Twice-daily Group Research Articles

Effects of Ampicillin/Sulbactam Dose and Dosing Frequency in Elderly Patients with Nursing- and Healthcare-Associated Pneumonia (Nhcap)

Japan has the most rapidly aging population in the world. This study aimed to examine the differences in the efficacy of ampicillin/sulbactam (ABPC/SBT) alone under different daily doses and daily dosing frequencies in elderly patients receiving healthcare at home and in elderly nursing home residents with pneumonia onset requiring hospitalization for treatment. By applying the Clinical Practice Guidelines for Nursing- and Healthcare-associated Pneumonia (NHCAP) of the Japanese Respiratory Society (JRS), we retrospectively analyzed clinical data, dose, dosing period, and the efficacy of antimicrobial agents, as well as outcomes of patients with NHCAP or community acquired pneumonia (CAP) who had been hospitalized at our department during the 3-year period of 2009 through 2011. The mean age of NHCAP patients (n=587) was 85 ± 9 years, significantly higher than the 77 ± 16 years of CAP patients (n=319). The serum albumin level in NHCAP patients was significantly lower than that in CAP patients. Among NHCAP patients, 82.5% received ABPC/SBT alone as the first-line therapy, with 50.7% receiving 1.5 g three times daily and 22.8% receiving 3 g twice daily. The mortality rate during hospitalization in the 1.5-g three-times-daily group was 12.4%, resulting in a significantly decrease as compared with the 3-g twice-daily group of 20.9% (p<0.01). In our study, which targeted the elderly in Japan, it was revealed that ABPC/SBT is an appropriate first choice of antibiotics in treating NHCAP and that administering 1.5 g three times daily is a suitable way of administration.

Effectiveness of different dosing regimens of risperidone and olanzapine in schizophrenia

The objective of this study was to evaluate the effectiveness and impact of once- versus twice-daily dosing of risperidone and olanzapine on clinical outcomes in patients with schizophrenia. Data from phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study were used. Patients with schizophrenia were randomly allocated to treatment with risperidone and olanzapine, and were also randomly assigned to once-daily (N=173 and 169, respectively) or twice-daily (N=168 and 167, respectively) dosing and followed for up to 18 months. Discontinuation rate and time to discontinuation were used as primary outcome measures to compare the two groups. The following outcome measures were also analyzed: efficacy, safety, medication adherence, adverse events, and concomitant psychotropic medications. No significant differences in discontinuation rates and time to discontinuation were observed between the once- and twice-daily dosing groups (P>0.05) in patients receiving risperidone or olanzapine. The once-daily dosing group demonstrated significantly lower mean daily doses of risperidone and olanzapine across phase 1, and lower rates of hospitalization for exacerbation of schizophrenia, sleepiness, and orthostatic faintness in patients receiving olanzapine (P<0.05) compared to the twice-daily dosing group. No significant differences were found in any other outcome measures between the two dosing groups. In conclusion, effectiveness and efficacy outcomes between once- and twice-daily dosing for risperidone and olanzapine were not significantly different. However, in view of the lower mean dose and better side effect profile, it is advisable to adhere to a once-daily dosing regimen, especially in the case of olanzapine.

Effects of Differing Dosages of Pomegranate Juice Supplementation after Eccentric Exercise

Dietary supplementation with pomegranate juice improves isometric strength recovery after unaccustomed eccentric exercise. The purpose of this study was to determine if there is a dose response effect of pomegranate juice supplementation after eccentric exercise isometric strength recovery. Forty-five nonresistance trained, recreationally active men were assigned once-daily pomegranate juice, twice-daily pomegranate juice, or placebo supplementation. On day four of supplementation, 20 min of downhill running and 40 maximal eccentric elbow flexion repetitions were performed. Isometric knee extensor and elbow flexor strength, muscular soreness, and serum myoglobin concentrations were measured prior to exercise and 2, 24, 48, 72, and 96 h after exercise. Throughout the postexercise time period, while isometric knee extensor and elbow flexor strength were similar between once-daily and twice-daily pomegranate juice supplementation groups, isometric strength was significantly higher in pomegranate juice groups than placebo. Knee extensor soreness, elbow flexor soreness, and myoglobin increased in response to exercise but were similar between groups. It is apparent that pomegranate juice supplementation improves strength recovery in leg and arm muscles following eccentric exercise; however, no dose response effect was present. We conclude that once-daily pomegranate juice supplementation is not different from twice-daily supplementation in regards to strength recovery after eccentric exercise.

Tozadenant (SYN115) in patients with Parkinson's disease who have motor fluctuations on levodopa: a phase 2b, double-blind, randomised trial

Many patients with Parkinson's disease have motor fluctuations despite treatment with available drugs. Tozadenant (SYN115) is an oral, selective adenosine A2A receptor antagonist that improves motor function in animal models of Parkinson's disease. We aimed to assess the safety and efficacy of tozadenant as an adjunct to levodopa in patients with Parkinson's disease who have motor fluctuations on levodopa. We did an international, multicentre, phase 2b, randomised, double-blind, placebo-controlled, parallel-group, dose-finding clinical trial of tozadenant in levodopa-treated patients with Parkinson's disease who had motor fluctuations (at least 2·5 h off-time per day). Eligible patients were randomly assigned via a computer-generated randomisation schedule to receive tozadenant 60, 120, 180, or 240 mg or matching placebo twice daily for 12 weeks. All study management, site personnel, and patients were masked to treatment assignment. The primary outcome was change from baseline to week 12 in hours per day spent in the off-state (assessed from Parkinson's disease diaries completed by patients). This study is registered at ClinicalTrials.gov, number NCT01283594. Of 420 randomised patients (mean age 63·3 [SD 8·3] years; mean duration of Parkinson's disease 8·7 [4·7] years), 403 provided post-baseline diary data and 337 completed study treatment. Compared with placebo, mean daily off-time was significantly reduced in the combined tozadenant 120 mg twice-daily and 180 mg twice-daily group (-1·1 h, 95% CI -1·8 to -0·5; p=0·0006), the tozadenant 120 mg twice-daily group (-1·1 h, -1·8 to -0·4; p=0.0039), and the tozadenant 180 mg twice-daily group (-1·2 h, -1·9 to -0·4; p=0·0039). The most common adverse events in these groups were dyskinesia (seven [8%] of 84 patients in the placebo group, 13 [16%] of 82 in the 120 mg twice-daily group, and 17 [20%] of 85 in the 180 mg twice-daily group), nausea (three [4%], 9 [11%], and ten [12%]), and dizziness (one [1%], four [5%], and 11 [13%]). Tozadenant 60 mg twice daily was not associated with a significant reduction in off-time, and tozadenant 240 mg twice daily was associated with an increased rate of discontinuation because of adverse events (17 [20%] of 84 patients). Tozadenant at 120 or 180 mg twice daily was generally well tolerated and was effective at reducing off-time. Further investigation of tozadenant treatment in phase 3 trials is warranted. Biotie Therapies.

PDE-5 inhibition improves skin flap viability in rats that are exposed to nicotine

Nicotine causes ischemia and necrosis of skin flaps. Phosphodiesterase-5 (PDE-5) inhibition enhances blood flow and vasculogenesis. This study examines skin flap survival in rats exposed to nicotine that are treated with and without PDE-5 inhibition. Eighty six rats were divided into five groups. Group 1 received saline subcutaneous (SC) once per day. Group 2 received nicotine SC 2 mg/kg day. Group 3 received sildenafil intraperitoneal (IP) 10 mg/kg day. Group 4 received nicotine SC 2 mg/kg and sildenafil IP 10 mg/kg day. Group 5 received nicotine SC 2 mg/kg day and sildenafil IP 10 mg/kg two times daily. After 28 days of treatment, modified McFarlane flaps were created, silicone sheets were interposed, and flaps were sutured. Photographs were taken on postoperative days 1, 3, and 7 and fluorescence angiography was used on day 7, both to evaluate for skin flap necrosis. Rats were euthanized and flaps were harvested for Vascular Endothelial Growth Factor (VEGF) Western blot analysis. Images were analyzed by three blinded observers using ImageJ, and necrotic indices were calculated. The nicotine and PDE-5 inhibition twice-daily group showed a 46% reduction in flap necrosis when compared to saline only (P < 0.05) and a 54% reduction when compared to nicotine only (P < 0.01). Fluorescence angiographic image analysis revealed reductions in flap necrosis (P < 0.01). VEGF analysis trended toward increased VEGF for all sildenafil-treated groups (P > 0.05). PDE-5 inhibition exhibits a dose-dependent reduction in skin flap necrosis in rats exposed to nicotine. This suggests that PDE-5 inhibition may mitigate the ill effects of smoking on skin flaps.

Impact of Once- Versus Twice-Daily Perphenazine Dosing on Clinical Outcomes

The objective of this study was to evaluate the impact of once- versus twice-daily dosing of perphenazine, which has a plasma half-life of 8-12 hours, on clinical outcomes in patients with schizophrenia. Data from phase 1 of the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) conducted between January 2001 and December 2004 were used in this post hoc analysis. Patients with schizophrenia (DSM-IV) randomly allocated to treatment with perphenazine were also randomly assigned to once-daily (N = 133) or twice-daily (N = 124) dosing and followed over 18 months. Discontinuation rate and time to discontinuation were used as primary outcomes to compare the 2 groups. The following clinical outcomes were analyzed as secondary measures: efficacy-Positive and Negative Syndrome Scale, Clinical Global Impressions-Severity scale, Calgary Depression Scale for Schizophrenia, and Drug Attitude Inventory and safety/tolerability-Abnormal Involuntary Movement Scale, Barnes Akathisia Rating Scale, Simpson-Angus Scale, and body weight. Data on treatment-emergent adverse events, concomitant psychotropic medications, and medication adherence (pill count and clinician rating scale) were also analyzed for each group. No significant differences were found in any outcome measures between the once-daily and twice-daily dosing groups, which remained the same when using the mean dose of perphenazine as a covariate. Perphenazine is routinely administered in a divided dosage regimen because of its relatively short plasma half-life. However, the present findings challenge such a strategy, suggesting that once-daily represents a viable treatment option. Results are discussed in the context of more recent evidence that challenges the need for high and continuous dopamine D2 receptor blockade to sustain antipsychotic response. ClinicalTrials.gov identifier: NCT00014001.

Pharmacokinetic Variability of Amikacin After Once-Daily and Twice-Daily Dosing Regimen in Full-Term Neonates

The purpose of the study was to compare peak (Cpeak) and trough (Ctrough) amikacin levels after twice-daily (TD) or once-daily dosing (OD) in full-term neonates. Additionally, the study aimed to address amikacin pharmacokinetics and its variability. Data included 31 patients born on term. Amikacin daily dose was 15 or 20 mg/kg depending on the neonate’s age. Patients randomly received amikacin every 12 or 24 h. In all patients corresponding Cpeak and Ctrough were taken. Volume of distribution (Vd), clearance (CL) and half-life (t1/2) were calculated. Mean Cpeak of 21.79 μg/ml in the TD group was statistically different from Cpeak of 36.39 μg/ml in the OD group. Average Ctrough in TD (5.67 μg/ml) was statistically different from the corresponding 3.99 μg/ml in the OD group. Mean amikacin Vd, CL, and t1/2 were 0.78 ± 0.38 l/kg, 86.99 ± 48.22 ml/h∙kg, and 6.81 ± 2.51 h, respectively. High interindividual pharmacokinetic variability was observed. Further analysis showed that neonatal age contributed to the pharmacokinetic parameters’ values. Statistically significant difference in CL and t1/2 was observed between patients age ≤ 2 and > 2 days on therapy initiation. As expected, amikacin given OD achieved higher Cpeak and lower Ctrough than TD. Based on the results, observed variability in amikacin pharmacokinetics was possibly due to the renal maturation process.

Effects of Switching from Insulin Glargine or Detemir to Insulin Degludec in Patients with Type 1 Diabetes Mellitus

IntroductionInsulin degludec is a new, ultra-long-acting basal insulin. The aim of this study was to analyze the changes of basal insulin dose and blood glucose profile in basal–bolus therapy of type 1 diabetes mellitus (T1DM) at the switching of basal insulin from insulin glargine or detemir to insulin degludec.MethodsSixteen patients with T1DM were enrolled. The patients underwent continuous glucose monitoring before and after the switching of insulin glargine or detemir to degludec. Ten patients treated with insulin glargine or detemir twice daily, were switched to insulin degludec with 80–90% of the prior insulin dose. The remaining six patients treated with insulin glargine once daily, were switched to insulin degludec without down titration. The changes of daily insulin dose and glycated hemoglobin (HbA1c) were also examined for 12 weeks after switching to insulin degludec.ResultsIn the patients switched from twice-daily basal insulin, no significant difference was found between before and after switching in the blood glucose profile. In the once-daily group, blood glucose levels showed a tendency to decrease after switching to the degludec treatment. During the study period, total daily insulin dose (TDD) and total daily basal insulin dose (TBD) decreased significantly in the twice-daily group, and TDD and TBD showed a tendency to decrease after switching to degludec in the once-daily group. In both groups, the changes of HbA1c were not significantly different.ConclusionIt is possible to achieve similar glycemic control with once-daily injection and lower doses of insulin degludec in patients with T1DM who have been treated with insulin glargine or detemir.

Comparison of once-daily versus twice-daily combination of Ropinirole prolonged release in Parkinson’s disease

BackgroundRopinirole prolonged release (RPR) is a once-daily formulation. However, there may be individual pharmacokinetic differences so that multiple dosing may be preferred in some individuals. This study compares once-daily and twice-daily RPR in patients with Parkinson’s disease.MethodsThis study was an open-label crossover study. We enrolled Parkinson’s disease patients on dopamine agonist therapy with unsatisfactory control such as motor fluctuation, dyskinesia and sleep-related problems. Agonists were switched into equivalent dose of RPR. Subjects were consecutively enrolled into either once-daily first or twice-daily first groups, and received the same amount of RPR in a single and two divided dosing for 8 weeks respectively in a crossover manner without a washout period.The primary outcome was a questionnaire of the preference completed by patients in the last visit. The secondary outcome measures included the Unified Parkinson’s Disease Rating Scale part 3 (mUPDRS), Hoehn and Yahr stage (H&Y); sleep questionnaire including overall quality of sleep, nocturnal off symptoms and early morning symptoms; Epworth Sleep Scale (ESS); compliances and patient global impression (PGI).ResultsA total of 82 patients were enrolled and 61 completed the study. 31 patients preferred twice-daily regimen, 17 preferred the once-daily regimen, and 13 had no preference. Their mean mUPDRS, H&Y, ESS, sleep quality, compliance and adverse events were not statistically different in both regimens. PGI-improvement on wearing off defined was better in twice-daily dosing regimen.ConclusionsRPR is a once-daily formulation, but multiple dosing was preferred in many patients. Multiple dosing of RPR might be a therapeutic option if once-daily dosing is unsatisfactory.Trial registrationThis study is registered with ClinicalTrials.gov, number NCT00986245.

A Systematic Review of Proton-Pump Inhibitor Therapy for Laryngopharyngeal Reflux

The author performed a MEDLINE literature search to identify and evaluate all randomized, placebo-controlled trials of the treatment of laryngopharyngeal reflux (LPR) with an oral proton-pump inhibitor (PPI) that have been published since 1966. Eight such trials that included a total of 358 patients were identified. These eight studies contained seven different definitions of LPR. Validity scores (maximum: 9) ranged from 5 to 9 (mean: 7.5). One study investigated low-dose once-daily therapy, two studies investigated low-dose twice-daily therapy, and five studies investigated high-dose twice-daily therapy. Outcomes measures were not consistent among studies, and most studies used unvalidated outcomes measures. Only two studies found that a PPI was significantly better than placebo-one in the low-dose twice-daily group and one in the high-dose twice-daily group. The author concludes that the current body of literature is insufficient to draw reliable conclusions about the efficacy of PPI therapy for the treatment of LPR.

Reduction of Stent Thrombosis in Patients With Acute Coronary Syndromes Treated With Rivaroxaban in ATLAS-ACS 2 TIMI 51

The aim of this study was to determine if rivaroxaban is associated with a reduction in stent thrombosis among patients with acute coronary syndromes (ACS) in the ATLAS-ACS 2 TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51) trial. Dual antiplatelet therapy (DAPT) has been the mainstay of efforts to prevent stent thrombosis. Because thrombin is a potent stimulant of platelet activation, we hypothesized that inhibition of thrombin generation via factor Xa inhibition may further reduce the risk of stent thrombosis. The ATLAS-ACS 2 TIMI 51 study was a placebo-controlled trial that randomly assigned 15,526 patients with recent ACS to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and upto 31 months. Among patients who had a stent placed before or at the time of the index event, rivaroxaban significantly reduced independently adjudicated Academic Research Consortium definite and probable stent thrombosis in the pooled (1.9% vs. 1.5%; hazard ratio [HR]: 0.65; p= 0.017) and the 2.5 mg twice-daily (1.9% vs. 1.5%; HR: 0.61; p= 0.023) treatment groups when compared with placebo, with a trend toward a reduction in the 5 mg twice-daily treatment group (1.9% vs. 1.5%; HR: 0.70; p= 0.089). Among patients who received both aspirin and a thienopyridine (stratum 2), the benefit of rivaroxaban emerged during the period of active treatment with DAPT (HR: 0.68; 95% CI:0.50 to 0.92, combined rivaroxaban group vs. placebo). Among stented patients who were treated with dual antiplatelet therapy, there was a mortality reduction among those treated with twice-daily rivaroxaban 2.5 mg (HR:0.56; 95% CI: 0.35 to 0.89; p= 0.014). Among stented patients with ACS treated with DAPT, the administration of twice-daily rivaroxaban 2.5 mg was associated with a reduction in stent thrombosis and mortality. (An Efficacy and Safety Study for Rivaroxaban in Patients With Acute Coronary Syndrome; NCT00809965).

Safety of mometasone furoate nasal spray in the treatment of nasal polyps in children

Mometasone furoate nasal spray (MFNS) improves nasal symptoms and reduces polyp size in adults with nasal polyposis. This 4-month, multinational, randomized, double-blind study was conducted to assess the safety of MFNS in pediatric subjects aged 6-17yr. Subjects aged 6-11yr with bilateral nasal polyps received MFNS 100μg once or twice daily or placebo; those aged 12-17yr received MFNS 200μg once or twice daily or placebo. End-points included change in 24-h urinary free cortisol (primary), change in 24-h urinary free cortisol corrected for creatinine (key secondary), and adverse events. Efficacy parameters included polyp size, nasal symptoms, and investigator-evaluated therapeutic response, although the study was not powered for statistical analysis of efficacy. Least squares baseline mean urinary free cortisol level (nmol/24h) for both age groups combined (N=127) was 49.5 in the MFNS once-daily group, 39.6 in the MFNS twice-daily group, and 49.8 in the placebo group. Change in 24-h urinary free cortisol did not significantly differ among MFNS- and placebo-treated subjects. Least squares mean 24-h urinary free cortisol levels corrected for creatinine also showed no significant differences among MFNS- and placebo-treated subjects. No safety issues emerged. Results of this study confirm the safety profile of MFNS in pediatric patients with bilateral nasal polyps over 4months, even at double the recommended pediatric dosage for allergic rhinitis.

Improved Adherence to Tacrolimus Once-Daily Formulation in Renal Recipients

With effective agents available to prevent posttransplantation acute organ rejection, medication adherence becomes a key factor for successful treatment outcomes after renal transplantation. A once-daily, modified-release oral formulation of tacrolimus has been developed to simplify dosing and improve medication adherence. Adherence Measurement in Stable Renal Transplant Patients Following Conversion From Prograft to Advagraf is a randomized multicenter controlled trial to evaluate adherence between a tacrolimus once-daily regimen and a tacrolimus twice-daily regimen using an electronic monitor to document drug intake. After enrolment, all patients continued the twice-daily regimen for 3 months and then were randomized 2:1 between the two formulations and followed for 6 months. Adherence was decomposed into patients' persistence and implementation of each regimen. Two hundred nineteen patients (45% male; 3±2 years after transplantation) were analyzed (145 once daily and 74 twice daily). At 6 months after randomization, 81.5% of the once-daily group and 71.9% of the twice-daily group remained persistent with the treatment (P=0.0824). Among patients who remained engaged with the regimen, 88.2% of the once-daily group and 78.8% of the twice-daily group (P=0.0009) took the prescribed number of daily doses. When the patients took the twice-daily regimen, the average percentage of missed doses was 11.7% in the morning and 14.2% in the evening (P=0.0035). Regimen implementation of tacrolimus once daily is significantly superior to the twice-daily regimen. There was a residual prevalence of suboptimal adherence that will have to be countered by means other than reformulation and regimen simplification. Electronically compiled dosing histories provide detailed data on patient adherence that can be used for efficient medication management.

Placebo-Controlled Phase 3 Study of Oral BG-12 for Relapsing Multiple Sclerosis

BackgroundBG-12 (dimethyl fumarate) was shown to have antiinflammatory and cytoprotective properties in preclinical experiments and to result in significant reductions in disease activity on magnetic resonance imaging (MRI) in a phase 2, placebo-controlled study involving patients with relapsing–remitting multiple sclerosis.MethodsWe conducted a randomized, double-blind, placebo-controlled phase 3 study involving patients with relapsing–remitting multiple sclerosis. Patients were randomly assigned to receive oral BG-12 at a dose of 240 mg twice daily, BG-12 at a dose of 240 mg three times daily, or placebo. The primary end point was the proportion of patients who had a relapse by 2 years. Other end points included the annualized relapse rate, the time to confirmed progression of disability, and findings on MRI.ResultsThe estimated proportion of patients who had a relapse was significantly lower in the two BG-12 groups than in the placebo group (27% with BG-12 twice daily and 26% with BG-12 thrice daily vs. 46% with placebo, P<0.001 for both comparisons). The annualized relapse rate at 2 years was 0.17 in the twice-daily BG-12 group and 0.19 in the thrice-daily BG-12 group, as compared with 0.36 in the placebo group, representing relative reductions of 53% and 48% with the two BG-12 regimens, respectively (P<0.001 for the comparison of each BG-12 regimen with placebo). The estimated proportion of patients with confirmed progression of disability was 16% in the twice-daily BG-12 group, 18% in the thrice-daily BG-12 group, and 27% in the placebo group, with significant relative risk reductions of 38% with BG-12 twice daily (P=0.005) and 34% with BG-12 thrice daily (P=0.01). BG-12 also significantly reduced the number of gadolinium-enhancing lesions and of new or enlarging T2-weighted hyperintense lesions (P<0.001 for the comparison of each BG-12 regimen with placebo). Adverse events associated with BG-12 included flushing and gastrointestinal events, such as diarrhea, nausea, and upper abdominal pain, as well as decreased lymphocyte counts and elevated liver aminotransferase levels.ConclusionsIn patients with relapsing–remitting multiple sclerosis, both BG-12 regimens, as compared with placebo, significantly reduced the proportion of patients who had a relapse, the annualized relapse rate, the rate of disability progression, and the number of lesions on MRI. (Funded by Biogen Idec; DEFINE ClinicalTrials.gov number, NCT00420212.)

Rapid Decline of Viral RNA in Chronic Hepatitis C Patients Treated Once Daily with IDX320: A Novel Macrocyclic HCV Protease Inhibitor

The addition of direct-acting antivirals to pegylated interferon-α plus ribavirin for the treatment of chronic HCV infection can result in an increased sustained viral response rate and may permit reduction in treatment duration. IDX320 is a potent non-covalent macrocyclic inhibitor of the HCV NS3/4A protease. This was a randomized double-blind placebo-controlled single- and multiple-dose study to assess the safety, tolerability, antiviral activity and pharmacokinetics of IDX320 in healthy volunteers (HV) and patients with chronic HCV genotype 1 infection. HV (n=48) received single or multiple ascending doses of IDX320. Two HCV-infected patients received a single dose of 200 mg IDX320. Dosages for other HCV-infected patients were as follows: placebo, 50, 100, 200 or 400 mg of IDX320 orally once daily for 3 days (n=30) or placebo/200 mg of IDX320 twice-daily for 3 days (n=8). In total, 48 HV and 40 HCV-infected patients were enrolled and all completed the study. There were no serious adverse events. The majority of adverse events were of mild or moderate intensity. Pharmacokinetics supported a once-daily dosing regimen. A rapid decline in plasma HCV RNA was observed in all patients. In the multiple-dose study, mean HCV RNA reductions were 2.6, 3.1, 3.1, 3.3 and 3.8 log(10) IU/ml after 3 days in the IDX320 50, 100, 200, 400 mg once-daily and 200 mg twice-daily treatment groups, respectively. This compared to a mean HCV RNA reduction of 0.04 log(10) in the placebo group. Once-daily IDX320 dosing demonstrated potent dose-dependent antiviral activity in treatment-naive HCV genotype-1-infected patients.

Comparison of adherence between twice‐ and thrice‐daily regimens of oral amoxicillin/clavulanic acid

Few studies have analysed adherence with antibiotic treatment in patients with respiratory tract infections. The aim of this study was to compare the compliance of patients taking a pharmacokinetically enhanced formulation of amoxicillin/clavulanic acid twice daily with that of patients taking the standard formulation thrice daily. Patients with suspected bacterial lower respiratory tract infections, pharyngitis and dental infections were included. Adherence was assessed by electronic monitoring, which recorded every opening of the patient's bottle of pills. The outcome variables were compliance with taking the medication, taking the correct dose and with timing of the dose. A total of 240 patients were enrolled (167 in the thrice-daily group and 73 in the twice-daily group). The percentage of doses taken was greater with the twice-daily regimen (84.5 ± 22.8%) than with the thrice-daily regimen (72.7 ± 20.1%; P < 0.001). Forty patients in the twice-daily group opened the container every 12 ± 6 h during at least 80% of the course (54.8%), while only 19.6% of the patients assigned to the thrice-daily formulation did so every 8 ± 4 h (P < 0.001). The percentage of patients who opened the container a satisfactory number of times per day was significantly higher among those taking the twice-daily regimen on days three, four, five, six and seven. Moreover, the thrice-daily group more frequently forgot to take the afternoon dose. The rate of compliance with amoxicillin/clavulanic acid therapy was very low. However, compliance with the new formulation that is taken twice-daily was significantly better.

The Effect of Decreasing the Dosage of Cyclosporine A 0.05% on Dry Eye Disease After 1 Year of Twice-Daily Therapy

To evaluate the effect of decreasing topical cyclosporine 0.05% (tCSA) (Restasis; Allergan, Irvine, CA) from twice-daily dosing to once-daily dosing in patients who have already completed 12 months of twice-daily therapy for dry eye disease. Prospective, randomized, single-masked, parallel group comparison. One hundred patients who had already been treated with tCSA twice daily for more than 1 year were randomized either to continue tCSA twice daily (n = 50) or to decrease tCSA once daily (n = 50). Clinical measurement of dry eye variables was performed for all patients at baseline, 3 months, and 6 months. Mean data were used for within-group (longitudinal analysis) and between-group comparisons (once daily vs. twice daily). Fluorescein tear break-up time, corneal fluorescein staining score, lissamine green staining score, Schirmer tear test, and ocular surface disease index. At the end of the study, patients whose treatment dose was decreased to once daily demonstrated statistically significant improvement in tear break-up time [4.13 seconds (n = 37) vs. 3.11 seconds at baseline (n = 50); P = 0.0003] and lissamine green staining score [4.42 (n = 37) vs. 6.51 at baseline (n = 50); P = 0.024]; fluorescein staining score, Schirmer test results, and ocular surface disease index did not change significantly (P > 0.05). Furthermore, the once-daily group demonstrated significantly superior ocular surface disease index compared with the twice daily group [15.91 (n = 37) vs. 22.62 (n = 48); P = 0.0496]. The remaining outcome measures between once daily and twice daily were not significantly different (P > 0.05). Seven of 50 patients (14%) in the once-daily group (vs. 0% in the twice-daily group) ended the study early because of worsening dry eye symptoms (P < 0.05) and went back to twice-daily dosing. For patients with dry eye that has been controlled with tCSA twice daily for at least 1 year, decreasing to tCSA once daily may still allow suppression of the dry eye disease.

Raltegravir once daily or twice daily in previously untreated patients with HIV-1: a randomised, active-controlled, phase 3 non-inferiority trial

Twice-daily raltegravir with once-daily tenofovir-emtricitabine is an effective initial antiretroviral regimen for patients with HIV-1. On the basis of pharmacokinetic data suggesting efficacy of once-daily raltegravir and because adherence is often improved with once-daily dosing, we aimed to compare these dosing schedules. In our international, double-blind, randomised, phase 3 non-inferiority study, we enrolled antiretroviral-naive patients with HIV RNA loads of more than 5000 copies per mL and no baseline resistance to tenofovir or emtricitabine at 83 centres worldwide. We randomly allocated patients (1:1) by use of a computer-generated sequence to receive raltegravir once daily (two 400 mg tablets taken together every 24 h), or twice daily (one 400 mg tablet every 12 h), both in combination with once-daily co-formulated tenofovir 300 mg plus emtricitabine 150 mg. The primary outcome was virological response at 48 weeks (viral RNA loads <50 copies per mL) in patients who received at least one dose of study drug, counting non-completers as failure. We assessed non-inferiority in terms of the proportion of patients in both treatment groups who achieved the primary outcome, with a non-inferiority margin of -10%. This study is registered with ClinicalTrials.gov, number NCT00745823. From Oct 15, 2008, to Nov 2, 2009, we randomly allocated 775 patients, of whom 382 (99%) of 386 patients in the once-daily group and 388 (99%) of 389 in the twice-daily group received at least one dose of study drug. At baseline, 304 (39%) of 770 treated patients had viral loads of more than 100,000 copies per mL and 188 (24%) had CD4 cell counts of fewer than 200 cells per μL. 318 (83%) of 382 patients in the once-daily group had virological response compared with 343 (89%) of 386 in the twice-daily group (difference -5·7%, 95% CI -10·7 to -0·83; p=0·044). Serious adverse events were reported in 26 (7%) of 382 once-daily recipients and 40 (10%) of 388 twice-daily recipients, and adverse events leading to discontinuation occurred in four (1%) patients in each group. Despite high response rates with both regimens, once-daily raltegravir cannot be recommended in place of twice-daily dosing. Merck.

A Randomized, Placebo-Controlled Phase 3 Trial (Study SB-767905/012) of Alvimopan for Opioid-Induced Bowel Dysfunction in Patients With Non-Cancer Pain

Gastrointestinal (GI) side effects are common with opioid medication, and constipation affects ∼40% of patients. Such symptoms considerably impair patients' quality of life. Alvimopan is an orally administered, systemically available, peripherally acting mu-opioid receptor (PAM-OR) antagonist approved in the US for short-term, in-hospital management of postoperative ileus in patients undergoing bowel resection. This double-blind, placebo-controlled trial was conducted as part of a recently discontinued clinical program, in which alvimopan was being developed for opioid-induced constipation (OIC). Patients (N = 518) receiving opioids for non-cancer pain were randomized to receive alvimopan .5 mg once daily, alvimopan .5 mg twice daily, or placebo for 12 weeks. The primary efficacy endpoint was the proportion of patients experiencing ≥ 3 spontaneous bowel movements (SBMs; bowel movements with no laxative use in the previous 24 hours) per week over the treatment period and an average increase from baseline of ≥ 1 SBM per week. A significantly greater proportion of patients in the alvimopan .5 mg twice-daily group met the primary endpoint compared with placebo (72% versus 48%, P < .001). Treatment with alvimopan twice daily improved a number of other symptoms compared with placebo and reduced the requirement for rescue laxative use. The opioid-induced bowel dysfunction Symptoms Improvement Scale (SIS) responder rate was 40.4% in the alvimopan .5 mg twice daily group, versus 18.6% with placebo (P < .001). In general, alvimopan .5 mg once daily produced qualitatively similar but numerically smaller responses than twice-daily treatment. Active treatment did not increase the requirement for opioid medication or increase average pain intensity scores. Over the 12-week treatment period, alvimopan appeared to be well tolerated. These results demonstrate the potential for a PAM-OR antagonist to improve the symptoms of OIC without antagonizing opioid analgesia.

Review of A Large Clinical Series: Once- Versus Twice-Daily Enoxaparin for Venous Thromboembolism Prophylaxis in High-Risk Trauma Patients

Consensus guidelines support the use of low-molecular-weight heparin for venous thromboembolism (VTE) prophylaxis in high-risk trauma patients but do not recommend a specific regimen. The current study compared the effectiveness and safety of enoxaparin 40 mg once-daily versus enoxaparin 30 mg twice-daily for VTE prophylaxis in high-risk trauma patients. A retrospective chart review was conducted of all trauma patients older than 18 years of age admitted to Shands at the University of Florida between July 1, 2005 and June 30, 2007, who received either dosing regimen. Excluded were patients with Injury Severity Score <9, surviving <2 days, hospital length of stay <2 days, receipt of >1 agent, and/or dosing regimen for VTE prophylaxis during hospitalization, interruption in therapy, pregnancy, or diagnosis of a VTE within 24 hours of admission. A total of 409 patients were treated with once-daily dosing and 278 patients were treated with twice-daily dosing. The overall rate of VTE was 2.9% (95% confidence interval, 1.52, 5.07) in the once-daily group and 1.1% in the twice-daily group (95% confidence interval, 0.22, 3.12; P = .118). Major bleeding occurred in 11 patients in the once-daily group and 5 patients in the twice-daily group (1.8% vs 2.7%; P = .608). Enoxaparin 30 mg twice-daily may be more effective than enoxaparin 40 mg once-daily for prevention of VTE in high-risk trauma patients; however, statistical significance was not achieved. There were no statistically significant differences observed in clinically significant bleeding. Further study is needed to clarify which dosing regimen of enoxaparin is superior with regard to safety and effectiveness.