. Conclusions: The beneficial effect of DBS on motor function was stable and comparable by target over 36 months. Slight declines in quality of life following initial gains and gradual decline in neurocognitive function likely reflect underlying disease progression and highlight the importance of nonmotor symptoms in determining quality of life. Classification of Evidence: This study provides Class III evidence that improvement of motor symptoms of PD by DBS remains stable over 3 years and does not differ by surgical target. Neurology® 2012;79:55–65

Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT

Background Knee osteoarthritis (OA) is a major cause of pain and functional limitation in older adults, yet longer-term studies of medical treatment of OA are limited. Objective To evaluate the efficacy and safety of glucosamine and chondroitin sulphate (CS), alone or in combination, as well as celecoxib and placebo on painful knee OA over 2 years. Methods A 24-month, double-blind, placebo-controlled study, conducted at nine sites in the US ancillary to the Glucosamine/chondroitin Arthritis Intervention Trial, enrolled 662 patients with knee OA who satisfied radiographic criteria (Kellgren/Lawrence grade 2 or 3 changes and baseline joint space width of at least 2 mm). This subset continued to receive their randomised treatment: glucosamine 500 mg three times daily, CS 400 mg three times daily, the combination of glucosamine and CS, celecoxib 200 mg daily, or placebo over 24 months. The primary outcome was a 20% reduction in Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain over 24 months. Secondary outcomes included an Outcome Measures in Rheumatology/Osteoarthritis Research Society International response and change from baseline in WOMAC pain and function. Results Compared with placebo, the odds of achieving a 20% reduction in WOMAC pain were celecoxib: 1.21, glucosamine: 1.16, combination glucosamine/CS: 0.83 and CS alone: 0.69, and were not statistically significant. Conclusions Over 2 years, no treatment achieved a clinically important difference in WOMAC pain or function as compared with placebo. However, glucosamine and celecoxib showed beneficial but not significant trends. Adverse reactions were similar among treatment groups and serious adverse events were rare for all treatments.

Intensive Multifactorial Intervention for Stable Coronary Artery Disease Optimal Medical Therapy in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) Trial

OBJECTIVES This paper describes the medical therapy used in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial and its effect on risk factors. BACKGROUND Most cardiovascular clinical trials test a single intervention. The COURAGE trial tested multiple lifestyle and pharmacologic interventions (optimal medical therapy) with or without percutaneous coronary intervention in patients with stable coronary disease. METHODS All patients, regardless of treatment assignment, received equivalent lifestyle and pharmacologic interventions for secondary prevention. Most medications were provided at no cost. Therapy was administered by nurse case managers according to protocols designed to achieve predefined lifestyle and risk factor goals. RESULTS The patients (n = 2,287) were followed for 4.6 years. There were no significant differences between treatment groups in proportion of patients achieving therapeutic goals. The proportion of smokers decreased from 23% to 19% (p = 0.025), those who reported <7% of calories from saturated fat increased from 46% to 80% (p < 0.001), and those who walked >or=150 min/week increased from 58% to 66% (p < 0.001). Body mass index increased from 28.8 +/- 0.13 kg/m(2) to 29.3 +/- 0.23 kg/m(2) (p < 0.001). Appropriate medication use increased from pre-randomization to 5 years as follows: antiplatelets 87% to 96%; beta-blockers 69% to 85%; renin-angiotensin-aldosterone system inhibitors 46% to 72%; and statins 64% to 93%. Systolic blood pressure decreased from a median of 131 +/- 0.49 mm Hg to 123 +/- 0.88 mm Hg. Low-density lipoprotein cholesterol decreased from a median of 101 +/- 0.83 mg/dl to 72 +/- 0.88 mg/dl. CONCLUSIONS Secondary prevention was applied equally and intensively to both treatment groups in the COURAGE trial by nurse case managers with treatment protocols and resulted in significant improvement in risk factors. Optimal medical therapy in the COURAGE trial provides an effective model for secondary prevention among patients with chronic coronary disease. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; NCT00007657).

The human pharmacokinetics of oral ingestion of glucosamine and chondroitin sulfate taken separately or in combination.

OBJECTIVE As part of the National Institutes of Health (NIH)-sponsored Glucosamine/Chondroitin sulfate Arthritis Intervention Trial (GAIT) our objective here was to examine (1) the pharmacokinetics (PK) of glucosamine (GlcN) and chondroitin sulfate (CS) when taken separately or in combination as a single dose in normal individuals (n=29) and (2) the PK of GlcN and CS when taken as a single dose after 3 months daily dosing with GlcN, CS or GlcN+CS, in patients with symptomatic knee pain (n=28). METHODS The concentration of GlcN in the circulation was determined by established fluorophore-assisted carbohydrate electrophoresis (FACE) methods. The hydrodynamic size and disaccharide composition of CS chains in the circulation and dosage samples was determined by Superose 6 chromatography and FACE. RESULTS We show that circulating levels of CS in human plasma are about 20 microg/ml. Most significantly, the endogenous concentration and CS disaccharide composition were not detectably altered by ingestion of CS, when the CS was taken alone or in combination with GlcN. On the other hand, the Cmax (single-dose study) and AUC values (multiple-dose study) for ingested GlcN were significantly reduced by combination dosing with CS, relative to GlcN dosing alone. CONCLUSIONS We conclude that pain relief perceived following ingestion of CS probably does not depend on simultaneous or prior intake of GlcN. Further, such effects on joint pain, if present, probably do not result from ingested CS reaching the joint space but may result from changes in cellular activities in the gut lining or in the liver, where concentrations of ingested CS, or its breakdown products, could be substantially elevated following oral ingestion. Moreover, since combined dosing of GlcN with CS was found to reduce the plasma levels seen with GlcN dosing alone, any improved pain relief by combination dosing cannot be explained by higher circulating concentrations of GlcN.

Chondroitin Product Selection for the Glucosamine/Chondroitin Arthritis Intervention Trial

OBJECTIVE To select a high-quality chondroitin dosage form and/or an appropriate source of sodium chondroitin for the National Institutes of Healths Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT). DESIGN Controlled experimental trials. SETTING Laboratory. PATIENTS OR PARTICIPANTS Not applicable. INTERVENTIONS Commercially available chondroitin products were reviewed, and purified sodium chondroitin from two suppliers was evaluated through tests (infrared and near-infrared identification, moisture content, pH, optical rotation, color and clarity of aqueous solutions prepared from the powders, protein contamination, total residue following ignition and nitrogen content, determination of sodium chondroitin molecular weight, disaccharide analysis, and measurement of chondroitin, sodium, and total glycosaminoglycan content) and an onsite supplier audit. MAIN OUTCOME MEASURES Purity, potency, and quality of sodium chondroitin powders. RESULTS No commercially available chondroitin product was deemed appropriate for use in GAIT. Samples of sodium chondroitin powder from two suppliers exhibited similar disaccharide and glycosaminoglycan content. Each contained approximately 2% hyaluronic acid and 8%-9% unsulfated disaccharide. Potency was inconsistent across groups, which might have resulted from different analytical methods and choice of reference standard. Mean potency obtained by five separate methods ranged from 82.2% to 95.5% for one supplier, 92.5% to 110.1% for another, and 95.1% to 112.5% for a commercially obtained reference standard. Critical issues raised by the results include choice of reference standard, selection of assay method, and the consistent appearance of an unidentifiable contaminant present in all three lots from one supplier. CONCLUSION This blinded study determined methods to identify acceptable agents and provided results, which, in addition to regulatory compliance supplier audits, formed the basis for chondroitin product selection in GAIT.

GI Risk Factors and Use of GI Protective Agents Among Patients Receiving Nonsteroidal Antiinflammatory Drugs

Background: Patient characteristics increase the risk of gastrointestinal (GI) complications associated with nonsteroidal antiinflammatory drugs (NSAIDs). Patients at risk may not be prescribed protective therapies that might mitigate their risk of NSAID-associated GI complications. Objective: To assess GI risk among Veterans Affairs (VA) patients on NSAID therapy, determine whether therapy conformed to VA guidelines for lessening the risk of GI complications, and identify patient risk factors associated with conformance. Methods: Using databases from 3 VA medical centers, we retrospectively identified patients receiving NSAIDs and obtained data regarding age, history of GI bleed over 8 years, GI adverse effects associated with NSAIDs, diagnoses, and medication history over one year. We inferred health status from age-adjusted Charlson comorbidity index values. Each patients risk of developing GI complications over one year was calculated using these data. Among patients at significant or substantial risk, we assessed conformance to VA guidelines. We used logistic regression to identify risk factors associated with conformance and determine adjusted ORs (AORs) with 95% CIs for each risk factor. Results: There were 19122 patients receiving NSAIDs. Of 4589 patients at significant risk and 1246 at substantial risk, 1161 (25.3%) and 356 (28.6%), respectively, were prescribed guideline-conformant therapy. Risk factors associated with conformance (p s 0.001) among patients at significant risk were rheumatoid arthritis (AOR 1.34; 95% CI 1.13 to 1.58) and GI adverse effects (AOR 1.53; 95% CI 1.42 to 1.64). For substantial risk patients, risk factors associated with conformance (p s 0.031) were rheumatoid arthritis (AOR 1.65; 95% CI 1.37 to 1.98), concomitant corticosteroids (AOR 1.21; 95% CI 1.02 to 1.43), GI hospitalization (AOR 2.01; 95% CI 1.57 to 2.59), and GI adverse effects (AOR 1.79; 95% CI 1.47 to 2.18). Conclusions: Many patients at risk for GI adverse events do not receive guideline-conformant therapy. Educational interventions to improve conformance could focus on specific risk factors for GI complications.

Trial of Prazosin for Post-Traumatic Stress Disorder in Military Veterans

BACKGROUND In randomized trials, prazosin, an α1‐adrenoreceptor antagonist, has been effective in alleviating nightmares associated with post‐traumatic stress disorder (PTSD) in military veterans. METHODS We recruited veterans from 13 Department of Veterans Affairs medical centers who had chronic PTSD and reported frequent nightmares. Participants were randomly assigned to receive prazosin or placebo for 26 weeks; the drug or placebo was administered in escalating divided doses over the course of 5 weeks to a daily maximum of 20 mg in men and 12 mg in women. After week 10, participants continued to receive prazosin or placebo in a double‐blind fashion for an additional 16 weeks. The three primary outcome measures were the change in score from baseline to 10 weeks on the Clinician‐Administered PTSD Scale (CAPS) item B2 (“recurrent distressing dreams”; scores range from 0 to 8, with higher scores indicating more frequent and more distressing dreams); the change in score from baseline to 10 weeks on the Pittsburgh Sleep Quality Index (PSQI; scores range from 0 to 21, with higher scores indicating worse sleep quality); and the Clinical Global Impression of Change (CGIC) score at 10 weeks (scores range from 1 to 7, with lower scores indicating greater improvement and a score of 4 indicating no change). RESULTS A total of 304 participants underwent randomization; 152 were assigned to prazosin, and 152 to placebo. At 10 weeks, there were no significant differences between the prazosin group and the placebo group in the mean change from baseline in the CAPS item B2 score (between‐group difference, 0.2; 95% confidence interval [CI], ‐0.3 to 0.8; P=0.38), in the mean change in PSQI score (between‐group difference, 0.1; 95% CI, ‐0.9 to 1.1; P=0.80), or in the CGIC score (between‐group difference, 0; 95% CI, ‐0.3 to 0.3; P=0.96). There were no significant differences in these measures at 26 weeks (a secondary outcome) or in other secondary outcomes. At 10 weeks, the mean difference between the prazosin group and the placebo group in the change from baseline in supine systolic blood pressure was a decrease of 6.7 mm Hg. The adverse event of new or worsening suicidal ideation occurred in 8% of the participants assigned to prazosin versus 15% of those assigned to placebo. CONCLUSIONS In this trial involving military veterans who had chronic PTSD, prazosin did not alleviate distressing dreams or improve sleep quality. (Funded by the Department of Veterans Affairs Cooperative Studies Program; PACT ClinicalTrials.gov number, NCT00532493.)

Is all glucosamine alike? Clarifying the controversies for product selection and clinical research.

In the United States, glucosamine is marketed as a dietary supplement therefore subject to less stringent manufacturing, labeling and marketing regulations than pharmaceuticals. The glucosamine product selected for the NIH-sponsored Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) was required to satisfy Investigational New Drug (IND) application (and therefore pharmaceutical manufacturing requirements). This review describes the procedure that was developed by the authors to identify a high-quality glucosamine product for GAIT and to clarify confusing product information and nomenclature.Proprietary glucosamine products and bulk glucosamine powders of various salt forms were evaluated. Both the published literature and information provided by suppliers of bulk glucosamine powders were evaluated. No proprietary glucosamine product was selected due to manufacturing practices that did not meet the pharmaceutical standards mandated by GAIT; i.e., no practices that control and document the quality issues of product purity and content variability. At the time this study was initiated dietary supplements were not required to meet these standards. Other problems identified with proprietary products included the presence of other dietary supplements and/or trace elements and the inability of a manufacturer to provide the appropriate quality of product within the time constraints of the study. A bulk powder of glucosamine hydrochloride was identified and capsules were manufactured for the trial in compliance with pharmaceutical Good Manufacturing Practices.