Cognitive function improvement with astaxanthin and tocotrienol intake: a randomized,double-blind,placebo-controlled study

We examined the effects of the mixed ingestion of astaxanthin derived from Haematococcus pluvialis and tocotrienols on the cognitive function of healthy Japanese adults who feel a memory decline. Forty-four subjects were randomly but equally assigned to the astaxanthin-tocotrienols or placebo group. An astaxanthin-tocotrienols or placebo capsule was taken once daily before or after breakfast for a 12-week intervention period. The primary outcome was composite memory from the Cognitrax cognitive test, and the secondary outcomes were other cognitive functions and subjective symptoms for memory. Each group included 18 subjects in the efficacy analysis (astaxanthin-tocotrienols group, 55.4 ± 7.9 years; placebo group, 54.6 ± 6.9 years). The astaxanthin-tocotrienols group showed a significant improvement in composite memory and verbal memory in Cognitrax at Δ12 weeks compared with the placebo group. Additionally, the astaxanthin-tocotrienols group showed a significant improvement in the subjective symptom of “During the last week, have you had trouble remembering people’s names or the names of things?” compared with the placebo group after 12 weeks. No adverse events were observed in this study. The results demonstrated that taking an astaxanthin-tocotrienols combination improves the composite memory and verbal memory of Japanese adults who feel a memory decline (UMIN 000031758).     

Soybean-derived phosphatidylserine improves memory function of the elderly Japanese subjects with memory complaints

Soybean-derived phosphatidylserine (Soy-PS) is a phosphatidylserine made from soybean lecithin by enzymatic reaction with L-serine. A double-blind, randomized controlled study was conducted to investigate the effects of Soy-PS on the cognitive functions of the elderly Japanese subjects with memory complaints. Seventy-eight elderly people with mild cognitive impairment (50–69 years old) were randomly allocated to take Soy-PS (100 mg, 300 mg/day) or placebo for 6 months. As a result, there was no difference in blood markers and vital signs during Soy-PS treatment and any side effect caused by Soy-PS treatment was not observed. Neuropsychological test scores were similarly increased in all groups including placebo group. However, in the subjects with relatively low score at baseline, the memory scores in PS treated groups were significantly increased against the baseline, while those of placebo group remained unchanged. And the memory improvements in Soy-PS-treated groups were mostly attributed to the increase in delayed verbal recall, a memory ability attenuated in the earliest stage of dementia. In conclusion, Soy-PS used in this study is considered as safety food ingredient and 6 months of Soy-PS supplementation could improve the memory functions of the elderly with memory complaints.     

Does caffeine modulate verbal working memory processes? An fMRI study

To assess the effect of caffeine on the functional MRI signal during a 2-back verbal working memory task, we examined blood oxygenation level-dependent regional brain activity in 15 healthy right-handed males. The subjects, all moderate caffeine consumers, underwent two scanning sessions on a 1.5-T MR-Scanner separated by a 24- to 48-h interval. Each participant received either placebo or 100 mg caffeine 20 min prior to the performance of the working memory task in blinded crossover fashion. The study was implemented as a blocked-design. Analysis was performed using SPM2. In both conditions, the characteristic working memory network of frontoparietal cortical activation including the precuneus and the anterior cingulate could be shown. In comparison to placebo, caffeine caused an increased response in the bilateral medial frontopolar cortex (BA 10), extending to the right anterior cingulate cortex (BA 32). These results suggest that caffeine modulates neuronal activity as evidenced by fMRI signal changes in a network of brain areas associated with executive and attentional functions during working memory processes.     

COMPARATIVE EFFECTS OF ZOPICLONE, TRIAZOLAM AND PLACEBO ON MEMORY AND PSYCHOMOTOR PERFORMANCE IN HEALTHY VOLUNTEERS

This study evaluated the effects of acute doses of zopiclone (7.5 mg), triazolam (0.25 mg) and placebo on memory and psychomotor performance of 12 normal volunteers. The subjects received both drugs in a repeated measure, double-blind Latin square design. The tests (CFF, CRT, DSST, memory assessments) were performed before and 2 and 6 hr after treatment. Zopiclone and triazolam induced an anterograde amnesia affecting short-term and long-term memory which lasted less than 6 hr. No retrograde amnesia was observed. Two hr after drug intake of both hypnotics psychomotor performances were significantly altered compared with placebo. The subjects also felt more drowsy, dizzy, clumsy and tired, and less alert and energetic 2 hr after zopiclone and triazolam compared to placebo. There was no difference between the effects of the two hypnotics at the doses studied.     

Effects of single-dose methylphenidate on cognitive performance in patients with traumatic brain injury: a double-blind placebo-controlled study

OBJECTIVES: To determine the effect of a single dose of methylphenidate on the cognitive performance of patients with traumatic brain injury (TBI), and particularly on working memory and visuospatial attention. DESIGN: A double-blind placebo-controlled study. The subjects were randomly divided into an experimental group taking methylphenidate and a control group taking a placebo. SETTING: The Department of Rehabilitation Medicine of a university hospital. SUBJECTS: Eighteen subjects with TBI (16 male and two female) were enrolled. INTERVENTIONS: The patients were given 20 mg methylphenidate or a placebo. Cognitive assessments were performed at three times: before the medication as a baseline, 2 h after medication and at follow-up (48 h later). MAIN MEASURES: Cognitive assessments consisted of working memory tasks and endogenous visuospatial attention tasks designed using SuperLabPro 2.0 software. Response accuracy and reaction time were measured. RESULTS: There were significant improvements in response accuracy in the methylphenidate group compared with the placebo group for both the working memory and visuospatial attention tasks. A significant decrease in the reaction time was also observed in the methylphenidate group only for the working memory task. CONCLUSIONS: The administration of single-dose methylphenidate has an effect in improving cognitive functioning following a TBI. The effects were most prominent regarding the reaction time of the working memory.     

Effects of two dosages of chlordesmethyldiazepam on mnestic-information processes in normal subjects

A double-blind, randomized protocol was used to investigate the activity of a benzodiazepine derivative, chlordesmethyldiazepam, at two different dosages, 1 mg and 2 mg (CDDZ1 and CDDZ2), on mnestic functions and information processing in normal subjects. CDDZ2 significantly impaired short-term shortage of logical and associative memory, without activity on spatial and visual memory, whereas CDDZ1 showed no difference from the placebo. Neither CDDZ1 nor CDDZ2 impaired the level of vigilance and the information processes the morning after use of the drug.     

TENS and Pain Control after Coronary Artery Bypass Surgery

This paper describes a randomised controlled trial to evaluate the effectiveness of TENS in controlling pain following coronary artery bypass grafting (CABG). A total of 59 men undergoing CABG with internal mammary artery (IMA) at Bristol Royal Infirmary were randomly allocated to receive TENS or placebo in conjunction with patient-controlled analgesia (PCA) for one hour on their first postoperative day. A visual analogue pain score and the hourly usage of the PCA were recorded before, during and after the application of TENS or placebo. The results show that although pain scores were significantly reduced in the hour in which TENS was applied, there was no significant difference in this reduction between the TENS and placebo groups. PCA use by patients during the study period was limited, with the majority making none or one successful request per hour. The results imply that the observed reductions in pain were due to a placebo effect and that the use of TENS in conjunction with PCA following CABG with IMA is unlikely to confer a clinically important reduction in post-operative pain.     

Memory and frontal lobe functions; possible relations with dopamine D2 receptors in the hippocampus

Cerebral cortical regions are thought to be important for cognitive functions such as memory and executive function. Although the functional associations between dopamine D2 receptors and motor and cognitive functions have been extensively examined in the striatum using positron emission tomography (PET), the role of dopamine D2 receptors in extrastriatal regions has been unexplored. We aimed to investigate the relationship between dopamine D2 receptors in extrastriatal regions and the performance of a broad spectrum of cognitive functions including memory, language, attention, and executive function in healthy subjects. Extrastriatal dopamine D2 receptors were measured in 25 male subjects using PET with [(11)C]FLB457. After the PET scans, a battery of neuropsychological tests was administered to all subjects. We found that the binding potential (BP) of [(11)C]FLB457 in the hippocampus was positively correlated with memory function. Furthermore, BP of [(11)C]FLB457 in the hippocampus, but not in the prefrontal cortex, was associated with frontal lobe functions such as executive function and verbal fluency. Our findings suggest that dopamine D2 receptors in the hippocampus might affect the local hippocampal function, but also brain functions outside the hippocampus such as the prefrontal cortex.     

Comparative effects of ginkgo biloba extracts on psychomotor performances and memory in healthy subjects

The effect on psychomotor and mnesic performances of acute oral dose (600 mg) of 2 Ginkgo biloba extracts were evaluated in twelve healthy female in a dummy placebo-controlled double blind study. Tests were performed comprising: objective measures of vigilance [critical flicker frequency (CFF), choice reaction time (CRT)], memory tasks (pictures and Sternberg scanning tests) and self-rating evaluation (visual analogue scales). Tests session took place before and 1 hour post-dosing. No statistically significant changes from placebo were observed on CFF, CRT or subjective rating of drug effects. No differences between treatment were evidenced on Sternberg scanning test and pictures recognition. Comparing to baseline, free recall score, while decreasing under placebo and Ginkgo, remained the same under Tanakan. As the differences between treatment are localized on one test, it appears important to examine the reproductility in healthy subjects. In order to verify the clinical relevance of these results, they need to be replicated in older healthy volunteers with age-associated memory impairment.     

Effects of Ginkgo biloba extract on cognitive function and blood pressure in elderly subjects

In this randomized, double-masked study, we assessed the effects of a Ginkgo biloba (GB-8) extract on elderly volunteers with age-related cognitive dysfunction. A total of 260 subjects were tested to obtain a homogeneous group of 60 elderly subjects with mild-to-moderate cognitive impairment, as defined by a clinical rating scale. The subjects were allocated to one of three groups and received either GB-8 40 mg or 80 mg or placebo three times daily for 3 months. Before therapy was started and after 1 and 3 months of treatment, standardized testing of attention, concentration, and memory was performed. The subjects completed self-assessments before and after 3 months of therapy, and arterial blood pressure was measured at the same intervals. Clinical ratings were done before and after 3 months of treatment. Six subjects withdrew from the study, whereas 54 subjects (31 women and 23 men; mean age, 74 years; age range, 61 to 88 years) completed the study. After randomization, the groups were similar with respect to age, social class, level of education, and demographic characteristics. Objective test results showed that attention, concentration, and short-term verbal memory improved significantly in subjects receiving the low-dose (standard) treatment. Similar improvements were seen in the results of the self-assessment test and the clinical rating. Diastolic blood pressure decreased significantly during low-dose treatment. Treatment with the GB-8 extract was found to improve objective measures of cerebral function in elderly subjects with mild-to-moderate cognitive impairment; the improvement appeared to be clinically relevant. The possible antihypertensive action of Ginkgo biloba extract is sufficient to warrant further investigation     

Implications of the study population in the early evaluation of anticholinesterase inhibitors for Alzheimer's disease.

OBJECTIVE: Velnacrine testing for tolerance and safety in both normal elderly subjects and patients with Alzheimer's disease (AD) is reviewed to illustrate the importance of Phase I trials in the target group as more predictive of safety and tolerance for subsequent multicenter trials than those conducted in healthy elderly subjects. DESIGN: Both a single-dose and a randomized, double-blind, placebo-controlled, ascending, multiple-dose study were performed with healthy, elderly men. In the multiple-dose study, the subjects were randomized to four groups of 14, with 10 subjects receiving velnacrine and 4 receiving placebo. The doses were velnacrine 25 (group 1), 50 (group 2), and 100 mg (group 3), respectively, administered twice daily; group 4 received 100 mg three times daily for 28 days. Blood and urine were collected serially for the pharmacokinetic assessment. With AD patients, 24 subjects were randomly assigned to receive either placebo or velnacrine for 10 days in a double-blind, sequential escalation study in a hospital setting. There were three groups of 8 subjects. Six patients in each group received velnacrine and 2 placebo. The three groups received respective dosages of 450, 300, and 225 mg/d three times daily. Adverse events were closely monitored and recorded. PATIENTS/PARTICIPANTS: The multiple-dose test in healthy elderly men included 56 men, aged 60-74 years. Rigorous screening for any potential complications that could affect absorption, distribution, metabolism, or excretion preceded patient entry in the AD patient study. Patients with a history of major psychiatric, neurologic, and cardiovascular disorders were excluded. The patients ranged in age from 56 to 89 years, and were equally distributed between gender. INTERVENTION: Velnacrine was administered in various doses. MAIN OUTCOME MEASURES: We emphasize the extreme adverse effects encountered in the AD patient group compared with the healthy group. Plasma concentrations of velnacrine over time in both groups are given, as well as the drug's half-life and excretion rates. RESULTS: The tolerable dosage predicted by studies performed in healthy elderly subjects was 300 mg/d. This dosage was not tolerable among the AD patients. A dosage as high as 450 mg/d resulted in a tonic seizure in one patient. The predicted dosage of 300 mg/d produced an adverse effect profile in AD patients that included dizziness, nausea and/or vomiting, headaches, and severe diarrhea. AD patients tolerated a dosage of 225 mg/d. CONCLUSIONS: A velnacrine dosage of 300 mg/d that was tolerated in healthy elderly subjects was not tolerated by AD patients.     

氯诺昔康用于学龄儿童术后自控镇痛的临床研究

目的评价氯诺昔康用于小儿术后自控镇痛的安全性及有效性。方法60例拟行臀筋膜松解术的患儿,随机均分为L组(氯诺昔康组)和T组(曲马多组)。均采用硬膜外加氯胺酮分离麻醉。术毕,L组静注氯诺昔康0.15mg/kg为负荷量,继用0.3mg/kg氯诺昔康加生理盐水稀释至100ml后置于PCA泵药池内。T组静注曲马多1mg/kg为负荷量,继用10mg/kg曲马多加生理盐水稀释至100ml后置于PCA泵药池内。PCA泵背景剂量为5ml/h,PCA量为2ml/次,锁定时间为15分钟。记录使用PCA后1h,4h,8h,12h,20h患儿的疼痛评分、对疼痛治疗总体印象评分及所出现的副作用。结果两组患儿镇痛治疗评分及对镇痛治疗总体印象评分,组间对比均无显著性差异(P>0.05);曲马多组出现恶心,呕吐的病例数目明显高于氯诺昔康组(P<0.01);两组患者PCA治疗前后肝肾功能及出凝血时间比较无统计学意义(P>0.05)。结论氯诺昔康用于小儿术后镇痛是安全有效的,可作为小儿术后镇痛治疗的一种选择药物。     

Onset of action of fexofenadine hydrochloride 60 mg/pseudoephedrine hydrochloride 120 mg in subjects aged 12 years with moderate to severe seasonal allergic rhinitis: a pooled analysis of two single-dose, randomized, double-blind, placebo-controlled allergen exposure unit studies

BACKGROUND: The onset of action of antihistamine-decongestant combinations is an important factor in the treatment of subjects with seasonal allergic rhinitis (SAR). OBJECTIVE: This was a pooled analysis of 2 published studies with identical designs investigating the onset of action of the combination of fexofenadine hydrochloride 60 mg/pseudoephedrine hydrochloride 120 mg (FEX60/PSE120) in subjects with moderate to severe SAR. METHODS: Subjects aged 12 years received single doses of FEX60/PSE120 or placebo in 2 randomized, double-blind, placebo-controlled, parallel-group, allergen exposure unit studies and recorded their SAR symptoms on diary cards before dosing, at 15-minute intervals for 2 hours after dosing, and at 30-minute intervals for the next 4 hours. The primary efficacy end point was onset of action, assessed in terms of absolute change in the major symptom complex (MSC) score, which was the sum of scores for the individual symptoms of stuffy nose, itchy nose, runny nose, watery eyes, itchy eyes, itchy ears/throat, and sneezing. Secondary end points included the absolute and percent change in the total symptom complex (TSC) score (the sum of the MSC score plus the scores for nose blowing, sniffles, postnasal drip, and cough) and individual symptom scores. Treatment-emergent adverse events (TEAEs) were recorded. Analyses were performed on the modified intention-to-treat (mITT) population, which included all subjects who were randomized to treatment and took the single dose of study medication according to the protocol. RESULTS: A total of 1693 subjects were screened in the 2 studies, and 786 were randomized (298 in study 1, 488 in study 2). Two subjects withdrew from study 2; therefore, the mITT population consisted of 784 subjects. Subjects' mean age was 33.4 years, and 64.4% were female. The onset of action of FEX60/PSE120 was 45 minutes; the least squares mean (SD) treatment difference in the change from baseline in absolute MSC score was 0.8 (0.31) (95% CI, 0.2-1.4; P = 0.008). All subsequent changes from baseline in MSC scores were statistically significant for FEX60/PSE120 compared with placebo (P < 0.001). The absolute and percent change in TSC score and the percent change in MSC score were significantly decreased at all time points from 45 minutes after dosing for FEX60/PSE120 compared with placebo (all, P < 0.05). Individual symptoms (mean of hours 1 to 5) also were significantly improved with FEX60/PSE120 compared with placebo (all, P < 0.05). TEAEs were reported by 2.3% (9/391) and 4.3% (17/393) of subjects receiving FEX60/PSE120 and placebo, respectively. The most commonly occurring TEAS in the FEX60/PSE120 and placebo groups was somnolence (n = 4 and n = 6, respectively). CONCLUSION: In this pooled analysis of 2 allergen exposure unit studies, FEX60/PSE120 had an onset of action of 45 minutes and a sustained effect throughout the 6-hour study period in subjects with moderate to severe SAR.     

Dose-response of inhaled diltiazem on airway reactivity to methacholine and exercise in subjects with mild asthma

Methacholine challenges were performed by 10 asthmatic subjects, 2 hours before and 15 minutes after placebo (diluent alone) and 5, 10, 15, 30, and 60 mg inhaled diltiazem given in a single-blind crossover manner. There was no significant change from placebo in the dose of methacholine required to produce a 20% decrease in forced expiratory volume in the first second (FEV1) (PD20); the fold increase in PD20 from baseline was 1.1 +/- 0.1 after placebo, 1.4 +/- 0.2 after 5 mg, 1.8 +/- 0.3 after 10 mg, 1.4 +/- 0.2 after 15 mg, 1.6 +/- 0.2 after 30 mg, and 1.2 +/- 0.1 after 60 mg. There was a 1% chance that we missed a twofold difference between placebo and the 10 mg dose because of inadequate sample size. Fifteen minutes before a standardized exercise challenge, 10 subjects received placebo, 10 mg, and the highest dose tolerated during the methacholine study (20 to 45 mg) in a randomized double-blind crossover design. The mean +/- SE maximum postexercise decrease in FEV1 was 28.8% +/- 5.7% after placebo, 23.4% +/- 4.6% after 10 mg, and 20.8% +/- 3.0% after high-dose diltiazem (P greater than 0.05). There was a 12% chance that we missed a 15% difference between placebo and the high-dose regimen because of inadequate sample size. We conclude that diltiazem does not attenuate airway reactivity to methacholine or exercise even when high concentrations are delivered to the lungs.     

Plasma Catecholamines in Long-Term Diabetics with and without Neuropathy and in Hypophysectomized Subjects

Employing a precise and sensitive double-isotope derivative technique, plasma catecholamine concentration (PCA) was measured in four groups of subjects: (a) long-term diabetics with neuropathy, (b) long-term diabetics without neuropathy, (c) hypophysectomized long-term diabetics with neuropathy, and (d) nondiabetic control subjects. Blood samples were obtained from subjects in the supine and in the standing position.In nondiabetic control subjects, PCA (mainly noradrenaline) increased from 0.26 ng/ml in the supine positon to 0.69 and 0.72 ng/ml 5 and 10 min after assuming the standing position. By plotting this increase in PCA on the y axis in a coordinate system vs. increase in pulse rate, PCA was divided into two components: one of these depended on the rise in pulse rate on standing (called CAH) and the other corresponded to the intercept on the y axis where rise in pulse rate equals zero (CAP).Long-term diabetics with neuropathy showed a significant reduction in PCA in both the supine and the standing position. Further analysis demonstrated that CAP was considerably reduced whereas CAH was normal. Long-term diabetics without neuropahty showed normal PCA values.Surprisingly, hypophysectomized diabetics with neuropathy exhibited mean PCA values in both the supine and the standing position which were similar to those found in the nondiabetic subjects and considerably elevated compared with the findings in the nonoperated, long-term diabetics with neuropathy. Further analysis in terms of CAP and CAH demonstrated, however, that CAP was just as abnormally reduced in the hypophysectomized as it was in the nonoperated patients whereas CAH was considerably increased.In contrast to the findings in the nonoperated diabetics with neuropathy, the hypophysectomized diabetic patients with neuropathy demonstrated a negative correlation between rise in PCA and blood pressure on standing indicating that the increase in PCA was at least partially a compensatory phenomenon in the interest of the maintenance of a normal level of blood pressure.An increased sympathetic tone (vasoconstriction) is believed to be at least partially responsible for the increased capillary resistance and decreased capillary permeability occuring after hypophysectomy.     

Effects of a standardized ginseng extract combined with dimethylaminoethanol bitartrate, vitamins, minerals, and trace elements on physical performance during exercise

The subjects of this double-blind, randomized, crossover study were 50 healthy male sports teachers aged 21 to 47 years. Every day for six weeks each subject received two capsules of a preparation containing ginseng extract, dimethylaminoethanol bitartrate, vitamins, minerals, and trace elements, or two capsules of placebo. The subjects then performed an exercise test on a treadmill at increasing work loads. The total work load and maximal oxygen consumption during exercise were significantly greater after the ginseng preparation than after placebo. At the same work load, oxygen consumption, plasma lactate levels, ventilation, carbon dioxide production, and heart rate during exercise were significantly lower after the ginseng preparation than after placebo. The effects of ginseng were more pronounced in the subjects with maximal oxygen consumption below 60 ml/kg/min during exercise than in the subjects with levels of 60 ml/kg/min or above. The results indicate that the ginseng preparation increased the subjects' work capacity by improving muscular oxygen utilization.     

Efficacy and tolerability of topiramate 200 mg/d in the prevention of migraine with/without aura in adults: a randomized, placebo-controlled, double-blind, 12-week pilot study

BACKGROUND: Several large, randomized, double-blind, placebo-controlled trials have found topiramate (TPM) to be effective and generally well tolerated as a preventive therapy for migraine. OBJECTIVE: This paper evaluates efficacy and safety data from a pilot study of TPM 200 mg/d as preventive therapy in adult subjects with a history of migraine with or without aura. METHODS: The pilot study had a randomized, double-blind, placebo-controlled design. Subjects were randomized in a 2:1 ratio to receive TPM 200 mg/d or placebo. The double-blind treatment phase consisted of an 8-week titration period (25 mg/d for the first week, followed by weekly increases of 25 mg) and a 12-week maintenance period. The primary efficacy measure was the change in mean monthly migraine frequency. Additional measures were the median percent reduction in monthly migraine frequency and the proportion of responders (those with > or =50%, > or =75%, or 100% reduction in monthly migraine frequency). RESULTS: The intent-to-treat (ITT) population included 211 subjects (138 TPM, 73 placebo; mean [SD] mean weight, 76.7 [18.7] kg). Of 45 subjects who discontinued the study in the TPM group, 21 discontinued during the titration period, compared with 3 of 13 subjects who discontinued in the placebo group. When the efficacy data were assessed using the per-protocol, analysis-of-covariance model, TPM 200 mg/d was not associated with a significant reduction in mean monthly migraine frequency compared with placebo. A post hoc analysis using a Poisson regression model in the ITT population suggested that TPM significantly reduced mean monthly migraine frequency compared with placebo (P=0.04). A significantly larger proportion of TPM-treated subjects had a > or =75% reduction in monthly migraine frequency compared with placebo (P=0.03). At least 1 adverse event was reported by 90.0% and 69.9% of the TPM and placebo groups, respectively. Treatment-emergent adverse events (AEs) occurring in > or =10% of subjects in the TPM group were paresthesia (45%), dizziness (16%), fatigue (16%), nausea (14%), and weight loss (14%). Most treatment-emergent AEs were rated mild or moderate in severity. Of 3 serious AEs (depression, abdominal pain, leg pain) occurring during the trial, none were considered related to either TPM or placebo. CONCLUSION: In this pilot study, mean monthly migraine frequency did not differ significantly between TPM and placebo.     

Efficacy of diclofenac sodium softgel 100 mg with or without caffeine 100 mg in migraine without aura: a randomized, double-blind, crossover study

OBJECTIVE: A phase II, randomized, double-blind, crossover study was designed to evaluate the efficacy of 100-mg diclofenac sodium softgel (formulated using ProSorb technology) with or without 100-mg caffeine versus placebo in migraineurs during migraine attacks. BACKGROUND: Diclofenac has been demonstrated to be an effective migraine treatment in several placebo-controlled studies. A rapidly absorbed softgel of diclofenac has been shown to be effective in the rapid relief of acute pain, and may have advantages in migraine treatment. In addition, caffeine has consistently been shown to increase both the efficacy and speed of onset of concurrently administered analgesics. The ability of caffeine to both enhance and accelerate analgesic effects has been documented with a variety of different medications (ie, aspirin, acetaminophen, ibuprofen, and ergotamine). METHODS: The 3-period crossover study was designed to compare diclofenac softgel 100 mg, diclofenac softgel 100 mg plus caffeine 100 mg, and placebo in the acute treatment of migraine. Subjects treated one moderate or severe attack with each study medication. The primary efficacy parameter was the percentage of subjects with headache relief at 60 minutes as defined by a reduction of headache severity from moderate or severe at baseline to absent or mild compared with placebo. Though the sample size estimate required that 72 subjects treat 3 separate attacks, 51 subjects treated 1 migraine attack, 44 treated 2 attacks, and 39 treated 3 attacks. Results.-In the placebo group, 6 (14%) of 43 subjects reported headache relief at 60 minutes versus 12 (27%) of 45 subjects in the diclofenac softgel group, and 19 (41%) of 46 subjects in the diclofenac softgel plus caffeine group. Differences were statistically significant for the diclofenac softgel plus caffeine group versus placebo (odds ratio, 4.2; 95% confidence interval, 1.3 to 13.7). Rescue medication was used by 27 (63%) of 43 subjects treated with placebo, 15 (33%) of 45 subjects treated with diclofenac softgel, and 14 (30%) of 46 subjects treated with diclofenac softgel plus caffeine. This result is highly statistically significant (chi22= 11.56, P=.003). Both the diclofenac plus caffeine (P <.03) and diclofenac only (P <.03) groups were significantly different from the placebo group in terms of the visual analog scale score at 60 minutes. CONCLUSIONS: The major finding of the present study is that diclofenac softgel plus caffeine produces statistically significant benefits relative to placebo at 60 minutes. Diclofenac softgel alone did not differ significantly from placebo, perhaps due to limits in sample size. Nonsignificant trends support the analgesic adjuvant benefit of caffeine when added to diclofenac softgels.     

Raloxifene exposure enhances brain activation during memory performance in healthy elderly males; its possible relevance to behavior

Raloxifene is a selective estrogen receptor modulator (SERM) that is prescribed in females only, but its use in male subjects is increasingly considered. With a growing number of patients having potential benefit from raloxifene, the need for an assessment of its effects on brain function is growing. Effects of estrogens on brain function are very subtle and difficult to detect by neuropsychological assessment. Functional imaging techniques, however, have been relatively successful in detecting such changes. This study used functional magnetic resonance imaging (fMRI) to examine effects of raloxifene treatment on memory function. Healthy elderly males (n = 28; mean age 63.6 years, SD 2.4) were scanned during performance on a face encoding paradigm. Scans were made at baseline and after 3 months of treatment with either raloxifene (n = 14) or placebo (n = 14). Treatment effects were analyzed using mixed-effects statistical analysis (FSL). Activation during task performance involved bilateral parietal and prefrontal areas, anterior cingulate gyrus, and inferior prefrontal, occipital, and mediotemporal areas bilaterally. When compared to placebo, raloxifene treatment significantly enhanced activation in these structures (Z > 3.1), except for mediotemporal areas. Task performance accuracy diminished in the placebo group (P = 0.02), but remained constant in the raloxifene group (P = 0.60). In conclusion, raloxifene treatment enhanced brain activation in areas spanning a number of different cognitive domains, suggesting an effect on cortical arousal. Such effects may translate into small effects on behavior, including effects on attention and working memory performance, executive functions, verbal skills, and episodic memory. Further neuropsychological assessment is necessary to test the validity of these predictions.     

A randomized, double-blind, placebo-controlled pilot study of IV morphine-6-glucuronide for postoperative pain relief after knee replacement surgery

OBJECTIVES: To determine the dose-response effect of intravenous morphine-6-glucuronide (M6G) on acute postoperative pain. METHODS: Patients undergoing knee replacement surgery under spinal anesthesia were randomly assigned to 1 of 4 single intravenous M6G doses, 0 (placebo), 10, 20, or 30 mg/70 kg, administered 150 minutes after the spinal anesthetic was given. Analgesic effects were evaluated by determining the cumulative patient controlled analgesia (PCA) morphine dose, consumed over a 12 and 24 hours period, after the initial dose of M6G. For pain assessments, a 10 cm visual analog scale was used. RESULTS: Data from 41 patients were evaluated (n=10, 10, 10, and 11 in the 0, 10, 20, and 30 mg M6G groups). Only at the highest M6G dose (30 mg/70 kg), morphine PCA consumption was significantly less compared with placebo: over the first 12 postoperative hours mean PCA morphine consumption was 3.0+/-2.0 mg/h after placebo and 1.4+/-0.5 mg/h after 30 mg M6G (P=0.03); over the first 24 h mean PCA morphine consumption was 2.5+/-2.1 mg after placebo and 1.0+/-0.4 mg after 30 mg M6G (P=0.04) (mean+/-SD). Visual analog scale values were similar across all groups during these time periods. DISCUSSION: The analgesic effect of M6G in postoperative pain was demonstrated with 30 mg/70 kg M6G superior to placebo. At this dose, M6G has a long duration of action as determined by a reduction in the use of morphine PCA over 12 and 24 hours.