10-mg Group Research Articles

Comparison of a split-dose bowel preparation with 2 liters of polyethylene glycol plus ascorbic acid and 1 liter of polyethylene glycol plus ascorbic acid and bisacodyl before colonoscopy

Recently, a low-volume polyethylene glycol formulation containing ascorbic acid (PEG-Asc) has proven as safe and effective as traditional 4-L PEG solutions for colonoscopy preparation. However, currently available aqueous purgative formulations are poorly tolerated. The aim of this study was to compare a split-dose 2-L PEG-Asc formulation and a 1-L PEG-Asc formulation with bisacodyl (10 mg) to determine the quality of bowel cleansing and patient tolerability. A single-center, randomized, observer-blinded study was performed between May 2015 and September 2015. Two hundred outpatients referred for colonoscopy were prospectively enrolled and assigned to either the split-dose 2-L PEG-Asc group or the 1-L PEG-Asc with bisacodyl 10-mg group. The Boston Bowel Preparation Scale (BBPS) and Aronchick Bowel Preparation Scale (ABPS) were used to evaluate bowel cleansing. The tolerability of the regimens and satisfaction of patients was determined based on a questionnaire. Two hundred patients received either 2-L PEG-Asc or 1-L PEG-Asc with bisacodyl. Regarding colon cleansing outcome (BBPS and ABPS), the 1-L PEG-Asc with bisacodyl group showed similar but non-inferior results compared with the 2-L PEG-Asc group on both BBPS (6.92 ± 1.63 vs 6.57 ± 1.37; P= .103) and ABPS (96% vs 95%; P= 1.000) scales. Tolerability was similar for both 1-L PEG-Asc with bisacodyl and 2-L PEG-Asc. 1-L PEG-Asc is a suitable alternative to low-volume bowel preparation for colonoscopy. Our study showed that the 1-L PEG-Asc plus bisacodyl preparation has comparable tolerability and results in adequate colon cleansing. Bowel preparation with bisacodyl and 1-L PEG-Asc is a suitable alternative to low-volume bowel preparation for colonoscopy. (Clinical trial registration number: NCT02980562.).

Safety and Tolerability of Neladenoson Bialanate, a Novel Oral Partial Adenosine A1 Receptor Agonist, in Patients With Chronic Heart Failure.

We studied safety and tolerability of neladenoson bialanate, a novel oral selective partial adenosine A1 receptor agonist that maintains the cardioprotective effects of adenosine without the undesired side effects of a full agonist, in 2 pilot studies in patients with heart failure with reduced ejection fraction (HFrEF). The β-blocker interaction study was a single-blind, placebo-controlled study on the effects of a 30-mg single dose of neladenoson bialanate on atrioventricular (AV) conduction in 11 patients with HFrEF treated with β-blockers. The PARSiFAL pilot study was a double-blind, placebo-controlled study on the effects of a 7-day treatment with 10 or 20 mg neladenoson bialanate or placebo in 31 patients with HFrEF on β-blocker therapy. In the β-blocker interaction study with 11 HFrEF patients, no second- or third-degree AV block was detected on 48-hour Holter monitoring. In the 31 HFrEF patients included in the PARSiFAL pilot study, no second- or third-degree AV blocks were observed during 24-hour Holter monitoring, and no effects were seen on heart rate and blood pressure. Median absolute changes in LVEF, measured by cardiac magnetic resonance, were 1.9% (interquartile range -1.1 to 4.3), 0.3% (-1.4 to 2.7), and 2.2% (0.4 to 4.5), in the placebo, 10-mg, and 20-mg groups, respectively. Treatment of HFrEF patients with the novel partial adenosine A1 agonist neladenoson bialanate appeared to be safe in 2 small pilot studies, and no atrioventricular conduction disorders or neurological side effects were observed. No significant early changes in cardiac function were detected.

Comparison of the Efficacy and Safety of Fixed-dose S-Amlodipine/Telmisartan and Telmisartan in Hypertensive Patients Inadequately Controlled with Telmisartan: A Randomized, Double-blind, Multicenter Study

PurposeThe objective of this study was to evaluate the efficacy and safety of the fixed-dose combination S-amlodipine plus telmisartan (S-AM/TEL) compared with TEL monotherapy in patients with hypertension inadequately controlled by TEL monotherapy. Methodsthis study was a randomized, multicenter, double-blind, parallel group, Phase III, 8-week clinical trial to compare the superiority of the S-AM/TEL 2.5/40-mg and S-AM/TEL 5/40-mg combinations with TEL 80-mg mono-therapy. The primary end point was the change in the mean sitting diastolic blood pressure from baseline (week 0) after 8 weeks of therapy between treatment groups. FindingsOf 325 patients screened, 183 were randomly assigned to 3 groups (61 in the S-AM/TEL 2.5/40-mg group, 60 in the S-AM/TEL 5/40-mg group, and 62 in the TEL 80-mg group). Mean (SD) age was 53.9 (7.5) years, and male patients comprised 87%. No significant differences were found among the 3 groups in baseline characteristics. The primary end points, the changes of mean (SD) diastolic blood pressure at week 8 from the baseline were −10.56 (7.23) mm Hg in the S-AM/TEL 2.5/40-mg group, −12.32 (9.23) mm Hg in the S-AM/TEL 5/40-mg group, and −2.44 (7.92) mm Hg in the TEL 80-mg group. Both the S-AM/TEL 2.5/40-mg group and the S-AM/TEL 5/40-mg group had a statistically superior hypotensive effect compared with the TEL 80-mg group (P < 0.0001 for both). For evaluation of the safety profile, the frequencies of adverse events (AEs) among the groups were also not significantly different (S-AM/TEL 2.5/40-mg group, 18.6%; S-AM/TEL 5/40-mg group, 20%; and TEL 80-mg group, 22.6%), and the incidences of AEs were not different among the groups. The most common AEs were respiratory disorders, followed by headache, dizziness, and peripheral edema. ImplicationsTreatment with S-AM/TEL 2.5/40 mg and S-AM/TEL 5/40 mg was superior to increasing the TEL dose in terms of hypotensive effect in patients with hypertension inadequately controlled by TEL monotherapy. S-AM/TEL fixed-dose combinations are an effective and tolerable option for patients inadequately responding to TEL monotherapy and also a good option for improving patients’ medication adherence. ClinicalTrials.gov identifier: NCT011426100.

A Randomized, Double-blind, Active-Controlled, Multi-center Study of Ilaprazole in the Treatment of Reflux Esophagitis

Proton pump inhibitors (PPIs) are the main drugs for the treatment of reflux esophagitis. Previous studies have indicated ilaprazole to be safer and more effective in treating duodenal ulcers as compared with omeprazole. Being a novel PPI, ilaprazole may be used in the treatment of reflux esophagitis. The purpose of this study was to evaluate the safety and efficacy of ilaprazole tablets in the treatment of reflux esophagitis. This study used a randomized, double-blind, multi-center, active-comparison design. The patients were randomly divided into an ilaprazole group (10mg once daily and 15mg once daily) and an esomeprazole group (40mg once daily). Both the groups were treated for 8weeks. Heartburn and reflux symptoms prior to treatment, and 4 and 8weeks after the treatment were assessed. Gastroscopy was performed after 4 and 8weeks. The healing rate after 4weeks treatment was compared. If esophagitis was healed at the end of 4weeks, patients did not undergo gastroscopy at the end of 8weeks. Three hundred and twenty-five patients were enrolled in this study. The 4-week full analysis set (per-protocol set) healing rates in the esomeprazole 40-mg group, the ilaprazole 10-mg group, and the ilaprazole 15-mg group were: 71.43% (78.89%), 81.31% (86.73%), and 71.70% (81.40%), respectively, p=0.1595 (0.4122); the 8-week healing rates were 84.76% (93.33%), 88.79% (94.90%), and 85.85% (97.67%), respectively, p=0.6689 (0.4049). Drug-related adverse events rate were 10.48%, 14.02%, and 15.09%, respectively, in the three groups (p=0.6114). The efficacy and safety of ilaprazole (10mg/day, 15mg/day) in treating reflux esophagitis was similar to esomeprazole (40mg/day). Ilaprazole (10mg/day) has a smaller dosage, hence it should be considered more in clinical uses. ClinicalTrials.gov NCT01107938.

A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis

BackgroundPrimary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease.MethodsIn this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5–10-mg group), or placebo. The primary end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a normal total bilirubin level.ResultsOf 216 patients who underwent randomization and received at least one dose of obeticholic acid or placebo, 93% received ursodiol as background therapy. The primary end point occurred in more patients in the 5–10-mg group (46%) and the 10-mg group (47%) than in the placebo group (10%; P<0.001 for both comparisons). Patients in the 5–10-mg group and those in the 10-mg group had greater decreases than those in the placebo group in the alkaline phosphatase level (least-squares mean, −113 and −130 U per liter, respectively, vs. −14 U per liter; P<0.001 for both comparisons) and total bilirubin level (−0.02 and −0.05 mg per deciliter [−0.3 and −0.9 μmol per liter], respectively, vs. 0.12 mg per deciliter [2.0 μmol per liter]; P<0.001 for both comparisons). Changes in noninvasive measures of liver fibrosis did not differ significantly between either treatment group and the placebo group at 12 months. Pruritus was more common with obeticholic acid than with placebo (56% of patients in the 5–10-mg group and 68% of those in the 10-mg group vs. 38% in the placebo group). The rate of serious adverse events was 16% in the 5–10-mg group, 11% in the 10-mg group, and 4% in the placebo group.ConclusionsObeticholic acid administered with ursodiol or as monotherapy for 12 months in patients with primary biliary cholangitis resulted in decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the changes observed with placebo. There were more serious adverse events with obeticholic acid. (Funded by Intercept Pharmaceuticals; POISE ClinicalTrials.gov number, NCT01473524; Current Controlled Trials number, ISRCTN89514817.)

Comparison of different regimens of estradiol benzoate treatments followed by long-acting progesterone to prepare noncycling mares as embryo recipients

The present study evaluated the influence of different regimens of estradiol benzoate (EB) treatments followed by a single dose of long-acting progesterone (LA P4) on plasma estrogen and P4 concentrations in noncyclic mares prepared as embryo recipients. Twenty-one anestrous mares were distributed into three groups (n = 7 mares per group), according to the EB dose received (single dose of 2.5 mg, total of 5 mg in decreasing doses, and total of 10 mg in decreasing doses), which was followed by a single administration of 1500 mg of LA P4 in all groups. Mares were reevaluated during the ovulatory phase and seven of them became part of the cyclic nontreated control group. Ultrasonography was performed to monitor endometrial edema, and blood samples were collected to measure estradiol (E2), estrogen conjugate (EC), and P4 by RIA. Maximum uterine edema was achieved 24 hours after administration of EB in all treated groups. Maximum E2 concentrations were observed 24 hours after the first EB injection in treated groups and there were no differences (P > 0.05) among treatments. Maximum EC concentration was observed 24 hours after the single EB injection in the 2.5-mg group, whereas in the 5- and 10-mg groups EC peaks were observed 48 hours after the first EB administration. Maximum P4 concentrations were detected 24 hours after LA P4 injection, although higher P4 concentrations were observed in the group treated with 2.5 mg of EB than in that treated with 10 mg of EB (P < 0.05). Because P4 concentrations were reduced after administration of high doses of EB, we also measured 17α-hydroxyprogesterone (17-OH-P) to test the hypothesis that high concentrations of EB would accelerate the conversion of P4 to 17-OH-P. However, 17-OH-P concentrations paralleled P4 profile in all groups, irrespective of EB doses. In summary, the three EB treatment regimens induced similar E2 peaks, although the observation of EC peaks 24 hours after E2 peaks in the 5- and 10-mg groups indicate that an excess of E2 was given, which was converted into EC to be inactivated. Administration of 10 mg of EB reduced P4 concentrations 24 hours after LA P4 was given. We demonstrated that the mechanism by which this reduction occurred was not by an increase in P4 metabolism to 17α-OH-P. In conclusion, the use of 2.5 mg of EB followed by 1500 mg of LA P4 appears to be a more appropriate regimen to treat noncyclic mares, although additional studies are needed to verify embryo survival with this treatment dose.

Heart rate control by carvedilol in Japanese patients with chronic atrial fibrillation: The AF Carvedilol study

Backgroundβ-Blockers are used to control heart rate (HR) in patients with atrial fibrillation (AF). However, the appropriate dosage and efficacy of carvedilol in Japanese AF patients are yet to be clarified. MethodsIn this multicenter, randomized, double-blind study, Japanese patients with persistent or permanent AF received carvedilol for 6 weeks in the following three dosage-regimen groups: 5-mg fixed-dose (n=42), 10-mg dose-escalation (n=42), or 20-mg dose-escalation (n=43). To evaluate the efficacy of each dosage regimen and the dose–response relationship, changes in 24-h mean HR (mHR) on Holter electrocardiograms from baseline to weeks 2, 4, and 6 were determined as primary endpoints. The effects on circadian changes in HR, the proportion of patients achieving target HR, clinical symptoms, and adverse events were also examined. ResultsAfter 2 weeks, carvedilol 5mg decreased 24-h mHR significantly [6.6 (95% CI: 5.2–8.0)beats/min, p<0.0001]. After 6 weeks, carvedilol showed a trend of dose-dependent HR reduction (p=0.0638): 7.6 (5.4–9.8) in the 5-mg fixed-dose group; 8.9 (6.7–11.1) in the 10-mg dose-escalation group; and 10.6 (8.4–12.8)beats/min in the 20-mg dose-escalation group. There were no serious adverse events related to carvedilol. ConclusionsIn Japanese patients with persistent or permanent AF, carvedilol at 5mg once daily demonstrated a significant HR reduction, and step-wise dose escalation from 5mg to 20mg showed a trend of dose-dependent HR reduction.

Optimal Dose of Calcium for Treatment of Nutritional Rickets: A Randomized Controlled Trial.

Calcium supplementation is indicated for the treatment of nutritional rickets. Our aim was to determine the optimal dose of calcium for treatment of children with rickets. Sixty-five Nigerian children with radiographically confirmed rickets were randomized to daily supplemental calcium intake of 500 mg (n = 21), 1000 mg (n = 23), or 2000 mg (n = 21). Venous blood, radiographs, and forearm areal bone density (aBMD) were obtained at baseline and at 8, 16, and 24 weeks after enrollment. The primary outcome was radiographic healing, using a 10-point radiographic severity score. The radiographic severity scores improved in all three groups, but the rate of radiographic healing (points per month) was significantly more rapid in the 1000-mg (-0.29; 95% confidence interval [CI] -0.13 to -0.45) and 2000-mg (-0.36; 95% CI -0.19 to -0.53) supplementation groups relative to the 500-mg group. The 2000-mg group did not heal more rapidly than the 1000-mg group. Of those who completed treatment for 24 weeks, 12 (67%), 20 (87%), and 14 (67%) in the 2000-mg, 1000-mg, and 500-mg groups, respectively, had achieved a radiographic score of 1.5 or less (p = 0.21). Serum alkaline phosphatase decreased and calcium increased similarly in all groups. Forearm diaphyseal aBMD improved significantly more rapidly in the 2000-mg group than in the 500-mg and 1000-mg groups (p < 0.001). Daily calcium intakes of 1000 mg or 2000 mg produced more rapid radiographic healing of rickets than 500 mg, but 2000 mg did not have greater benefit than 1000 mg. Some children require longer than 24 weeks for complete healing of nutritional rickets. © 2016 American Society for Bone and Mineral Research.

Dose-ranging effect of systemic diphenhydramine on postoperative quality of recovery after ambulatory laparoscopic surgery: a randomized, placebo-controlled, double-blinded, clinical trial

Study objectiveDiphenhydramine is an antihistamine with previously demonstrated analgesic and antiemetic properties. However, it is unknown if the beneficial perioperative properties of diphenhydramine can translate to a better quality of postsurgical recovery. The main objective of the current investigation was to investigate dose-ranging effects of diphenhydramine on quality of recovery after surgery. SettingTertiary hospital in the United States. DesignA prospective, randomized, double-blind trial. InterventionSaline, diphenhydramine 25 >mg, or diphenhydramine 50 mg given intravenously before induction. MeasurementsThe primary outcome was global Quality of Recovery–40 at 24hours. Postoperative pain, nausea, opioid consumption, and discharge time were also evaluated. Main resultsNinety subjects were randomized, and 75 completed the study. The median (interquartile range) Quality of Recovery–40 scores were not different among study groups: 164 (151-189), 169 (159-181), and 172 (157-185) for the saline, 25-mg diphenhydramine, and 50-mg diphenhydramine groups, respectively (P=.74). Postoperative nausea was decreased in the 50-mg group, 3 of 24 (12.5%), compared with the saline group, 12 of 27 (44%), P=.01. There was an inverse linear association between postoperative opioid consumption and quality of recovery (R2=0.37, P<.001). ConclusionsDiphenhydramine does not provide dose-ranging improvements on postoperative quality of recovery after ambulatory laparoscopic gynecologic surgery. Our results support a recent concept that not all postoperative nausea and vomiting symptoms are clinically important. Future studies evaluating postoperative nausea and vomiting should include patient-centered outcomes to validate the clinical importance of the examined interventions.

Efficacy, Safety, and Tolerability of Fulranumab as an Adjunctive Therapy in Patients With Inadequately Controlled, Moderate-to-Severe Chronic Low Back Pain: A Randomized, Double-blind, Placebo-controlled, Dose-ranging, Dose-loading Phase II Study

PurposeFulranumab is an investigational, fully human recombinant monoclonal antibody (IgG2) that neutralizes the biological actions of human nerve growth factor. Low back pain is a common cause of noncancer chronic pain and represents one of the most significant socioeconomic health-related problems in developed countries. This randomized, double-blind, placebo-controlled study was conducted to evaluate the analgesic effect of fulranumab in patients with moderate-to-severe chronic low back pain. MethodsPatients (aged 18–80 years) were randomized to receive subcutaneous injections every 4 weeks in 1 of 5 parallel treatment groups: placebo or fulranumab 1mg (1mgQ4wk), 3mg (3mgQ4wk), 3mg after a 6mg loading dose (6mgLD+3mgQ4wk), or 10mg (10mgQ4wk) every 4 weeks. FindingsA total of 385 patients (median age, 53 years; women, 54%) received at least 1 injection of study medication. No statistically significant differences were observed in improvement of pain intensity scores between the fulranumab treatment regimens and the placebo group at week 12 (primary end point; mean [SD], placebo: −2.0 [2.17], 1mgQ4wk: −1.9 [2.14], 3mgQ4wk: −2.2 [1.89], 6mgLD+3mgQ4wk: −2.0 [1.72] and 10mgQ4wk: −2.1 [2.18]). Results for secondary efficacy parameters (change in the Oswestry Disability Index, Brief Pain Inventory–Short Form, and Patient Global Assessment scales) were consistent with the primary outcome. A placebo effect was observed; the overall percentage of patients with treatment-emergent adverse events (TEAEs) was similar between the placebo (76%) and fulranumab treatment groups (77%–90%). Across all phases, the most common TEAEs in at least 10% of patients (combined fulranumab group vs placebo) were arthralgia (15% vs 12%), back pain (15% vs 18%), upper respiratory tract infection (15% vs 8%), paresthesia (14% vs 8%), diarrhea (12% vs 4%), headache (12% vs 8%), hypoesthesia (11% vs 5%), pain in extremity (11% vs 8%), sinusitis (10% vs 5%), and nasopharyngitis (10% vs 9%). Across all phases, neurologic TEAEs were less frequent in the placebo group (14%) versus the fulranumab treatment groups (25%). In the posttreatment phase, 8 patients had joint replacement operations, which were considered a result of normal progression of osteoarthritis. One case in the 10-mg group was determined to be rapid progession of osteoarthritis and was considered to be possibly related to study drug. ImplicationsFulranumab did not demonstrate efficacy compared with placebo in patients with chronic low back pain but was generally well-tolerated. ClinicalTrials.gov identifier: NCT00973024.

Effect of Statin Treatment on Modifying Plaque Composition: A Double-Blind, Randomized Study

BackgroundHow statins alter the natural course of coronary atherosclerosis with compositional changes remains unclear. ObjectivesThis study aimed to determine the effect of statin therapy on modifying plaque composition. MethodsThe STABLE (Statin and Atheroma Vulnerability Evaluation) prospective, single-center, double-blind, randomized study evaluated the effect of statins on functionally insignificant coronary stenoses. We randomly assigned 312 patients with a virtual histology (VH) intravascular ultrasound–defined fibroatheroma-containing index lesion to rosuvastatin 40 mg versus 10 mg (2:1 ratio). In 225 (72%) patients, grayscale- and VH-intravascular ultrasound were completed at baseline and 12 months. The primary endpoint was the change in VH-defined percent compositional volume within the target segment from baseline to follow-up in the per-protocol analysis set. ResultsPercent necrotic core (NC) volume within the target segment significantly decreased from 21.3 ± 6.8% to 18.0 ± 7.5% during 1-year follow-up, whereas the percent fibrofatty volume increased (11.7 ± 5.8% vs. 14.8 ± 9.3%; all p < 0.001). Percent fibrous (59.4 ± 7.8% vs. 59.2 ± 8.6%) and dense calcium (7.6 ± 5.1% vs. 7.8 ± 5.6%) volumes were unchanged. Frequencies of VH (55% vs. 29%) decreased significantly. Normalized total (202.9 ± 72.3 mm3 vs. 188.5 ± 67.8 mm3; p = 0.001) and percent (51.4 ± 8.3% vs. 50.4 ± 8.8%; p = 0.018) atheroma volumes decreased. Independent predictors of percent NC volume change were body mass index (β = 0.37; 95% confidence interval [CI]: 0.05 to 0.70), high sensitivity C-reactive protein (β = −3.16; 95% CI: −5.64 to −0.69), and baseline percent NC volume (β = −0.44; 95% CI: −0.68 to −0.19; all p < 0.05). VH-defined percent compositional volume changes in the rosuvastatin 40- and 10-mg groups were similar. ConclusionsRosuvastatin reduced NC and plaque volume and decreased thin-cap fibroatheroma rate. There were no significant differences between high- versus moderate-intensity rosuvastatin. (Statin and Atheroma Vulnerability Evaluation [STABLE]; NCT00997880)

A double-blind randomized study assessing safety and efficacy following one-year adjunctive treatment with bitopertin, a glycine reuptake inhibitor, in Japanese patients with schizophrenia.

BackgroundBitopertin, a glycine reuptake inhibitor, was investigated as a novel treatment for schizophrenia. We report all the results of a double-blind randomized study assessing safety and efficacy following 52-week adjunctive treatment with bitopertin in Japanese patients with schizophrenia.MethodsThis study enrolled Japanese outpatients with schizophrenia who met criteria for either “negative symptoms”, i.e., patients with persistent, predominant negative symptoms of schizophrenia even after long-term treatment with antipsychotics or “sub-optimally controlled symptoms”, i.e., patients with insufficiently improved symptoms of schizophrenia even after long-term treatment with antipsychotics, respectively. One hundred sixty-one patients were randomly assigned to receive 52-week treatments with bitopertin doses of 5, 10, or 20 mg/day at ratio of 1:5:5, where existing antipsychotics were concomitantly administered. Efficacy endpoints included Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression (CGI), and Personal and Social Performance (PSP). The purpose of the present study is primarily to evaluate the safety, and secondarily to investigate the clinical efficacy of bitopertin.ResultsOne hundred fourteen patients (71 %) completed 52-week treatment with bitopertin. Most of the adverse events were mild or moderate in their severity. The patients in the 20-mg group experienced more adverse events than the patients in the other two groups. Common dose-dependent adverse events were somnolence and insomnia associated with worsening schizophrenia. The blood hemoglobin levels gradually decreased from baseline in a dose-dependent manner, but there were no patients with the decrease below 10 g/dL that would have led to their discontinuation. All the efficacy endpoints gradually improved in all the treatment groups for both of the two symptoms, while there were no clear differences among the three dose groups.ConclusionsAltogether, bitopertin was found to be generally safe and well-tolerated for the treatment of patients with schizophrenia. All three bitopertin treated groups showed improvements in all the efficacy endpoints for both of the two symptoms, i.e., “negative symptoms” and “sub-optimally controlled symptoms”, throughout the duration of the study.Trial registrationJapan Pharmaceutical Information Center, number JapicCTI-111627 (registered on September 20, 2011)Electronic supplementary materialThe online version of this article (doi:10.1186/s12888-016-0778-9) contains supplementary material, which is available to authorized users.

Effects of Atorvastatin Dose and Concomitant Use of Angiotensin-Converting Enzyme Inhibitors on Renal Function Changes over Time in Patients with Stable Coronary Artery Disease: A Prospective Observational Study.

Angiotensin-converting enzyme inhibitors (ACEI) and statins are widely used in patients with coronary artery disease (CAD). Our aim was to compare changes in glomerular filtration rate (GFR) over time in subjects with stable CAD according to atorvastatin dose and concomitant use of ACEI. We studied 78 men with stable CAD referred for an elective coronary angiography who attained the then-current guideline-recommended target level of low-density lipoproteins (LDL) cholesterol below 2.5 mmol/L in a routine fasting lipid panel on admission and were receiving atorvastatin at a daily dose of 10–40 mg for ≥3 months preceding the index hospitalization. Due to an observational study design, atorvastatin dosage was not intentionally modified for other reasons. GFR was estimated during index hospitalization and at about one year after discharge from our center. Irrespective of ACEI use, a prevention of kidney function loss was observed only in those treated with the highest atorvastatin dose. In 38 subjects on ACEI, both of the higher atorvastatin doses were associated with increasing beneficial effects on GFR changes (mean ± SEM: −4.2 ± 2.4, 1.1 ± 1.6, 5.2 ± 2.4 mL/min per 1.73 m2 for the 10-mg, 20-mg and 40-mg atorvastatin group, respectively, p = 0.02 by ANOVA; Spearman’s rho = 0.50, p = 0.001 for trend). In sharp contrast, in 40 patients without ACEI, no significant trend effect was observed across increasing atorvastatin dosage (respective GFR changes: −1.3 ± 1.0, −4.7 ± 2.1, 4.8 ± 3.6 mL/min per 1.73 m2, p = 0.02 by ANOVA; rho = 0.08, p = 0.6 for trend). The results were substantially unchanged after adjustment for baseline GFR or time-dependent variations of LDL cholesterol. Thus, concomitant ACEI use appears to facilitate the ability of increasing atorvastatin doses to beneficially modulate time-dependent changes in GFR in men with stable CAD.

Eluxadoline for Irritable Bowel Syndrome with Diarrhea

BackgroundEffective and safe treatments are needed for patients who have irritable bowel syndrome (IBS) with diarrhea. We conducted two phase 3 trials to assess the efficacy and safety of eluxadoline, a new oral agent with mixed opioid effects (μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist), in patients with IBS with diarrhea.MethodsWe randomly assigned 2427 adults who had IBS with diarrhea to eluxadoline (at a dose of 75 mg or 100 mg) or placebo twice daily for 26 weeks (IBS-3002 trial) or 52 weeks (IBS-3001 trial). The primary end point was the proportion of patients who had a composite response of decrease in abdominal pain and improvement in stool consistency on the same day for at least 50% of the days from weeks 1 through 12 and from weeks 1 through 26.ResultsFor weeks 1 through 12, more patients in the eluxadoline groups (75 mg and 100 mg) than in the placebo group reached the primary end point (IBS-3001 trial, 23.9% with the 75-mg dose and 25.1% with the 100-mg dose vs. 17.1% with placebo; P=0.01 and P=0.004, respectively; IBS-3002 trial, 28.9% and 29.6%, respectively, vs. 16.2%; P<0.001 for both comparisons). For weeks 1 through 26, the corresponding rates in IBS-3001 were 23.4% and 29.3% versus 19.0% (P=0.11 and P<0.001, respectively), and the corresponding rates in IBS-3002 were 30.4% and 32.7% versus 20.2% (P=0.001 and P<0.001, respectively). The most common adverse events associated with 75 mg of eluxadoline and 100 mg of eluxadoline, as compared with placebo, were nausea (8.1% and 7.5% vs. 5.1%), constipation (7.4% and 8.6% vs. 2.5%), and abdominal pain (5.8% and 7.2% vs. 4.1%). Pancreatitis developed in 5 (2 in the 75-mg group and 3 in the 100-mg group) of the 1666 patients in the safety population (0.3%).ConclusionsEluxadoline is a new therapeutic agent that reduced symptoms of IBS with diarrhea in men and women, with sustained efficacy over 6 months in patients who received the 100-mg dose twice daily. (Funded by Furiex Pharmaceuticals, an affiliate of Allergan; IBS-3001 and IBS-3002 ClinicalTrials.gov numbers, NCT01553591 and NCT01553747, respectively.)

Bixin uptake and antioxidative effect and role in immunoregulation in domestic cats.

Bixin, a carotenoid found in the seed of the Annatto plant, , is a potent antioxidant. Carotenoids are readily absorbed from the diet; therefore, the purpose of this study was to examine uptake of bixin by plasma, lipoproteins, and leukocytes after dietary supplementation in domestic cats and to assess effects on immune response. Female domestic short hair cats (3 yr old; 4.79 ± 0.13 kg BW) were fed a single dose of 0, 1, 5, or 10 mg bixin, and blood was taken at 0, 1, 2, 4 and 8 h after administration ( = 6/treatment) to determine acute absorption rate. Then, bixin was fed daily for 14 d to examine steady-state plasma concentrations and subcellular distribution. Following these preliminary experiments, cats ( = 8/treatment) were fed diets containing 0, 1, 5, or 10 mg bixin/d for 16 wk and blood was collected on wk 0, 6, 12, and 16 for analysis of leukocyte subpopulations, cell-mediated responsiveness, and inflammatory and oxidative biomarkers. Maximal uptake in plasma occurred 1 h after a single oral dose of bixin, with a maximal concentration of 0.119 μ and elimination half-life of 1.8 to 2.2 h. Daily feeding of bixin showed a steady-state plasma concentration of 0.110 μ at the greatest doses. Bixin was primarily associated with the high-density lipoprotein fraction of blood lipoproteins and was primarily distributed in mitochondrial fractions (58-59%) of but also in microsomal and nuclear fractions (37-44%). Leukocyte subpopulations in blood were variably affected by dietary bixin, with an increase ( < 0.05) in total T cells but a concurrent decrease ( < 0.05) in CD18+ and B cell subpopulations. However, plasma IgG increased ( < 0.05) in the 10-mg treatment group by wk 6. Lymphoproliferation was stimulated ( < 0.05) in the 5-mg bixin treatment group by wk 16, and delayed-type hypersensitivity response increased after nonspecific antigenic challenge. Conversely, when a specific challenge of vaccine was assessed on wk 12 and 16, responsiveness decreased ( < 0.05) in the 10-mg bixin treatment group. Bixin supplementation surprisingly caused an increase ( < 0.05) in α-acid glycoprotein but had no effect on natural killer cell activity, other subpopulations of leukocytes, or 8-oxo-2›-deoxyguanosine, a DNA damage biomarker. This experiment demonstrated dose-dependent uptake of bixin in plasma and blood lipoproteins and distribution in leukocyte subcellular components and an impacted immune response through cell-mediated and humoral actions.

Uptake and immunomodulatory role of bixin in dogs.

Carotenoids are readily absorbed from the diet and distributed in blood leukocyte subcellular organelles. Bixin, a potent bioactive found in the seed of the Annatto plant, , possesses antioxidant and anti-inflammatory properties. The purpose of this study was to determine the uptake of bixin by plasma, lipoproteins, and leukocytes in domestic dogs and to examine immunoprotective properties. To determine uptake kinetics, female Beagle dogs (2 yr; 9.1 ± 0.1 kg BW) were first fed a single dose by oral gavage of 0, 5, 10, 20, or 40 mg bixin, with blood collected at 0 to 16 h after administration ( = 6/treatment), and then fed daily with 0, 5, 10, 20, or 40 mg bixin/d, with blood collected at 0, 1, 2, 4, 6, 10, and 14 d. In a consecutive experiment, cell-mediated and humoral responses as well as oxidative biomarkers were measured following 16 wk of dietary supplementation with 0, 5, 10, or 20 mg bixin/d. Maximal absorption in plasma occurred by 0.5 h with an elimination half-life of 2.6 to 3.3 h after a single dose of bixin. Steady-state plasma concentrations were 0.053 μ after 14 d of 40 mg bixin/d. The majority of subcellular bixin was found in the leukocyte mitochondria and was associated with the high-density lipoprotein and low-density lipoprotein fractions of lipoproteins. Specific (vaccine) response increased ( < 0.05) but nonspecific mitogen response was unchanged after 12 wk of dietary bixin, as assessed by a delayed-type hypersensitivity assay. Both B cell plasma leukocyte subpopulations at 6 and 16 wk and IgG plasma concentration at 12 wk in the 10-mg treatment group increased ( < 0.05), although IgM production and other cell populations were unaffected. In addition, 8-oxo-2'-deoxyguanosine (8-OHdG), a DNA damage biomarker, was substantially reduced ( < 0.05) in all treatment groups by wk 16, and C-reactive protein (CRP) was suppressed at wk 12 ( < 0.05). Dietary supplementation with bixin showed no changes in lymphoproliferation in response to in vitro mitogenic challenge and had no effect in enhancing natural killer cell activity. In conclusion, bixin was readily absorbed in a dose-dependent manner in blood following oral administration and was then taken up by leukocytes, where it was primarily distributed to mitochondria but in other subcellular organelles as well. Bixin also appeared to stimulate immune response, as seen with cell-mediated responses, and exerted anti-inflammatory (reduced CRP) as well as antioxidative (reduced 8-OHdG) effects in dogs.

Distribution of Anti-Factor Xa Activity in Patients on Edoxaban Therapy for Non-Valvular Atrial Fibrillation.

The distribution of anti-factor Xa activity (AXA) values in non-valvular atrial fibrillation (NVAF) patients on edoxaban therapy has not been fully elucidated. The steady-state trough and peak AXA values were measured in 66 NVAF patients. The trough AXA value did not differ significantly between the 60-mg and the 30-mg OD groups (0.17±0.13 IU/ml vs. 0.12±0.11 IU/ml, respectively; P=0.17). Similarly, the peak AXA value did not differ significantly between the 2 groups (1.45±0.81 IU/ml vs. 1.25±0.48 IU/ml, respectively; P=0.26). Recommended dosing should be followed for sufficient efficacy of edoxaban. (Circ J 2016; 80: 745-747).

A Phase 1b Study of Panobinostat in Combination with Idarubicin and Ara-C in Patients with High-Risk Acute Myeloid Leukemia

A Phase 1b Study of Panobinostat in Combination with Idarubicin and Ara-C in Patients with High-Risk Acute Myeloid Leukemia

Inhaled alpha1-proteinase inhibitor therapy in patients with cystic fibrosis

BackgroundInhaled alpha1-proteinase inhibitor (PI) is known to reduce neutrophil elastase burden in some patients with CF. This phase 2a study was designed to test inhaled Alpha-1 HC, a new aerosolized alpha1-PI formulation, in CF patients. MethodsWe performed a randomized, double-blind, placebo-controlled study and evaluated the safety of 100 or 200mg of inhaled Alpha-1 HC once daily for 3weeks in subjects with CF. Thirty adult subjects were randomized in a 2:1 ratio to receive Alpha-1 HC or placebo. ResultsDrug delivery was confirmed by a dose-dependent increase in the sputum alpha1-PI. Seven (20.0%) of the 35 adverse events in the 100-mg dose group, 3 (13.0%) of 23 in the 200-mg dose group, and 4 (14.3%) of 28 in the placebo group were drug-related in these subjects. One serious adverse event occurred in 1 subject within each group. ConclusionsAlpha-1 HC inhalation was safe and well tolerated.

Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia

BackgroundApolipoprotein C-III (APOC3) is a key regulator of plasma triglyceride levels. Elevated triglyceride levels are associated with a risk of adverse cardiovascular events and pancreatitis. ISIS 304801 is a second-generation antisense inhibitor of APOC3 synthesis.MethodsWe conducted a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 study to evaluate ISIS 304801 in untreated patients with fasting triglyceride levels between 350 mg per deciliter (4.0 mmol per liter) and 2000 mg per deciliter (22.6 mmol per liter) (ISIS 304801 monotherapy cohort), as well as in patients receiving stable fibrate therapy who had fasting triglyceride levels between 225 mg per deciliter (2.5 mmol per liter) and 2000 mg per deciliter (ISIS 304801–fibrate cohort). Eligible patients were randomly assigned to receive either ISIS 304801, at doses ranging from 100 to 300 mg, or placebo, once weekly for 13 weeks. The primary outcome was the percentage change in APOC3 level from baseline.ResultsA total of 57 patients were treated in the ISIS 304801 monotherapy cohort (41 received active agent, and 16 received placebo), and 28 patients were treated in the ISIS 304801–fibrate cohort (20 received active agent, and 8 received placebo). The mean (±SD) baseline triglyceride levels in the two cohorts were 581±291 mg per deciliter (6.6±3.3 mmol per liter) and 376±188 mg per deciliter (4.2±2.1 mmol per liter), respectively. Treatment with ISIS 304801 resulted in dose-dependent and prolonged decreases in plasma APOC3 levels when the drug was administered as a single agent (decreases of 40.0±32.0% in the 100-mg group, 63.8±22.3% in the 200-mg group, and 79.6±9.3% in the 300-mg group, vs. an increase of 4.2±41.7% in the placebo group) and when it was administered as an add-on to fibrates (decreases of 60.2±12.5% in the 200-mg group and 70.9±13.0% in the 300-mg group, vs. a decrease of 2.2±25.2% in the placebo group). Concordant reductions of 31.3 to 70.9% were observed in triglyceride levels. No safety concerns were identified in this short-term study.ConclusionsWe found that treatment with ISIS 304801 was associated with significant lowering of triglyceride levels, among patients with a broad range of baseline levels, through selective antisense inhibition of APOC3 synthesis. (Funded by Isis Pharmaceuticals; ClinicalTrials.gov number, NCT01529424.)