Effect of a patient-support program on once-daily teriparatide adherence and persistence in the Japan Fracture Observational Study (JFOS).

Japanese patients with osteoporosis prescribed once-daily teriparatide for 24 months could enroll in a patient-support program designed to aid adherence and persistence. Patients enrolled in the program had higher adherence and persistence rates than those who did not enroll, highlighting the value of patient-support programs for improving adherence and persistence. OBJECTIVE: To assess the effect of a patient-support program on once-daily teriparatide adherence and persistence of patients who did and did not enroll. METHODS: In the 24-month Japan Fracture Observational Study, patients with osteoporosis prescribed teriparatide 20 µg/day (N = 1996) could freely enroll in a patient-support program (call center support, monthly calendar, certificates of recognition). Outcome measures were medication adherence (investigator assessed) and persistence (first date of teriparatide use to last date of use or study end). Multivariate logistic models were applied for adherence, and Kaplan-Meier survival curve for persistence. RESULTS: Overall, mean ± standard deviation (SD) age was 76.9 ± 7.9 years, and the proportion of female patients was 90.1%. Program enrollment status was 39.6% yes (n = 790), 22.9% no (n = 458), and 37.5% unknown (n = 748). In the analysis sample (1248 patients), adherence (> 75%) to teriparatide was more likely for patients enrolled in the support program (54.2 vs. 48.3%; adjusted odds ratio 1.44 [95% confidence intervals 1.04-2.00], p = 0.030). Good to very good (> 75%) adherence was also associated with smoking (negative association) and previous osteoporosis therapy (marginal positive association). Persistence rates were greater for patients enrolled in the support program than not enrolled (12 months 77.2 vs. 69.6%; 24 months 63.2 vs. 54.8%). CONCLUSIONS: Once-daily teriparatide adherence and persistence rates were higher among patients who enrolled in a patient-support program than among those who did not, highlighting the value of patient-support programs for improving adherence and persistence.

Effectiveness and safety of oral olanzapine treatment transitioned from rapid-acting intramuscular olanzapine for agitation associated with schizophrenia.

OBJECTIVE: To assess the effectiveness and safety of oral olanzapine treatment transitioned from rapid-acting intramuscular olanzapine (RAIM) in patients with acute agitation associated with schizophrenia in a real-world clinical setting. METHODS: The postmarketing surveillance study with a 3-day observational period after the last RAIM administration was conducted (original study). Following this, an extended study was added for patients who received oral olanzapine after RAIM administration during the original study period, in order to additionally observe them for 7 days after initial RAIM administration. Effectiveness and safety from initial RAIM administration were evaluated using the Positive and Negative Syndrome Scale-Excited Component score and treatment-emergent adverse events (TEAEs), respectively. RESULTS: The effectiveness and safety analysis set included a total of 521 and 522 patients, respectively. A majority of patients received 10 mg of RAIM (475/522 patients, 91.0%). The mean ± SD total Positive and Negative Syndrome Scale-Excited Component score was 23.6±6.2 (n=318) at baseline (before initial RAIM administration), 17.4±6.8 (n=280) at 2 hours after initial administration, 16.2±6.8 (n=246) 2 days after final administration, 14.9±6.2 (n=248) 3 days after final administration, 13.8±5.9 (n=242) 4 days after final administration, 13.2±5.8 (n=221) 7 days after initial administration, and 13.4±6.2 (n=351) at final observation (with the last observation carried forward approach), showing that reduction in agitation seen with RAIM was sustained with oral dose of olanzapine. The most common TEAEs were dyslalia and somnolence (each event occurred in four patients), and abnormal hepatic function and constipation (occurred in three patients). One serious adverse event of sudden cardiac death occurred after transitioned to oral olanzapine with many other antipsychotic drugs. CONCLUSION: In the treatment of acute agitation associated with schizophrenia, RAIM could be generally transitioned to oral olanzapine without exacerbating adverse events or losing treatment effect.

Safety and effectiveness of rapid-acting intra-muscular olanzapine for agitation associated with schizophrenia - Japan postmarketing surveillance study.

OBJECTIVE: The objective of this study was to evaluate the safety and effectiveness of rapid-acting intramuscular (IM) olanzapine in the treatment of acute agitation associated with schizophrenia in real-world clinical settings in Japan. METHODS: In this multicenter, postmarketing surveillance (PMS) study, patients with acute agitation associated with schizophrenia were treated with IM olanzapine daily in a daily clinical setting. The observational period ranged from 1 to 7 days, including the day of initial administration. Safety was assessed by reporting treatment-emergent adverse events (TEAEs) and adverse drug reactions (ADRs). The Positive and Negative Syndrome Scale - Excited Component (PANSS-EC) score was used to evaluate effectiveness at baseline and at 2 hours (after each administration), 2 days, and 3 days (end of the observational period) from the last administration of the IM olanzapine injection. RESULTS: The safety analysis set included 999 patients, and the initial dose of 10 mg was administered to 955 patients. TEAEs were reported in 28 patients (36 events), the most common of which were dyslalia (5 patients), akathisia and somno lence (4 patients each), hepatic function abnormal (3 patients), and constipation and dehydration (2 patients each). One serious adverse event of akathisia occurred during the observation period. The PANSS-EC score (mean ± standard deviation) was 23.3±6.4 (n=625) at baseline, 16.9±7.0 (n=522) at 2 hours after initial injection, and 14.9±6.5 (n=650) at the last observation carried forward. CONCLUSION: The results of this Japanese PMS study demonstrated that IM olanzapine is safe and has a favorable effectiveness profile in the treatment of schizophrenia patients with acute agitation.

Real-world effectiveness of daily teriparatide in Japanese patients with osteoporosis at high risk for fracture: final results from the 24-month Japan Fracture Observational Study (JFOS).

OBJECTIVE: The Japan Fracture Observational Study (JFOS), a prospective observational study, investigated the real-world effectiveness of daily teriparatide to reduce clinical fracture risk in osteoporotic patients. METHODS: In routine clinical practice, Japanese patients initiated on teriparatide 20 µg/day by subcutaneous injection were enrolled. The primary end-point was the rate of clinical fractures at 6-month intervals over 24 months. Bone mineral density (BMD), procollagen type 1 aminoterminal propeptide (P1NP), back pain, and health-related quality-of-life (HRQoL) information was collected. RESULTS: Of 1,996 patients at baseline, 90.1% were female, and mean age was 76.9 years. Teriparatide persistence at 12 and 24 months was 68.0% and 51.6%, respectively. Compared to the first 6-month treatment interval, the odds ratio of fractures decreased by 56.4% during 6-12 months, 51.6% during 12-18 months, and 58.8% during 18-24 months (all p < .01). After 24 months, BMD increased by 17.2% (lumbar spine) and 7.9% (total hip). After 6 months, P1NP levels increased by 259.3%. A reduction in back pain (100 mm visual analog scale) of 16.1 mm at 3 months was maintained through 24 months. HRQoL (pain, daily living activities, general health) improved by ≥10% at each post-baseline time point. Of 279 (14.6%) patients with ≥1 adverse event (AE), 71 (3.7%) experienced ≥1 drug-related AE (investigator assessed), including nausea (0.7%), dizziness (0.4%), and decreased appetite (0.3%). Osteosarcoma was not reported; there were no new safety signals. CONCLUSIONS: JFOS demonstrated effectiveness of teriparatide 20 µg/day to reduce the risk of clinical fractures in Japanese patients in a real-world setting.

Efficacy and safety of teriparatide in bisphosphonate-pretreated and treatment-naive patients with osteoporosis at high risk of fracture: Post hoc analysis of a prospective observational study.

BACKGROUND: Teriparatide is the first anabolic agent shown to reduce the risk of fractures in patients with osteoporosis. In Japan, teriparatide is prescribed to treat patients at high risk of fracture. Given that bisphosphonates are commonly used prior to teriparatide as treatment for osteoporosis, information on the effectiveness and safety of teriparatide with or without previous bisphosphonate treatment is helpful for physicians in clinical practice. This study aims to report the effectiveness and safety of teriparatide in treatment-naive and bisphosphonate-pretreated patients in Japan as real-world evidence. METHODS: A post hoc analysis of a postmarketing surveillance study was conducted in Japanese patients with osteoporosis at high risk of fracture who received 24-month treatment of daily teriparatide. Changes in bone turnover biomarkers and bone mineral density and incidence of new fractures were analyzed in treatment-naive as well as bisphosphonate-pretreated patients. RESULTS: The analysis included 1433 patients (treatment-naive, n = 659; bisphosphonate-pretreated, n = 774). Bone mineral density increased significantly from baseline at 24 months in both treatment-naive (lumbar spine, 13.45%; femoral neck, 5.16%; total hip, 4.46%) and bisphosphonate-pretreated (lumbar spine, 11.20%; femoral neck, 2.22%; total hip, 0.67%) patients. The incidence rates of new vertebral and nonvertebral fractures at 24 months were 1.69% and 3.37%, respectively, in treatment-naive patients and 3.60% and 5.56%, respectively, in bisphosphonate-pretreated patients. The incidence of adverse drug reactions was 6% in treatment-naive patients and 10% in bisphosphonate-pretreated patients. The most common adverse drug reaction in treatment-naive and bisphosphonate-pretreated patients was nausea (0.91%) and hyperuricaemia (1.81%), respectively. CONCLUSIONS: In this post hoc analysis, no new safety concerns and similar effectiveness of teriparatide were observed in Japanese patients with osteoporosis at high risk of fracture, regardless of their previous treatment status with bisphosphonates.

Safety and effectiveness of daily teriparatide for osteoporosis in patients with severe stages of chronic kidney disease: post hoc analysis of a postmarketing observational study.

Teriparatide (recombinant 1-34 N-terminal sequence of human parathyroid hormone) for the treatment of osteoporosis should be prescribed with caution in patients with severe stages of chronic kidney disease (CKD). However, in clinical settings, physicians and surgeons who treat such patients have few available options. We sought to further explore the safety and effectiveness of teriparatide for the treatment of osteoporosis in Japanese patients with severe stages of CKD. This was a post hoc analysis of a postmarketing surveillance study that included patients with osteoporosis at high risk of fracture and stage 4 or 5 CKD. Patients received subcutaneous teriparatide 20 µg daily for up to 24 months. Safety profiles were assessed by physician-reported adverse drug reactions (ADRs). Effectiveness was assessed by measuring bone formation (via procollagen type 1 N-terminal propeptide [P1NP]), bone mineral density (BMD), and the incidence of clinical vertebral or nonvertebral fragility fractures. A total of 33 patients with severe stages of CKD (stage 4, n=30; stage 5, n=3) were included. All patients were female, and 81.8% had a history of previous fracture. No serious ADRs were recorded; a total of 4 ADRs were recorded for 4 of 33 patients. Increases in BMD and P1NP levels were observed both overall and in most individual patients. New fractures occurred in 1 patient with stage 5 CKD, but not in patients with stage 4 CKD. In this post hoc analysis conducted in Japan, teriparatide appeared to be effective for the treatment of osteoporosis in elderly female patients with severe stages of CKD, and no new safety concerns were observed.

Prenatal alcohol exposure alters synaptic activity of adult hippocampal dentate granule cells under conditions of enriched environment.

Prenatal alcohol exposure (PAE) results in fetal alcohol spectrum disorder (FASD), which is characterized by a wide range of cognitive and behavioral deficits that may be linked to impaired hippocampal function and adult neurogenesis. Preclinical studies in mouse models of FASD indicate that PAE markedly attenuates enrichment-mediated increases in the number of adult-generated hippocampal dentate granule cells (aDGCs), but whether synaptic activity is also affected has not been studied. Here, we utilized retroviral birth-dating coupled with whole cell patch electrophysiological recordings to assess the effects of PAE on enrichment-mediated changes in excitatory and inhibitory synaptic activity as a function of DGC age. We found that exposure to an enriched environment (EE) had no effect on baseline synaptic activity of 4- or 8-week-old aDGCs from control mice, but significantly enhanced the excitatory/inhibitory ratio of synaptic activity in 8-week-old aDGCs from PAE mice. In contrast, exposure to EE significantly enhanced the excitatory/inhibitory ratio of synaptic activity in older pre-existing DGCs situated in the outer dentate granule cell layer (i.e., those generated during embryonic development; dDGCs) in control mice, an effect that was blunted in PAE mice. These findings indicate distinct electrophysiological responses of hippocampal DGCs to behavioral challenge based on cellular ontogenetic age, and suggest that PAE disrupts EE-mediated changes in overall hippocampal network activity. These findings may have implications for future therapeutic targeting of hippocampal dentate circuitry in clinical FASD. © 2016 Wiley Periodicals, Inc.

Fate analysis of adult hippocampal progenitors in a murine model of fetal alcohol spectrum disorder (FASD).

Prenatal alcohol exposure can lead to fetal alcohol spectrum disorder (FASD) and associated behavioral impairments that may be linked to disruptions in adult hippocampal neurogenesis. Social and physical enrichment has been proposed as a potential therapeutic approach toward reversing behavioral deficits associated with FASD and is also a potent stimulator of adult hippocampal neurogenesis. In the present study, we utilized a genetic fate mapping approach in nestin-CreER(T2)/YFP bitransgenic mice to identify the stage-specific impact of prenatal alcohol exposure on the stepwise maturation of adult hippocampal progenitors. Using a limited alcohol access "drinking-in-the-dark" model of FASD, we confirm previous findings that moderate prenatal alcohol exposure has no effect on adult neurogenesis under standard housing conditions, but abolishes the neurogenic response to enriched environment (EE). Furthermore, we demonstrate that this effect is primarily due to failed EE-mediated survival of postmitotic neurons. Finally, we demonstrate that the neurogenic deficit is associated with impaired spatial pattern recognition, as demonstrated by delayed learning of FASD-EE mice in an A-B contextual discrimination task. These results identify a potential maturational stage-specific mechanism(s) underlying impaired neurogenic function in a preclinical model of FASD, and provide a basis for testing regulatory pathways in this model through conditional and inducible manipulation of gene expression in the adult hippocampal progenitor population.