Use of new once-daily 5-aminosalicylic acid preparations in the treatment of ulcerative colitis： Is there anything new under the sun？

5-aminosalicylate （5-ASA） agents remain the mainstay treatment in ulcerative colitis （UC）. A number of oral 5-ASA agents are commercially available, including azo- bond pro-drugs, as well as delayed- and controlled- release forms of mesalazine. However, poor adherence due to frequent daily dosing and a large number of tablets has been shown to be an important barrier to successful management of patients with UC. Recently, new, once-daily formulations of mesalazine, including the unique multi-matrix delivery system and mesalazine granules, were proven to be efficacious in inducing and maintaining remission in mild-to-moderate UC, with a good safety profile comparable to that of other oral mesalazine formulations. In addition, they offer the advantage of a low pill burden and might contribute to increased long-term compliance and treatment success in clinical practice. This editorial summarizes the available literature on the short- and medium-term efficacy and safety of the new once-daily mesalazine formulations.     

Long-term safety and effectiveness of once-daily,single-entity,extended-release hydrocodone over 76 weeks of an open-label study in patients with chronic noncancer and nonneuropathic pain

Objective: To evaluate long-term use of Hysingla^® ER (HYD), a single-entity, extended-release, once-daily hydrocodone bitartrate tablet with abuse-deterrent properties in patients with moderate-to-severe chronic noncancer and nonneuropathic pain.

Methods: This open-label study consisted of a dose-titration period (up to 45 days), a 52-week maintenance period and a 24-week extension period. Opioid-naïve or opioid-experienced patients with controlled or uncontrolled chronic pain conditions were treated with HYD 20–120 mg daily. Supplemental nonopioid and short-acting opioid analgesics were permitted. This paper presents the results of 106 patients who continued HYD treatment for up to 76 weeks.

Primary safety measures included the incidence of adverse events, as well as audiologic, clinical laboratory and electrocardiogram measurements. Effectiveness was measured by the change between baseline and the overall 76-week treatment period in “average pain over the last 24 h” (0 = no pain, 10 = pain as bad as you can imagine), Brief Pain Inventory-Short Form survey, Medical Outcomes Study 36-Item Short Form Health Survey, Medical Outcomes Study Sleep Scale-Revised and concomitant nonstudy opioid analgesic use.

Results: Among 410 patients who completed the maintenance period, 106 continued into the extension. Of these, 83 (78%) completed the entire 76-week treatment period. Treatment-emergent adverse events were typical of those observed with μ-opioid agonists. No study drug abuse or diversion was reported. Clinically important analgesia and functional improvement were achieved during the dose-titration period and were maintained in most patients throughout 76 weeks without the need for continued HYD dose increases or changes in concomitant nonstudy opioid analgesics. The mean pain score was 6.1 at baseline, 3.8 at the end of the dose titration period and 3.8 through 76 weeks.

Conclusions: HYD was generally well tolerated. No unexpected safety concerns emerged. Pain control was sustained throughout 76 weeks of treatment.     

Fluctuation of the volume of distribution of amikacin and its effect on once-daily dosage and clearance in a seriously ill patient

Objective The main aim of the trial was to determine the extent to which the volume of distribution of amikacin fluctuates in a seriously ill patient receiving copious quantities of i.v. fluid over an extended term of treatment. The impact of the volume fluctuation on amikacin therapeutic peak concentrations was also assessed.Design and setting The case report describes a young, previously healthy male adult admitted to the surgical ICU of a teaching hospital following trauma to the head and central nervous system.Intervention The patient received 1 g of amikacin once-daily i. v. for 35 consecutive days as part of an antimicrobial regimen. Blood samples were drawn for routine amikacin concentration determinations on 14 occasions, extending over the entire term of treatment, from which the required pharmacokinetic parameters were determined.Results The volume of distribution of amikacin varied extensively from 0.27 to 0.61 l/kg (normal range 0.27±0.06 l/kg) notwithstanding the fact that amikacin clearance remained satisfactorily high throughout the term of treatment.Conclusions Once-daily therapeutic amikacin concentrations fluctuate extensively and rapidly in the seriously ill patient receiving copious quantities of i.v. fluids, despite competent renal function. The volume expansion seen in our patient is difficult to account for in terms of the extracellular fluid compartment only.Recommendations (a) Once-daily regimen amikacin peak concentrations should be frequently monitored in the seriously ill patients; (b) once-daily amikacin regimens are best monitored using blood specimens drawn at 1 and 6–8 h post administration.     

The Novartis view on emerging drugs and novel targets for the treatment of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease characterized by airflow limitation and chronic inflammation in the lungs. The mainstay of drug therapy for COPD is represented by long-acting bronchodilators, an important aspect of Novartis' development program. Novel once-daily dosing bronchodilators, such as the long-acting muscarinic antagonist (LAMA) glycopyrronium and the LAMA/long-acting β₂-agonist (LABA) fixed-dose combination QVA149, have been shown to provide significant benefits to patients with COPD in terms of improvement in lung function, exercise tolerance, health-related quality of life, symptoms and reduction in the rate of exacerbations. Despite the benefits provided by these new treatment options, prevention of disease progression and control of exacerbations in certain patient phenotypes remain key challenges in the treatment of COPD. In order to address these needs and gain new insights into the complexity of COPD, Novartis is, in addition to bronchodilator-only therapies, developing LABA/inhaled corticosteroids (ICS) combinations to target inflammation, such as QMF149, as well as non-steroid based anti-inflammatory agents against key novel targets. These commitments are central to the Novartis' final goal of improving the standard of care in respiratory medicine and offering a better quality of life to patients with COPD.     

Early tacrolimus exposure does not impact long-term outcomes after liver transplantation

BACKGROUNDTacrolimus trough levels (TTL) during the first weeks after liver transplantation (LT) have been related with long-term renal function and hepatocellular carcinoma recurrence. Nevertheless, the significance of trough levels of tacrolimus during the early post-transplant period for the long-term outcome is under debateAIMTo evaluate the effect of TTL during the first month on the long-term outcomes after LT.METHODSOne hundred fifty-five LT recipients treated de novo with once-daily tacrolimus were retrospectively studied. Patients with repeated LT or combined transplantation were excluded as well as those who presented renal dysfunction prior to transplantation and/or those who needed induction therapy. Patients were classified into 2 groups according to their mean TTL within the first month after transplantation: ≤ 10 (n = 98) and > 10 ng/mL (n = 57). Multivariate analyses were performed to assess risk factors for patient mortality.RESULTSMean levels within the first month post-transplant were 7.4 ± 1.7 and 12.6 ± 2.2 ng/mL in the ≤ 10 and > 10 groups, respectively. Donor age was higher in the high TTL group 62.9 ± 16.8 years vs 45.7 ± 17.5 years (P = 0.002) whilst mycophenolate-mofetil was more frequently used in the low TTL group 32.7% vs 15.8% (P = 0.02). Recipient features were generally similar across groups. After a median follow-up of 52.8 mo (range 2.8-81.1), no significant differences were observed in: Mean estimated glomerular filtration rate (P = 0.69), hepatocellular carcinoma recurrence (P = 0.44), de novo tumors (P = 0.77), new-onset diabetes (P = 0.13), or biopsy-proven acute rejection rate (12.2% and 8.8%, respectively; P = 0.50). Eighteen patients died during the follow-up and were evenly distributed across groups (P = 0.83). Five-year patient survival was 90.5% and 84.9%, respectively (P = 0.44), while 5-year graft survival was 88.2% and 80.8%, respectively (P = 0.42). Early TTL was not an independent factor for patient mortality in multivariate analyses.CONCLUSIONDifferences in tacrolimus levels restricted to the first month after transplant did not result in significant differences in long-term outcomes of LT recipients.     

Tolerance,pharmacokinetics and efficacy of once daily amikacin for treatment of Pseudomonas aeruginosa pulmonary exacerbations in cystic fibrosis patients

Twenty cystic fibrosis patients aged 1.8–22 years (mean ±SD: 9.6 ± 4.8 years) withPseudomonas aeruginosa pulmonary exacerbations were treated with amikacin (AM) (35 mg/kg/day in one daily 30 min infusion) associated with either ceftazidime (200 mg/kg/day in 3 i.v. injections) (n = 19) or imipenem (n = 1) at the same dose. Glomerular and tubular functions (creatinine clearance, 24-h proteinuria, ₂ microglobulinuria, lysozymuria) and audiometry remained within normal ranges from day 0 to day 14. A peak concentration of AM of 83 ± 19 mg/l and a trough concentration of 0.8 ±0.5 mg/l were observed in blood while AM levels in sputum were above the minimal inhibitory concentration 50 from 30 min to 16 h. No serum accumulation of AM was observed during the treatment. From day 0 to day 14, the following changes were observed: weight/height ratio: 96%–100% (P < 0.001); daily energy intake: 111%–128% of RDA (P < 0.001); prealbumin: 195–290 mg/l (P < 0.001); forced vital capacity (FVC): 66%–81% (P < 0.01); forced expiratory volume in 1 s: 60%–75% (P < 0.01); forced expiratory flow between 25% and 75% of FVC: 42%–56% (P < 0.01); nocturnal SaO₂ also improved significantly; cardiac rate decreased from 89 ±18/min to 76 ± 16/min (P < 0.001); respiratory rate decreased from 31 ±15/min to 26 ± 10/min (P < 0.05); inflammatory parameters (white blood cells, polymorphonuclear cells, erythrocyte sedimentation rate) also improved.     

Effects of Once-Daily Tadalafil on Erectile Function in Men with Erectile Dysfunction and Signs and Symptoms of Benign Prostatic Hyperplasia

Background

Lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH; BPH-LUTS) may be associated with erectile dysfunction (ED).

Objective

To evaluate the effects of once-daily tadalafil on erectile function in men with ED and BPH-LUTS.

Design, setting, and participants

Post hoc analysis of a phase 2–3, multinational, randomized, double-blind, placebo-controlled, parallel-group study of men with ED and moderate-to-severe LUTS secondary to BPH who reported being sexually active. In contrast to typical ED trials, no sexual activity threshold was required to participate.

Interventions

Screening and 4-wk washout period for patients taking BPH and/or ED treatments; 4-wk placebo run-in period; then once-daily placebo or tadalafil 2.5, 5, 10, or 20 mg for 12 wk.

Measurements

International Index of Erectile Function–Erectile Function (IIEF-EF) domain score, International Prostate Symptom Score (IPSS), peak urinary flow rate (Q_max), and postvoid residual volume (PVR). Analyses were performed in men who reported being sexually active with a female partner and who expected to remain so throughout the study. IIEF-EF data are presented for the BPH/ED population overall and for subgroups stratified by baseline age group, body mass index, BPH-LUTS severity, prostate-specific antigen, prior α-blocker use, and prior ED therapy.

Results and limitations

Overall, 581 men were included (placebo, n = 115; tadalafil 2.5 mg, n = 113; tadalafil 5 mg, n = 117; tadalafil 10 mg, n = 120; tadalafil 20 mg, n = 116). IIEF-EF domain score improvements from baseline to end point with tadalafil were 5.4 (2.5 mg), 6.8 (5 mg), 7.9 (10 mg), and 8.2 (20 mg) versus 2.0 with placebo (least-squares means; all p values <0.001). IIEF-EF domain score improvements were observed with tadalafil for all subgroup analyses, with no significant differences between subgroup or subgroup-by-treatment interaction terms. IPSS improvements from baseline to end point were significantly greater for all tadalafil doses versus placebo (all p values <0.05). Changes in Q_max and PVR were small and not clinically meaningful.

Conclusions

These data support the use of once-daily tadalafil in men with ED and BPH-LUTS.

Trial registration

http://www.clinicaltrials.gov: NCT00384930.     

Evaluation of once-daily dosing and target concentrations in therapeutic drug monitoring for arbekacin: A meta-analysis

IntroductionArbekacin is the first aminoglycoside antibacterial agent approved for treating methicillin-resistant Staphylococcus aureus infection in Japan. Although therapeutic drug monitoring (TDM) is recommended during arbekacin treatment, little evidence for the target exposure and once-daily dosing has been reported. This study aimed to clarify the target peak/trough concentrations and the effectiveness of once-daily dosing of arbekacin against nephrotoxicity or treatment failure via meta-analysis.MethodsA literature search was performed using MEDLINE, Cochrane Library, and Ichushi-Web.ResultsNine observational cohort studies met the inclusion criteria. A peak arbekacin concentration of ≥15–16 μg/mL did not exhibit a statistically significant lower risk of treatment failure (risk ratio [RR] = 0.61, 95% confidence interval [CI] = 0.30–1.24). A trough arbekacin concentration of <2 μg/mL resulted in a significantly lower risk of nephrotoxicity (RR = 0.30, 95% CI = 0.15–0.61). Once-daily dosing significantly reduced the risk of treatment failure (RR = 0.61, 95% CI = 0.39–0.97) but not nephrotoxicity (RR = 0.54, 95% CI = 0.16–1.75).ConclusionsOnce-daily dosing can improve the therapeutic efficacy of arbekacin, and a trough arbekacin concentration of <2 μg/mL can reduce the risk of nephrotoxicity. A peak arbekacin concentration of ≥15–16 μg/mL did not exhibit the significant lower risk of treatment failure. Additional clinical trials are required to confirm these findings.     

Safety and Efficacy of Once-Daily Intravenous Busulfan in Allogeneic Transplantation: A Matched-Pair Analysis

Compared with 4-times-daily infusion of intravenous busulfan (ivBU4), the safety and efficacy of once-daily infusion of ivBU (ivBU1) has not been fully clarified. We have been routinely using ivBU1 in a conditioning regimen in adult patients with myeloid malignancy who undergo allogeneic hematopoietic stem cell transplantation. In this study, a total of 91 patients who received ivBU1 for 2 days (n?=?18) or 4 days (n?=?73) in our institutions were compared with 273 control patients who received ivBU4, who were matched for age, sex, performance status, disease risk, conditioning regimen, and donor type, selected from the database of the Japanese Society for Hematopoietic Cell Transplantation using optimal matching algorithms. One-year overall survival (56.8% versus 57.1%, P?=?.94), disease-free survival (51.6% versus 50.8%, P?=?.73), relapse rate (28.5% versus 26.2%, P?=?.94), nonrelapse mortality (19.9% versus 23.0%, P?=?.71), and the incidence of graft-versus-host disease were not significantly different between the ivBU1 and ivBU4 groups. In patients who received ivBU1, neutrophil recovery was slower (median days: 22 versus 17, P?=?.001), and the incidence of veno-occlusive disease was lower (2.6% versus 17.4%, P?=?.04). In conclusion, ivBU1 can be safely administered with clinical outcomes similar to those with ivBU4.