Double-blind study of the actively transported levodopa prodrug XP21279 in Parkinson's disease.

The objective of this study was to assess the efficacy, safety, and pharmacokinetics of XP21279-carbidopa in patients with Parkinson's disease who experience motor fluctuations compared with immediate-release carbidopa-levodopa tablets. XP21279 is a levodopa prodrug that is actively absorbed by high-capacity nutrient transporters expressed throughout the gastrointestinal tract and then rapidly converted to levodopa by carboxylesterases. XP21279-carbidopa sustained-release bilayer tablets were developed to overcome pharmacokinetic limitations of levodopa by providing more continuous exposure. Patients with motor fluctuations who required carbidopa-levodopa four or five times daily were optimized for 2 weeks each on carbidopa-levodopa four or five times daily and XP21279-carbidopa three times daily in a randomized sequence. Next, they received each optimized treatment for 2 weeks in a double-blind/double-dummy, randomized sequence. The primary outcome measure was change from baseline in daily off time at the end of each double-blind treatment period. All patients at 2 sites underwent pharmacokinetic analyses. Twenty-eight of 35 enrolled patients completed both double-blind treatments. The mean total daily off time was reduced from baseline by a mean (± standard error) of 2.7 hours (± 0.48 hours) for immediate-release carbidopa-levodopa and 3.0 hours (± 0.57 hours) for XP21279-carbidopa (P = 0.49). Among 11 patients who completed pharmacokinetic sampling on each optimized treatment, the percentage deviation from the mean levodopa concentration was lower (P < 0.05) for XP21279-carbidopa than carbidopa-levodopa. Both treatments had a similar incidence of new or worsening dyskinesias. XP21279-carbidopa administered three times daily produced a reduction in off time similar to that of carbidopa-levodopa administered four or five times daily, and the difference was not statistically significant. XP21279-carbidopa significantly reduced variability in levodopa concentrations compared with carbidopa-levodopa.

Randomised clinical trial: arbaclofen placarbil in gastro-oesophageal reflux disease--insights into study design for transient lower sphincter relaxation inhibitors.

BACKGROUND: Arbaclofen placarbil is a pro-drug of the gamma-aminobutyric acid-B agonist R-baclofen that has been shown to reduce reflux episodes in patients with gastro-oesophageal reflux disease (GERD). AIM: To evaluate the efficacy and safety of arbaclofen placarbil vs. placebo as adjunctive therapy in subjects with troublesome GERD symptoms despite therapy with once-daily doses of a proton pump inhibitor (PPI) and to identify the characteristics of patients who were responders. METHODS: Patients (n = 460) with symptomatic GERD experiencing troublesome symptoms on once-daily PPI therapy were enrolled in this phase II, randomised, multicentre, double-blind, placebo-controlled, dose-ranging study. Patients were randomised to receive placebo or arbaclofen placarbil (20 or 40 mg once daily, 20 or 30 mg twice daily) with their current PPI for 6 weeks. Patients recorded heartburn and other GERD symptoms in a daily diary and rated severity of each event. The primary endpoint was percent change from baseline in heartburn events per week. RESULTS: In the primary analysis, there was no significant difference between arbaclofen placarbil and placebo. Post hoc analyses removing mild and very mild heartburn events resulted in greater percent reductions for all arbaclofen placarbil doses with nominal P values <0.05 for each dose compared with placebo. There was a dose-related increase for the most common adverse events. CONCLUSIONS: Arbaclofen placarbil was not superior to placebo in the primary analysis. Post hoc analyses suggest that subjects with more clinically relevant moderate or severe symptoms are more likely to respond to arbaclofen placarbil (clinicaltrials.gov NCT00978016).

Actively transported levodopa prodrug XP21279: a study in patients with Parkinson disease who experience motor fluctuations.

OBJECTIVE: The objectives of this study were to assess the pharmacokinetic profile, efficacy, and safety of XP21279 administered with carbidopa (CD) in subjects with Parkinson disease (PD) experiencing motor fluctuations and explore dose correspondence between CD-levodopa (LD) and XP21279 administered with CD. METHODS: Subjects received CD-LD 3 or 4 times daily for 2 weeks, followed by XP21279 plus CD 3 times daily for 2 weeks at fixed dosing times, allowing dose adjustment to optimize clinical response, in this multiple-dose, multicenter, open-label, 2-period, sequential-treatment study. Pharmacokinetic parameters, including LD exposure, were assessed over 16 hours on the last day of each treatment period. Levodopa exposure variability was assessed for each treatment using the absolute % deviation from average concentration (Cavg) in each subject. Efficacy assessments included daily self-ratings of OFF time, ON time, and dyskinesias. RESULTS: XP21279 provided significantly less variability in LD concentration compared with CD-LD (P < 0.05) in 10 PD subjects with motor fluctuations, consistent with lower peak-to-trough fluctuation for XP21279. Patterns of percentage of subjects OFF were consistent with the LD concentration-time profiles for each respective treatment. Compared with CD-LD treatment, 6 of 10 study completers experienced reduction of 30% or greater in average daily OFF time during the last 4 days in the XP21279 treatment period. XP21279 resulted in an increase in the time spent ON without troublesome dyskinesias, and the mean time to ON after the first morning XP21279 dose was not delayed, as compared with CD-LD. CONCLUSIONS: XP21279 provided improved pharmacokinetic performance (highlighted by reduction in variability of LD concentration) compared with CD-LD and therefore may provide better control of PD motor fluctuations.

Efficacy and safety study of arbaclofen placarbil in patients with spasticity due to spinal cord injury.

STUDY DESIGN: Randomized, double-blind, placebo-controlled, two-period crossover. OBJECTIVES: To evaluate the efficacy and safety of arbaclofen placarbil (AP) in patients with spasticity secondary to spinal cord injury (SCI). SETTING: United States and Canada. METHODS: Patients received extended-release AP tablets 10, 20 or 30 mg every 12 h in one of two AP/placebo sequences, with 26 days of each treatment. The primary analysis compared Ashworth scale assessments of muscle tone between AP and placebo for the muscle group with maximum baseline Ashworth score. Secondary endpoints included a patient-rated Severity of Spasticity Scale. RESULTS: In the primary analysis, AP significantly improved Ashworth scores compared with placebo over the dosing interval: least-squares mean reduction versus placebo was 0.60 for AP 20 mg (P=0.0059) and 0.88 for AP 30 mg (P=0.0007). The difference was significant for the pre-morning dose time point, 12 h after the prior evening dose, indicating that efficacy was maintained throughout the dosing interval. Treatment differences for AP 10 mg versus placebo were not significant. Severity of Spasticity ratings were significantly reduced for the combined 20/30-mg group versus placebo (P=0.018). No statistically significant differences between AP and placebo were observed for muscle strength. AP-related AEs were generally mild to moderate in intensity, and none led to early withdrawal or were serious. CONCLUSION: AP was well tolerated at all investigated dosages and, when administered at doses of 20 or 30 mg twice daily, was efficacious in reducing spasticity due to SCI.

Arbaclofen placarbil in GERD: a randomized, double-blind, placebo-controlled study.

OBJECTIVES: It has been shown that arbaclofen placarbil (AP) inhibits reflux in gastroesophageal reflux disease (GERD) following single oral dosing. This study evaluated the efficacy and safety of AP over 4 weeks in subjects with symptomatic GERD. METHODS: One hundred fifty-six subjects with heartburn and/or regurgitation ≥3 days/week and either no history of taking proton pump inhibitors (PPIs naive, n=58) or at least partial symptom response to PPI therapy (PPI responsive, n=98) were enrolled in this randomized, double-blind, placebo-controlled trial. All GERD therapies including PPIs were discontinued 2 weeks before randomization to AP 20, 40, or 60 mg daily, 30 mg twice daily, or placebo for 4 weeks. Randomization was stratified by prior PPI use. RESULTS: In the primary analysis, change from baseline in weekly heartburn events between AP and placebo for the entire study group was not statistically significant. However, a significant interaction was observed between prior PPI use and response to AP treatment. In pre-planned secondary analyses of the PPI-responsive subgroup, percent reductions from baseline in weekly heartburn events were greater for each AP dose vs. placebo (P<0.05) and the percentage of subjects who reported complete resolution of heartburn during week 4 was higher in each AP treatment group (21, 28, 30, and 50% for AP 20, 40, 60 mg daily, and 30 mg twice daily, respectively) compared with placebo (6%) (P<0.05 for 30 mg twice daily). Corresponding analyses of the PPI-naive subgroup showed no significant differences. AP was well tolerated; withdrawals due to adverse events were infrequent. CONCLUSIONS: AP was not superior to placebo in reducing the number of weekly heartburn events over 4 weeks in the primary analysis of the entire study population. Exploratory subgroup analyses suggest that response to PPI treatment before the study was associated with a response to AP treatment.

The effect of food with varying fat content on the clinical pharmacokinetics of gabapentin after oral administration of gabapentin enacarbil.

UNLABELLED: Gabapentin enacarbil, an actively transported prodrug of gabapentin, provides sustained and dose-proportional exposure to gabapentin. OBJECTIVE: To evaluate the effect of food of varying fat content on the pharmacokinetics and tolerability of gabapentin enacarbil. METHODS, MATERIALS AND SUBJECTS: A randomized, open-label, crossover study of 1,200 mg gabapentin enacarbil was conducted in 12 healthy adults, under four conditions: fasted, or following low-fat (200 - 300 kcal total, approximately 6% from fat), moderate-fat (500 - 600 kcal total, approximately 30% from fat) or high-fat meals (1,000 kcal total, approximately 50% from fat), separated by a washout period of >or= 5 days. RESULTS: Ten subjects completed treatment under all four conditions. Data from all subjects were used for pharmacokinetic and safety analyses unless stated otherwise. Mean (standard deviation) bioavailability (based on urinary recovery) of gabapentin from gabapentin enacarbil was 42.0 (6.1)% (fasted), 64.3 (13.2)% (low-fat meal), 64.9 (16.9)% (moderate-fat meal), and 76.1 (14.4)% (high-fat meal). Gabapentin exposures (AUC(inf)) in fed conditions were 23% (low-fat meal), 31% (moderate-fat meal), and 40% (high-fat meal) greater than the exposure under fasted condition. Fed conditions did not significantly delay median t(max), but a trend for delayed gabapentin enacarbil absorption was seen in t(max) ranges following moderate- and high-fat meals compared with the fasted state or low-fat meal. The most commonly reported treatment-emergent adverse events (TEAEs) were dizziness (4 subjects), balance disorder (4 subjects) and somnolence (3 subjects). All TEAEs were rated as mild in intensity. CONCLUSION: Administration of gabapentin enacarbil with food enhanced gabapentin exposure compared with fasted conditions, regardless of the fat or caloric content, and gabapentin enacarbil was generally well tolerated.

Arbaclofen placarbil decreases postprandial reflux in patients with gastroesophageal reflux disease.

OBJECTIVES: Arbaclofen placarbil (AP), previously designated as XP19986, is an investigational prodrug of the active R-isomer of baclofen, a gamma-aminobutyric acid agonist reflux inhibitor. The aim of this study was to assess the efficacy and safety of AP for decreasing meal-induced reflux episodes in patients with gastroesophageal reflux disease (GERD). METHODS: We conducted a multicenter, randomized, double-blind, crossover study comparing single doses of AP with placebo. Different patients were enrolled at each of four escalating AP doses: 10, 20, 40, and 60 mg. Enrolled patients had GERD symptoms at least three times a week and 20 reflux episodes on impedance/pH monitoring over a period of 2 h. During study visits separated by periods of 3-7 days, patients received single doses of AP or placebo, followed by high-fat meals 2 and 6 h after treatment. The primary end point was the number of reflux episodes over 12 h after treatment. RESULTS: A total of 50 patients were treated; efficacy analysis included 44 patients who received both AP and placebo and had technically satisfactory impedance/pH data. For the combined data from all dose cohorts, there was a statistically significant (P=0.01) decrease in reflux episodes over 12 h after treatment with AP compared with placebo. The mean (s.d.) number of reflux episodes over 12 h after AP treatment was 50.5 (27.2), with a mean reduction of 10.4 (23.9) episodes (17%) compared with placebo, for which a mean (s.d.) number of 60.9 (35.3) episodes was observed. Heartburn events associated with reflux were reduced during treatment with AP compared with placebo. AP seemed to be the most efficacious in the 60-mg dose group, and was well tolerated at all dose levels. CONCLUSIONS: AP decreased reflux and associated symptoms with good tolerability in patients with GERD.

Visual identification and spatial location in Alzheimer's disease.

Twelve patients with Alzheimer's disease (AD) and 15 healthy elderly control subjects were shown sets of luminance-defined letters, texture-defined letters, luminance-defined squares, and texture-defined squares. They were asked to name the letters or point to the target square on each page. The stimuli were graded into four levels of difficulty based on the amount of contrast between the figure and the background. Performance was measured in terms of the maximum level of difficulty at which the participant correctly identified or located the three figures. Contrary to expectations, no significant difference was found between the performance of AD patients and control subjects on texture discrimination tasks vs. luminance discrimination tasks. However, results indicate that AD patients are impaired in performing a task requiring them to locate a texture-defined target of known shape in a noisy background field. By contrast, AD patients show no significant deficit in a task requiring them to locate a texture-defined shape in a known location. This argues that the observed deficit in the location task is not due to a failure in the system that discriminates target texture from background texture (since both location and identification tasks require the same textural discriminations), but rather to an impairment of the system responsible for "finding things" (i.e., locating known targets at unknown locations). This observation suggests that AD patients may suffer selective damage to the dorsal "Where" pathway, which is responsible for localizing objects in space.

Prospective study of risk factors for Alzheimer's disease: results at 7.5 years.

OBJECTIVE: The primary goal of this study was to evaluate increased platelet membrane fluidity as a putative risk factor for Alzheimer's disease and its relationship to the APOE epsilon4 genotype. METHOD: This report describes the results of a prospective, longitudinal study of 330 initially asymptomatic, first-degree relatives of probands with Alzheimer's disease. RESULTS: Nine incident cases of Alzheimer's disease were detected during the first 2,220 subject-years of the follow-up period. Age, increased platelet membrane fluidity, and the APOE epsilon4 allele made significant independent contributions to the risk of developing Alzheimer's disease, while sex and years of education did not. Increased platelet membrane fluidity was associated with incident Alzheimer's disease cases between the ages of 64 and 71, while the epsilon4 allele was associated with incident Alzheimer's disease cases from age 64 until at least age 80. CONCLUSIONS: These results indicate that increased platelet membrane fluidity is not produced by the APOE epsilon4 allele. Instead, increased platelet membrane fluidity and the epsilon4 allele appear to make significant independent contributions to the risk of developing Alzheimer's disease among the first-degree relatives of patients with this disorder. Moreover, the age ranges over which these risk factors operate appear to be different.

Educating for collaborative practice.

OBJECTIVE: To describe a baccalaureate-level course which is designed to help allied health professions students develop an understanding of collaborative practice among interdisciplinary components of a health care system and to report on a survey which assessed the effectiveness of the course for clinical laboratory science graduates. SETTING: University of Kentucky, a large (24,000 students) state-assisted institution PRACTICE DESCRIPTION: Baccalaureate clinical laboratory science program PRACTICE INNOVATION: A college-wide course helps students develop an understanding of the linkages of the major components of a health care system and introduces the techniques necessary to function in an interdisciplinary team. MAIN OUTCOMES MEASURE: Perception of benefit from the course by clinical laboratory science graduates. RESULTS: Graduates report that the course helped them develop a larger perspective of health care delivery beyond that of their own discipline and aided in their understanding of group processes and group problem-solving. CONCLUSIONS: Clinical laboratory science curricula can benefit from the inclusion of a college wide course which introduces a broad perspective of health care delivery and group process concepts.

Prospective study of increased platelet membrane fluidity as a risk factor for Alzheimer's disease: results at 5 years.

OBJECTIVE: The primary goal of this study was to evaluate increased platelet membrane fluidity as a putative risk factor for Alzheimer's disease. METHOD: This report describes the initial results of a prospective, longitudinal study of 330 initially asymptomatic, first-degree relatives of probands with Alzheimer's disease. RESULTS: Five incident cases of Alzheimer's disease were detected during the first 1,582 subject-years of the follow-up period. The age-specific incidence of Alzheimer's disease was several-fold higher than corresponding figures that were obtained in two prospective community studies. Most important, both age and increased platelet membrane fluidity made significant independent contributions to the risk of developing Alzheimer's disease. CONCLUSIONS: These results validate age and a family history of Alzheimer's disease as risk factors for this disorder and provide the first prospective evidence of increased platelet membrane fluidity as a biological risk factor for Alzheimer's disease.

A treatment and withdrawal trial of besipirdine in Alzheimer disease.

Besipirdine hydrochloride (HP 749) is an indole-substituted analog of 4-aminopyridine. Besipirdine enhances both cholinergic and adrenergic neurotransmission in the central nervous system. The present study examined the efficacy and tolerability of two doses of besipirdine (5 and 20 mg b.i.d.) in 275 patients with Alzheimer disease during 3 months of treatment and for 3 months after withdrawal of treatment. Assessment after withdrawal of treatment was used in an effort to distinguish persistent efficacy attributable to a neuroprotective mechanism from reversible symptomatic efficacy. Besipirdine was generally well tolerated. The level of performance on the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog) was sustained during 3 months of treatment with besipirdine, whereas some deterioration in the performance of patients treated with placebo was observed over the same period. The small difference between active and placebo treatment groups approached, but did not reach statistical significance in the primary intent-to-treat analysis (p = 0.067); analysis of patients who completed all assessments was supportive (p = 0.031). Global ratings using the Clinician Interview-Based Impression of Change did not detect a besipirdine treatment benefit, possibly because of an adverse effect on mood and behavior in some patients. A high ratio of adrenergic to cholinergic potency may have resulted in the adverse effects of besipirdine and hence its failure to support the hypothesis that multiple neurotransmitter treatment may be more efficacious than monotherapy. The efficacy apparent on the ADAS-Cog after 3 months of treatment did not persist 3 months after withdrawal of treatment, suggesting that the benefit was symptomatic. This study provides a practical example of the use of treatment withdrawal assessment to distinguish neuroprotective from symptomatic efficacy.

Preliminary evaluation of besipirdine for the treatment of Alzheimer's disease. Besipirdine Study Group.

Besipirdine hydrochloride (HP 749) is an indole-substituted analog of 4-aminopyridine. Besipirdine enhances both cholinergic and adrenergic neurotransmission in the central nervous system, and may have greater efficacy than purely cholinergic agents in treating dementia due to Alzheimer's disease. The present study examined the efficacy and tolerability of two doses of besipirdine (5 and 20 mg BID) in 275 patients with Alzheimer's disease during 3 months of treatment and during 3 months after withdrawal of treatment. Besipiridine was generally well tolerated. The level of performance on a cognitive test was sustained during 3 months of treatment with besipirdine, whereas the performance of patients treated with placebo deteriorated over the same time period. The results suggest a dose-response relationship, with greater efficacy after 3 months of treatment and longer persistence after treatment withdrawal for besipiridine 20 mg BID than for 5 mg BID. A clinical global rating did not detect a besipirdine treatment effect. The full efficacy after 3 months of treatment did not persist after withdrawal of treatment, suggesting that the benefit is primarily symptomatic. Treatment with higher doses and for longer periods may enhance efficacy on both cognitive and clinical global assessments.

Potential patterns--conceptual and practical issues in interdisciplinary education.

Interdisciplinary education is, again, a timely topic. It has been seen as an important strategy in recent reports and commissions dealing with the future of the health care system and its personnel needs. The present article reviews conceptual and practical issues in the design, development, and implementation of interdisciplinary education in allied health. A foundation for planning involves the integration of an interdisciplinary practice model with the usual model of psychomotor skills, cognitive skills, and knowledge domain for a particular discipline. Planning issues are addressed in a series of six questions for allied health administrators and faculty to consider.

A "bridging" (safety/tolerance) study of besipirdine hydrochloride in patients with Alzheimer's disease.

Besipirdine hydrochloride is a novel compound with cholinergic and adrenergic activity being investigated as a treatment for Alzheimer's disease (AD). The pharmacodynamics of some anti-dementia drugs are known to differ in patients with AD as compared with elderly normals. The present study was designed to determine the maximum tolerated dose (MTD) of multiple oral doses of besipirdine in AD patients. Twelve AD patients (NINCDS/ADRDA criteria; 7M, 5F, ages 58-75, mean age 65) were randomized to besipirdine (n = 9) or placebo (n = 3) in a double-blind, parallel-group, rising-dose design. Doses were 10, 20, 30, and 40 mg bid for 2 days each, followed by 50 and 60 mg bid for 5 days each. The most common adverse events were asymptomatic postural hypotension and asymptomatic bradycardia. Two patients on active drug developed severe adverse events: 1 after 3 days at 50 mg bid (nausea and vomiting); 1 after 3 days at 60 mg bid (angina). Due to the anginal episode, the study was terminated on Day 17. Plasma concentrations increased linearly with dose for besipirdine and its major metabolite. The two patients who developed severe adverse events had the highest plasma concentrations measured. Besipirdine 50 mg bid was considered the maximum tolerated dose (MTD).

Sensitivity and specificity for dementia of population-based criteria for cognitive impairment: the MoVIES project.

BACKGROUND: Few norms exist for the elderly on the cognitive tests commonly used to screen for dementia; conventional cutpoints used in clinical settings may be of limited value in population screening. A particular problem is posed by elderly populations with low educational levels, as performance on most cognitive tests is affected by education. Thus, a healthy but poorly educated population may obtain test scores in the range considered impaired in the clinical setting. METHODS: A random sample of 1,367 subjects aged 65+ years was screened for dementia in a rural community in Southwestern Pennsylvania. Two sets of cognitive measures were used: a global cognitive scale (the MMSE) and a brief battery of tests tapping a variety of cognitive domains. Rather than using a priori cutoff scores, we examined the specificity and sensitivity for dementia of two operationally defined levels of cognitive impairment, at the 5th and 10th percentiles of the study sample on each set of measures. RESULTS: Results suggest that the screening of multiple cognitive domains at the 10th percentile had significantly greater sensitivity but not lower specificity for definite dementia than did the use of the single global scale. CONCLUSION: Our data support the use of population-based cutpoints over standard cutoff scores, in that the global scale at the conventional cutoff was less sensitive than the battery at the same percentile, and because adequate norms do not exist for tests such as those in the battery.

Serum autoantibodies in patients with Alzheimer's disease and vascular dementia and in nondemented control subjects.

BACKGROUND AND PURPOSE: In this study we sought to evaluate the clinical significance of serum autoantibodies to dementing processes. METHODS: We assessed 40 age-matched subjects: 10 patients with probable Alzheimer's disease, 10 with possible Alzheimer's disease with cerebrovascular disease, 10 with vascular dementia, and 10 nondemented control subjects. Serum from each subject was tested for the presence of antithyroglobulin antibody, thyroid antimicrosomal antibody, gastric anti-parietal cell antibody, anti-smooth muscle antibody, antinuclear antibody, rheumatoid factor, antineuronal antibody, and anticardiolipin antibody. In addition, we investigated the sera of these patients for the presence of an antivascular antibody directed against the vascular basement membrane proteoglycan antigen and for circulating immune complexes. RESULTS: Autoantibodies were present in 100% of the patients with possible Alzheimer's disease with cerebrovascular disease, 80% of those with vascular dementia, 40% of those with probable Alzheimer's disease, and 30% of the nondemented control subjects. The highest number of autoantibodies was observed in patients with vascular dementia and possible Alzheimer's disease with cerebrovascular disease. Antinuclear antibody was present in 60% of vascular dementia patients and antineuronal antibody in 50% of these patients. However, no individual autoantibody could differentiate Alzheimer's disease from cerebrovascular disorders. Immune complexes were detected in the serum of 20-30% of each patient group. Neither the patient nor the control sera was found to contain antiendothelial antibody. CONCLUSIONS: Despite the relatively small number of individuals examined in each category, the elevated number of autoantibodies associated with possible Alzheimer's disease with cerebrovascular disease and vascular dementia indicates a possible link between the presence of autoantibodies and cerebrovascular disorders in dementia.

Time dependency of cognitive recovery with cobalamin replacement: report of a pilot study.

OBJECTIVE: To examine the effects of cobalamin repletion on cognition in elderly subjects with low serum cobalamin and evidence of cognitive dysfunction. DESIGN: Time series data collected in an open trial of parenteral cobalamin therapy. SETTINGS: Outpatient geriatric assessment centers, inpatient geropsychiatry unit, and tertiary care university hospital. PARTICIPANTS: Twenty-two subjects with low serum cobalamin (less than 150 pmol/L) and evidence of cognitive dysfunction were entered consecutively over an 8-month period of time. Eighteen subjects completed the study. INTERVENTIONS: Subjects received 1000 micrograms of cyanocobalamin intramuscularly daily for 1 week, then weekly for 1 month, then monthly thereafter for a minimum of six months. OUTPATIENT MEASURE: The Mattis Dementia Rating Scale (DRS) was administered both before and at least 6 months after full cobalamin replacement therapy. The hypothesis that cognitive improvement was dependent on the duration of cognitive symptoms was formulated a posteriori. RESULTS: After a minimum of 6 months of cobalamin therapy, 11 of 18 patients showed cognitive improvement. There was a striking correlation between duration of cognitive symptoms and response to therapy. Patients symptomatic for less than 12 months gained an average of twenty points on the DRS (paired t test P = 0.0076), whereas patients symptomatic greater than 12 months lost an average of three points (paired t test P = .34). Two patients symptomatic for only 3 months normalized their DRS scores, gaining 31 and 28 points, respectively. CONCLUSION: There may be a time-limited window of opportunity for effective intervention in patients with cognitive dysfunction and low serum cobalamin.