2-period Crossover Research Articles

Balance of Unsaturated Fatty Acids Is Important to a Cholesterol-Lowering Diet: Comparison of Mid-Oleic Sunflower Oil and Olive Oil on Cardiovascular Disease Risk Factors

Objective To evaluate the effects of a trans fat-free monounsaturated fatty acid-rich vegetable oil (NuSun sunflower oil, National Sunflower Association, Bismark, ND) that is a good source of polyunsaturated fatty acids (PUFA) and low in saturated fatty acids on lipid and lipoprotein levels and oxidative stress. Design A double-blinded, randomized, three period crossover, controlled feeding study. Subjects/setting Thirty-one men (n=12) and women (n=19) with moderate hypercholesterolemia who were 25 to 64 years of age. Intervention Experimental diets provided 30% fat (olive oil or NuSun sunflower oil contributed one half of the total fat), 8.3% vs 7.9% saturated fatty acid, 17.2% vs 14.2% monounsaturated fatty acid, and 4.3% vs. 7.7% PUFA (olive oil and NuSun sunflower oil, respectively), and 294 mg cholesterol. The control diet was an average American diet (34% fat, 11.2% saturated fatty acid, 14.9% monounsaturated fatty acid, 7.8% PUFA). Subjects consumed each diet for 4 weeks with a 2-week compliance break before crossing over to another diet. Main outcome measures Lipid and lipoprotein levels were measured, and measures of oxidative stress, including lag time, rate of oxidation, total dienes, and lipid hydroperoxides, were assessed. Statistical analysis The mixed model procedure was used to test for main effects of diet, feeding period, and order of diets. Tukey-Kramer adjusted P values were used to determine diet effects. Results The NuSun sunflower oil diet decreased both total and low-density lipoprotein cholesterol levels compared with the average American diet and the olive oil diet. There was no effect of the olive oil diet compared with the average American diet. Total cholesterol decreased 4.7% and low-density lipoprotein cholesterol decreased 5.8% on the NuSun sunflower oil diet vs the average American diet. There was no effect of the experimental diets on triglyceride levels, rate of oxidation, total dienes, lipid hydroperoxides, or α-tocopherol. Lag time was the longest following the olive oil diet and shortest following the NuSun sunflower oil diet. Conclusions The higher PUFA content appeared to account for the greater total and low-density lipoprotein cholesterol lowering and reduction in lag time of the NuSun sunflower oil diet. However, the fact that there were no differences in the resulting oxidation products suggests there were no adverse effects on low-density lipoprotein oxidation. Since PUFAs are important for cholesterol lowering, foods that replace saturated fatty acids should include a balance of unsaturated fatty acids.

Phase III double-blinded, randomized trial to evaluate the use of black cohosh in the treatment of hot flashes: A North Central Cancer Treatment Group study

8013 Background: Hot flashes can cause significant morbidity in post-menopausal women and women undergoing or finished with breast cancer treatment. Based on initial pilot data suggesting black cohosh could be efficacious in the treatment of hot flashes, a phase III trial was initiated. Methods: A double-blind, randomized, cross-over methodology with two 4 week periods, was used to study the efficacy of black cohosh (1 capsule, Cimicifuga racemosa 20 mg BID) for the treatment of hot flashes in women. Participants kept a daily hot flash diary during a baseline week and then during an 8-week cross-over treatment period. Treatment effectiveness was measured using the mean daily numbers of hot flashes and the hot flash scores; the latter measured by assigning points (1–4, for mild to very severe) to each hot flash based on severity and then adding the points for a given time period. The study design provided 80% power to detect a moderate effect size difference (1/2 standard deviation) in the hot flash scores between the two treatment groups. Results: 132 patients were randomized between 10/31/03 - 3/4/04. Data on 80% of patients have been analyzed and are reported here. Toxicity was minimal and not different by treatment group with 83% of patients receiving black cohosh and 76% of patients receiving placebo reporting no adverse events. Patients receiving black cohosh reported a mean decrease in hot flash score (comparing the fourth treatment week to the baseline week) of 20% compared to 27% for patients on placebo (p=0.53). Mean hot flash frequency was reduced 17% on black cohosh and 26% on placebo (p=0.36). Patient treatment preferences were measured after completion of both treatment periods by ascertaining which treatment period, if any, the patient’s preferred: 34% of patients preferred the black cohosh treatment, 38% preferred placebo, and 28% did not prefer either treatment. Conclusion: This trial failed to provide any evidence that black cohosh reduced hot flashes more than the placebo did. No significant financial relationships to disclose.

Supplementation of xylanase and phospholipase to wheat‐based diets for weaner pigs

The effects of supplementing a wheat-based diet for weaner pigs with exogenous xylanase and phospholipase on ileal and faecal nutrient digestibilities and on the level of microbial metabolites in ileal digesta were examined. Fourteen piglets, weaned at 11 days, were fitted with a simple T-cannula at the distal ileum. The pigs were offered a control diet or diets supplemented with xylanase and phospholipase individually or in combination, in a two period crossover design. The combination of xylanase and phospholipase tended to increase the ileal recovery of the amino sugar galactosamine, whereas the concentration expressed in mg/kg dry matter intake of glucosamine was slightly decreased (p < 0.10). There was neither an effect of enzyme supplementation on ileal and faecal digestibility of the other nutrients and energy, nor was there an effect on pH and on the level of microbial metabolites in ileal digesta. However, an increase in ileal and faecal nutrient and energy digestibility with increasing age was observed. The ileal and faecal digestibility coefficients (except for ether extract) were significantly (p < 0.05) higher in experimental period I than in period II. These higher values may be attributed to a lower feed intake during period I. Since a lower level of feed intake is generally associated with a slower rate of passage and a longer retention time of digesta, a positive impact on digestion and absorption of nutrients can be assumed, which, on the other hand, limits the potential of additional enzyme effects.

Effect of the administration schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: a randomized, three-way crossover study

Oral pancreatic enzyme supplements should be properly administered in order to ensure an adequate gastric mixing with the food and simultaneous gastric emptying with the chyme. To evaluate, in a prospective, randomized, open, comparative, three-way, crossover study, the effect of the administration schedule on the efficacy of oral pancreatic enzymes for the treatment of exocrine pancreatic insufficiency. Twenty-four consecutive chronic pancreatitis patients with maldigestion secondary to exocrine pancreatic insufficiency were treated with 40 000 U lipase in the form of capsules containing enteric-coated mini-microspheres. Capsules were taken just before meals (schedule A), just after meals (schedule B) or distributed along with meals (schedule C) for three consecutive 1-week crossover periods in a randomized order. Fat digestion before and during the three treatment periods was evaluated by an optimized mixed (13)C-triglyceride breath test. Before therapy, the (13)CO(2) recovery in the breath test was 23.8 +/- 15.8% (normal >58.0%). During therapy, the (13)CO(2) recovery tended to be higher when capsules were taken along with meals ((13)CO(2) recovery 61.4 +/- 21.4%) or just after meals ((13)CO(2) recovery 60.6 +/- 21.8%) than when taken just before meals ((13)CO(2) recovery 53.9 +/- 20.3%). The percentage of patients who normalized fat digestion under therapy was 50, 54 and 63% with schedules A, B and C respectively. The efficacy of pancreatic enzyme supplements for the treatment of exocrine pancreatic insufficiency may be optimized by administration during or after meals.

Speak Memory: Reflections on the Doppelgänger Trilogy

January 01 2005 Speak Memory: Reflections on the Doppelgänger Trilogy Slater Bradley Slater Bradley Search for other works by this author on: This Site Google Scholar Author and Article Information Slater Bradley Online Issn: 1537-9477 Print Issn: 1520-281X © 2005 Slater Bradley2005 PAJ: A Journal of Performance and Art (2005) 27 (1 (79)): 108–110. https://doi.org/10.1162/1520281052863962 Cite Icon Cite Permissions Share Icon Share Twitter LinkedIn Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Search Site Citation Slater Bradley; Speak Memory: Reflections on the Doppelgänger Trilogy. PAJ: A Journal of Performance and Art 2005; 27 (1 (79)): 108–110. doi: https://doi.org/10.1162/1520281052863962 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsPAJ: A Journal of Performance and Art Search Advanced Search This content is only available as a PDF. © 2005 Slater Bradley2005 Article PDF first page preview Close Modal You do not currently have access to this content.

Effect of Fluoridated Toothpicks and Dental Flosses on Enamel and Dentine and on Plaque Composition in situ

The aim was to evaluate the effect of two toothpicks and two dental flosses on demineralized enamel and dentine and on plaque composition, using an in situ model with simulated approximal spaces within dentures. Fifteen subjects with full dentures were recruited and 14 completed the study. It consisted of two crossover periods, the first comparing a birch toothpick with AmF and a birch toothpick with NaF, and the second comparing a dental floss with AmF + NaF and a dental floss without F. Between these four periods, there was a control period without any approximal cleaning. In small, rectangular sample holders, one enamel and one dentine specimen were embedded, forming a triangular, approximal-like space. Two sample holders were mounted in the premolar-molar region of the upper or lower dentures. The subjects used the toothpicks or dental flosses 3 times/day for 4 weeks. The results showed that all toothpicks and dental flosses inhibited further demineralization compared to the control period (p < 0.001). The dental flosses were somewhat more effective in this respect than the toothpicks, especially in dentine. There were relatively small numerical differences between AmF and NaF toothpicks, but in favour of NaF regarding mineral gain (p < 0.05). The fluoridated floss gave somewhat less lesion depth in dentine than the non-fluoridated floss (p < 0.01). Toothpicks and flosses resulted in lower counts of microorganisms in plaque compared to the control period (p < 0.001); the AmF toothpick gave a more pronounced reduction than the NaF toothpick (p < 0.001).

Virtuosity and the Musical Work: The Transcendental Studies of Liszt (review)

WORKS, PERFORMANCE, CREATIVITY Virtuosity and Musical Work: The Transcendental Studies of Liszt. By Jim Samson. Cambridge: Cambridge University Press, 2003. [viii, 240 p. ISBN 0-521-81494-4. $75.] Music examples, bibliography, index. For some time now, musicology has sought methodology that offers persuasive response to assertions of Critical Studies discipline (called Theory in U.K., as opposed to Music Theory) regarding musicology's insufficient acknowledgment and treatment of social, cultural, and economic context of work (sometimes called its context). The criticism has long history; it is true that musicological preoccupations were, for long time, bibliographical and editorial. It is also true that discipline's putative myopia regarding all other kinds of inquiry has been exaggerated to point of falsity, with the music itself and cognate phrases now carrying talismanic power to belabor discipline from within and conjure up Bad Old Days. An example of this would be Matthew Head's identification of a recourse to 'the musical' as one of contemporary musicological ploys that amount to an unscholarly resistance to ... cultural There is no scholarly escape route from this theory. (Musicology on Safari, Music Analysis 22/1-2 [2003]: 218.) According to this common paradigm, Theory first, then (maybe) music, as it relates to Theory. Whatever music, and whatever cultural complications, there is still good deal to be said for responsibility of discipline devoted to scholarly study of music to address music, and to do so without fear of kind of reflexive criticism that has sometimes resulted when discussion has wandered too far from particular political agenda, such as that just quoted. In this volume, Jim Samson meets challenge head on; as he says in introduction, I believe that direct, close-to-thetext engagement with musical materials is likely to prove more revealing than seductive of 1980s and 1990s, and that such an engagement may provide necessary ballast for more thoroughly grounded, evidence-based hermeneutics (p. 2). A more direct (yet still civil) statement of difference to some of recent trends in musicology and cultural criticism cannot be imagined. While Samson does not specifically offer this book as catalyst of major hermeneutic paradigm shift, that, it seems to me, is its potential: thick context (including musical context), musicking (i.e., understanding and treatment of music as practice), and tracing of genre's development in one composer's hands against backdrop of broader musical environment. Theory is here, too, and it informs some of questions asked and complications identified, but it is neither melody to Liszt's accompaniment nor treated with fundamentalist awe. Samson's book draws on traditions of two musicological genres: studies devoted to specific large work or group of small works, such as Cambridge Guides (same publisher, different series), and genre history such as William Newman's monumental, three-volume study of sonata. It is happy pairing, due to special history of Transcendental Studies; set was published in three different versions, each dating from crucial period in Liszt's life. The first incarnation was Etude en 12 exercices, op. 1 (1826; first published salvo of young virtuoso); 12 grandes etudes followed, dedicated to Carl Czerny (1837; from midst of his career as touring virtuoso); and finally Liszt revised it again, and it took its most familiar form, Etudes d'execution transcendante (1851), also dedicated to Czerny, and dating from crossover period when composer had stopped touring and was moving directly into more concentrated composition and conducting. He was also revising earlier versions of other works, such as Paganini Studies and what would become Hungarian Rhapsodies. …

Macrolides in the treatment of asthma and cystic fibrosis

Asthma and cystic fibrosis are two respiratory diseases characterized by chronic inflammation, leading to remodelling of the airways. Macrolides are widely used antibiotics, with a peculiar anti-inflammatory effect. On the basis of the methodologies used by the Cochrane collaboration, this review discusses the evidence for their long-term use as anti-inflammatory agents in these two diseases. Three randomized-controlled trials (RCTs) were identified for both asthma and cystic fibrosis. A positive effect of macrolides on reducing eosinophil numbers and markers of eosinophilic inflammation was demonstrated in patients with asthma. Data on cystic fibrosis demonstrated an effect on lung function with an increase of 5.4% in forced vital capacity (FVC) in patients treated with macrolide vs. placebo, but without a significant effect on FEV1. Side-effects were rare, mild and reversible on withdrawal of treatment. Although preliminary data from small studies are promising, the role of macrolides in the treatment of these chronic disorders needs to be more firmly established with larger, well-designed trials, targeted to investigate major clinical outcomes.

Effect of amlodipine–atorvastatin combination on fibrinolysis in hypertensive hypercholesterolemic patients with insulin resistance

The aim of this study was to evaluate the effect of the amlodipine-atorvastatin combination on plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) activity in hypercholesterolemic, hypertensive patients with insulin resistance. The study population included 45 patients, aged 41 to 70 years, with mild to moderate essential hypertension (diastolic blood pressure [BP] > or = 95 and < or = 105 mm Hg), hypercholesterolemia (total cholesterol > 200 and < 350 mg/dL), and insulin resistance (HOMA index > 2.5) After a 4-week wash-out period, they were randomized to amlodipine (5 mg) or atorvastatin (20 mg) or their combination at the same oral dosage for 12 weeks in three cross-over periods each separated by a 4-week placebo period (3 by 3 latin square design). At the end of the placebo wash-out and of each treatment period, office BP, total cholesterol, PAI-1, and t-PA activity were evaluated. The amlodipine-atorvastatin combination, in addition to the expected hypocholesterolemic effect, produced: 1) a greater decrease in PAI-1 activity (-10.2 U/mL, P <.01 v placebo) and an even greater increase in t-PA activity (+0.26 U/mL, P <.01 v placebo) than amlodipine (-0.5 U/mL for PAI-1, P = not significant; +0.17 U/mL for t-PA, P <.01 v placebo) and atorvastatin alone (respectively, -9.9 U/mL, P <.01 v placebo and +0.08 U/mL, P <.05 v placebo); and 2) a greater systolic BP/diastolic BP mean reduction (-22/17 mm Hg, P <.005 v placebo) than amlodipine (-18/14 mm Hg, P <.01 v placebo) and atorvastatin alone (-2.8/3.8 mm Hg, P <.05 v placebo only for diastolic BP). The positive effect on fibrinolytic balance and BP control observed suggests that in hypertensive, hypercholesterolemic patients with impaired fibrinolysis, the combination of amlodipine and atorvastatin could be the treatment of choice.

A randomized, double‐blinded, placebo‐ controlled multicenter study on the efficacy of a diet with high levels of eicosapentaenoic acid and gamma‐linolenic acid in the control of canine atopic dermatitis

The purpose of this study was to evaluate the efficacy of a diet with high levels of eicosapentaenoic acid (EPA) (480 mg/megajoule) and gamma‐linolenic acid (GLA) (50 mg/megajoule) in the control of clinical signs in dogs with atopic dermatitis. Selection of dogs with atopic dermatitis occurred according to a strict protocol; dogs with ectoparasites, endoparasites, dermatophytosis, Malassezia infection, active flea allergy dermatitis, hypothyroidism or food allergy were excluded, as well as dogs currently treated with hyposensitization, glucocorticoids, antihistamines, NSAIDs and dietary fatty acid supplements. Dogs were only selected if they met the diagnostic criteria for atopy and when atopy was confirmed by a positive intradermal test correlating with the history and clinical signs. During the entire study, flea control was applied and secondary pyoderma or Malassezia infections were controlled with antibiotics or topically applied lotions. The owners were informed that the diet and/or capsules might be treatment or placebo. The dogs received either a treatment with the test diet plus a daily placebo capsule, or the dog's usual diet plus a daily placebo capsule for a period of 10 weeks. The treatment diet provided 240 mg EPA/kg metabolic weight and 25 mg GLA/kg metabolic weight. Owners who judged that the treatment during the study had not been effective could participate in a double‐blinded crossover period during which the dog received another treatment. At the start and end of the study, the severity of the following clinical signs was scored: pruritus, shedding, scaling, dry skin, erythema, smell of coat and alopecia. In total, 13 dogs received the control treatment and 15 dogs the test diet. Of the 13 control dogs, nine followed a crossover period on the test diet, which brought the total number of dogs on the diet to 24. The score after 10 weeks of treatment was expressed as percentage of the score at week 0. After 10 weeks of treatment, scores for intensity, frequency and total score for pruritus in dogs fed the test diet were significantly lower than scores for the control dogs (P = 0.005, P = 0.013, P = 0.005, respectively); the average score was reduced to 67, 65 and 53% of the initial score, respectively. For dogs on the diet, the score for erythema was significantly lower than the score from the control dogs (P = 0.019) and was reduced to 66% of the initial score. Thirteen of the 24 owners of the dogs fed the test diet (54%) indicated that the skin and coat condition of their dog had improved compared to four of 13 control dogs (31%, P = 0.030). The dogs’ plasma and cutaneous fatty acid compositions changed significantly on the test diet and were similar for responders and nonresponders. From this study, it can be concluded that a diet with high levels of EPA and GLA is effective in the reduction of pruritus and erythema in dogs with atopic dermatitis, but that not all dogs respond to the diet. Funding: LEO Animal Health.

Effects of Monensin on Ruminal Forage Degradability and Total Tract Diet Digestibility in Lactating Dairy Cows During Grain-Induced Subacute Ruminal Acidosis

The effects of monensin premix supplementation on ruminal pH characteristics and forage degradability, and total tract diet digestibility during grain-induced subacute ruminal acidosis (SARA) in lactating dairy cows receiving a total mixed ration were investigated. Six multiparous, rumen-fistulated Holstein cows were used in a 2-treatment, 2-period (5 wk per period) crossover design. During wk 5 (d 29 to 35) of each period, SARA was induced using a grain challenge model, and ruminal pH was measured continuously using indwelling pH probes. Ruminal degradation of corn silage and alfalfa haylage was determined using the in situ (nylon bag) technique, and total tract diet digestibility was determined by total fecal collection during wk 5. Monensin supplementation did not affect dry matter intake, milk yield, and composition, and ruminal pH characteristics under these experimentally induced SARA conditions. Rates of ruminal forage fiber degradability were similar between control and monensin-treated cows; however, monensin supplementation increased total tract fiber digestion. This study indicates that monensin altered total tract nutrient digestion by increasing fiber digestion at postruminal sites.

Placebo-controlled study on efficacy and safety of daily apomorphine SL intake in premenopausal women affected by hypoactive sexual desire disorder and sexual arousal disorder

Objectives To verify whether apomorphine SL is effective in premenopausal women affected by arousal disorder with hypoactive sexual desire disorder. Methods Sixty-two volunteer women, aged 26 to 45 years, affected by arousal disorders and hypoactive sexual desire disorder participated in the study, which consisted of two parts. The first was 4 weeks of a taken-as-needed, open-label, dose-escalation regimen starting at 2 or 3 mg of apomorphine SL. The second part of the study was for the nonresponders, who were randomly allocated to treatment in one of six possible sequences of three 2-week double-blind, crossover study periods with apomorphine 2 mg or 3 mg, washout, and placebo. Efficacy was assessed with the Personal Experiences Questionnaire using the 5-point Likert scale. The Personal Experiences Questionnaire quantified subjective arousal, desire, orgasm, enjoyment, and frequency of sexual relationships. Results Fifty women completed the 4-week “as required” drug regimen, and 6 of them benefited from this treatment regimen ( P <0.05). The 44 women who reported no change with respect to baseline participated in the double-blind crossover part of the study. Six women stopped taking the drug because of a fear of problems (two each during the 2-mg apomorphine, 3-mg apomorphine, and placebo periods). Adverse events were mild or moderate, both occurred during the “as required” part (10 patients) and during daily usage (6 patients) and were mainly nausea, vomiting, dizziness, or headache. However, during the placebo period, 2 women had adverse events, mainly headache. The daily intake of the drug was effective with both the 2-mg and 3-mg dosages compared with placebo for arousal and desire ( P <0.05). The effects of 3 mg of apomorphine were better than those obtained with 2 mg ( P <0.05). The orgasm, enjoyment, and satisfied by frequency scores improved during treatment with daily apomorphine compared with baseline and placebo. Conclusions The results of our study suggest that daily apomorphine SL may improve the sexual life of women affected by sexual difficulties. Additional studies are needed to define the daily use of apomorphine SL in large subgroups of women on the basis of etiology and the severity of sexual dysfunction.

Shear and normal load perturbations on a two‐dimensional continuous fault: 2. Dynamic triggering

We study the consequences of temporal stress perturbations on earthquake nucleation in a continuous fault model. Using a two‐dimensional (2‐D) quasi‐dynamic model of a strike‐slip fault governed by a rate‐and‐state friction law with depth variable properties, we show that dynamic triggering (due to stress pulses or wave packets), although allowed by our results, is an exception rather than a rule and should be limited to understressed areas such as areas of high pore pressures or to faults at the very end of their earthquake cycle. When periodic stress perturbations are sensitive, the response of the fault is frequency‐independent for periods lower than a period T0 but strongly depends on the frequency for periods larger than T0. We demonstrate that the crossover period T0 is equal to the time left until the earthquake instability. According to our model, high frequencies are demonstrated to have a higher triggering potential than low ones, which makes tidal triggering very unlikely before the end of the cycle due to the very low amplitudes of the stress perturbations involved.

Antisecretory factor counteracts secretory diarrhoea of endocrine origin

Background: Dietary induction of antisecretory factor (AF) can reduce diarrhoea in patients with inflammatory bowel disease. Patients with neuroendocrine tumours may suffer from diarrhoea with a prominent secretory component. We studied if AF-therapy could affect this type of diarrhoea. Methods: Six patients with the midgut carcinoid syndrome and two with metastasizing medullary thyroid carcinoma (MTC) participated. Effects of intake of AF, in the form of AF-rich egg powder (AF-egg), and induction of endogenous AF-activity by intake of specially processed cereals (SPCs) were studied. In an initial open part of the study all patients received AF-egg for 4 weeks, followed by a double-blind crossover period with SPC and control cereals (CCs) for 6 weeks each. Daily number of bowel movements at the end of each treatment period was registered. Results: Treatment with AF-egg resulted in a decrease of bowel movements in seven patients ( P<0.01). Registrations of bowel movements from both SPC and CC diet periods were obtained from five patients. The daily number of bowel movements was lower during the SPC-period compared to the period with CC ( P<0.05). All patients had low levels of AF-activity in serum at baseline. During treatment with AF-egg, the mean level increased slightly. AF-activity was higher (P<0.05) after SPC compared to the CC diet. Conclusions: In a group of patients with endocrine diarrhoea, AF-activity could be induced, and AF-therapy reduced the number of bowel movements.

Effects of cardiac resynchronization therapy on heart rate variability in patients with chronic systolic heart failure and intraventricular conduction delay

C resynchronization therapy (CRT) by atriobiventricular pacing has been proposed to treat severe heart failure in patients with intraventricular conduction delay resulting in ventricular mechanical discoordination. The clinical efficacy of CRT was recently demonstrated in a single-blind, randomized, crossover trial, namely the MUltisite STimulation In Cardiomyopathies (MUSTIC) study.1 The purpose of this substudy was to assess the effect of CRT on heart rate variability (HRV) and to analyze its correlation with clinical efficacy. • • • All patients provided written informed consent before enrollment. All had severe heart failure due to idiopathic or ischemic left ventricular systolic dysfunction, left ventricular ejection fraction 35%, and end-diastolic diameter 60 mm. All patients were in sinus rhythm with a QRS interval 150 ms and no classic indication for pacemaker implantation.2 Patients had been in New York Heart Association (NYHA) class III for 1 month before inclusion while receiving individually optimized treatment, including diuretics and angiotensin-converting enzyme inhibitors at the maximum tolerated dose. Exclusion criteria have been already reported.1 The study included a 6-month randomized crossover phase during which atriobiventricular (active) pacing was compared with inhibited (inactive) ventricular pacing at the basic rate of 40 beats/min, each for a period of 3 months in random order (Figure 1). Implantation was performed after a 1-month observation period to verify the stability of heart failure. Pacemakers were programmed as inactive after implantation. Patients were randomly assigned to experimental groups within the following 2 weeks after verification of pacemaker proper performance. Treatment order randomization followed a block design with stratification according to center. The single-blind, crossover phase was followed by a complementary 6-month period during which the pacing system was programmed according to patients’ preferences. All leads were implanted transvenously. The left ventricular lead was placed in a tributary of the coronary sinus according to a previously described method.3 Specially designed electrodes were used. The preferred target site was the lateral wall. The pacemakers were triple-output devices using standard dual-chamber technology, with built-in adapters to synchronize pacing in both ventricles. Pacemakers were programmed as either active or inactive at randomization. The baseline pacing rate was set at 40 beats/min and the upper rate limit at 85% of the highest predictable heart rate according to patients’ age and gender. Each patient underwent Doppler echocardiography to determine their optimal atrioventricular delay (electrical delay between atrial and ventricular excitation) during atriobiventricular pacing. No modification of medical treatment except diuretic dose adjustment was permitted between enrollment and the end of the crossover phase of the study. Twenty-four-hour ambulatory electrocardiograms with a 2-channel recorder (ELA Medical, le PlessisRobinson, France) were obtained in all subjects during normal activity at baseline, at randomization, at the end of each of the 2 crossover periods, and at the end of each longitudinal follow-up period (9 and 12 months). Tapes were replayed through a Elatec analyzer (ELA Medical). HRV analysis used specifically validated software.4 Ambulatory electrocardiographic recordings that lasted 16 hours and whose analyzable proportion was 90% were excluded to avoid bias linked to HRV circadian variations. After initial arrhythmia analysis and editing, the remaining normal-to-normal RR intervals in suitable recordings were measured and HRV time-domain analyses were performed according to published guidelines.5 For the purposes of this study, 4 different time-domain HRV indexes were measured: (1) the SD of the normal-to-normal (NN) interval over the recording duration (SDNN); (2) the SD of the 5-minute mean NN interval over the entire recording (SDANN [milliseconds]). Because SDANN values are obtained from successive 5-minute periods, they reflect heart rate changes caused by 5-minute cycles. They reflect long-term variations but provide no short-term variability data; (3) the square root of the mean squared successive differences between adjacent RR intervals over the entire recording (rMSSD [milliseconds]). This correlates more with the parasympathetic (vagal) activity; (4) proportion of successive interval differences 50 ms as computed over the entire recording (pNN50 [percent]). This also reflects parasympathetic activity. From the Departement de Cardiologie et Maladies Vasculaires, Centre Cardio-Pneumologique, Hopital Pontchaillou-CHU, Rennes, France. Dr. Daubert’s address is: Departement de Cardiologie et Maladies Vasculaires, Centre Cardio-Pneumologique, Hopital PontchaillouCHU, 35033 Rennes Cedex, France. E-mail: jean-claude. daubert@chu-rennes.fr. Manuscript received August 23, 2002; revised manuscript received and accepted January 23, 2003.

A placebo-controlled, cross-over trial of lamotrigine in depersonalization disorder

There is evidence to support the view that glutamate hyperactivity might be relevant to the neurobiology of depersonalization. We tested the efficacy of lamotrigine, which reduces glutamate release, as a treatment for patients with depersonalization disorder. A double-blind, placebo-controlled, cross-over design was used to evaluate 12 weeks of treatment of lamotrigine. Subjects comprised nine patients with DSM-IV depersonalization disorder. Changes on the Cambridge Depersonalization Scale and the Present State Examination depersonalization/derealization items were compared across the two cross-over periods. Lamotrigine was not significantly superior to placebo. None of the nine patients was deemed a responder to the lamotrigine arm of the cross-over. Lamotrigine does not seem to be useful as a sole medication in the treatment of depersonalization disorder.

Pharmacokinetics and electrocardiographic pharmacodynamics of artemether‐lumefantrine (Riamet®) with concomitant administration of ketoconazole in healthy subjects

To evaluate whether the potent CYP3A4 inhibitor ketoconazole has any influence on the pharmacokinetic and electrocardiographic parameters of the antimalarial co-artemether (artemether-lumefantrine) in healthy subjects. Sixteen subjects were randomized in an open-label, two period crossover design study. Subjects received a single dose of co-artemether (day 1) either alone or in combination with multiple oral doses of ketoconazole (400 mg on day 1 followed by 200 mg o.d. for 4 additional days). Serial blood samples were taken and assayed for artemether and its main active metabolite dihydroartemisinin (DHA), and lumefantrine. The pharmacokinetics of artemether, its metabolite DHA, and lumefantrine were influenced by the presence of ketoconazole. AUC(0, infinity ) was increased from 320 to 740 ng ml-1 h (ratio 2.4, 90% CI 2.00, 2.86) for artemether, from 331 to 501 ng ml-1 h (ratio 1.7, 90% CI 1.40, 1.98) for DHA, and from 207 to 333 micro g ml-1 h (ratio 1.7, 90% CI 1.23, 2.21) for lumefantrine in the presence of ketoconazole. Cmax also increased in similar proportions for the three compounds (ratio 2.2 (90% CI 1.78, 2.83), 1.4 (90% CI 1.12, 1.74), and 1.3 (90% CI 0.96, 1.64), respectively). The terminal elimination half-life was increased for artemether (2.5 vs 1.9 h, 90% CI 1.12, 1.72) and DHA (3.1 vs 2.1 h, 90% CI 0.02, 3.36), but remained unchanged for lumefantrine (88 vs 95 h, 90% CI 0.81, 1.04). These increases in exposure to the antimalarial combination were much smaller than observed with food intake (up to 16 fold), and were not associated with increased side-effects or changes in electrocardiographic parameters. The study medications were well tolerated. The concurrent administration of ketoconazole with co-artemether led to modest increases in artemether, DHA, and lumefantrine exposure in healthy subjects. Dose adjustment of co-artemether is probably unnecessary in falciparum malaria patients when administered in association with ketoconazole or other potent CYP3A4 inhibitors.

Formoterol provides long-lasting protection against exercise-induced bronchospasm

Patients with exercise-induced bronchospasm (EIB) may benefit from a prophylactic beta2-adrenergic agonist that combines rapid onset with long duration of action. To compare the protective effect against EIB of a single inhaled dose of formoterol powder delivered via the Aerolizer inhaler (Novartis Pharmaceuticals, East Hanover, NJ) with the effect of placebo and albuterol. Eighteen patients with EIB were randomized to treatment in a double-blind, placebo-controlled, four-way, crossover study. Seventeen patients completed all four crossover periods. Each patient received in random sequence a single dose of formoterol (12 or 24 microg), albuterol (180 microg), or placebo at intervals of 5 +/- 2 days. Pulmonary function measurements were taken before and after exercise challenge tests (ECTs) at 15 minutes postdosing and at 4, 8, and 12 hours postdosing. Both doses of formoterol produced significantly greater protection against EIB, compared with placebo, at all timepoints (P < or = 0.016). The two doses of formoterol were not significantly different from one another at any time. Protection against EIB with albuterol was clinically significant only for the 15-minute ECT and was statistically superior to placebo for the 15-minute and 4-hour ECTs. Although formoterol and albuterol exhibited a rapid onset of action, formoterol provided longer-lasting protection over the 12-hour observation period. Rescue medication was used substantially less with either dose of formoterol, compared with albuterol or placebo. All treatments were well tolerated. Two-hour postdosing electrocardiograms and vital signs were unremarkable for all study treatments. A single dose of formoterol (12 or 24 microg) provides protection against EIB within 15 minutes of dosing and persists for up to 12 hours. Formoterol is safe and well tolerated.

Using a clinical and evidence-based strategy to preserve access to psychiatric medications.

Using a clinical and evidence-based strategy to preserve access to psychiatric medications.

Postprandial glucose and insulin responses to a postexercise grain meal.

Many studies have examined the effect of pre-exercise feeding on glucose and insulin responses of horses. The objective of this study was to determine whether exercise performed one hour prior to a meal would attenuate the glucose and insulin responses to a meal. Data collected from 8 mature geldings in a 2 period crossover design experiment were used to determine the postprandial glucose and insulin responses to a meal of oats offered 1 h postexercise. During each period, 4 horses received a test meal following a 14 h fast (NoEx) or a 14 h fast and exercise bout (PostEx) that consisted of 48 min walking and trotting. Blood samples were collected before and at 30 min intervals for 5 h after the meal was offered. Glucose and insulin concentrations were similar between treatments at all time points (P>0.15). Postprandial glucose and insulin concentrations increased at similar rates in both groups from 0 to 90 min. Peak glucose and insulin concentrations and area under the response curves were similar between treatment groups. Glucose:insulin was not different between treatment groups at any time point before or after the meal (P>0.17). Overall, the 48 min of light work performed 1 h before a meal did not affect glucose or insulin responses to the meal. A one hour interval after mild exercise appears to be sufficient to allow normal glucose metabolism of a grain meal.