Development of a quantitative semi-mechanistic model of Alzheimer's disease based on the amyloid/tau/neurodegeneration framework (the Q-ATN model).

INTRODUCTION: A quantitative model of Alzheimer's disease (AD) based on the amyloid/tau/neurodegeneration biomarker framework (Q-ATN model) was developed to sequentially link amyloid positron emission tomography (PET), tau PET, medial temporal cortical thickness, and clinical outcome (Clinical Dementia Rating - Sum of Boxes; CDR-SB). METHODS: Published data and biologically plausible mechanisms were used to construct, calibrate, and validate the model. Clinical trial simulations were performed for different anti-amyloid antibodies, including a 5-year simulation of subcutaneous gantenerumab treatment. RESULTS: The simulated time-course of biomarkers and CDR-SB was consistent with natural history studies and described the effects of several anti-amyloid antibodies observed in trials with positive and negative (or non-significant) outcomes. The 5-year simulation predicts that the beneficial effects of continued anti-amyloid treatment should increase markedly over time. DISCUSSION: The Q-ATN model offers a novel approach for linking amyloid PET to CDR-SB, and provides theoretical support for the potential clinical benefit of anti-amyloid therapy. HIGHLIGHTS: A semi-mechanistic model was developed to link amyloid/tau/neurodegeneration biomarkers to clinical outcome (Q-ATN model). The Q-ATN model describes the disease progression seen in natural history studies. Model simulations agree well with mean data from the aducanumab EMERGE study. A 5-year simulation of gantenerumab predicts greater benefit with longer treatment.

Trial of Prasinezumab in Early-Stage Parkinson's Disease.

BACKGROUND: Aggregated α-synuclein plays an important role in the pathogenesis of Parkinson's disease. The monoclonal antibody prasinezumab, directed at aggregated α-synuclein, is being studied for its effect on Parkinson's disease. METHODS: In this phase 2 trial, we randomly assigned participants with early-stage Parkinson's disease in a 1:1:1 ratio to receive intravenous placebo or prasinezumab at a dose of 1500 mg or 4500 mg every 4 weeks for 52 weeks. The primary end point was the change from baseline to week 52 in the sum of scores on parts I, II, and III of the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 236, with higher scores indicating greater impairment). Secondary end points included the dopamine transporter levels in the putamen of the hemisphere ipsilateral to the clinically more affected side of the body, as measured by 123I-ioflupane single-photon-emission computed tomography (SPECT). RESULTS: A total of 316 participants were enrolled; 105 were assigned to receive placebo, 105 to receive 1500 mg of prasinezumab, and 106 to receive 4500 mg of prasinezumab. The baseline mean MDS-UPDRS scores were 32.0 in the placebo group, 31.5 in the 1500-mg group, and 30.8 in the 4500-mg group, and mean (±SE) changes from baseline to 52 weeks were 9.4±1.2 in the placebo group, 7.4±1.2 in the 1500-mg group (difference vs. placebo, -2.0; 80% confidence interval [CI], -4.2 to 0.2; P = 0.24), and 8.8±1.2 in the 4500-mg group (difference vs. placebo, -0.6; 80% CI, -2.8 to 1.6; P = 0.72). There was no substantial difference between the active-treatment groups and the placebo group in dopamine transporter levels on SPECT. The results for most clinical secondary end points were similar in the active-treatment groups and the placebo group. Serious adverse events occurred in 6.7% of the participants in the 1500-mg group and in 7.5% of those in the 4500-mg group; infusion reactions occurred in 19.0% and 34.0%, respectively. CONCLUSIONS: Prasinezumab therapy had no meaningful effect on global or imaging measures of Parkinson's disease progression as compared with placebo and was associated with infusion reactions. (Funded by F. Hoffmann-La Roche and Prothena Biosciences; PASADENA ClinicalTrials.gov number, NCT03100149.).

A Phase II Study to Evaluate the Safety and Efficacy of Prasinezumab in Early Parkinson's Disease (PASADENA): Rationale, Design, and Baseline Data.

Background: Currently available treatments for Parkinson's disease (PD) do not slow clinical progression nor target alpha-synuclein, a key protein associated with the disease. Objective: The study objective was to evaluate the efficacy and safety of prasinezumab, a humanized monoclonal antibody that binds aggregated alpha-synuclein, in individuals with early PD. Methods: The PASADENA study is a multicenter, randomized, double-blind, placebo-controlled treatment study. Individuals with early PD, recruited across the US and Europe, received monthly intravenous doses of prasinezumab (1,500 or 4,500 mg) or placebo for a 52-week period (Part 1), followed by a 52-week extension (Part 2) in which all participants received active treatment. Key inclusion criteria were: aged 40-80 years; Hoehn & Yahr (H&Y) Stage I or II; time from diagnosis ≤2 years; having bradykinesia plus one other cardinal sign of PD (e.g., resting tremor, rigidity); DAT-SPECT imaging consistent with PD; and either treatment naïve or on a stable monoamine oxidase B (MAO-B) inhibitor dose. Study design assumptions for sample size and study duration were built using a patient cohort from the Parkinson's Progression Marker Initiative (PPMI). In this report, baseline characteristics are compared between the treatment-naïve and MAO-B inhibitor-treated PASADENA cohorts and between the PASADENA and PPMI populations. Results: Of the 443 patients screened, 316 were enrolled into the PASADENA study between June 2017 and November 2018, with an average age of 59.9 years and 67.4% being male. Mean time from diagnosis at baseline was 10.11 months, with 75.3% in H&Y Stage II. Baseline motor and non-motor symptoms (assessed using Movement Disorder Society-Unified Parkinson's Disease Rating Scale [MDS-UPDRS]) were similar in severity between the MAO-B inhibitor-treated and treatment-naïve PASADENA cohorts (MDS-UPDRS sum of Parts I + II + III [standard deviation (SD)]; 30.21 [11.96], 32.10 [13.20], respectively). The overall PASADENA population (63.6% treatment naïve and 36.4% on MAO-B inhibitor) showed a similar severity in MDS-UPDRS scores (e.g., MDS-UPDRS sum of Parts I + II + III [SD]; 31.41 [12.78], 32.63 [13.04], respectively) to the PPMI cohort (all treatment naïve). Conclusions: The PASADENA study population is suitable to investigate the potential of prasinezumab to slow disease progression in individuals with early PD. Trial Registration: NCT03100149.

Treatment Patterns in Patients with Incident Parkinson's Disease in the United States.

BACKGROUND: Treatment patterns in Parkinson's disease (PD) have not been extensively studied for nearly two decades. Insurance claims are appropriate for such analysis. OBJECTIVE: To understand the standard of care use of symptomatic treatments in new cases of PD and factors associated with treatment choice. METHODS: Retrospective cohort study using claims data from the United States between 2008 and 2016. We used Kaplan-Meier methodology to estimate time to treatment start and switch or add-on therapy and Cox proportional hazards models to identify predictors. RESULTS: We identified 68,532 patients eligible for treatment pattern analyses. Median time from diagnosis until first treatment was 37 days (95% confidence interval: 36-38). Two distinct patterns of treatment initiation were identified: fast initiators and patients with delayed treatment start (or no recorded treatment). Levodopa therapies were the most commonly prescribed treatment class (52.6%). Increased age was associated with shorter time to start of treatment with levodopa. Younger age was associated with shorter time to initiation of dopamine agonists and other symptomatic treatments. Patients that initiated treatment with levodopa/combinations had the fewest switches/add-ons [30.4%; median time 7.29 (6.71, 8.13) years]. Older patients had fewer switch/add-on therapies, but only in the group that started with levodopa/combination therapy. CONCLUSIONS: Time from diagnosis to treatment start was relatively short, suggesting that PD diagnosis, as reflected in the database, is closely linked to start of symptomatic treatment. Levodopa treatment remains the most common treatment, especially for older patients. Delayed treatment start was associated with increased age and comorbidity.

Progressive Decline in Gray and White Matter Integrity in de novo Parkinson's Disease: An Analysis of Longitudinal Parkinson Progression Markers Initiative Diffusion Tensor Imaging Data.

Background: Progressive neuronal loss in neurodegenerative diseases such as Parkinson's disease (PD) is associated with progressive degeneration of associated white matter tracts as measured by diffusion tensor imaging (DTI). These findings may have diagnostic and functional implications but their value in de novo PD remains unknown. Here we analyzed longitudinal DTI data from Parkinson's Progression Markers Initiative de novo PD patients for changes over time relative to healthy control (HC) participants. Methods: Baseline and 1-year follow-up DTI MRI data from 71 PD patients and 45 HC PPMI participants were included in the analyses. Whole-brain fractional anisotropy (FA) and mean diffusivity (MD) images were compared for baseline group differences and group-by-time interactions. Baseline and 1-year changes in DTI values were correlated with changes in DTI measures and symptom severity, respectively. Results: At baseline, PD patients showed significantly increased FA in brainstem, cerebellar, anterior corpus callosal, inferior frontal and inferior fronto-occipital white matter and increased MD in primary sensorimotor and supplementary motor regions. Over 1 year PD patients showed a significantly stronger decline in FA compared to HC in the optic radiation and corpus callosum and parietal, occipital, posterior temporal, posterior thalamic, and vermis gray matter. Significant increases in MD were observed in white matter of the midbrain, optic radiation and corpus callosum, while gray matter of prefrontal, insular and posterior thalamic regions. Baseline brainstem FA white matter (WM) values predicted 1-year changes in FA white matter and MD gray matter values. White but not gray matter changes in both FA and MD were significantly associated with changes in symptom severity. Conclusion: Significant gray and white matter DTI alterations are observable at the time of PD diagnosis and expand in the first year of de novo PD to other cortical and white matter regions. This pattern of DTI changes is in line with preclinical and neuroanatomical studies suggesting that the increased spatial spread of alpha-synuclein neuropathology is the key mechanism of PD progression. Taken together, these findings suggest that DTI may serve as a sensitive biomarker of disease progression in early-stage PD.

Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti-α-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease: A Randomized Clinical Trial.

Importance: Aggregated α-synuclein is believed to be central to the pathogenesis of Parkinson disease (PD). PRX002/RG7935 (PRX002) is a humanized monoclonal antibody designed to target aggregated forms of α-synuclein, thereby inhibiting neuron-to-neuron transfer of presumed pathogenic forms of α-synuclein, potentially resulting in neuronal protection and slowing disease progression. Objective: To evaluate the safety and tolerability of multiple intravenous infusions of PRX002 in patients with idiopathic PD. Design, Setting, and Participants: Multicenter, randomized, double-blind, placebo-controlled, multiple ascending-dose trial at 8 US study centers from July 2014 to September 2016. Eligible participants were aged 40 to 80 years with mild to moderate idiopathic PD (Hoehn and Yahr stages 1-3). Interventions: Participants were enrolled into 6 ascending-dose cohorts and randomly assigned to receive PRX002 (0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, 10 mg/kg, 30 mg/kg, or 60 mg/kg) or placebo. Participants received 3 intravenous infusions every 4 weeks of PRX002 or placebo and were monitored during a 24-week observational period. Main Outcomes and Measures: Safety and tolerability assessments included physical and neurological examinations, laboratory tests, vital signs, and adverse events. Pharmacokinetic parameters included maximum PRX002 concentration, area under the curve, and half-life. Results: Of the 80 participants, most were white (97.5%; n = 78) and male (80%; n = 64); median (SD) age was 58 (8.4) years. PRX002 was generally safe and well tolerated; no serious or severe PRX002-related treatment-emergent adverse events (TEAEs) were reported. The TEAEs experienced by at least 5% of patients receiving PRX002, irrespective of relatedness to study drug, were constipation (9.1%; n = 5), infusion reaction (7.3%; n = 4), diarrhea (5.5%; n = 3), headache (5.5%; n = 3), peripheral edema (5.5%; n = 3), post-lumbar puncture syndrome (5.5%; n = 3), and upper respiratory tract infection (5.5%; n = 3). No antidrug antibodies were detected. Serum PRX002 levels increased in an approximately dose-proportional manner; mean terminal elimination half-life was similar across all doses (10.2 days). Rapid dose- and time-dependent mean reductions from baseline vs placebo in free serum α-synuclein levels of up to 97% were seen after a single infusion at the highest dose (F78,284 = 1.66; P = .002), with similar reductions after 2 additional infusions. Mean cerebrospinal fluid PRX002 concentration increased with PRX002 dose and was approximately 0.3% relative to serum across all dose cohorts. Conclusions and Relevance: Single and multiple doses of PRX002 were generally safe and well tolerated and resulted in robust binding of peripheral α-synuclein and dose-dependent increases of PRX002 in cerebrospinal fluid, reaching cerebrospinal fluid concentrations that may be expected to engage extracellular aggregated α-synuclein in the brain. Findings support the design of an ongoing phase 2 clinical study (NCT03100149). Trial Registration: ClinicalTrials.gov Identifier: NCT02157714.

Characterization of 3 Novel Tau Radiopharmaceuticals, 11C-RO-963, 11C-RO-643, and 18F-RO-948, in Healthy Controls and in Alzheimer Subjects.

11C-RO-963, 11C-RO-643, and 18F-RO-948 (previously referred to as 11C-RO6924963, 11C-RO6931643, and 18F-RO6958948, respectively) have been reported as promising PET tracers for tau imaging based on in vitro and preclinical PET data. Here we describe the first, to our knowledge, human evaluation of these novel radiotracers. Methods: Amyloid PET-positive Alzheimer disease (AD) subjects and younger controls each received 2 different tau tracers. Dynamic 90-min scans were obtained after bolus injection of 11C-RO-963, 11C-RO-643, or 18F-RO-948. Arterial blood sampling was performed on 11 healthy controls and 11 AD subjects. Regions were defined on MR images, and PET data were quantified by plasma reference graphical analysis (for total distribution volume) and target cerebellum ratio (SUV ratios of 60- to 90-min frames). SUV ratio images were also analyzed voxelwise. Five older controls each underwent 2 scans with 18F-RO-948 for evaluation of test-retest variability. Four AD subjects underwent a repeated 18F-RO-948 scan 6-22 mo after the first scan. Six additional healthy controls (3 men and 3 women; age range, 41-67 y) each underwent 1 whole-body dosimetry scan with 18F-RO-948. Results: In younger controls, SUVpeak was observed in the temporal lobe with values of approximately 3.0 for 11C-RO-963, 1.5 for 11C-RO-643, and 3.5 for 18F-RO-948. Over all brain regions and subjects, the trend was for 18F-RO-948 to have the highest SUVpeak, followed by 11C-RO-963 and then 11C-RO-643. Regional analysis of SUV ratio and total distribution volume for 11C-RO-643 and 18F-RO-948 clearly discriminated the AD group from the healthy control groups. Compartmental modeling confirmed that 11C-RO-643 had lower brain entry than either 11C-RO-963 or 18F-RO-948 and that 18F-RO-948 showed better contrast between (predicted) areas of high versus low tau accumulation. Thus, our subsequent analysis focused on 18F-RO-948. Both voxelwise and region-based analysis of 18F-RO-948 binding in healthy controls versus AD subjects revealed multiple areas where AD subjects significantly differed from healthy controls. Of 22 high-binding regions, 13 showed a significant group difference (after ANOVA, F(1,21) = 45, P < 10-5). Voxelwise analysis also revealed a set of symmetric clusters where AD subjects had higher binding than healthy controls (threshold of P < 0.001, cluster size > 50). Conclusion:18F-RO-948 demonstrates characteristics superior to 11C-RO-643 and 11C-RO-963 for characterization of tau pathology in AD. Regional binding data and kinetic properties of 18F-RO-948 compare favorably with other existing tau PET tracers.

Evaluation of smartphone-based testing to generate exploratory outcome measures in a phase 1 Parkinson's disease clinical trial.

BACKGROUND: Ubiquitous digital technologies such as smartphone sensors promise to fundamentally change biomedical research and treatment monitoring in neurological diseases such as PD, creating a new domain of digital biomarkers. OBJECTIVES: The present study assessed the feasibility, reliability, and validity of smartphone-based digital biomarkers of PD in a clinical trial setting. METHODS: During a 6-month, phase 1b clinical trial with 44 Parkinson participants, and an independent, 45-day study in 35 age-matched healthy controls, participants completed six daily motor active tests (sustained phonation, rest tremor, postural tremor, finger-tapping, balance, and gait), then carried the smartphone during the day (passive monitoring), enabling assessment of, for example, time spent walking and sit-to-stand transitions by gyroscopic and accelerometer data. RESULTS: Adherence was acceptable: Patients completed active testing on average 3.5 of 7 times/week. Sensor-based features showed moderate-to-excellent test-retest reliability (average intraclass correlation coefficient = 0.84). All active and passive features significantly differentiated PD from controls with P < 0.005. All active test features except sustained phonation were significantly related to corresponding International Parkinson and Movement Disorder Society-Sponsored UPRDS clinical severity ratings. On passive monitoring, time spent walking had a significant (P = 0.005) relationship with average postural instability and gait disturbance scores. Of note, for all smartphone active and passive features except postural tremor, the monitoring procedure detected abnormalities even in those Parkinson participants scored as having no signs in the corresponding International Parkinson and Movement Disorder Society-Sponsored UPRDS items at the site visit. CONCLUSIONS: These findings demonstrate the feasibility of smartphone-based digital biomarkers and indicate that smartphone-sensor technologies provide reliable, valid, clinically meaningful, and highly sensitive phenotypic data in Parkinson's disease. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Impact of comorbidities on pharmacotherapy of painful diabetic neuropathy in clinical practice.

AIMS: We evaluated the impact of baseline comorbidities on the effectiveness of duloxetine and anticonvulsants (pregabalin/gabapentin) in patients with painful diabetic neuropathy in clinical care. METHODS: Outcomes from a 6-month, observational study with 2575 patients initiating/switching DPNP treatment were analyzed post-hoc. Propensity scoring was used to adjust for baseline factors influencing treatment choice in 1523 patients receiving duloxetine or anticonvulsants. Analysis of covariance models with fixed effects for baseline pain, treatment, propensity score, baseline characteristics or comorbidities, and their interaction with treatment were used to estimate LSmean effects on Brief Pain Inventory (BPI) average pain and interference scores. RESULTS: 89.5% of patients reported comorbidities, including hypertension (70.5%), hyperlipidemia (39.2%), and depression (24.8%). Macrovascular complications (37.0%) and 'other chronic pain' (41.5%), particularly joint pain had an impact on both pain treatments, i.e. less improvement of average pain and interference of pain. Better treatment responses with duloxetine vs. anticonvulsants were observed in patients with depression, those with high baseline BPI total interference score, especially general activity, and in patients with joint pain. CONCLUSIONS: Comorbidities such as macroangiopathy and depression as well as pain characteristics should be considered in the treatment of DPNP as they may predict the effectiveness of duloxetine and anticonvulsants.

Effectiveness of duloxetine compared with pregabalin and gabapentin in diabetic peripheral neuropathic pain: results from a German observational study.

OBJECTIVES: This study aimed to compare the effectiveness of duloxetine (DLX) and the anticonvulsants pregabalin (PGB) and gabapentin (GBP) for the treatment of diabetic peripheral neuropathic pain (DPNP) in routine clinical care. MATERIALS AND METHODS: Data from a 6-month, noninterventional study involving 2575 patients in whom treatment of DPNP was initiated with or changed to DLX, PGB, or GBP (n=1523) were analyzed post hoc; patients treated with other medications or combinations were excluded from this analysis. Propensity scoring was used to compare patient groups, assessing Brief Pain Inventory (BPI), Clinical and Patient Global Impression (CGI/PGI), the Hospital Anxiety and Depression Scale (HADS), the Sheehan Disability Scale (SDS), and the Short Form Health Survey (SF 12). RESULTS: Mean median daily dosage over 6 months was 53.9 mg for DLX (N=931), 173.5 mg for PGB (N=248), and 727.8 mg for GBP (N=351). BPI average pain severity (last observation carried forward, mean [SD]) decreased by 2.3 [2.30] points for DLX patients, and by 1.9 [2.22] in PGB, and 1.1 [2.15] in GBP patients. This difference remained statistically significant (DLX vs. PGB: P=0.029; DLX vs. GBP: P<0.001) after adjustment by propensity scores. Similar findings were also seen for the BPI interference score, CGI and PGI, the HADS anxiety score, the HADS depression score. DISCUSSION: When compared with DLX, the low doses of PGB and GBP used in this noninterventional study might have contributed to the lower effectiveness found for both anticonvulsants in the treatment of patients with DPNP.

Tadalafil once daily in men with erectile dysfunction: an integrated analysis of data obtained from 1913 patients from six randomized, double-blind, placebo-controlled, clinical studies.

BACKGROUND: This analysis explores tadalafil once-daily treatment for 12 wk in clinical subpopulations of men with erectile dysfunction (ED). OBJECTIVE: Assess the efficacy and safety of once-daily tadalafil 2.5mg and 5mg in patients with different ED characteristics and comorbidities. DESIGN, SETTING, AND PARTICIPANTS: This analysis integrated data from six randomized, double-blind, placebo-controlled studies that assigned 1913 men with ≥3-mo history of ED either to once-daily placebo (n=596), tadalafil 2.5mg (n=394), or tadalafil 5mg (n=923). Clinical factors examined included: ethnicity, age, obesity, alcohol consumption, smoking, comorbidities, concomitant medication, and ED characteristics (etiology, duration, severity). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Descriptive statistics were reported for efficacy and safety, including International Index of Erectile Function Erectile Function Domain (IIEF-EF) scores and Sexual Encounter Profile question 3 (SEP3) responses. Clinical factors were included in analysis of covariance models using last observation carried forward for SEP3 and IIEF-EF scores. RESULTS AND LIMITATIONS: Both tadalafil doses significantly improved SEP3 responses (least-squares [LS] mean change: 17.8% and 23.6%, respectively) and IIEF-EF scores (LS mean change: 4.2; 5.4) compared with placebo (p<0.01). Treatment with 2.5mg and 5mg tadalafil resulted in IIEF-EF LS mean improvements ≥4 (minimal clinically important difference [MCID]) in patients with hypertension (4.3 [95% confidence interval (CI), 2.9-5.7]; 4.7 [95% CI, 3.5-5.8]), cardiac disorder (7.0 [95% CI, 4.7-9.3]; 6.3 [95% CI, 4.4-8.2]), or hyperlipidemia (5.3 [95% CI, 3.4-7.1]; 5.8 [95% CI, 4.3-7.4]). Obese patients (4.7 [95% CI, 3.4-6.0]), smokers (4.8 [95% CI, 3.0-6.7]), and psychogenic ED (7.3 [95% CI, 5.0-9.6]) reached MCID only after treatment with 5mg tadalafil. Severity-specific MCID (IIEF-EF change ≥7) was achieved by 44.5% of patients with severe baseline ED treated with tadalafil 5mg, compared with 11.6% of placebo-treated patients. No unexpected safety findings were observed. These analyses were performed on integrated data and can only provide descriptive results to guide further investigations. CONCLUSIONS: Treatment with tadalafil 2.5mg or 5mg once daily was well tolerated and resulted in clinically important improvements in patients with mild (54.3% and 74.8%, respectively), moderate (51.3% and 63.1%, respectively), or severe (33.7% and 44.5%, respectively) ED.

Adherence to initial PDE-5 inhibitor treatment: randomized open-label study comparing tadalafil once a day, tadalafil on demand, and sildenafil on demand in patients with erectile dysfunction.

INTRODUCTION: Phosphodiesterase type 5 (PDE-5) inhibitor treatment for erectile dysfunction (ED) is frequently discontinued; adherence may vary depending on the initial regimen. AIM: To evaluate the effects of initiating treatment with tadalafil once a day (OaD), tadalafil on demand (pro re nata [PRN]), or sildenafil PRN on treatment adherence. METHODS: In this multicenter, open-label study, men (≥ 18 years) with ED, naïve to PDE-5 inhibitors, were randomized (1:1:1) to tadalafil 5 mg OaD, tadalafil 10 mg PRN, or sildenafil 50 mg PRN. An 8-week randomized treatment (RT) period (dose adjustment possible) was succeeded by 16 weeks of pragmatic treatment (switches between PDE-5 inhibitors allowed). MAIN OUTCOME MEASURES: Treatment adherence was measured as time to discontinuation of RT (any cause), estimated by Kaplan-Meier product-limit method. Treatment-group differences were estimated as hazard ratio (HR; Cox proportional hazards). RESULTS: Seven hundred seventy patients (mean age 53 years) were randomized to tadalafil OaD (N = 257), tadalafil PRN (N = 252), and sildenafil PRN (N = 261). Kaplan-Meier estimates for patients discontinuing RT were 52.2, 42.0, and 66.7%, respectively. Median time to discontinuation of RT was significantly longer for tadalafil OaD and PRN (130 and >168 days) compared with sildenafil (67 days) (HR [97.5% confidence interval]: 0.66 [0.51, 0.85] and 0.49 [0.37, 0.65]; P < 0.001). Reasons for discontinuation with significant differences between groups (P < 0.05) included "lack of efficacy (duration of erection)" (sildenafil 9.2% vs. tadalafil OaD 4.3%, PRN 2.8%), "time constraints due to short window of action" (sildenafil 4.2% vs. tadalafil OaD 0%, PRN 0.4%), and "feel medication controls my sexual life" (sildenafil 2.7% vs. tadalafil OaD 0%). No between-group differences were found in International Index of Erectile Function-Erectile Function domain change from baseline to end of RT (least squares mean: 9.4-10.0, P = 0.359) or discontinuations due to adverse events (1.2-1.6%). The most common adverse event (≥ 4%) was headache. CONCLUSIONS: ED patients assigned to tadalafil OaD or PRN adhered significantly longer to initial treatment than patients assigned to sildenafil PRN. Improvement of erectile function and safety profiles were similar in all three treatment groups.

Pharmacological and behavioral profile of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-chinolincarboxamide (EVP-5141), a novel α7 nicotinic acetylcholine receptor agonist/serotonin 5-HT3 receptor antagonist.

RATIONALE AND OBJECTIVE: Agonists of α7 nicotinic acetylcholine receptors (nAChRs) may have therapeutic potential for the treatment of cognitive deficits. This study describes the in vitro pharmacology of the novel α7 nAChR agonist/serotonin 5-HT3 receptor (5-HT3R) antagonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-chinolincarboxamide (EVP-5141) and its behavioral effects. RESULTS: EVP-5141 bound to α7 nAChRs in rat brain membranes (K i = 270 nM) and to recombinant human serotonin 5-HT3Rs (K i = 880 nM) but had low affinity for α4ß2 nAChRs (K i > 100 µM). EVP-5141 was a potent agonist at recombinant rat and human α7 nAChRs expressed in Xenopus oocytes. EVP-5141 acted as 5-HT3R antagonist but did not block α3ß4, α4ß2, and muscle nAChRs. Rats trained to discriminate nicotine from vehicle did not generalize to EVP-5141 (0.3-30 mg kg(-1), p.o.), suggesting that the nicotine cue is not mediated by the α7 nAChR and that EVP-5141 may not share the abuse liability of nicotine. EVP-5141 (0.3-3 mg kg(-1)) improved performance in the rat social recognition test. EVP-5141 (0.3 mg kg(-1), p.o.) ameliorated scopolamine-induced retention deficits in the passive avoidance task in rats. EVP-5141 (1 mg kg(-1), i.p.) improved spatial working memory of aged (26- to 32-month-old) rats in a water maze repeated acquisition task. In addition, EVP-5141 improved both object and social recognition memory in mice (0.3 mg kg(-1), p.o.). CONCLUSIONS: EVP-5141 improved performance in several learning and memory tests in both rats and mice, supporting the hypothesis that α7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits in Alzheimer's disease or schizophrenia.

Tolerability aspects in duloxetine-treated patients with depression: Should one use a lower starting dose in clinical practice?

OBJECTIVE: This study questions whether a lower starting dose of duloxetine (DLX) could be beneficial for patients with depression, in terms of tolerability and safety in routine clinical care. RESEARCH DESIGN AND METHODS: Post-hoc analyses of a multicenter, prospective, non-interventional, 6-month study in adult outpatients with a depressive episode was undertaken. MAIN OUTCOME MEASURES: Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), discontinuations due to TEAEs and hospitalizations due to depression, were all documented at 2 weeks, 4 weeks, 3 months and 6 months after treatment initiation/switch to DLX. RESULTS: Of 4517 patients enrolled, 4313 were included for TEAE evaluation. TEAEs occurred in 17.2% of patients, and SAEs occurred in 0.79% of patients, including one case of suicidal ideation. 1404 patients discontinued within 6 months (TEAEs: n = 119). Starting treatment with 30 mg/day DLX (72.7%) was favored in females, or after inadequate efficacy of previous antidepressant treatment; 60 mg/day DLX was favored in more severe depression and patients receiving concomitant pain medication. CONCLUSION: Initiating treatment with 60 mg/day DLX was not associated with poorer tolerability in this study. Physicians may be guided by their clinical experience to carefully consider the individual benefit/risk ratio and TEAE susceptibility when deciding to start treatment with a higher or a lower dose of DLX.

EVP-6124, a novel and selective α7 nicotinic acetylcholine receptor partial agonist, improves memory performance by potentiating the acetylcholine response of α7 nicotinic acetylcholine receptors.

EVP-6124, (R)-7-chloro-N-quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide, is a novel partial agonist of α7 neuronal nicotinic acetylcholine receptors (nAChRs) that was evaluated here in vitro and in vivo. In binding and functional experiments, EVP-6124 showed selectivity for α7 nAChRs and did not activate or inhibit heteromeric α4ß2 nAChRs. EVP-6124 had good brain penetration and an adequate exposure time. EVP-6124 (0.3 mg/kg, p.o.) significantly restored memory function in scopolamine-treated rats (0.1 mg/kg, i.p.) in an object recognition task (ORT). Although donepezil at 0.1 mg/kg, p.o. or EVP-6124 at 0.03 mg/kg, p.o. did not improve memory in this task, co-administration of these sub-efficacious doses fully restored memory. In a natural forgetting test, an ORT with a 24 h retention time, EVP-6124 improved memory at 0.3 mg/kg, p.o. This improvement was blocked by the selective α7 nAChR antagonist methyllycaconitine (0.3 mg/kg, i.p. or 10 µg, i.c.v.). In co-application experiments of EVP-6124 with acetylcholine, sustained exposure to EVP-6124 in functional investigations in oocytes caused desensitization at concentrations greater than 3 nM, while lower concentrations (0.3-1 nM) caused an increase in the acetylcholine-evoked response. These actions were interpreted as representing a co-agonist activity of EVP-6124 with acetylcholine on α7 nAChRs. The concentrations of EVP-6124 that resulted in physiological potentiation were consistent with the free drug concentrations in brain that improved memory performance in the ORT. These data suggest that the selective partial agonist EVP-6124 improves memory performance by potentiating the acetylcholine response of α7 nAChRs and support new therapeutic strategies for the treatment of cognitive impairment. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues.

Cyclic nucleotide-specific phosphodiesterases (PDEs) play a critical role in signal transduction by regulating the level of adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) in cells. The gene expression pattern of a PDE provides important information regarding its role in physiological and pathological processes. In this study, we have established the mRNA expression profile all PDE isoenzymes (PDE1A/B/C, 2A, 3A/B, 4A/B/C/D, 5A, 6A/B/C, 7A/B, 8A/B, 9A, 10A, 11A) in a human cDNA collection consisting of 10 brain regions (parietal, frontal, temporal cortex, hippocampus, striatum, thalamus, hypothalamus, substantia nigra, nucleus accumbens, cerebellum), spinal cord, dorsal root ganglia and 12 peripheral tissues (skeletal muscle, heart, thyroid, adrenal gland, pancreas, bladder, kidney, liver, lung, small intestine, spleen, and stomach). Using quantitative real-time polymerase chain reaction and parallel analysis of a carefully selected group of reference genes, we have determined the relative expression of each PDE isoenzyme across the 24 selected tissues, and also compared the expression of selected PDEs to each other within a given tissue type. Several PDEs show strikingly selective expression (e.g. PDE10A and PDE1B mRNA levels in the caudate nucleus are 20-fold higher than in most other tissues; PDE1C and PDE3A are highly expressed in the heart and PDE8B is expressed very strongly in the thyroid gland). This comprehensive approach provides a coherent and quantitative view of the mRNA expression of the PDE gene family and enables an integration of data obtained with other non-quantitative methods.

Use of behavioural and long-term potentiation models in the development of memory-improving drugs.

BACKGROUND: There is a great need to develop memory-enhancing drugs for the treatment of memory dysfunctions. Although many targets have been identified in preclinical studies, the number of clinically effective drugs is limited. OBJECTIVE: In this overview, the relation between drug effects on hippocampal long-term potentiation (LTP) and memory-enhancing effects is explored for drugs that modulate cholinergic or glutamatergic neurotransmission or inhibit cyclic nucleotide metabolism. METHODS: We limited our analysis to drug targets that are in clinical use or in development for the treatment of cognitive deficits and that have been tested in LTP. RESULTS/CONCLUSION: Although these drugs have been shown to improve in vitro or in vivo LTP and memory performance in many different models, no clear correlation between positive effects in LTP and behavioural assays is possible. The effectiveness in behavioural models is based on various models assessing different aspects of cognition. More uniformity in the use of behavioural tests is encouraged to better understand drug effects on different memory processes (i.e., acquisition, consolidation and retrieval). The systematic use of in vitro models such as LTP improves our understanding of the molecular mechanism of drug efficacy. This may lead to a better selection of models relevant to the specific cognitive processes disrupted in different pathological conditions and a more differentiated development of memory-enhancing drugs.

The novel alpha7 nicotinic acetylcholine receptor agonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide improves working and recognition memory in rodents.

The relative contribution of alpha4beta2, alpha7 and other nicotinic acetylcholine receptor (nAChR) subtypes to the memory enhancing versus the addictive effects of nicotine is the subject of ongoing debate. In the present study, we characterized the pharmacological and behavioral properties of the alpha7 nAChR agonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide (ABBF). ABBF bound to alpha7 nAChR in rat brain membranes (Ki=62 nM) and to recombinant human 5-hydroxytryptamine (5-HT)3 receptors (Ki=60 nM). ABBF was a potent agonist at the recombinant rat and human alpha7 nAChR expressed in Xenopus oocytes, but it did not show agonist activity at other nAChR subtypes. ABBF acted as an antagonist of the 5-HT3 receptor and alpha3beta4, alpha4beta2, and muscle nAChRs (at higher concentrations). ABBF improved social recognition memory in rats (0.3-1 mg/kg p.o.). This improvement was blocked by intracerebroventricular administration of the alpha7 nAChR antagonist methyllycaconitine at 10 microg, indicating that it is mediated by alpha7 nAChR agonism. In addition, ABBF improved working memory of aged rats in a water maze repeated acquisition paradigm (1 mg/kg p.o.) and object recognition memory in mice (0.3-1 mg/kg p.o.). Rats trained to discriminate nicotine (0.4 mg/kg s.c.) from vehicle did not generalize to ABBF (0.3-30 mg/kg p.o.), suggesting that the nicotine cue is not mediated by the alpha7 nAChR and that selective alpha7 nAChR agonists may not share the abuse liability of nicotine. Our results support the hypothesis that alpha7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits with low abuse potential.

Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance.

An essential element of the signalling cascade leading to synaptic plasticity is the intracellular second messenger molecule guanosine 3',5'-cyclic monophosphate (cGMP). Using the novel, potent, and selective inhibitor Bay 60-7550, we show that the enzyme 3',5'-cyclic nucleotide phosphodiesterase type 2 (PDE2) is responsible for the degradation of newly synthesized cGMP in cultured neurons and hippocampal slices. Inhibition of PDE2 enhanced long-term potentiation of synaptic transmission without altering basal synaptic transmission. Inhibition of PDE2 also improved the performance of rats in social and object recognition memory tasks, and reversed MK801-induced deficits in spontaneous alternation in mice in a T-maze. Our data provide strong evidence that inhibition of PDE2 can improve memory functions by enhancing neuronal plasticity.

AR-R 17779 improves social recognition in rats by activation of nicotinic alpha7 receptors.

RATIONALE: Nicotine and agonists at alpha(4)beta(2) and alpha(7) nicotinic acetylcholine receptors (nAChRs) improve learning and memory. The alpha(7)-nAChR subtype is of special interest, since it appears to play no role in the abuse liability of nicotine. OBJECTIVES AND METHODS: To further investigate the role of the alpha(7)-nAChR in learning and memory, the effects of the specific alpha(7)-nAChR agonist AR-R17779 on cognition were measured in the rat social recognition test (SRT) and the effect of the alpha(7)-nAChR antagonist methyllycaconitine (MLA) was studied. The SRT and a scopolamine-induced deficit version were validated with the acetylcholinesterase inhibitor metrifonate. Social memory was measured by the ability of an adult rat to recognize a juvenile rat after a delay. The difference in social interaction time (SIT) was measured between two encounters. The difference in SIT is expressed as percent reduction in social interaction time (%RSIT). RESULTS: Metrifonate (10 and 30 mg/kg PO) increased %RSIT in a behaviorally specific manner, employing a 24-h interval and reversed the scopolamine-induced deficit at a retention time of 15 min. Likewise, AR-R17779 increased %RSIT in unimpaired animals (1, 3, 10 and 30 mg/kg SC) employing a 24-h retention interval, and reversed the scopolamine-induced deficit (0.3 and 1 mg/kg SC) after a 15-min retention interval. The effects of AR-R17779 (1 mg/kg SC) in unimpaired animals were reversed by MLA (10 micro g ICV), which induced a decrease of %RSI at a 15-min retention interval when given alone. CONCLUSIONS: AR-R17779 increased social recognition memory by activation of alpha(7)-nAChRs, suggesting that alpha(7)-nAChR agonists possess cognitive-enhancing properties.