Allergy medication in Japanese volunteers: treatment effect of single doses on nocturnal sleep architecture and next day residual effects

OBJECTIVES: To evaluate the acute effects of two histamine H(1)-receptor antagonists on nocturnal sleep architecture and on next day cognitive function and psychomotor performance. METHODS: This was a single-site, randomized, double-blind, 3-way crossover study, comparing the effects of a single dose of chlorpheniramine (6 mg), fexofenadine (120 mg) and placebo in 18 healthy (male and female) Japanese volunteers aged 20-55 years. Volunteers were resident for 3 days and each period was separated by a minimum 5-day washout period. The three treatments were administered at 23.00 h. Overnight sleep was measured from 23.00 h to 07.00 h using polysomnography. Residual effects were studied at 07.00 h and 9.00 h the next morning, with the latency to sleep (sleep latency test) measured at 09.30 h. RESULTS: Compared with placebo, chlorpheniramine increased the latencies to sleep onset and rapid eye movement (REM) sleep (p < or = 0.05 for both), and reduced the duration of REM sleep (p 相似文献   

Efficacy and safety of eszopiclone across 6-weeks of treatment for primary insomnia

SUMMARY

Objective: Eszopiclone is a new, single-isomer, non-benzodiazepine, cyclopyrrolone agent under investigation for the treatment of insomnia. The present study was a randomized, double-blind, multicenter, placebo-controlled trial conducted to assess the efficacy and safety of eszopiclone in adults with chronic primary insomnia.

Research design and methods: Patients (n = 308) were randomized to receive placebo or eszopiclone (2?mg or 3?mg) for 44 consecutive nights, followed by 2 nights of single-blind placebo. Efficacy was evaluated with polysomnography (Nights 1, 15 and 29) and patient-reports (Nights 1, 15, 29 and 43/44). Next-day residual effects were evaluated using the Digit-Symbol Substitution Test (DSST).

Results: Eszopiclone 3?mg had significantly less time to sleep onset (?p ≤ 0.0001), more total sleep time and sleep efficiency (?p ≤ 0.0001), better sleep maintenance (p ≤ 0.01), and enhanced quality and depth of sleep (?p < 0.05) across the double-blind period compared with placebo. Eszopiclone 2?mg had significantly less time to sleep onset (?p ≤ 0.001), more total sleep time (?p ≤ 0.01) and sleep efficiency (?p ≤ 0.001), and enhanced quality and depth of sleep (?p < 0.05) compared with placebo, but did not significantly improve sleep maintenance. There was no evidence of tolerance or rebound insomnia after therapy discontinuation. Median DSST scores showed no decrement in psychomotor performance relative to baseline and did not differ from placebo in either eszopiclone group. Treatment was well tolerated; the most common adverse event related to eszopiclone was unpleasant taste.

Conclusions: Patients treated with nightly eszopiclone 3?mg had better polysomnographic (through Night 29) and patient-reported measures (through Night 44) of sleep over the 6-week trial. There was no evidence of tolerance or rebound insomnia and no detrimental effects on next-day psychomotor performance using the DSST.     

The efficacy of rofecoxib 50 mg and hydrocodone/acetamino­phen 7.5/750 mg in patients with post-arthroscopic pain

ABSTRACT

Objective: To compare the efficacy and tolerability of rofecoxib, hydrocodone/acetaminophen 7.5?mg/750?mg (H/A) and placebo in treating pain after arthroscopy of the knee.

Methods: A randomized, double-blind, placebo-controlled, single dose study enrolling patients experiencing moderate or severe pain after knee arthroscopy. Patients with moderate-to-severe postoperative pain received either rofecoxib 50?mg (n = 151), H/A (n = 145), or placebo (n = 147). Pain was measured over 24?h. The primary endpoint was total pain relief at 6?h for rofecoxib 50?mg compared with placebo.

Results: H/A (?p = 0.003), but not rofecoxib (?p = 0.256) was significantly more effective than placebo for total pain relief at 6?h (TOPAR6). Although analgesic onset and peak were significantly better for H/A than for both rofecoxib (?p < 0.01, p < 0.05, respectively) and placebo (?p < 0.05, p < 0.001, respectively), rofecoxib patients used significantly less rescue analgesia (?p < 0.001) over 24?h. Rofecoxib also provided better Brief Pain Inventory Severity (?p = 0.008) and Interference Domain (?p = 0.045) scores at 24?h compared to placebo and had lower 24?h Pain Severity scores than H/A (?p < 0.05). Treatments were generally well tolerated, with no significant difference in the frequency of patient-reported adverse events between groups.

Conclusions: Rofecoxib 50?mg did not provide significantly different pain relief than placebo at 6?h, and the primary endpoint TOPAR was not attained, although it did show several efficacy benefits at 24?h, including a significant opioid-sparing effect. All treatments were well tolerated, with no significant differences observed. The limited efficacy of rofecoxib in this study contrasts to the results of previous surgical studies evaluating rofecoxib, and may be partially explained by the postoperative dosing in this arthroscopic surgical model.     

The efficacy and safety of armodafinil as treatment for adults with excessive sleepiness associated with narcolepsy

ABSTRACT

Objective: This study assessed the efficacy and safety of armodafinil, the longer half-life enantiomer of modafinil, for the treatment of excessive sleepiness in patients with narcolepsy.

Research design and methods: This was a multicenter double-blind study with 196 patients (aged 18–65 years) randomized to receive armodafinil 150?mg (n = 65), armodafinil 250?mg (n = 67), or placebo (n = 64) once daily for 12 weeks.

Main outcome measures: Efficacy was assessed using the Maintenance of Wakefulness Test (MWT) (six 20‐min subtests across the day), the Clinical Global Impression of Change (CGI-C), subjective measures of sleepiness (Epworth Sleepiness Scale), patient diaries, and evaluations of cognitive performance (Cognitive Drug Research) and fatigue (Brief Fatigue Inventory).

Results: Armodafinil significantly increased MWT mean sleep latency (at 0900–1500) compared with placebo. The mean change from baseline at final visit for armodafinil was an increase of 1.3, 2.6, and 1.9?min in the 150‐mg, 250‐mg, and combined groups, respectively, compared with a decrease of 1.9?min for placebo (?p < 0.01 for all three comparisons). Mean late-day MWT latency (1500–1900) was also significantly improved (difference of armodafinil combined group relative to placebo at final visit: 2.8?min, p = 0.0358). The proportions of patients who showed at least minimal improvement in the CGI-C rating from baseline to final visit in the armodafinil 150‐mg, 250‐mg, and combined groups were 69%, 73%, and 71%, respectively, compared with 33% for placebo (?p < 0.0001). Both doses were associated with statistically significant improvements in memory, attention, and fatigue (?p < 0.05). The most common adverse events in patients receiving armodafinil were headache, nausea, and dizziness.

Conclusions: Armodafinil significantly improved ability to sustain wakefulness throughout the day in patients with narcolepsy. Armodafinil also significantly improved overall clinical condition, memory, attention, and fatigue when compared with placebo.     

A 2-night, 3-period,crossover study of ramelteon's efficacy and safety in older adults with chronic insomnia

ABSTRACT

Objective: To assess the efficacy and safety of ramelteon, a selective melatonin MT₁/MT₂-receptor agonist, for insomnia treatment in older adults.

Methods: In a randomized, 9?week, 3?period crossover trial conducted at 17 sleep centers, older adults (N = 100) with chronic primary insomnia (37 men, 63 women; mean age [range], 70.7 [65–83] years) were administered placebo, ramelteon 4?mg, and ramelteon 8?mg in three treatment phases for two consecutive nights. Each phase was separated by 5- to 12?day washout periods. Sleep was monitored via polysomnography. Subjective sleep parameters, using a Postsleep Questionnaire, were recorded, and residual pharmacologic effects were assessed.

Results: Statistically significant reductions in latency to persistent sleep were observed with both ramelteon 4?mg and 8?mg compared to placebo (28.7?min vs. 38.4?min, p < 0.001; 30.8?min vs. 38.4?min, p = 0.005, respectively). Total sleep time (p = 0.036 and p = 0.007,respectively) and sleep efficiency (p = 0.037 and p = 0.007, respectively) were also significantly improved with ramelteon 4?mg and 8?mg compared to placebo. Statistically significant reductions in subjective sleep latency on a Postsleep Questionnaire were reported with ramelteon 4?mg versus placebo (p = 0.037), but not ramelteon 8?mg (p = 0.120); no significant differences on other subjective sleep assessments were reported. A lack of power limits interpretation of self-reported sleep parameters. Incidences of adverse events considered treatment related were placebo (7%), ramelteon 4?mg (11%), and ramelteon 8?mg (5%). No residual pharmacologic effects were observed via Digit Symbol Substitution Test, memory recall tests (immediate and delayed), visual analog scales (feelings and mood), and Postsleep Questionnaire (level of alertness and ability to concentrate).

Conclusions: In older adults with chronic primary insomnia, ramelteon produced significant reductions in latency to persistent sleep and increases in total sleep time and sleep efficacy, and showed no evidence of adverse next-day psychomotor or cognitive effects.     

A polysomnography study of eszopiclone in elderly patients with insomnia

ABSTRACT

Objective: To evaluate the safety and efficacy of eszopiclone 2?mg in elderly patients (aged 64-86 years) with chronic insomnia.

Methods: This was a randomized, double-blind, placebo-controlled 2‐week study. Patients meeting DSM-IV criteria for primary insomnia and screening polysomnography criteria (wakefulness after sleep onset [WASO] ≥ 20?min and latency to persistent sleep ≥ 20?min) were randomized to 2 weeks of nightly treatment with eszopiclone 2?mg (n = 136) or placebo (n = 128). Efficacy was assessed using polysomnography (Nights 1, 2, 13, and 14) and patient reports (Nights 1–14); safety was assessed using adverse events, clinical labs, physical examination, and vital signs. The mean of all efficacy results during the double-blind period was used for the efficacy analysis.

Results: Results indicated that eszopiclone was associated with significantly shorter sleep onset, less WASO, higher sleep efficiency, more total sleep time, and greater patient-reported quality and depth of sleep scores than placebo (?p < 0.05 for all) with a trend in patient-reported morning sleepiness (?p = 0.07). Other measures of daytime functioning (ability to function, daytime alertness, and sense of well-being) were not significantly different between the two treatment groups. Among patients who napped, eszopiclone patients reported fewer naps (?p = 0.03) and less cumulative naptime (median: 98?min placebo, 70?min eszopiclone, p = 0.07). Unpleasant taste, dry mouth, somnolence, and dizziness were higher in the eszopiclone group (12.5%, 8.8%, 6.6%, and 6.6%, respectively) than in the placebo group (0%, 1.6%, 5.5%, and 1.6%, respectively).

Conclusion: In this study, eszopiclone was well tolerated and produced significant improvements in both polysomnographic and patient-reported measures of sleep maintenance, sleep induction, and sleep duration in elderly patients with chronic primary insomnia.     

A randomized controlled study comparing rofecoxib,diclofenac sodium,and placebo in post-bunionectomy pain

SUMMARY

Objective: The relative efficacy of rofecoxib, diclofenac sodium, and placebo were compared in the treatment of acute pain after bunionectomy surgery.

Research design and methods: This was a double-blind, randomized, two-part study of 252 patients with moderate-to-severe pain the day after first metatarsal bunionectomy. Patients were treated with a single dose of rofecoxib 50?mg (N = 85), enteric-coated diclofenac sodium 100?mg (N = 85), or placebo (N = 82) on study Day 1 (Part I), and subsequently with daily rofecoxib 50?mg or placebo (diclofenac patients switched to placebo) over study Days 2–5 (Part II). Patients rated their pain at 16 time points over the first 24?h. Primary endpoint was total pain relief over 8?h (TOPAR8). Pre-specified secondary endpoints on Day 1 included onset of analgesia, peak pain relief, and duration of response. For Part II, supplemental analgesia use with rofecoxib compared to placebo was pre-specified for analysis over Days 2–5, with the focus on Days 2–3. Adverse experiences were recorded over Days 1–5.

Results: For TOPAR8 scores, rofecoxib 50?mg was significantly more effective than placebo (9.5 vs. 3.7, p < 0.001) and diclofenac (9.5 vs. 5.0, p < 0.001). Onset of analgesia was more rapid with rofecoxib than placebo (?p = 0.003) and diclofenac (?p = 0.019); proportion of patients achieving onset within 4?h with rofecoxib, diclofenac, and placebo was 46%, 27%, and 23%, respectively. Peak pain relief was greater with rofecoxib (1.8) than diclofenac (1.2, p = 0.004) and placebo (1.0, p < 0.001). Diclofenac and placebo patients required supplemental analgesia sooner than rofecoxib patients (2:03?h vs. 4:02?h, p < 0.001 and 1:41?h vs. 4:02?h, p < 0.001). Rofecoxib patients used significantly less (?p < 0.001) supplemental analgesia than placebo patients over Days 2–3 (1.1?tablets/day vs. 2.1?tablets/day) and Days 2–5 (0.9?tablets/day vs. 1.8?tablets/day). No significant differences in adverse experiences between treatments were seen.

Conclusion: Rofecoxib 50?mg was significantly more effective than placebo on all measures of treatment of post-bunionectomy pain. Rofecoxib 50?mg was significantly more effective than diclofenac sodium 100?mg based on Day 1 endpoints of total pain relief, onset time, and duration of response. All study medications were generally well tolerated.     

The efficacy of tadalafil in improving sexual satisfaction and overall satisfaction in men with mild,moderate, and severe erectile dysfunction: a retrospective pooled analysis of data from randomized,placebo-controlled clinical trials

ABSTRACT

Background: Satisfaction with the sexual experience is considered important when evaluating the impact of treatments for erectile dysfunction (ED), yet satisfaction has been infrequently assessed in clinical trials.

Objective: To evaluate satisfaction with, and enjoyment of, the sexual experience in men with ED enrolled in 11 placebo-controlled clinical trials of tadalafil.

Study design and methods: Retrospective pooled analysis of data from 11 randomized, double blind, placebo-controlled clinical trials of tadalafil. Men with mild (N = 838), moderate (N = 558), or severe (N = 703) ED who were randomized to tadalafil 10?mg or 20?mg or placebo taken as needed for 12 weeks were included in this analysis. Efficacy measures included the International Index of Erectile Function (IIEF). Reported herein are the scores on the IIEF overall satisfaction domain and individual IIEF questions (IIEF‐Q7, satisfaction with intercourse; and IIEF‐Q8, enjoyment of intercourse).

Results: At least moderate satisfaction (IIEF overall satisfaction domain) was reported by 55% and 72% of patients with mild ED taking tadalafil 10?mg and 20?mg, respectively, compared with 33% taking placebo (?p < 0.002); 60% and 65% vs. 19% of patients with moderate ED (?p < 0.001); and 32% and 49% vs. 9% with severe ED (?p < 0.001). Satisfactory intercourse during most attempts or almost always/always (IIEF‐Q7) was reported by 59% and 79% of patients with mild ED taking tadalafil 10?mg and 20?mg vs. 32% taking placebo (?p < 0.001); 52% and 65% vs. 18% with moderate ED (?p < 0.001); and 28% and 49% vs. 5% with severe ED (?p < 0.001). Highly or very highly enjoyable intercourse (IIEF‐Q8) was reported by 45% and 63% of patients with mild ED taking tadalafil 10?mg and 20?mg vs. 21% taking placebo (?p < 0.001); 43% and 56% vs. 16% with moderate ED (?p < 0.001); and 19% and 44% vs. 5% with severe ED (?p < 0.001).

Conclusions: Compared with placebo, tadalafil 10?mg and 20?mg improved overall satisfaction with the sexual experience, intercourse satisfaction, and intercourse enjoyment in men with mild, moderate, and severe ED.     

Comparison of rofecoxib and a multidose oxycodone/acetaminophen regimen for the treatment of acute pain following oral surgery: a randomized controlled trial

SUMMARY

Objective: To compare the efficacy of a single dose of rofecoxib 50?mg with a single dose of oxycodone/acetaminophen 10/650?mg over 6?h as well as with a multidose regimen of oxycodone/acetaminophen 10/650?mg followed by oxycodone/acetaminophen 5/325?mg over 24?h.

Research design and methods: In this double-blind, randomized, two-phase study, patients with moderate to severe pain after surgical extraction of ≥ 2 third molars, including one mandibular impaction, were treated with rofecoxib 50?mg, oxycodone/acetaminophen 10/650?mg (single-dose phase) followed by 5/325?mg every 6?h as needed (multidose phase), or placebo. Patients rated their pain relief and intensity at 18 time points over 24?h. Efficacy was measured over 6 and 24?h by total pain relief (TOPAR), sum of pain intensity difference (SPID), and patient global assessment of response to therapy (PGART). Primary endpoint for the single dose comparison was TOPAR over 6?h; SPID was the key 24-h endpoint. Onset of analgesic effect, peak analgesic effect, and duration of analgesic effect were also evaluated. Adverse experiences were recorded.

Results: 271 patients were randomized to treatment with rofecoxib (n = 121), oxycodone/acetaminophen (n = 120), or placebo (n = 30). For the single dose comparison, rofecoxib-treated patients achieved pain relief at least as effective as oxycodone/acetaminophen-treated patients as assessed by TOPAR6 (12.9 vs 11.3, 95% CI on difference = [–0.1, 3.2], p = 0.059). Patients also rated a single dose of rofecoxib as at least as effective as multidose oxycodone/acetaminophen over 24?h on SPID24 (21.9 vs 18.1, 95% CI on difference = [–1.0, 8.8], p = 0.122). Patients treated with oxycodone/acetaminophen had a shorter time to onset of analgesia than patients treated with rofecoxib (24 vs 35?min, p < 0.05). Patients in the active treatment groups achieved similar peak effects during the single-dose phase. Individuals treated with rofecoxib demonstrated a longer duration of analgesic effect than those treated with a single dose of oxycodone/acetaminophen. Patients on active treatment demonstrated better efficacy than patients on placebo on these prespecified endpoints (?p < 0.001 for both comparisons). Fewer rofecoxib than oxycodone/acetaminophen patients experienced adverse events (47.9 vs 75.8%, p < 0.001), including nausea (19.0 vs 42.5%, p < 0.001), vomiting (9.9 vs 24.2%, p < 0.01), and dizziness (7.4 vs 31.7%, p < 0.001).

Conclusion: Patients treated with a single dose of rofecoxib 50?mg achieved an overall analgesic effect at least as effective as patients treated with a single-dose of oxycodone/acetaminophen 10/650?mg over 6?h and multidose oxycodone/acetaminophen over 24?h, with fewer adverse experiences of nausea (?p < 0.001), vomiting (?p < 0.01), and dizziness (?p < 0.001).     

Post-bedtime dosing with indiplon in adults and the elderly: results from two placebo-controlled,active comparator crossover studies in healthy volunteers

ABSTRACT

Objective: To assess the effects of post-bedtime dosing with indiplon on next-day function in adults and the elderly.

Research design and methods: Two randomized, double-blind, placebo-controlled crossover studies were conducted in two groups of healthy volunteers: an adult study (18–45 years) and an elderly study (65–80 years). In adults, a single post-bedtime dose of indiplon 10?mg and 20?mg was compared to placebo, with zolpidem 10?mg and zopiclone 7.5?mg included as controls. In the elderly, a single post-bedtime dose of indiplon 5?mg and 10?mg was compared to placebo, with zopiclone 3.75?mg included as a control. Next-day residual effects were evaluated in the morning at 4 and 6?h post-dose in adults, and 4, 6, and 8?h in the elderly, by a Visual Analog Scale of sleepiness (VAS-sleepiness), Digit Symbol Substitution Test (DSST), and the Symbol Copying Test (SCT).

Results: In adults, there were no statistically significant differences between indiplon and placebo on the VAS-sleepiness, DSST, or SCT at any timepoint for either dose. In contrast, a significant increase versus placebo in VAS-sleepiness was observed for both zopiclone (at 4 and 6?h post-dose; p < 0.0001 and p = 0.002, respectively) and zolpidem (at 4?h post-dose; p = 0.042). In the elderly, there were no statistically significant differences between indiplon 5?mg and placebo on the VAS-sleepiness, DSST, or SCT at any timepoint. DSST was significantly reduced for indiplon 10?mg versus placebo at 4?h only (?p = 0.022), compared with a significant reduction in DSST for zopiclone at both 4 and 8?h post-dose (?p = 0.002 and p = 0.003, respectively). In adults, the overall incidence of adverse events was higher on zopiclone compared to indiplon, zolpidem, and placebo. In the elderly, the incidence of adverse events was similar for indiplon, zopiclone, and placebo. Potential limitations of the current study include recruitment of healthy volunteers and the use of a limited pharmacodynamic battery.

Conclusions: Indiplon, at doses of 10?mg in adults and 5?mg in the elderly, was not associated with next day residual sedation or impairment in simple cognitive and psychomotor tasks when administered during the night 4?h prior to awakening.     

Efficacy and tolerability of twice-daily pregabalin for treating pain and related sleep interference in postherpetic neuralgia: a 13‐week,randomized trial

ABSTRACT

Objective: This trial evaluated the efficacy and safety of pregabalin dosed twice daily (BID) for relief of neuro-pathic pain associated with postherpetic neuralgia (PHN).

Research design and methods: The 13‐week, double-blind, placebo-controlled study randomized 370 patients with PHN to pregabalin (150, 300, or 600?mg/day BID) or placebo.

Main outcome measures: Primary efficacy measure was endpoint mean pain score from daily pain diaries. Secondary efficacy measures included endpoint mean sleep-interference score from daily sleep diaries and Patient Global Impression of Change (PGIC). Safety evaluations included adverse events (AEs), physical and neurologic examinations, 12-lead ECG, vital signs, and laboratory testing.

Results: Pregabalin provided significant, dose-proportional pain relief at endpoint: difference from placebo in mean pain score, 150?mg/day, –0.88, p = 0.0077; 300?mg/day, –1.07, p = 0.0016; 600?mg/day, –1.79, p = 0.0003. Weekly mean pain scores significantly improved as early as week 1. Sleep interference in all pregabalin groups was also significantly improved at endpoint, compared with placebo (?p < 0.001), beginning at week 1 (?p < 0.01). At study termination, patients in the 150 (p = 0.02) and 600?mg/day (p = 0.003) groups were more likely to report global improvement than were those in the placebo group.

Most AEs were mild or moderate. Among pregabalin-treated patients, 13.5% withdrew due to AEs, most commonly for dizziness (16 patients, 5.8%), somnolence (8, 2.9%), or ataxia (7, 2.5%).

Conclusions: Pregabalin, dosed BID, reduced neuropathic pain associated with PHN and was well tolerated. It also reduced the extent to which pain interfered with sleep. Pregabalin's effects were seen as early as week 1 and were sustained throughout the 13‐week study.     

The analgesic effect of etoricoxib relative to that of two opioid-acetaminophen analgesics: a randomized,controlled single-dose study in acute dental impaction pain

ABSTRACT

Background: To compare the analgesic effect of single doses of etoricoxib 120?mg, oxycodone/acetaminophen 10?mg/650?mg and codeine/acetaminophen 60?mg/600?mg in acute pain using the dental impaction model.

Methods: In this randomized, double-blind, placebo-controlled, parallel-group study, patients reported pain intensity and pain relief (16 times) and global scores (twice) during a 24-h period. The primary endpoint was the overall analgesic effect, total pain relief over 6?h (TOPAR6). Other endpoints were patient global evaluation, time to onset (2-stopwatch method), duration of analgesic effect (median time to and amount of rescue medication use). Tolerability was evaluated by overall and opioid-related (nausea and vomiting) adverse experiences.

Results: 302 patients (mean age 23; 63% women; 63 % White) were randomized to etoricoxib 120?mg, oxycodone/acetaminophen 10?mg/650?mg, codeine/acetaminophen 60?mg/600?mg, and placebo (2:2:1:1). Etoricoxib demonstrated significantly greater overall analgesic efficacy (TOPAR6) (13.2?units) versus oxycodone/acetaminophen (10.2?units); and codeine/acetaminophen (6.0?units); p < 0.001 for all. All active treatments were superior to placebo. Median time to onset was significantly (?p < 0.001) shorter for oxycodone/acetaminophen (20?min) and numerically but not significantly shorter (?p = 0.259) for codeine/acetaminophen (26?min) compared with etoricoxib (40?min). Etoricoxib (24?h) had a significantly longer lasting analgesic effect than oxycodone/acetaminophen (5.3?h), codeine/acetaminophen (2.7?h), and placebo (1.7?h) (?p < 0.001 for all). Etoricoxib patients experienced fewer clinical adverse experiences than patients on oxycodone/acetaminophen and codeine/acetaminophen, specifically, significantly (?p < 0.05) fewer episodes of nausea.

Conclusion: Etoricoxib 120?mg provided superior overall analgesic effect with a smaller percentage of patients experiencing nausea versus both oxycodone/acetaminophen 10?mg/650?mg and codeine/acetaminophen 60?mg/600?mg.     

Lipid-altering efficacy of the ezetimibe/simvastatin single tablet versus rosuvastatin in hypercholesterolemic patients

ABSTRACT

Objective: To assess the lipid-altering efficacy and safety of ezetimibe/simvastatin single tablet product compared with rosuvastatin at the approved usual starting, next highest, and maximum doses.

Research design and methods: Double-blind, multicenter, 6‐week, parallel-group study in hypercholesterolemic patients (n = 2959). Patients were randomized based on stratification by low-density lipoprotein cholesterol (LDL-C) levels to ezetimibe/simvastatin or rosuvastatin, respectively, at the usual starting (10/20 or 10?mg/day), the next highest (10/40 or 20?mg/day), and maximum doses (10/80 or 40?mg/day).

Results: At all doses and across doses, ezetimibe/simvastatin reduced LDL‐C levels significantly more (52–61%) than rosuvastatin (46–57%; p ≤ 0.001). Significantly greater percentages of all patients (p < 0.001) and high risk patients (p ≤ 0.005) attained LDL‐C levels < 70?mg/dL (1.8?mmol/L) following ezetimibe/simvastatin treatment compared with rosuvastatin at the prespecified doses and across doses. Ezetimibe/simvastatin also produced significantly greater reductions in total cholesterol (?p < 0.001), non-high-density lipoprotein cholesterol (?p < 0.001), lipid ratios (?p ≤ 0.003), and apolipoprotein B (?p < 0.05). Reductions in triglycerides were significantly greater with ezetimibe/simvastatin than rosuvastatin at the usual starting (?p = 0.004) and next highest (?p = 0.006) doses, and across all doses (?p < 0.001). Increases in high-density lipoprotein cholesterol, and decreases in high sensitivity C reactive protein (hsCRP) were similar between treatment groups. Safety profiles were comparable for both treatments; however, the percent of patients with proteinuria was significantly higher following rosuvastatin treatment than ezetimibe/simvastatin, respectively at 10?mg versus 10/20?mg/day (?p = 0.004) and 40?mg versus 10/80?mg/day (?p < 0.001).

Conclusion: Ezetimibe/simvastatin was more effective than rosuvastatin in LDL‐C lowering, and provided greater or comparable improvements in other lipid measures and hsCRP at the approved usual starting, next highest, and maximum doses in hypercholesterolemic patients. Although the doses compared in this study were not equivalent on a milligram basis, the results provide clinically relevant information regarding the use of these drugs for initial therapy and for subsequent use at higher doses when appropriate. Both treatments were generally well-tolerated; however, this study was not powered nor of sufficient duration to assess the prevalence of rare clinical adverse effects. Overall, ezetimibe/simvastatin offers an effective and tolerable treatment option for lipid management. An assessment of its full clinical benefit awaits evaluation in longer-term clinical studies.     

Randomized,placebo-controlled comparison of early use of frovatriptan in a migraine attack versus dosing after the headache has become moderate or severe

SUMMARY

Objective: To evaluate whether frovatriptan would provide greater relief if given early during a migraine attack.

Research design and methods: Adults with a history of migraine of at least 1?year, and who had 2–8 headaches in the previous month were recruited from 19 US centres for a prospective, placebo-controlled crossover study over 2 migraine attacks. Dose 1 was taken at the onset of mild migraine headache, Dose 2 was taken at least 2?h later if the headache progressed to moderate/severe. Patients were randomized to receive Dose 1 frovatriptan then Dose 2 placebo or Dose 1 placebo followed by Dose 2 frovatriptan. Treatment order was reversed for the second attack. This schedule enabled a comparison of frovatriptan with placebo and a comparison of early and later treatment with frovatriptan.

Main outcome measures: Freedom from pain at 2?h for frovatriptan versus placebo as Dose 1; use of Dose 2 and/or rescue medication, pain severity, functional impairment and headache recurrence.

Results: In 241 patients who each treated 2 migraine attacks, Dose 1 frovatriptan was more effective than placebo in terms of the proportion of patients who were pain free at 2?h (28% vs 20%, p = 0.04). This benefit was sustained up to 4?h post-dose (?p = 0.003). Early use of frovatriptan significantly reduced re-medication (?p < 0.001). Twenty-four-hour headache recurrence was low in both early (4%) and later use (6%) groups. Sustained pain-free response occurred in 40% of frovatriptan early use patients compared with 31% of later use patients (?p < 0.05). Early use prevented headache progression: 69%–78% had mild/no headache 2–4?h after Dose 1 frovatriptan compared with 54%–63% taking Dose 1 placebo (?p < 0.001). Early use reduced pain burden and functional disability (?p ≤ 0.001). More patients rated early use of frovatriptan as excellent or good (57% vs 46%).

Conclusions: Early use of frovatriptan resulted in a higher, earlier and sustained pain-free response, prevented progression to moderate/severe headache and reduced pain burden and functional disability.     

Pain relief and pain-related sleep disturbance with extended-release tramadol in patients with osteoarthritis

ABSTRACT

Objective: This analysis evaluated changes in pain and pain-related sleep disturbance with extended-release tramadol (tramadol ER) in patients with moderate, chronic osteoarthritis pain, and the influence of pain reduction on pain-related sleep disturbance.

Methods: Data were obtained from a 12?week, randomized, double-blind, placebo-controlled, fixed-dose study of tramadol ER 100?mg, 200?mg, 300?mg, or 400?mg once daily. Subjects reported osteoarthritis pain intensity with a 100?mm visual analog scale (VAS; 0 = no pain, 100 = extreme pain). A Sleep Problems Index score from 0 to 100?mm (0 = never, 100 = always) was determined from the mean of three subject-reported scores of pain-related sleep disturbance.

Results: A total of 815 subjects received tramadol ER (all doses combined) and 205 received placebo. Mean pain reduction at 12 weeks was –30.4?mm and –21.5?mm for tramadol ER and placebo, respectively (?p < 0.001). Tramadol ER-treated subjects were nearly twice as likely as placebo subjects to have clinically meaningful pain reduction at 12 weeks, defined as 30?mm or greater reduction (odds ratio [OR] = 1.84, p < 0.001) or 30% or greater reduction (OR = 1.95, p < 0.001) in pain. Clinically meaningful reduction of pain-related sleep disturbance at 12 weeks, defined as 16?mm or greater improvement on the Sleep Problems Index, was more common for tramadol ER than placebo (51% vs. 42%, respectively, p = 0.022). Pain reduction was associated with reduced pain-related sleep disturbance (R = 0.51). Study treatment was generally well tolerated. Possible limitations included homogeneity of pain scores at baseline and the effect of adverse events on sleep analyses.

Conclusions: In patients with chronic osteoarthritis pain, pain reduction is associated with decreased pain-related sleep disturbance.     

Effectiveness of simvastatin therapy in raising HDL-C in patients with type 2 diabetes and low HDL-C

SUMMARY

Objective: To evaluate the efficacy of high and moderate doses of simvastatin (80 and 40?mg), for raising high density lipoprotein-cholesterol (HDL-C), improving HDL sub-fractions, and affecting other parameters, including high sensitivity C-reactive protein (hs-CRP), in patients with type 2 diabetes mellitus (DM) and low HDL-C.

Research design and methods: This double-blind, placebo-controlled, randomized, 3-period, complete block, 6-week crossover study examined the efficacy of simvastatin in adult men and women (N = 151) with stable type 2 DM (HbA_1C < 9%), low density lipoprotein-cholesterol (LDL-C) > 100?mg/dL (2.6?mmol/L), HDL-C < 40?mg/dL (< 1?mmol/L), and fasting triglyceride level > 150 (> 1.7?mmol/L) and < 700?mg/dL (< 7.9?mmol/L). This study included adult men (71%) and women (29%) of various races (89% white, 6% black, 1% Asian, 3% other) enrolled from 29 practice-based sites in the United States.

Main outcome measures: Percentage change in HDL-C from baseline at the end of each 6-week treatment interval.

Results: Both simvastatin 80 and 40?mg significantly increased total HDL-C from baseline (mean increases of 8% ± 1 [SE] and 5% ± 1, respectively; p < 0.001) compared with placebo, and significantly reduced plasma concentrations of LDL-C (?p < 0.001), triglycerides (?p < 0.001), apolipoprotein B (?p < 0.001), and hs-CRP (?p ≤ 0.012). Compared with simvastatin 40?mg, the 80?mg dose provided additional efficacy. Simvastatin 80?mg also significantly (?p < 0.001) increased HDL₂ from baseline (14% ± 3[SE]) and placebo phases (10 ± 3). An exploratory analysis showed 87% (simvastatin 80?mg) and 82% (simvastatin 40?mg) of patients reached the NCEP ATP III treatment goals for LDL-C compared with 14% on placebo.

Conclusions: Both simvastatin 80 and 40?mg raise HDL-C and improve other measures associated with elevated coronary risk in patients with type 2 DM and low HDL-C.     

Efficacy of a paracetamol and caffeine combination in the treatment of the key symptoms of primary dysmenorrhoea

ABSTRACT

Objective: Primary dysmenorrhoea is characterised by pain, cramping and backache at the time of menses. Despite the high prevalence of dysmenorrhoea, few sufficiently powered, placebo-controlled studies have examined the efficacy of over the counter analgesics in this condition. Furthermore, even fewer studies have directly examined the efficacy of analgesics on specific dysmenorrhoea symptoms.

Research design and main outcome measures: This was a single-dose, placebo-controlled, double blind, crossover study carried out in 320 women with moderate-to-severe dysmenorrhoea pain. At 2?h following dosing, 1?g paracetamol plus 130?mg caffeine led to significantly greater pain relief compared to 1?g paracetamol alone (?p < 0.05), 130?mg caffeine alone (?p < 0.01) or placebo (?p < 0.01). The combination was also significantly more effective in relieving abdominal cramping and backache compared to the other treatment arms. No major treatment related adverse events were reported during this study.

Conclusions: When taken at recommended doses, both paracetamol and the combination of paracetamol and caffeine are safe and effective treatments for primary dysmenorrhoea. Consistent with results from other acute pain states, caffeine acts as an analgesic adjuvant and enhances the efficacy of paracetamol.     

Effect of pramlintide as an adjunct to basal insulin on markers of cardiovascular risk in patients with type 2 diabetes

ABSTRACT

Objective: Intensification of insulin therapy in patients with type 2 diabetes, while improving glycemic control, often leads to an increase in body weight and other markers of cardiovascular risk. The effects of pramlintide as an adjunct to basal insulin titration (without mealtime insulin) on glycemia and cardiovascular risk markers were examined.

Research design and methods: This was a post hoc analysis of a 16-week, double-blind, placebo-controlled study in patients with type 2 diabetes (N?=?211) using insulin glargine (without mealtime insulin)?±?oral agents. Patients were randomized to treatment with placebo or pramlintide (60 or 120?µg with major meals), and insulin glargine was titrated to target a fasting plasma glucose concentration of ≥70 to <100?mg/dL.

Main outcome measures: Endpoints included the change from baseline to Week 16 in body weight, high sensitivity C-reactive protein (hsCRP), triglycerides, HDL, LDL, and blood pressure.

Results: Pramlintide-treated patients lost weight and placebo-treated patients gained weight during 16 weeks of treatment (?1.6?±?0.3?kg vs. +0.7?±?0.3?kg, p?<?0.001; mean?±?SE). hsCRP was reduced in pramlintide-treated versus placebo-treated patients (?0.8?±?0.2?mg/L vs. 0.1?±?0.2?mg/L, p?<?0.01; mean?±?SE). Patients with baseline hsCRP?>?3?mg/L (high cardiovascular risk) demonstrated greater hsCRP reductions with pramlintide versus placebo treatment at Week 16 (p?<?0.05). Patients with baseline triglycerides ≥150?mg/dL or ≥200?mg/dL (high cardiovascular risk) showed significant reductions from baseline in triglyceride concentrations with pramlintide (?43?±?14?mg/dL or ?59?±?19?mg/dL; p?<?0.05; mean?±?SE) but not with placebo (1?±?29?mg/dLor ?3?±?54?mg/dL; mean?±?SE). No significant differences between pramlintide and placebo were observed for changes in HDL, LDL, or blood pressure. Pramlintide treatment was generally well tolerated. The most frequent adverse event related to pramlintide was mild-to-moderate nausea (31% pramlintide vs. 10% placebo). Pramlintide added to basal insulin did not increase the incidence of hypoglycemia. A limitation of the study was its relatively short duration.

Conclusions: Pramlintide, as an adjunct to basal insulin, was associated with improvements in several cardiovascular risk markers, warranting long-term clinical studies to determine its potential effects on cardiovascular risk.     

The Effects of Single and Repeated Administration of Ebastine on Cognition and Psychomotor Performance in Comparison to Triprolidine and Placebo in Healthy Volunteers

Summary

Objective:The cognitive and psychomotor effects of 10?mg, 20?mg and 30?mg ebastine, a second generation H1-receptor antagonist, were compared with sustained release triprolidine 10mg (as averum) and placebo in 10 healthy volunteers in a double-blind, randomised crossover study.

Methods: Following each dose, subjects were required to perform a series of tests of cognitive function and psychomotor performance at 1?h, 2?h, 4?h and 8?h post-dose on days 1 and 5. The test battery consisted of critical flicker fusion, choice reaction time, simulated car tracking task, Sternberg memory scanning task, assessment of subjective sedation (LARS) and subjective evaluation of sleep (LSEQ).

Results: Ebastine at all doses investigated was not statistically significant from placebo in any of the objective tests used. However, as expected for a positive internal control, a number of objective measures were significantly disrupted by triprolidine (p?<?0.05). Triprolidine produced an overall increase of the peripheral reaction time component of the simulated car tracking task (SCTT), the I difference with placebo reaching statistical significance on day 1,8?h post-dose (p?<?0.05). The mean tracking accuracy scores were also significantly impaired following the administration of triprolidine after 8?h on day 1 (p?<?0.05). Triprolidine also produced a clear decrement on the SMST (Sternberg Memory Scanning Task), which was significantly different from placebo, at 4?h and 8?h post-dose on day 1. Subjective reports of sedation (LARS) were significantly greater at 2?h and 4?h following triprolidine administration on day 1 and ebastine (30?mg) was rated as sedative 4?h following administration on day 5. The perceived sedative activity of ebastine 30?mg was also reflected in the subjective reports on the LSEQ on day 1 (p?<?0.05).

Conclusions: These results allow the conclusion that ebastine, at its recommended therapeutic doses of 10–20?mg, is demonstrably free from impairment on objective aspects of psychomotor and cognitive function in a study where the psychometric assessments were shown to be sensitive to disruptive effects, as evidenced by the action of the positive control, triprolidine 10?mg.     

Exenatide effects on diabetes,obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years

ABSTRACT

Background: Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes (T2DM), reduced hemoglobin A_1c (A1C) and weight in clinical trials. The objective of this study was to evaluate the effects of?≥?3 years exenatide therapy on glycemic control, body weight, cardiometabolic markers, and safety.

Methods: Patients from three placebo-controlled trials and their open-label extensions were enrolled into one open-ended, open-label clinical trial. Patients were randomized to twice daily (BID) placebo, 5?µg exenatide, or 10?µg exenatide for 30 weeks, followed by 5?µg exenatide BID for 4 weeks, then 10?µg exenatide BID for ≥3 years of exenatide exposure. Patients continued metformin and/or sulfonylureas.

Results: 217 patients (64% male, age 58?±?10 years, weight 99?±?18?kg, BMI 34?±?5?kg/m², A1C 8.2?±?1.0% [mean?±?SD]) completed 3 years of exenatide exposure. Reductions in A1C from baseline to week 12 (?1.1?±?0.1% [mean?±?SEM]) were sustained to 3 years (?1.0?±?0.1%; p?<?0.0001), with 46% achieving A1C?≤?7%. Exenatide progressively reduced body weight from baseline (?5.3?±?0.4?kg at 3 years; p?<?0.0001). Patients with elevated serum alanine aminotransferase (ALT) at baseline (n?=?116) had reduced ALT (?10.4?±?1.5?IU/L; p?<?0.0001) and 41% achieved normal ALT. Patients with elevated ALT at baseline tended to lose more weight than patients with normal ALT at baseline (?6.1?±?0.6?kg vs. ?4.4?±?0.5?kg; p?=?0.03), however weight change was minimally correlated with baseline ALT (r?=??0.01) or ALT change (r?=?0.31). Homeostasis Model Assessment B (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. A subset achieved 3.5 years of exenatide exposure and had serum lipids available for analysis (n?=?151). Triglycerides decreased 12% (p?=?0.0003), total cholesterol decreased 5% (p?=?0.0007), LDL-C decreased 6% (p?<?0.0001), and HDL-C increased 24% (p <?0.0001). Exenatide was generally well tolerated. The most frequent adverse event was mild-to-moderate nausea. The main limitation of this study is the open-label, uncontrolled nature of the study design which does not provide a placebo group for comparison.

Conclusion: Adjunctive exenatide treatment for ≥3 years in T2DM patients resulted in sustained improvements in glycemic control, cardiovascular risk factors, and hepatic biomarkers, coupled with progressive weight reduction.