Safety and effectiveness of risedronate in Paget's disease of bone: postmarketing surveillance study in Japan.

INTRODUCTION: We conducted an all-case postmarketing surveillance study between 2008 and 2017 to evaluate the safety and effectiveness of risedronate for Paget's disease of bone (PDB) in Japan. MATERIAL AND METHODS: This study registered all patients who received once-daily risedronate 17.5 mg for the treatment of PDB and collected data over a 48-week follow-up period per treatment cycle for each patient. RESULTS: The safety analysis set included 184 patients (mean age, 63.7 years), 81 (44.0%) of whom previously received a bisphosphonate. Of them, 41 (22.3%) experienced 72 adverse drug reactions (ADRs), and 8 (4.3%) experienced 14 serious ADRs. Common ADRs included gastrointestinal disorders (20 patients, 10.9%) and hypocalcemia (6 patients, 3.3%). The effectiveness analysis set included 182 patients, 124 of whom completed only one treatment cycle and 58 of whom completed multiple treatment cycles. The proportions of patients who normalized serum alkaline phosphatase (ALP) concentration were 71.1% (113/159 patients) and 67.3% (33/49 patients) for the first and second treatment cycles, respectively. The relapse rate according to ALP levels after the end of treatment for the first cycle was 5.0% (95% confidence interval [CI] = 2.1-11.5) at 24 weeks and 12.9% (95% CI = 7.5-21.7) at 40 weeks. Regarding pain relief, the achievement rates were 70.0% (49/70 patients) and 30.8% (4/13 patients) for the first and second treatment cycles, respectively. CONCLUSION: To conclude, risedronate 17.5 mg/day is safe and effective for treating patients with PDB in daily practice.

Impact of elobixibat on serum and fecal bile acid levels and constipation symptoms in patients with chronic constipation.

BACKGROUND AND AIM: Elobixibat is a locally acting inhibitor of the ileal bile acid transporter. We compared bile acid metabolism between healthy subjects and patients with chronic constipation and assessed changes in the bile acid profile after elobixibat administration in the latter group. METHODS: Healthy subjects (n = 10) and patients with chronic constipation (n = 19) were assessed as inpatients for 7 days, during which they received meals containing ~60 g/day of fat. Patients with chronic constipation remained as inpatients for a further 7 days for once-daily elobixibat administration. Assessments included concentrations of fecal and serum bile acids, serum 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19, and bowel movements and constipation symptoms. RESULTS: Fecal total and primary bile acids were significantly lower in patients with chronic constipation versus healthy subjects. Serum C4 and fibroblast growth factor 19 levels were comparable between groups. Elobixibat treatment increased fecal total and primary bile acids and decreased levels of fecal lithocholic acid and serum total as well as secondary bile acids in patients with chronic constipation. Bowel movements and other constipation-related symptoms were also improved by elobixibat to levels almost comparable with those of healthy subjects. CONCLUSIONS: Despite comparable C4 levels, patients with chronic constipation demonstrated decreased levels of fecal bile acids versus healthy subjects. Elobixibat treatment increased fecal bile acid excretion and reduced serum bile acid concentrations. The improvement of constipation after elobixibat treatment was associated with increased total bile acids, particularly primary bile acids.

Efficacy, long-term safety, and impact on quality of life of elobixibat in more severe constipation: Post hoc analyses of two phase 3 trials in Japan.

BACKGROUND: In two phase 3 trials, elobixibat, a locally acting ileal bile acid transporter inhibitor, resolved constipation and was well tolerated in Japanese patients with chronic constipation. We analyzed the efficacy, safety, and impact on quality of life (QOL) of elobixibat in patients with symptomatically more severe constipation in the two phase 3 trials. METHODS: This post hoc analysis of elobixibat treatment outcomes included data from a 2-week, randomized, placebo-controlled, phase 3 trial (10 mg/d), and a 52-week, open-label trial (5-15 mg/d) in subgroups with severe constipation defined as ≤2 spontaneous bowel movements (SBMs) and ≤3 Bristol Stool Form Scale score during the second week of the 2-week run-in period. We also analyzed the rates of abdominal pain, diarrhea, and QOL in subgroups according to sex, presence of constipation-predominant irritable bowel syndrome (IBS-C) and side effects. KEY RESULTS: In patients with severe constipation, there was significant improvement in the 10 mg elobixibat group compared to the placebo group in change in SBMs from baseline at week 1 (primary endpoint) of the 2-week trial. The differences between groups were reduced in patients with more severe constipation. Increasing the dose to 15 mg was effective for more severe constipation in improving the number of SBMs per week in the 52-week trial. Overall, elobixibat was well tolerated and improved QOL scores, irrespective of gender, presence of IBS-C or side effects. CONCLUSIONS & INFERENCES: Elobixibat is effective for symptomatically severe constipation, is well tolerated and improves QOL, irrespective of potentially confounding patient characteristics.

Pharmacological characterization of repeated corticosterone injection-induced depression model in rats.

Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in patients with psychotic major depression (PMD), and a higher rate of cortisol hypersecretion is observed in PMD than in nonpsychotic patients. Approximately 19% of patients who meet the criteria for major depressive disorder (MDD) have psychotic features. Accumulated studies have indicated that repeated corticosterone (CORT) injections induce depressive behavioral and neurochemical manifestations in rodents. However, the pharmacological characterization of this model has not been fully established. In the present study, we investigated the pharmacological characteristics of this model. Rats received CORT injections (20 mg/kg, subcutaneously), once per day for 21 consecutive days prior to a behavioral test. The rats were then tested for depressive behavior using a forced swimming test. The repeated CORT injections increased the immobility time in the forced swimming test, indicating an increase in depressive-like behavior. An acute treatment with a glucocorticoid receptor antagonist, mifepristone, counteracted the depressive-like behavior. In contrast, an acute treatment with a selective serotonin reuptake inhibitor (SSRI), fluvoxamine, and a tricyclic antidepressant (TCA), imipramine, did not have any effect on this condition, while a combination of fluvoxamine and risperidone exerted an antidepressant-like effect. This observation is of interest in the light of the clinical findings that a combination of antidepressants and antipsychotics, but not SSRIs and TCAs, is effective for the treatment of patients with PMD. Based on previous findings and the present results, this model could be used as an animal model of PMD and may be useful for evaluating the antidepressant-like potential of compounds targeting the HPA axis.

Depolarizing stimuli cause persistent and selective loss of orexin in rat hypothalamic slice culture.

A hypothalamic neuropeptide orexin (hypocretin) is a critical regulator of physiological processes including sleep/wakefulness and feeding. Using organotypic slice culture of rat hypothalamus, we found that exposure to elevated extracellular concentration of K(+) (+10-30 mM) for 24-72h led to a substantial decrease in the number of neurons immunoreactive for orexin and a co-existing neuropeptide dynorphin-A. In contrast, the same treatment affected neither the number of melanin-concentrating hormone-immunoreactive neurons nor the number of total neurons. A substantial decrease of orexin-immunoreactive neurons was also induced by 72h treatment with 1-10 microM veratridine, a Na(+) channel activator. The effect of elevated K(+) was only partially reversible, and that of veratridine was virtually irreversible, although the decrease in orexin immunoreactivity was not associated with signs of cell damage assessed by propidium iodide uptake and Hoechst 33342 nuclear staining. In addition, the level of preproorexin mRNA did not decrease during treatment with elevated K(+) or veratridine. After treatment with elevated K(+) and veratridine, c-Fos immunoreactivity appeared in orexin-immunoreactive neurons but not in melanin-concentrating hormone-immunoreactive neurons, suggesting selective excitation of orexin neurons. However, the amount of orexin released extracellularly was paradoxically decreased by treatment with elevated K(+) and veratridine. Overall, these characteristics of orexin neurons may be taken into consideration to understand the behaviors of these neurons under physiological and pathophysiological conditions.

Effects of agents targeting glutamatergic systems on marble-burying behavior.

Accumulating evidence has implicated glutamatergic systems in psychiatric disorders. Abnormalities in glutamatergic systems have consistently been identified in obsessive-compulsive disorder (OCD). Marble-burying behavior has been described in literature as a potentially useful measure for modeling OCD in mice. However, involvement of glutamatergic systems in marble-burying behavior has largely remained unexplored. Here, the effects of an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiator, CX546, and an NR2B subunit-containing N-methyl-D-aspartate (NMDA) receptor antagonist, Ro25-6981, were examined using a marble-burying test. Treatment with highest dose (30.0mg/kg) of CX546 significantly inhibited the marble-burying behavior. Moreover, treatment with Ro25-6981 also significantly reduced the marble-burying behavior. In contrast, both drugs did not affect locomotor activity in mice. The present results suggest that glutamatergic systems might be related to marble-burying behavior. Furthermore, agents targeting glutamateric systems such as an AMPA receptor potentiator and an NR2B receptor antagonist, may be useful in treating OCD.