Evidence Of Residual Effects Research Articles

Daridorexant in Japanese patients with insomnia disorder: A phase 3, randomized, double-blind, placebo-controlled study

ObjectiveThis Phase 3 double-blind, placebo-controlled study evaluated the efficacy and safety of daridorexant in Japanese patients with insomnia disorder. Patients/methods490 patients with insomnia disorder from 95 sites in Japan were randomized to daridorexant 50 mg (n = 163), 25 mg (n = 163) or placebo (n = 164) for 4 weeks, followed by a 7-day placebo run-out and a 30-day safety follow-up. The primary efficacy endpoints, in hierarchical order, were change from baseline at Week 4 in subjective total sleep time (sTST) and subjective latency to sleep onset (sLSO), for daridorexant 50 mg vs placebo. sTST and sLSO were also evaluated (secondary endpoints) for daridorexant 25 mg vs placebo. Safety endpoints included adverse events and next-morning sleepiness (Visual Analog Scale, VAS). ResultsDaridorexant 50 mg significantly increased sTST and decreased sLSO versus placebo at Week 4 (least-squares mean difference [LSMD]: sTST 20.3 min [95 % CI 11.4, 29.2] p < 0.001; sLSO −10.7 min [−15.8, −5.5] p < 0.001). Daridorexant 25 mg also significantly improved both endpoints versus placebo (LSMD: sTST 9.2 min [0.3, 18.1] p = 0.042; sLSO −7.2 min [-12.3, −2.0] p = 0.006). Overall incidence of adverse events was similar across groups (50 mg: 22 %; 25 mg: 18 %; placebo 23 %); somnolence, the most common event, increased with increasing dose (50 mg: 6.8 %; 25 mg: 3.7 %; placebo 1.8 %). However, daridorexant did not increase VAS next-morning sleepiness. No rebound or withdrawal-related symptoms were observed after treatment discontinuation. ConclusionsIn Japanese patients with insomnia disorder, daridorexant (25 and 50 mg) was well tolerated and significantly improved subjective sleep outcomes, with no evidence of residual effects.

Acute and residual effects of smoked cannabis: Impact on driving speed and lateral control, heart rate, and self-reported drug effects

BackgroundAlthough driving under the influence of cannabis is increasingly common among young adults, little is known about residual effects on driver behavior. This study examined acute and residual effects of smoked cannabis on simulated driving performance of young cannabis users. MethodsIn this double-blind, placebo-controlled, parallel-group randomized clinical trial, cannabis users (1–4 days/week) aged 19–25 years were randomized with a 2:1 allocation ratio to receive active (12.5% THC) or placebo (0.009% THC) cannabis in a single 750 mg cigarette. A median split (based on whole-blood THC concentrations at the time of driving) was used to divide the active group into low and high THC groups. Our primary outcome was simulated driving performance, assessed 30 min and 24 and 48 h after smoking. Secondary outcomes included blood THC concentrations, subjective drug effects, and heart rate. ResultsNinety-six participants were randomized, and 91 were included in the final analysis (30 high THC, 31 low THC, 30 placebo). Mean speed (but not lateral control) significantly differed between groups 30 min after smoking cannabis (p ≤ 0.02); low and high THC groups decreased their speed compared to placebo. Heart rate, VAS drug effect and drug high increased significantly immediately after smoking cannabis and declined steadily after that. There was little evidence of residual effects in any of the measures. ConclusionAcutely, cannabis caused decreased speed, increased heart rate, and increases in VAS drug effect and drug high. There was no evidence of residual effects on these measures over the two days following cannabis administration.

Risk Assessment of Anatoxin-A

Current natural conditions as well as human activities have been promoting changes and increasing stress in the freshwater and marine environment. One of the consequences is the worldwide occurrence of cyanobacterial (blue-green algae) blooms, which is considered a serious environmental and economic problem (ARAOZ, et al 2005). Risk assessment of cyanotoxins is made more difficult by the lack of scientifically-sound toxicological and epidemiological studies. The available animal data is limited, principally chronic or long term effects. The lack of data is reflected in the fact that a WHO guideline has been agreed only for one group of cyanotoxins (microcystins) (CHORUS and BARTRAM, 2003). Until now, there has been paid little attention to the assessment of risk to drinking water consumers of anatoxin-a, mainly because the suspicion of the rapid excretion of this toxin from the body, no evidence of residual effects and low free-water concentrations in lakes (FALCONER and HUMEPAGE, 2005). Therefore, the aim of this work is to accomplish the risk assessment of anatoxin-a, by approaching three main steps of this process: hazard identification and characterization, exposure assessment, and risk characterization, since the presence of Anabaena sp. blooms capable to produce anatoxin-a are common in Sao Paulo reservoirs, mainly in spring and summer seasons. Additionally, previous data has shown that this toxin can be found in other Brazilian freshwater reservoirs.

Effects of suvorexant, an orexin receptor antagonist, on sleep parameters as measured by polysomnography in healthy men.

Suvorexant (MK-4305) is an orexin receptor antagonist being developed for the treatment of insomnia. This report describes the effects of nighttime administration of suvorexant on polysomnography (PSG) sleep parameters in healthy young men. Randomized, double-blind, placebo-controlled, 4-period crossover PSG study, followed by an additional 5(th) period to assess pharmacokinetics. Sleep laboratory. Healthy young men between 18 and 45 years of age (22 enrolled, 19 completed). Periods 1-4: suvorexant (10 mg, 50 mg, or 100 mg) or placebo 1 h before nighttime PSG recording. Period 5: suvorexant 10 mg, 50 mg, or 100 mg. In Periods 1-4, overnight sleep parameters were recorded by PSG and next-morning residual effects were assessed by psychomotor performance tests and subjective assessments. Statistically significant sleep-promoting effects were observed with all doses of suvorexant compared to placebo. Suvorexant 50 mg and 100 mg significantly decreased latency to persistent sleep and wake after sleep onset time, and increased sleep efficiency. Suvorexant 10 mg significantly decreased wake after sleep onset time. There were no statistically significant effects of suvorexant on EEG frequency bands including delta (slow wave) activity based on power spectral analysis. Suvorexant was well tolerated. There was no evidence of next-day residual effects for suvorexant 10 mg. Suvorexant 50 mg statistically significantly reduced subjective alertness, and suvorexant 100 mg significantly increased reaction time and reduced subjective alertness. There were no statistically significant effects of any suvorexant dose on digit symbol substitution test performance. In Period 5, plasma samples of suvorexant were collected for pharmacokinetic evaluation. The median T(max) was 3 hours and apparent terminal t(½) was 9-13 hours. In healthy young men without sleep disorders, suvorexant promoted sleep with some evidence of residual effects at the highest doses.

The Effect of Sleep Medications on Cognitive Recovery From Traumatic Brain Injury

To summarize the literature on the available pharmacotherapy for insomnia and the adverse cognitive effects of those options in persons with traumatic brain injury (TBI). Ovid/MEDLINE databases were searched by using the following key words: "brain injury," "sleep initiation and maintenance disorders," "hypnotics and sedatives," "benzodiazepines," "trazodone," and "neuronal plasticity." The reviewed literature consistently reported that benzodiazepines and atypical gamma-aminobutyric acid (GABA) agonists result in cognitive impairment when plasma levels are at their peak. Evidence of residual effects on cognition was reported for benzodiazepines but was seen less often in atypical GABA agonists. However, evidence has also been presented that GABA agonists have adverse effects on neuroplasticity, raising concerns about their use in patients recovering from TBI. Use of benzodiazepines in TBI has been discouraged and some authors also advocate caution in prescribing atypical GABA agonists. Alternate treatments including trazodone and a newer class of agents, melatonin agonists, are highlighted, along with the limited data available addressing the use of these medications in TBI. Finally, suggestions are offered for further research, especially on topic related to neural plasticity and functional recovery.

Development of Bacterial Spot on Near-Isogenic Lines of Bell Pepper Carrying Gene Pyramids Composed of Defeated Major Resistance Genes

ABSTRACT Disease severity caused by races 1 through 6 of Xanthomonas campestris pv. vesicatoria on eight near-isogenic lines (isolines) of Early Calwonder (ECW) with three major resistance genes (Bs1, Bs2, and Bs3) in different combinations was evaluated in the greenhouse and field. Strains representing races 1, 3, 4, and 6 caused similar high levels of disease severity, followed by races 2 and 5 on susceptible ECW. Race 3 caused severe disease on all isolines lacking resistance gene Bs2. Race 4, which defeats Bs1 and Bs2, caused less disease on isoline ECW-12R (carries Bs1 + Bs2), than on isolines ECW, ECW-10R (carries Bs1), and ECW-20R (carries Bs2). Similar results were obtained with race 4 strains in field studies conducted during 1997 and 1998. In greenhouse studies, race 6, which defeats all three major genes, caused less disease on isoline ECW-13R (carries Bs1 + Bs3) and ECW-123R (carries Bs1 + Bs2 + Bs3) than on isolines ECW, ECW-10R, ECW-20R, and ECW-30R (carries Bs3), but not on ECW-23R (carries Bs2 + Bs3). In greenhouse studies with commercial hybrids, strains of races 4 and 6 caused less disease on Boynton Bell (carries Bs1 + Bs2) than on Camelot (carries no known resistance genes), King Arthur (carries Bs1), and X3R Camelot (carries Bs2). Race 6 caused less disease on hybrid R6015 (carries Bs1 + Bs2 + Bs3) and Sentinel (carries Bs1 + Bs3) than on Camelot. Residual effects were not as evident in field studies with race 6 strains. Defeated major resistance genes deployed in specific gene combinations (i.e., gene pyramids) were associated with less area under the disease progress curve than when genes were deployed individually in isolines of ECW or commercial hybrids. Successful management of bacterial spot of pepper is achieved incrementally by integrating multiple tactics. Although there is evidence of residual effects from defeated genes, these effects alone likely will not provide acceptable bacterial spot control in commercial production fields. However, when combined with sanitation practices and a judicious spray program, pyramids of defeated resistance genes may aid in reducing the risk of major losses due to bacterial spot.

Effects of forage type and protein supplementation on voluntary intakes and particle breakdown of forages by dry dairy cows

There is now considerable evidence of residual effects of both energy and protein supply during the dry period on performance in the next lactation. Changes in forage intake and eating/rumination behaviour in the dry period have been implicated in predisposition to metabolic disorders in the subsequent lactation. In particular, there is a close association between intake either side of calving (Grummer, 1995). The primary objective of this experiment was to identify the effects, and interactions, of pre-partum energy and protein supply on forage intake and particle size reduction (as an index of rumination behaviour) of cows in the dry period.Fifty-two Holstein-Friesian cows, calving from September to November 1996, were used in a continuous design experiment The cows were dried off 8 weeks before their anticipated calving date and grazed on bare pasture for one week before training to use Calan gates (using grass silage only).

Developmental Rate, Weight, and Ovarian Parameters of Apple Aphids, Aphis pomi (Homoptera: Aphididae), Reared at One or Two Constant Temperatures, with Evidence of Residual Effects

Developmental rate, mature weight, number of eyed embryos, and size of the largest embryo of apple aphids, Aphis pomi (De Geer), reared at constant temperatures, were nonlinear functions of temperature, with gradual decline phases above optima that occurred at relatively moderate temperatures. Rearing experiments using paired combinations of high, moderate, and low temperatures demonstrated departures from expected values for these bionomic parameters, calculated by extrapolating results of single temperature rearings. These results suggest unequal responses to temperature by different developmental stages, residual effects, or both, including delayed acclimation and apparent non-reversible injury. Development, weight, and ovarian parameters of fundatrices, oviparae, and males are compared with those of viviparous apterae.

Studies in general practice with brotizolam.

Brotizolam (0.25 mg) was compared with placebo, and in a separate study, with nitrazepam (5.0 mg) in patients being treated for insomnia in general practice. Brotizolam (0.25 mg) and nitrazepam (5.0 mg) were equally effective and there was no evidence of residual effects the next day with either drug.

A Study of the Effects of Repeated Irradiation on the Cysts of a Ciliate, Tillina magna

Experiments with repeated x irradiation of Tillina magna cysts indicate that there is a decrease in the number of divisions with higher present doses of radiation, both when these doses have been preceded by one or more radiation exposures and when they have not. Since previous dose seems not to increase the division rate after a given present dose, Tillina magna does not acquire resistance to radiation. There is slight evidence for accumulation of radiation effect from repeated exposures. The average number of divisions appears to be more nearly a function of the present dose than of the total accumulated dose. Since there is little evidence of residual effect from radiation it must be concluded that there is recovery in Tillina magna cysts.