Different symptomatic improvement pattern revealed by factor analysis between placebo response and response to Esketamine in treatment resistant depression.

AIMS: The aim of this study is to determine whether there is difference in the change in each symptom of depression and in symptomatic improvement pattern between placebo and antidepressant responses. METHODS: Using data from a randomized, double-blind (DB), placebo-controlled trial of esketamine (ESK) in patients with treatment-resistant depression (TRD), we conducted exploratory analyses. To determine differences in the change in each depressive symptom on the MADRS subscale between placebo and antidepressant responses, a two-way factorial analysis was conducted using the amount of change on Day 2 and 28 of treatment. In addition, exploratory and confirmatory factor analyses were conducted on the MADRS subtotal variables on Day 2 and 28 of treatment to determine symptomatic improvement pattern between placebo response and antidepressant responses. RESULTS: We found that as well as MADRS total score, each subscale of MADRS score did not significantly differ between esketamine and placebo at Day 2 and 28. On the other hand, factor analysis revealed that the factor structure of the response was different between esketamine and placebo at the 2nd day. There was no difference in the factor structure between esketamine and placebo in response on Day 28 of treatment. CONCLUSION: Factor analysis revealed different patterns of symptom improvement in the early phase of the intervention between esketamine and placebo. This finding suggests that a data driven approach may provide detailed efficacy information in clinical trials for antidepressants. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02918318. Registered: 28 September 2016.

Effects of hydrophilic/hydrophobic blocks ratio of PEG-b-PLGA on emission intensity and stability of over-1000 nm near-infrared (NIR-II) fluorescence dye-loaded polymeric micellar nanoparticles.

Polymeric micellar nanoparticles (PNPs) composed of an amphiphilic block copolymer formed from hydrophilic and hydrophobic blocks and over-thousand-nanometer (OTN) near-infrared (NIR) fluorescent dye are promising fluorophores for the dynamic imaging of deep tissue. In this study, we examined the effect of the ratio of hydrophilic/hydrophobic blocks of a block copolymer, poly(ethylene glycol) (PEG)-b-poly(lactide-co-glycolide) (PLGA), on the properties of OTN-PNPs encapsulating IR-1061. OTN-PNPs with a higher molecular weight of PLGA cores showed higher emission and stabilities under physiological conditions. The PEG ratio to PLGA in the block copolymer decreased the stability of OTN-PNPs probably due to the invasion of water molecules into the polymer core. The results show that the in vivo stability and fluorescence properties can be tuned by adjusting the chain lengths of block copolymers and estimated using in vitro assays, which evaluates the brightness retention rate of the OTN-PNPs under physiological conditions.

Heat Treatment Effects for Controlling Dye Molecular States in the Hydrophobic Core of Over-1000 nm Near-Infrared (NIR-II) Fluorescent Micellar Nanoparticles.

Organic molecules that emit near-infrared (NIR) fluorescence at wavelengths above 1000 nm, also known as the second NIR (NIR-II) biological window, are expected to be applied to optical in vivo imaging of deep tissues. The study of molecular states of NIR-II dye and its optical properties are important to yield well-controlled fluorescent probes; however, no such study has been conducted yet. Among the two major absorption peaks of the NIR-II dye, IR-1061, the ratio of the shorter wavelength (900 nm) to the longer one (1060 nm) increased with an increase in the dye concentration in tetrahydrofuran, suggesting that the 900 nm peak is due to the dimer formation of IR-1061. Both absorption peaks are also observed when IR-1061 is encapsulated in the hydrophobic (stearyl) core of micellar nanoparticles (MNPs) of a phospholipid-poly(ethylene glycol). The dimers in the MNP cores decreased via dimer dissociation by enhancing the mobility of the hydrophobic stearyl chains by heat treatment of the dye-encapsulating MNPs at 50-70 °C. The MNPs maintained the dissociated IR-1061 monomers in the core after recooling to 25 °C and showed a higher NIR-II fluorescence intensity than those before heat treatment. This concept will provide better protocols for the preparation of NIR-II fluorescent probes with well-controlled fluorescence properties.

Early Improvement of Psychiatric Symptoms with Long-Acting Injectable Antipsychotic Predicts Subsequent Social Functional Remission in Patients with Schizophrenia.

PURPOSE: The aim of this study was to clarify whether early symptomatic improvement in response to a long-acting injectable antipsychotic (LAI) contributes to subsequent social functional remission in patients with schizophrenia using the previous clinical trial data (EudraCT registration number: 2011-004889-15). Associations between other factors and social functional remission were also explored. PATIENTS AND METHODS: We analyzed 428 patients with schizophrenia in which the personal and social performance scale (PSP) and the involvement evaluation questionnaire (IEQ) at the time of the base line were recorded. Social functional remission was defined as participants who scored PSP >70 at the end of 65 weeks. Logistic regression analyses were done to examine associations between social functional remission and clinical and demographic characteristics including early symptomatic response evaluated by Positive and Negative Syndrome Scale (PANSS) at week one. RESULTS: One hundred out of 428 patients showed social functional remission at the end of the observation period. Shorter duration of illness, higher baseline score of supervision evaluated by IEQ and higher baseline PSP were significantly associated with the social functional remission. Improvement of positive subscale of PANSS at one week was significantly associated with later social functional remission when baseline PSP scores were excluded from predictive variables. CONCLUSION: Shorter duration of illness, residual type of schizophrenia, higher baseline score of supervision and higher baseline social functioning were predictors of subsequent social functional remission. Although its effect seems to be limited, early symptomatic improvement could be also was a predictor of social functional remission.

Design of Over-1000 nm Near-Infrared Fluorescent Polymeric Micellar Nanoparticles by Matching the Solubility Parameter of the Core Polymer and Dye.

Polymeric micellar nanoparticles (PNPs) encapsulating over-thousand-nanometer (OTN) near-infrared (NIR) fluorescent dye molecules in block polymers having hydrophobic and hydrophilic chains are promising agents for the dynamic imaging of deep tissue. To achieve OTN-NIR fluorescent PNPs (OTN-PNPs) having high brightness, it is crucial to increase the affinity between the core polymer and dye molecules by matching their polarities; thus, criteria and methods to evaluate the affinity are required. In this study, we used the Hansen solubility parameter (HSP), including the polarity term, to evaluate the affinity between the two substances. HSP values of the OTN-NIR fluorescent dye IR-1061 and four core polymers, poly(lactic-co-glycolic acid) (PLGA), poly(lactic acid) (PLA), poly(ε-caprolactone) (PCL), and polystyrene (PSt), were calculated using the Hansen solubility sphere method and molecular group contribution method, respectively. The relative energy density between IR-1061 and each core polymer calculated using their HSP values revealed that the affinities of PLGA and PLA for IR-1061 are higher than those of PCL and PSt. Therefore, OTN-PNPs composed of PLGA, PLA, and PCL core polymers were prepared and compared. The OTN-PNPs having PLGA and PLA cores could be loaded with larger amounts of IR-1061, had higher photoluminescence intensities, and showed higher stability in phosphate buffered saline than those having PCL cores. Moreover, the OTN-PNPs having PLGA or PLA cores were used for the dynamic imaging of live mice. Thus, matching the solubility parameters of the core polymer and dye molecule is a useful approach for designing high-performance OTN-NIR fluorescent probes.

Designing highly emissive over-1000 nm near-infrared fluorescent dye-loaded polystyrene-based nanoparticles for in vivo deep imaging.

Polystyrene-based nanoparticles (PSt NPs) prepared by emulsion polymerization are promising organic matrices for encapsulating over-thousand-nanometer near-infrared (OTN-NIR) fluorescent dyes, such as thiopyrilium IR-1061, for OTN-NIR dynamic live imaging. Herein, we propose an effective approach to obtain highly emissive OTN-NIR fluorescent PSt NPs (OTN-PSt NPs) in which the polarity of the PSt NPs was adjusted by changing the monomer ratio (styrene to acrylic acid) in the PSt NPs and the dimethyl sulfoxide concentration in the IR-1061 loading process. Moreover, OTN-PSt NPs covalently modified with poly(ethylene glycol) (PEG) (OTN-PSt-PEG NPs) showed high dispersion stability under physiological conditions and minimal cytotoxicity. Notably, the optimized OTN-PSt-PEG NPs were effective in the dynamic live imaging of mice. This methodology is expected to facilitate the design of certain polar thiopyrilium dye-loaded OTN-NIR fluorescent imaging probes with high emissivity.

Effectiveness of golimumab in rheumatoid arthritis patients with inadequate response to first-line biologic therapy: Results from a Japanese post-marketing surveillance study.

OBJECTIVES: To assess the real-world effectiveness of golimumab in Japanese patients with rheumatoid arthritis who had previously received first-line biologic therapy. METHODS: A post-hoc analysis of post-marketing surveillance was performed. The effectiveness of golimumab was assessed in 731 patients with an inadequate response to first-line biologic therapy stratified by their prior biologic agents. Outcome variables included DAS28-CRP, DAS28-ESR, SDAI and CDAI, and medication persistence. Logistic regression analyses were conducted to identify factors associated with the likelihood of achieving a DAS28-CRP response (good/moderate) after 24 weeks of golimumab treatment. RESULTS: Patients demonstrated significant improvement in the clinical signs and symptoms of rheumatoid arthritis at 24 weeks, as indicated by the reduction of DAS28-CRP (Δ0.87), DAS28-ESR (Δ0.85), SDAI (Δ7.32), and CDAI (Δ6.98) scores. This result was consistent across the subgroups stratified by previous biologic therapy. Multivariate analysis failed to identify any factors associated with response to golimumab. CONCLUSION: In the real-world clinical setting, switching to golimumab was effective for Japanese patients with an inadequate response to first-line biologic therapy regardless of the biologic agent, including both TNF and non-TNF inhibitors.

Clinical response among golimumab-treated Japanese patients with rheumatoid arthritis by number of previous biologic therapies: Real-world evidence from post-hoc analysis of post-marketing surveillance data.

OBJECTIVES: To assess the real-world effectiveness of golimumab in Japanese patients with rheumatoid arthritis who had previously received one or more biologic therapies. METHODS: A post-hoc analysis of post-marketing surveillance was performed. The clinical response to golimumab was analyzed in 1216 patients who had previously received one or more biologic agents including non-TNF inhibitors with stratification by the number of previous biologic agents. Logistic regression analyses were conducted to identify factors associated with DAS28-CRP response to golimumab. RESULTS: While treatment persistence is comparable, the response to golimumab declined with an increasing number of previous biologic therapies. When stratified by golimumab dose, patients receiving golimumab at 100 mg had higher disease activity at baseline with an increasing number of previous bDMARDs, but they still achieved comparable disease activity at 24 weeks regardless of how many bDMARDs had been previously used. Univariate and multivariate analyses both identified concomitant oral corticosteroid therapy as a factor negatively associated with the likelihood of achieving a DAS28-CRP response. CONCLUSION: Switching to golimumab was effective regardless of how many biologic agents had been previously used, but the response declined with an increasing number of prior biologic agents. A golimumab dose of 100 mg was also effective for those who previously received three or more bDMARDs.

Correction to: Effect of Golimumab Dose Escalation in Japanese Patients With Rheumatoid Arthritis: Post-Hoc Analysis of Post-Marketing Surveillance Data.

Under Results section, heading: Effectiveness of GLM Stratified by the Time to Dose Escalation, the remission based on values of DAS28, SDAI, and CDAI was published incorrectly. The correct values are: 16.1%, 5.0% and 4.3.

The Effects of Paliperidone Palmitate 1 Month on the Employment Status and Social Functioning of Patients with Schizophrenia.

Objective: We sought to evaluate the effects of a one-month paliperidone palmitate formulation (PP1M) on employment status, social function, symptomatology, and safety and conducted a two-year postmarketing surveillance study of Paliperidone Palmitate 1 Month (PP1M). Methods: Patients diagnosed with schizophrenia participated in the study. Employment status was recorded at baseline and changes were measured at one and two years. Social functioning and symptomatology were assessed using the Social and Occupational Functioning Assessment Scale (SOFAS) and the Clinical Global Impression-Schizophrenia (CGI-SCH). Data on adverse events were also collected. Results: A total of 1,319 patients were enrolled in this investigation, including 1,306 who were evaluable for safety and 1,279 who were evaluable for efficacy. The maintenance rate during the observation period was 49.4 percent. During the observation period, the percentages of patients reporting employment significantly increased: 24.3 percent of patients were employed in some capacity at baseline, 32.5 percent of patients were employed at one year, and 34.6 percent of patients were employed at two years. Significant improvements were observed in both SOFAS and CGI-SCH scores during the observation period. The percentage of patients with socially functional remission also significantly increased. A strong association between the improvement of social function, gender, and monotherapy versus polypharmacy and the improvement of employment status was observed. A total of 29.3 percent of patients experienced at least one adverse event. There were no unexpected findings from long-term treatment and a safety profile, including mortality. Conclusion: PP1M treatment appears to improve not only schizophrenic symptoms but also functional outcomes.

Effect of Golimumab Dose Escalation in Japanese Patients With Rheumatoid Arthritis: Post-Hoc Analysis of Post-Marketing Surveillance Data.

INTRODUCTION: While dose escalation of golimumab has been used for patients with rheumatoid arthritis who demonstrate an inadequate response to the standard dose, its effectiveness has not been fully evaluated. The aim of this study was to assess the clinical outcome observed by dose escalation of golimumab for patients with rheumatoid arthritis in the daily clinical setting. METHODS: A post hoc analysis was performed of data from the 24-week post-marketing surveillance conducted in Japan (n = 5154). A total of 301 patients with moderate or high disease activity at baseline who underwent dose escalation of golimumab were assessed for effectiveness at 24 weeks based on several variables, such as DAS28-CRP, SDAI, and CDAI, as well as for medication persistence through 24 weeks. In addition, the study population was stratified by the time to dose escalation, and effectiveness was likewise evaluated. Logistic regression analysis was performed to identify factors associated with a moderate/good EULAR response to golimumab at 24 weeks. RESULTS: Patients with golimumab dose escalation showed significant improvement of the clinical signs and symptoms of rheumatoid arthritis at 24 weeks, as indicated by reduction of the DAS28-CRP (∆0.89), SDAI (∆8.64), and CDAI (∆8.28) scores. This result was relatively consistent across the subgroups stratified by the timing of dose escalation. According to Kaplan-Meier analysis, 78.1% of the patients continued to receive golimumab at 24 weeks, and this was also similar among the subgroups stratified by the time to dose escalation. Multivariate analysis identified male sex and previous biologic therapy as factors that were significantly associated with the clinical response at 24 weeks. CONCLUSION: In real-world clinical practice, improvement of disease activity was observed after uptitration of golimumab from 50 to 100 mg regardless of the timing. Male patients and biologic-naive patients were more likely to respond to dose escalation of golimumab. TRIAL REGISTRATION: UMIN-CTR, Identifier: UMIN000015895.

Patient and Physician Preferences for Therapy Characteristics for Psoriasis: A Discrete Choice Experiment in Japan.

BACKGROUND: With progress being made in the treatment of psoriasis, a variety of clinical research and treatment options are being pursued. This study used a discrete choice experiment (DCE) to estimate treatment characteristic preferences for both patients and physicians in Japan. Subgroup analysis was also applied in order to examine differences within the range of patients and within the range of physicians. METHODS: The DCE was developed with the input of clinical experts in the treatment of psoriasis to ensure inclusion of the most relevant attributes at appropriate levels in a way that is understandable to both physicians and patients. The study was conducted on parallel samples of Japanese physicians (n = 161) and Japanese psoriasis patients (n = 306) through an online panel. For each sample, a conditional logit statistical model and subgroup analysis were then performed to estimate respondent preferences for treatment attributes. RESULTS: The overall findings are that better treatment efficacy as measured by proportion of patients achieving 90% reduction in the Psoriasis Area and Severity Index score (PASI 90), lower risk of adverse events and the availability of a bio-holiday are important decision factors for both patients and physicians. Low injection frequency is less of a priority for both samples. Also, while both groups demonstrate a preference to receive the treatment injections at a clinic by a healthcare professional rather than self-injection at home, this is more pronounced for the patient sample. The physician sample shows considerably more emphasis on the type of injection, though both samples prefer subcutaneous injections to intravenous injections. IMPLICATIONS: This study reveals the importance of addressing both clinical effectiveness and process factors in systemic, non-topical psoriasis treatments to gain acceptance by both physicians and patients. As well as efficacy (as measured by PASI 90), which remains a consistent priority in treatment, administration and development of new treatments should also consider process factors such as the mode of administration and possibility for a bio-holiday.

Psychiatric Comorbidities in Adult Attention-deficit/Hyperactivity Disorder: Prevalence and Patterns in the Routine Clinical Setting.

Objective: While attention-deficit/hyperactivity disorder (ADHD) is associated with a high prevalence of comorbid psychiatric disorders in every age group, the etiology and epidemiology of comorbid disorders are less clear in adult patients with ADHD. In this surveillance study, investigators sought to assess the prevalence of comorbid psychiatric disorders, evaluate relationships between comorbid psychiatric disorders and demographic characteristics, and explore the patterns of these comorbid disorders and their relationships with ADHD subtypes. Methods: Data obtained from postmarketing surveillance of methylphenidate extended-release tablets for adult ADHD were used to evaluate the prevalence of psychiatric comorbidities. Age, sex, age at diagnosis, number of comorbidities, and severity of ADHD symptoms were used as external variables for exploratory analyses. Nonmetric multidimensional scaling (NMDS) was performed to explore correlations among comorbidities and ADHD subtypes and extract major dimensions underlying variations in the pattern of comorbid disorders. Results: Data were collected from 575 patients with adult ADHD, including 301 (52.35%) with at least one concurrent psychiatric disorder. Analysis by NMDS demonstrated that different patterns of psychiatric comorbidities were related to the subtypes of ADHD. Conclusions: Psychiatric comorbidities have a high prevalence in patients with adult ADHD. Understanding these patterns could provide useful information in the diagnosis of adult ADHD and future investigations of its etiology.

Shared Decision-Making in Patients With Prostate Cancer in Japan: Patient Preferences Versus Physician Perceptions.

This article adds the Japanese perspective to our knowledge of shared decision-making (SDM) preferences by surveying patients with prostate cancer (PCA) and physicians in Japan. In 2015, 103 Japanese patients with PCA were asked about their SDM preferences by using an Internet-based 5-point-scale questionnaire. Concurrently, 127 Japanese physicians were surveyed regarding their perceptions of patient preferences on SDM. Drivers of preferences and perceptions were analyzed using univariable ordinal logistic regression and graphing the fitted response probabilities. Although 41% of both patients and physicians expressed and expected a desire for active involvement in treatment decisions (a higher rate than in a similar study for the United States in 2001), almost half the Japanese patients preferred SDM, but only 33% of physicians assumed this was their choice. That is, 29% of Japanese physicians underestimated patients' preference for involvement in making treatment decisions. Patients with lower health-related quality of life (as measured by the Functional Assessment of Cancer Therapy-Prostate [FACT-P]) expressed a stronger preference for SDM. The study shows that the worse the medical situation, the more patients with PCA prefer to be involved in the treatment decision, yet physicians tend to underestimate the preferences of their patients. Perhaps in contrast to common assumptions, Japanese patients are as interested in being involved in decision making as are patients in the United States.

Patient Preferences and Urologist Judgments on Prostate Cancer Therapy in Japan.

The purpose of the present study is to investigate the concordance of treatment preferences between patients and physicians in prostate cancer (PCa) in Japan. An internet-based discrete choice experiment was conducted. Patients and physicians were asked to select their preferred treatment from a pair of hypothetical treatments consisting of four attributes: quality of life (QOL), treatment effectiveness, side effects, and accessibility of treatment. The data were analyzed using a conditional logistic regression model to calculate coefficients and the relative importance (RI) of each attribute. A total of 103 PCa patients and 127 physicians responded. The study looked at 37 patients considered as advanced PCa and 66 who were non-advanced PCa. All of the physicians were urologists. Advanced PCa patients ranked the attributes as follows: treatment effectiveness (RI: 32%), accessibility of treatment (RI: 26%), QOL (RI: 23%), and side effects (RI: 19%). For physicians, the RI ranking was the same as for advanced PCa patients; treatment effectiveness (RI: 29%), accessibility of treatment (RI: 27%), QOL (RI: 26%), and side effects (RI: 18%). For non-advanced PCa patients, accessibility of treatment ranked the highest RI (27%) and treatment effectiveness ranked as the lowest RI (14%). Our study suggests that the ranking of the attributes was consistent between advanced PCa patients and physicians. The most influential attribute was treatment effectiveness. Treatment preferences also vary by disease stage.

Safety, Effectiveness, and Treatment Persistence of Golimumab in Elderly Patients with Rheumatoid Arthritis in Real-World Clinical Practice in Japan.

INTRODUCTION: Golimumab has been proven as an effective treatment for rheumatoid arthritis in clinical trials. However, there is a scarcity of data regarding its use in elderly patients in a real-world setting. This study aims to evaluate the safety, effectiveness, and treatment persistence of golimumab in elderly Japanese patients (≥ 75 years) with rheumatoid arthritis. METHODS: This study was a post hoc analysis of post-marketing surveillance data on 5137 Japanese patients with active rheumatoid arthritis who received golimumab for 24 weeks. The study population was divided into two age groups (younger: < 75 years and elderly: ≥ 75 years), and the safety, effectiveness, and treatment persistence of golimumab were assessed. Also, the reasons for discontinuing golimumab treatment were analyzed by multi-logistic regression. RESULTS: During golimumab treatment over 24 weeks, younger and elderly groups exhibited comparable improvement of disease activity as measured by EULAR response criteria with similar overall rates of adverse events. However, the survival curve of golimumab for elderly patients was significantly different from that for younger patients due largely to the discontinuation at 4 weeks. The most common reason for discontinuation in elderly patients was patient choice, while it was disease progression in younger patients. Analysis of elderly patients who discontinued treatment by their own decision identified EULAR good response as a factor associated with continuation of golimumab treatment whereas no predictive factor associated with discontinuation was identified. CONCLUSIONS: The safety and effectiveness of golimumab treatment in elderly Japanese patients aged 75 years or older were comparable to those in younger patients in real-world clinical practice. Analysis of the survival curves suggested that continuous use of golimumab might further improve clinical benefit of golimumab in elderly patients, underpinning the importance of effective communication between physicians and elderly patients based on the treat-to-target strategy. FUNDING: Janssen Pharmaceutical K.K. and Mitsubishi Tanabe Pharma Corporation.

Real-World Treatment Patterns for Golimumab and Concomitant Medications in Japanese Rheumatoid Arthritis Patients.

INTRODUCTION: The aim of this study was to investigate real-world treatment patterns for use of golimumab and concomitant medications in Japanese patients with rheumatoid arthritis. METHODS: This study was a post hoc retrospective analysis from post-marketing surveillance data on 2350 Japanese patients with moderate/severe rheumatoid arthritis who received golimumab for 24 weeks. The study population was divided based on initiation treatment or dose adjustment patterns with golimumab, methotrexate, or oral glucocorticoids. RESULTS: Logistic regression analysis revealed that the baseline factors associated with administration of golimumab (100 mg) were higher body weight, failure of prior biological therapy (bio-failure), no previous methotrexate use, and respiratory disease, while previous methotrexate use and absence of renal impairment or respiratory disease were associated with concomitant methotrexate therapy, and previous glucocorticoid use was associated with concomitant glucocorticoid therapy. The following associations were identified with regard to dose adjustment during treatment: bio-failure, no previous methotrexate use, previous csDMARDs use, presence of respiratory disease, allergy history, and higher CRP for golimumab dose escalation; shorter disease duration, previous GC, and no previous methotrexate use for methotrexate dose escalation; no prior biological therapy and renal impairment for methotrexate dose reduction; no previous GC use for glucocorticoid dose escalation; and absence of Steinbrocker's stage II/III/IV, absence of Steinbrocker's class II, no bio-failure, and no previous csDMARDs use for glucocorticoid dose reduction. CONCLUSIONS: This study revealed that various baseline factors were associated with initiation of treatment and dose adjustment of golimumab, methotrexate, or oral glucocorticoids, reflecting both the treatment strategies of physicians for improving RA symptoms and/or reducing adverse events. FUNDING: Janssen Pharmaceutical K.K. and Mitsubishi Tanabe Pharma Corporation.

Long-term effect of galantamine on cognitive function in patients with Alzheimer's disease versus a simulated disease trajectory: an observational study in the clinical setting.

BACKGROUND: Long-term maintenance of cognitive function is an important goal of treatment for Alzheimer's disease (AD), but evidence about the long-term efficacy of cholinesterase inhibitors is sparse. To evaluate the long-term efficacy and safety of galantamine for AD in routine clinical practice, we conducted a 72-week post-marketing surveillance study. The effect of galantamine on cognitive function was estimated in comparison with a simulated disease trajectory. PATIENTS AND METHODS: Patients with mild-to-moderate AD received flexible dosing of galantamine (16-24 mg/day) during this study. Cognitive function was assessed by the mini mental state examination (MMSE) and the clinical status was determined by the Clinical Global Impression-Improvement (CGI-I). Changes of the MMSE score without treatment were estimated in each patient using Mendiondo's model. Generalized linear mixed model analysis was performed to compare the simulated MMSE scores with the actual scores. RESULTS: Of the 661 patients who were enrolled, 642 were evaluable for safety and 554 were assessed for efficacy. The discontinuation rate was 46.73%. Cognitive decline indicated by the mean change of actual MMSE scores was significantly smaller than the simulated decline. Individual analysis demonstrated that >70% of patients had better actual MMSE scores than their simulated scores. Significant improvement of CGI-I was also observed during the observation period. Adverse events occurred in 28.5% of patients and were serious in 8.41%. The reported events generally corresponded with the safety profile of galantamine in previous studies. CONCLUSION: These findings support the long-term efficacy of galantamine for maintaining cognitive function and the clinical state in AD patients. Treatment with galantamine was generally safe. Importantly, this study revealed that galantamine improved cognitive function above the predicted level in >70% of the patients.

Self-efficacy, pros, and cons as variables associated with adjacent stages of change for regular exercise in Japanese college students.

This study examined self-efficacy (confidence to exercise), pros (exercise's advantages), and cons (exercise's disadvantages) as variables associated across the transtheoretical model's six stages of change in 403 Japanese college students. A series of logistic regression analyses were conducted. Results showed that higher pros and lower cons were associated with being in contemplation compared to precontemplation. Lower cons were associated with being in preparation compared to contemplation. Higher self-efficacy was associated with being in action compared to preparation as well as being in maintenance compared to action. Lower cons were associated with being in termination compared to maintenance.

Use of Fentanyl Patch for Treatment of Moderate-to-severe Chronic Noncancer Pain: Postmarketing Surveillance of Medical Practice in Japan Using a Risk Minimization Action Plan.

OBJECTIVE: The purpose of this study was to discuss the safety, treatment profile, and clinical effectiveness of 12-month treatment with fentanyl patch (FP), a strong opioid, in medical practice in Japan under the risk minimization action plan (RMAP). METHODS: Patients with moderate-to-severe chronic noncancer pain who had switched to FP from another opioid were registered to take this survey to assess adverse drug reactions (ADRs), therapeutic effect, and pain intensity for up to 12 months. RESULTS: A total of 517 patients were enrolled, and 499 patients (male, 50.9%; mean [SD] age, 63.0 [15.4] years) were included in the safety population. During the 12-month observation period, an ADR occurred in 262 patients (52.5%); most frequent ADRs included nausea (24.2%), somnolence (22.4%), constipation (18.2%), vomiting (9%), and dizziness (4.6%). The prespecified priority survey items, including respiratory depression, drug dependence, and drug withdrawal syndrome, occurred in 2 (both nonserious), 3 (all serious), and 9 (all serious) patients, respectively. In 418 patients from the efficacy population, the response rate was 77.3%, the rate of achievement of the therapeutic goal was 64.5%, and the visual analog scale (VAS) scores for pain severity decreased by 22.3 (26.9) mm. CONCLUSION: Our results identified a reasonable risk-benefit profile for the management of moderate-to-severe chronic noncancer pain in patients previously treated with opioids under long-term treatment with FP under the RMAP. Respiratory depression, drug dependency, and drug withdrawal were rarely observed even under the RMAP in Japan.