Placebo Phase Research Articles

Treatment of interictal epileptiform discharges can improve behavior in children with behavioral problems and epilepsy

It is generally agreed that children should be treated for epilepsy only if they have clinical seizures. The aim of this study was to examine whether suppressing interictal discharges can affect behavior in children with epilepsy. In a double-blinded, placebo-controlled, crossover study, 61 children with well-controlled or mild epilepsy were randomly assigned to add-on therapy with either lamotrigine followed by placebo or placebo followed by lamotrigine. Ambulatory electroencephalographic recordings and behavioral scales were performed during baseline and at the end of placebo and drug phases. The primary hypothesis to be tested was that behavioral scales would improve specifically in patients with a reduction of electroencephalographic discharges during active drug treatment. Global rating of behavior significantly improved only in patients who showed a significant reduction in either frequency ( P < .05) or duration of discharges ( P < .05) during active treatment but not in patients with without a significant change in discharge rate. This improvement was mainly seen in patients with partial epilepsy ( P < .005). Our data suggest that suppressing interictal discharges can improve behavior in children with epilepsy and behavioral problems, particularly partial epilepsy. Focal discharges may be involved in the underlying mechanisms of behavioral problems in epilepsy.

Treatment of Vasodepressor Carotid Sinus Syndrome with Midodrine: A Randomized, Controlled Pilot Study

To evaluate the efficacy of treatment of the vasodepressor form of carotid sinus hypersensitivity (carotid sinus syndrome (CSS)) with midodrine. A prospective, double-blind, randomized, controlled trial of crossover design. A dedicated outpatient facility with access to tilt-table, digital arterial photoplethysmography, and 24-hour ambulatory blood pressure (BP) monitoring equipment. Ten older adults (4 male, 6 female, mean age 75, range 66-86 years) with a history of unexplained syncope who displayed an asymptomatic decrease in systolic BP (SBP) of more than 50 mmHg or a symptomatic decrease of more than 30 mmHg within 30 seconds of carotid sinus massage (CSM). Symptom reproduction and BP and heart rate changes were evaluated after CSM in supine and semierect positions on the right and then left sides. These measurements were performed on the final day of placebo and active-treatment phases. Ambulatory 24-hour BP monitoring took place on the penultimate and final days of each treatment phase. Eight patients were symptomatic after their initial CSM. The mean+/-standard deviation SBP decrease after initial CSM was 54+/-22 mmHg. Initial mean 24-hour ambulatory BP was 127/70+/-7/5 mmHg. Eight patients reported symptoms after CSM at the end of the placebo phase. The mean SBP decrease at the end of the placebo phase was 49+/-12 mmHg. The mean 24-hour ambulatory BP was 127/69+/-9/7 mmHg. One patient reported symptoms after CSM at the end of the active-treatment phase. The mean SBP decrease at the end of the active-treatment phase was 36+/-9 mmHg. The mean 24-hour ambulatory BP at the end of the treatment phase was 133/75+/-7/6 mmHg. The differences in symptom reporting and mean SBP decrease after CSM were both significant (P<.01 and P=.03, respectively). The results of this pilot study suggest that treatment of vasodepressor CSS with midodrine significantly reduced the rate of symptom reporting and attenuated SBP decreases after CSM but increased mean 24-hour ambulatory BP.

A Placebo Controlled Crossover Trial of Liquid Fluoxetine on Repetitive Behaviors in Childhood and Adolescent Autism

Repetitive behaviors are a core symptom domain in autism that has been linked to alterations in the serotonin system. While the selective serotonin-receptive inhibitor fluvoxamine has been shown to be effective in adults with autism, as yet no published placebo controlled trials with these agents document safety and efficacy in children with autism. This study examines the selective serotonin reuptake inhibitor liquid fluoxetine in the treatment of repetitive behaviors in childhood and adolescent autism spectrum disorders (ASDs). In total, 45 child or adolescent patients with ASD were randomized into two acute 8-week phases in a double-blind placebo-controlled crossover study of liquid fluoxetine. Study design included two randomized 8-week fluoxetine and placebo phases separated by a 4-week washout phase. Outcome measures included measures of repetitive behaviors and global improvement. Low-dose liquid fluoxetine (mean final dose: 9.9+/-4.35 mg/day) was superior to placebo in the treatment of repetitive behaviors by CY-BOCS compulsion scale. The effect size was in the moderate to large range, and the doses used were low. Liquid fluoxetine was only slightly, and not significantly, superior to placebo on CGI autism score partially due to a phase order effect. However, fluoxetine was marginally superior to placebo on a composite measure of global effectiveness. Liquid fluoxetine did not significantly differ from placebo on treatment emergent side effects. Liquid fluoxetine in low doses is more effective than placebo in the treatment of repetitive behaviors in childhood autism. Limitations include small sample size and the crossover design of the study. Further replication and long-term maintenance trials are needed.

Dietary intervention in prostate cancer patients: PSA response in a randomized double‐blind placebo‐controlled study

The objective of this study was to show or to exclude an effect of dietary supplement on rising prostate-specific antigen (PSA) levels. We have studied the effect of a dietary supplement (verum, administered for 6 weeks) containing plant estrogens, antioxidants, including carotenoids, selenium and other putative prostate cancer inhibiting substances in a randomized placebo-controlled double-blind crossover study in 37 hormonally untreated men with prostate cancer and increasing PSA levels. Outcome measures were changes in the rates of change of serum concentrations of total and free PSA and changes in male sex hormone levels. Male sex hormone levels were significantly lower during the verum phase (DHT: -0.11 nmol/L, p = 0.005; testosterone: -1 nmol/L, p = 0.02). Total PSA doubling time was unaffected. Free PSA, which increased during the placebo phase (average doubling time of 68 weeks), decreased during the verum period (average half-life of 13 weeks; p = 0.02). In those men in whom the free androgen index decreased (21 out of 32), a significant decrease in the slopes of both total and free PSA was observed (p = 0.04). Overall total PSA doubling times did not increase significantly during verum. However, the study demonstrates that this dietary intervention reduces DHT and testosterone levels and increases free PSA doubling time (and total PSA doubling time in a relevant subgroup). If future studies confirm that these observations translate into a slowing of disease progression, a dietary intervention may become an attractive option for prostate cancer treatment and prevention.

Ciprofloxacin greatly increases concentrations and hypotensive effect of tizanidine by inhibiting its cytochrome P450 1A2?mediated presystemic metabolism

Tizanidine, a centrally acting skeletal muscle relaxant, is metabolized mainly by cytochrome P450 (CYP) 1A2 and has a low oral bioavailability. The fluoroquinolone antibiotic ciprofloxacin is only a moderately potent inhibitor of CYP1A2. Our objective was to study the extent and mechanism of a possible interaction of ciprofloxacin with tizanidine. In a double-blind, randomized, 2-phase crossover study, 10 healthy volunteers ingested 500 mg ciprofloxacin or placebo twice daily for 3 days. On day 3, a single dose of 4 mg tizanidine was ingested 1 hour after the morning dose of ciprofloxacin. Plasma concentrations of tizanidine and ciprofloxacin and pharmacodynamic variables were measured. A caffeine test was used as a marker for CYP1A2 activity. Ciprofloxacin increased the area under the plasma concentration-time curve from time 0 to infinity [AUC(0-infinity)] of tizanidine by 10-fold (range, 6-fold to 24-fold; P < .001) and its peak concentration by 7-fold (range, 4-fold to 21-fold; P < .001), whereas its elimination half-life was only prolonged from 1.5 to 1.8 hours (P = .007). The pharmacodynamic effects of tizanidine were much stronger during the ciprofloxacin phase than during the placebo phase with regard to changes in systolic blood pressure (-35 mm Hg versus -15 mm Hg, P = .001), diastolic blood pressure (-24 mm Hg versus -11 mm Hg, P < .001), Digit Symbol Substitution Test (P = .02), subjective drug effect (P = .002), and subjective drowsiness (P = .009). The AUC(0-infinity) of tizanidine and its change correlated (P < .01) with the caffeine/paraxanthine ratio and its change. Ciprofloxacin greatly elevates plasma concentrations of tizanidine and dangerously potentiates its hypotensive and sedative effects, mainly by inhibiting its CYP1A2-mediated metabolism, at least when administered 1 hour before tizanidine. Tizanidine seems to be a useful probe drug for measuring presystemic metabolism by CYP1A2. Care should be exercised when tizanidine is used concomitantly with ciprofloxacin.

Docosahexaenoic acid restores endothelial function in children with hyperlipidemia: results from the EARLY Study

The primary objective of this study was to determine whether the National Cholesterol Education Program Step II (NCEP-II) diet or supplementation with docosahexaenoic acid (DHA) with the diet, affects endothelial function in children with familial hypercholesterolemia (FH) or the phenotype of familial combined hyperlipidemia (FCH). As secondary endpoints, the influence of diet and DHA supplementation on lipid profiles as well as biomarkers for oxidative stress and inflammation, and asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, were all evaluated. In a double-blind, placebo-controlled, randomized, crossover study design, 20 children (ages 9-19 years) with FH (n = 12) and FCH (n = 8) received nutritional counseling based on the National Cholesterol Education Program Step II (NCEP-II) and food guide pyramid dietary guidelines for 6 weeks. They were then randomly assigned to supplementation with docosahexaenoic acid (DHA 1.2 g/d) or placebo for 6 weeks, followed by a washout phase of 6 weeks and crossover phase of 6 weeks while continuing the NCEP-II diet. Endothelium-dependent flow-mediated dilation (FMD) of the brachial artery was determined by high-resolution ultrasound. Plasma levels of total cholesterol, triglycerides and lipoprotein classes (LDL, HDL, VLDL) were measured by ultracentrifugation and enzymatic methods, plasma F2 isoprostanes by gas chromatography/mass spectrometry, urinary 8-OH-2' deoxyguanosine by liquid chromatography, high sensitivity C-reactive protein by immunonephelometry and ADMA by liquid chromatography. FMD increased significantly after DHA supplementation compared to baseline (p < 0.001), diet alone (p < 0.002), placebo (p < 0.012) and washout (p < 0.001) phases of the study without affecting biomarkers for oxidative stress, inflammation or ADMA. DHA supplementation was associated with increased levels of total cholesterol (p < 0.01), LDL- and HDL cholesterol concentrations (p < 0.001) compared to the NCEP-II diet. This study demonstrates that DHA supplementation restores endothelial-dependent FMD in hyperlipidemic children. The endothelium may thus be a therapeutic target for DHA. This is consistent with a hypothesis of increasing NO bioavailability, with the potential for preventing the progression of early coronary heart disease in high-risk children.

Therapeutic profile of manidipine and lercanidipine in hypertensive patients

Manidipine and lercanidipine are considered effective and safe in the treatment of chronic arterial hypertension and are equipotent in reducing blood pressure (BP) levels. Their main side effect is ankle-foot edema. After a 2-week placebo run-in period, these 2 drugs were compared in a controlled parallel-group study lasting 3 months, involving 53 patients with mild-to-moderate essential hypertension (26 assigned to manidipine and 27 to lercanidipine). At the end of the active treatment period, BP was significantly reduced in comparison with the end of the placebo phase in both the manidipine and the lercanidipine groups, without significant differences between the 2 drugs. Daytime BP was significantly reduced by 5.5%/5.6% with manidipine and by 3.8%/6.6% with lercanidipine, while smaller reductions were seen at nighttime. The smoothness index was the same with both drugs. Unlike lercanidipine, manidipine significantly reduced both basal (-30%) and minimal vascular resistance (-39%), qualifying it as a potent vasodilator. Despite vasodilation, heart rate was not increased but was even slightly reduced by treatment. Ankle-foot edema was observed with both drugs but was less pronounced with manidipine, probably because of greater postcapillary dilatation. In conclusion, manidipine and lercanidipine are both effective and safe in mild-to-moderate essential hypertension, although the former seems to have a more favorable tolerability profile than the latter.

Cholinergic augmentation with donepezil enhances recovery in short-term memory and sustained attention after traumatic brain injury 1,2

Zhang L, Plotkin RC, Wang G, Sandel ME, Lee S. Cholinergic augmentation with donepezil enhances recovery in short-term memory and sustained attention after traumatic brain injury. Arch Phys Med Rehabil 2004;85:1050-5. Objective To examine effects of donepezil on short-term memory and sustained attention in postacute patients with traumatic brain injury (TBI). Design A 24-week, randomized, placebo-controlled, double-blind crossover trial. Setting Outpatient clinics in 2 teaching hospitals. Participants Eighteen postacute TBI patients with cognitive impairment. Intervention Patients were randomly assigned to group A or group B. Patients in group A received donepezil for the first 10 weeks and then a placebo for another 10 weeks. The 2 treatment phases were separated by a washout period of 4 weeks. Patients in group B received the preparations in the opposite order. Main outcome measures Short-term memory and sustained attention were assessed by 2 indexes (Auditory Immediate Index [AII], Visual Immediate Index [VII]) of the Wechsler Memory Scale-III and the Paced Auditory Serial Addition Test (PASAT), at baseline, week 10, and week 24 of the trial. Results Intragroup comparison of different phases of the trial in both groups showed that donepezil significantly increased the testing scores of the AII and VII, as well as PASAT scores, compared with baseline. There was no significant change in the testing scores between assessment at baseline and the end of the placebo phase in group B. Intergroup comparison at the 10-week assessment showed significantly improved testing scores in group A with donepezil over group B with the placebo. The improved testing scores with donepezil in group A were sustained after the washout period and placebo phase, suggesting a carry-over effect of the medication. Conclusions Donepezil increased neuropsychologic testing scores in short-term memory and sustained attention in postacute TBI patients. Cholinergic augmentation may be a viable approach to restore memory and attention after TBI.

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

SUMMARYObjective: 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 (HbA1C < 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.

Creatine monohydrate enhances strength and body composition in Duchenne muscular dystrophy

To determine whether creatine monohydrate (CrM) supplementation increases strength and fat-free mass (FFM) in boys with Duchenne muscular dystrophy (DD). Thirty boys with DD (50% were taking corticosteroids) completed a double-blind, randomized, cross-over trial with 4 months of CrM (about 0.10 g/kg/day), 6-week wash-out, and 4 months of placebo. Measurements were completed of pulmonary function, compound manual muscle and handgrip strength, functional tasks, activity of daily living, body composition, serum creatine kinase and gamma-glutamyl transferase activity and creatinine, urinary markers of myofibrillar protein breakdown (3-methylhistidine), DNA oxidative stress (8-hydroxy-2-deoxyguanosine [8-OH-2-dG]), and bone degradation (N-telopeptides). During the CrM treatment phase, there was an increase in handgrip strength in the dominant hand and FFM (p < 0.05), with a trend toward a loss of global muscle strength (p = 0.056) only for the placebo phase, with no improvements in functional tasks or activities of daily living. Corticosteroid use, but not CrM treatment, was associated with a lower 8-OH-2-dG/creatinine (p < 0.05), and CrM treatment was associated with a reduction in N-telopeptides (p < 0.05). Four months of CrM supplementation led to increases in FFM and handgrip strength in the dominant hand and a reduction in a marker of bone breakdown and was well tolerated in children with DD.

Clinical efficacy of sildenafil in primary pulmonary hypertension: A randomized, placebo-controlled, double-blind, crossover study

ObjectivesIn a randomized, double-blind, crossover design, we compared the efficacy of sildenafil with placebo in patients with primary pulmonary hypertension (PPH). The primary end point was the change in exercise time on treadmill using the Naughton protocol. Secondary end points were change in cardiac index and pulmonary artery systolic pressure as assessed by Doppler echocardiography and quality of life (QOL) as assessed by a questionnaire. BackgroundPrimary pulmonary hypertension is a disorder with limited treatment options. Uncontrolled studies had shown sildenafil to be beneficial in the treatment of PPH. MethodsAfter initial clinical evaluation, including Doppler echocardiography and treadmill exercise test, patients were randomized to placebo or sildenafil with dosages ranging from 25 to 100 mg thrice daily on the basis of body weight. The evaluation was repeated after six weeks. Then patients were crossed over to alternate therapy. Final evaluation was performed after another six weeks of treatment. ResultsTwenty-two patients completed the study. Exercise time increased by 44% from 475 ± 168 s at the end of placebo phase to 686 ± 224 s at the end of sildenafil phase (p < 0.0001). With sildenafil, cardiac index improved from 2.80 ± 0.9 l/m2to 3.45 ± 1.1 l/m2(p < 0.0001), whereas pulmonary artery systolic pressure decreased insignificantly from 105.23 ± 17.82 mm Hg to 98.50 ± 24.38 mm Hg. There was significant improvement in the dyspnea and fatigue components of the QOL questionnaire. During the placebo phase, one patient died and another had syncope. There were no serious side effects with sildenafil. ConclusionsSildenafil significantly improves exercise tolerance, cardiac index, and QOL in patients with PPH.

Low dose intranasal lysine-aspirin in patients with aspirin-sensitive nasal polyps

Rationale Intranasal lysine-aspirin is a potential alternative to oral desensitization in patients with aspirin-sensitive nasal polyposis. Uncritical trials have suggested its effectiveness 1,2 . We have undertaken the first scientifically controlled trial. Methods Randomized, double blind, placebo controlled, crossover trial using low dose (8mgs) intranasal lysine-aspirin (LAS) in polyp patients who reacted positively to nasal challenge with lysine aspirin. Nasal polyp size was measured using acoustic rhinometry. Patients maintained a daily diary of nasal and chest scores, nasal inspiratory peak flow (NIPF) and peak expiratory flow rate (PEFR). No other polyp therapy was permitted. Results Nine patients completed both phases. Multivariate analysis did not show any significant difference between the placebo or LAS phase. Volume and minimal cross sectional area changes were similar in both phases (p=.587, p=.774). Diary scores were similar (nasal score, p=.82; chest score p=.82; NIPF, p=.44; PEFR, p=.95). Conclusions Low dose intranasal lysine-aspirin over 6 months is not effective in reducing polyp growth, but does not adversely affect asthma. However, nasal biopsies showed a significant reduction in CysLT 1 receptor expression following LAS 3 . This suggests that desensitization occurs at a molecular level, but translation into clinical benefit may require more prolonged LAS use, possibly at higher doses as part of combined therapy.

Wirksamkeit von hausstaubmilben- und allergendichten Encasings bei Patienten mit Hausstaubmilbenallergie

The clinical impact of allergen tight mattress encasings has still been debated. Beside encasings, recommended measures include the use of HEPA filter in the vacuum cleaner, reducing the humidity by increased ventilation rate and weekly change of bed linen. Materials and methods: A double-blind, placebo-controlled crossover study was performed to evaluate the clinical efficacy of mattress covers (VarioProtect encasings, Sanders, Germany). We included 30 patients with rhinitis or asthma due to house dust mite allergy of which 26 completed the study. At an initial visit for evaluation of the inclusion criteria, patients received a hygrometer and were seen 4 additional times for blood sampling and delivery of the active cover and later the placebo cover (cotton cover) or vice versa. Both study phases lasted 9 - 11 weeks, the wash-out period in-between lasted 2 - 10 weeks to avoid any interference with pollen allergy. At the patients' homes, a study-independent person collected dust samples which were analyzed for house dust mite allergen using an immunodot assay with monoclonal antibodies against the house dust mite allergen Der p 1, Der f 1 and mite group 2. For the evaluation of allergen content, the sum of the 3 allergens was used. Serum eosinophil cationic protein was measured to define the underlying allergic inflammation. Subjective clinical complaints regarding rhinoconjunctivitis and asthma were asked using a standardized questionnaire by E. Juniper. All patients were informed to wash their bed linen weekly and to increase the level of air exchange. A score for medication intake was calculated and the sleeping comfort with the active or placebo covers was evaluated. Results: A statistically significant reduction of the allergen content from 1.43 μg/m 2 /2 min to 0.65 μg/m 2 /2 min was found after using the active cover, but not after using the placebo cover (1.49 μg/m 2 /2 min). The measurement of the relative humidity in the air revealed no change throughout the study. At the beginning of the study, 49.5% relative humidity was measured, at the end of the study in summer time 64.3% were measured. The clinical complaints did not significantly change comparing both groups (active/placebo or placebo/active). A carry-over effect could be excluded since baseline values were similar. Pooling all data for the subjective rhinitis score revealed a statistically significant decrease in all 26 patients receiving either placebo or active treatment. In 8 patients with an elevated serum ECP level (> 16 μg/l), an amelioration of rhinitis could be seen in the active phase compared to the placebo phase. In addition, 12 patients with asthma reported fewer symptoms using the active cover compared with the placebo cover. After the active cover phase, 6 of the 8 patients with elevated ECP had a lower level of ECP, while 6 patients with the placebo cover had a higher level of ECP (p < 0.025). The medication intake was reduced during the active phase as well as during the placebo phase. The general comfort using the active cover was good with the exception of some rustling. The data confirm the clinical efficacy of allergen impermeable covers: an allergen reduction as well as a clinical relieve can be achieved, whereby the patients with elevated ECP may be particularly susceptible to allergen avoidance measurements.

A multicenter, randomized, double-blind, crossover study of patient preference for tadalafil 20 mg or sildenafil citrate 50 mg during initiation of treatment for erectile dysfunction

Background: Tadalafil is a phosphodiesterase 5 (PDE5) inhibitor approved in >30 countries for the treatment of erectile dysfunction (ED). It has been shown to improve erectile function compared with placebo in Phase III studies, but clinical experience comparing tadalafil with the PDE5 inhibitor sildenafil citrate is lacking. Objective: This study compared patient preference for tadalafil 20 mg or sildenafil 50 mg during initial treatment for ED. It also compared the tolerability of the 2 agents at these doses. Methods: This randomized, double-blind, fixed-dose, 2-period crossover trial took place at 13 sites in the United States and Germany. Patients were randomized 1:1 to receive 4 weeks of treatment with tadalafil 20 mg or sildenafil 50 mg, followed by the alternative treatment, to be taken as needed up to once daily before sexual activity. Results: The study enrolled 215 men with ED, 109 randomized to the tadalafil-sildenafil sequence and 106 to the sildenafil-tadalafil sequence. Their mean age was 49.8 years; 84.7% were sildenafil naive and 15.3% had undergone a previous inadequate trial of sildenafil. Most patients had moderate ED (60.5%) of ≥1 year's duration (74.9%). Of 190 evaluable patients, 126 (66.3%) preferred to initiate treatment with tadalafil, compared with 64 (33.7%) with sildenafil ( P < 0.001). Patients' preference did not differ by age, duration of ED, treatment sequence, or previous sildenafil exposure. Both medications were well tolerated, with no significant differences in the incidence of treatment-emergent adverse events. Headache (11.2% tadalafil, 8.8% sildenafil), dyspepsia (6.0% and 4.2%, respectively), nasopharyngitis (4.7% and 2.8%), and flushing (2.8% and 4.7%) were the most common adverse events. The rate of ocular disturbances was low: 1 patient experienced intermittent bilateral reduction in visual acuity with tadalafil, and 2 exhibited conjunctival hyperemia or eyelid edema with sildenafil. Conclusions: Tadalafil 20 mg was preferred to sildenafil 50 mg for the initiation of ED therapy in this study population. Both medications were well tolerated.

Inhibitory effect of stiripentol on carbamazepine and saquinavir metabolism in human.

To characterize the in vitro and in vivo inhibitory effect of stiripentol, a new anticonvulsant, on the metabolism of carbamazepine and saquinavir, which are substrates of CYP3A4. Human liver microsomes and cDNA-expressed CYP enzymes were used for the in vitro experiments. Pharmacokinetic data from epileptic children and healthy adults were used for the carbamazepine and saquinavir in vivo studies, respectively. Carbamazepine biotransformation to its 10,11-epoxide by human liver microsomes (Vmax = 10.3 nmol min(-1) nmol(-1) P450, apparent Km = 362 microm), cDNA-expressed CYP3A4 (Vmax = 1.17 nmol min(-1) nmol(-1) P450, apparent Km = 119 microm) and CYP2C8 (Vmax = 0.669 nmol min(-1) nmol(-1) P450, apparent Km = 757 microm) was inhibited by stiripentol (IC50 14, 5.1, 37 microM and apparent Ki 3.7, 2.5, 35 microm, respectively). Saquinavir biotransformation to its major metabolite M7 by human liver microsomes (Vmax = 5.7 nmol min(-1) nmol(-1) P450, apparent Km = 0.79 microm) was inhibited by stiripentol (IC50 163 microM, apparent Ki 86 microm). In epileptic children treated with carbamazepine and stiripentol, the plasma concentration ratio of carbamazepine epoxide/carbamazepine was decreased by 65%. The in vivo apparent Ki for stiripentol ranged from 10.5 to 41.4 microm. The pharmacokinetics of saquinavir was not modified by stiripentol in healthy adults. The 95% confidence intervals for the difference for Cmax and AUC of saquinavir between the placebo and stiripentol phase were (-39.8, 39.8) and (-33.2, 112), respectively. These results showed that stiripentol was a weak inhibitor of saquinavir metabolism both in vitro and in vivo. In contrast, stiripentol is a potent inhibitor of carbamazepine 10,11-epoxide formation in vitro and in vivo in epileptic patients.

Effect of Ascorbic Acid Consumption On Urinary Stone Risk Factors

Ascorbic acid (AA) has been implicated as a risk factor for calcium oxalate stones due to its conversion to oxalate and potential acidifying properties. We evaluated the effect of AA consumption on urinary saturation of calcium oxalate (CaOx) and urinary pH. A total of 12 normal subjects (NS) and 12 CaOx stone formers (SF) underwent 2, 6-day phases of study while maintained on a controlled metabolic diet. In each phase subjects ingested 1 gm AA or an identical appearing placebo twice daily. On the last 2 days of each phase 2, 24-hour urine collections were analyzed for pH and stone risk factors, and blood specimens were submitted for serum chemistry studies. No difference in urinary pH was found between placebo and AA phases in NS (6.02 versus 6.02) and SF (6.0 versus 6.0). However, urinary oxalate was statistically significantly higher in the AA versus placebo phase for NS (34.7 versus 28.5 mg, p = 0.008) and SF (41.0 versus 30.5 mg, p <0.001). Likewise, the CaOx relative saturation ratio was significantly higher in the AA versus placebo phase for both groups. Ingestion of 2 gm AA daily results in no change in urinary pH but a moderate though statistically significant increase in urinary oxalate in NS (20%) and SF (33%). Stone formers respond no differently to AA than normal subjects. We recommend limiting AA use to less than 2 gm daily in CaOx stone formers.

Comparison of the blood pressure-lowering effects and tolerability of Losartan- and Amlodipine-based regimens in patients with isolated systolic hypertension

Background: Elevated systolic blood pressure is a more important risk factor for cardiovascular and renal disease than elevated diastolic blood pressure. Isolated systolic hypertension (ISH) is the predominant form of hypertension in the elderly. Effects of angiotensin II on the vascular wall and endothelium may contribute to development of ISH. Objective: The primary objective of this study was to compare the effects on trough sitting systolic blood pressure (SiSBP) of a regimen of losartan, a selective angiotensin II-receptor antagonist, and an amlodipine-based regimen in patients with ISH. Methods: This multicenter, prospective, randomized, double-blind, parallel-group study consisted of a 4-week placebo phase and an 18-week active-treatment phase. The losartan-based regimen consisted of losartan 50 mg, increased as needed to losartan 50 mg/hydrochlorothiazide (HCTZ) 12.5 mg at week 6 and to losartan 100 mg/HCTZ 25 mg at week 12 to achieve a target SiSBP <140 mm Hg. the amlodipine-based regimen consisted of amlodipine 5 mg, increased as needed to amlodipine 10 mg at week 6 and to amlodipine 10 mg/HCTZ 25 mg at week 12. The primary efficacy measure was change in trough SiSBP from baseline to week 18. Information on the tolerability of study treatments was collected at each visit, including the investigator's and patient's observations of clinical adverse experiences (CAEs), laboratory adverse experiences, and responses to a symptom questionnaire. Results: Eight hundred fifty-seven patients (65.6% female) were randomized to treatment, 432 in the losartan group and 425 in the amlodipine group. Their mean age was 67.6 years, and they had a mean duration of hypertension of 6.7 years at baseline. The losartan and amlodipine groups (intent-to-treat population) had baseline mean SiSBP values of 171.2 and 171.9 mm Hg, respectively. At week 18 (the primary end point), the mean change from baseline in SiSBP was −27.4 mm Hg for 426 patients who received losartan and −28.1 mm Hg for 419 patients who received amlodipine (estimated least-square mean difference, 0.3 mm Hg; 95% CI, −1.4 to 2.0), indicating that losartan's effect on systolic blood pressure was noninferior to that of amlodipine. The proportion of patients who responded (SiSBP <140 mm Hg or a ≥20-mm Hg decrease in SiSBP from baseline) was comparable between groups (73.9% losartan, 75.4% amlodipine). The incidence of CAEs and drug-related CAEs was significantly greater in the amlodipine group (amlodipine, 79.8% and 43.8%, respectively; losartan, 67.8% and 25.5%; P ≤ 0.001). In addition, more patients in the amlodipine group discontinued therapy due to a drug-related CAE compared with patients in the losartan group (12.9% vs 4.4%, respectively; P ≤ 0.001). Lower-extremity edema was the most common drug-related CAE in the amlodipine group (24.0% amlodipine, 2.5% losartan; P ≤ 0.001); dizziness was the most common drug-related CAE in the losartan group (6.0% losartan, 4.0% amlodipine). Conclusions: In these patients with ISH, losartan and amlodipine produced comparable clinically relevant reductions in SiSBP; however, losartan was better tolerated, as evidenced by fewer CAEs and discontinuations compared with amlodipine. Losartan may be considered for the initial treatment of ISH.

Itraconazole increases but grapefruit juice greatly decreases plasma concentrations of celiprolol

Our objective was to evaluate the effects of itraconazole and grapefruit juice on the pharmacokinetics of the beta-adrenergic receptor-blocking agent celiprolol in healthy volunteers. In a randomized 3-phase crossover study, 12 healthy volunteers took itraconazole 200 mg orally or placebo twice a day or 200 mL grapefruit juice 3 times a day for 2 days. On the morning of day 3, 1 hour after ingestion of itraconazole, placebo, or grapefruit juice, each subject ingested 100 mg celiprolol with 200 mL of water (placebo and itraconazole phases) or grapefruit juice. In addition, 200 mL of water or grapefruit juice was ingested 4 and 10 hours after celiprolol intake. The plasma concentrations of celiprolol, itraconazole, and hydroxyitraconazole and the excretion of celiprolol into urine were measured up to 33 hours after dosing. Systolic and diastolic blood pressures and heart rate were recorded with subjects in a sitting position before the administration of celiprolol and 2, 4, 6, and 10 hours later. During the itraconazole phase, the mean area under the plasma concentration-time curve from 0 to 33 hours [AUC(0-33)] of celiprolol was 80% greater (P <.05) than in the placebo phase. During the grapefruit juice phase, the mean AUC(0-33) and peak plasma concentration values of celiprolol were reduced to about 13% (P <.001) and 5% (P <.001) of the respective placebo phase values. The cumulative excretion into urine of celiprolol was increased by 59% by itraconazole (P <.05) and decreased by 85% by grapefruit juice (P <.001). Hemodynamic variables did not differ between the phases. Itraconazole almost doubles but grapefruit juice greatly reduces plasma concentrations of celiprolol. The itraconazole-celiprolol interaction most likely resulted from increased absorption of celiprolol possibly as a result of P-glycoprotein inhibition in the intestine. The reduced celiprolol concentrations during the grapefruit juice phase were probably caused by physicochemical factors that interfered with celiprolol absorption, although other mechanisms cannot be excluded. The grapefruit juice-celiprolol interaction is probably of clinical relevance.

D-Cycloserine for the treatment of ataxia in spinocerebellar degeneration

We studied the effects of d-cycloserine, a partial NMDA receptor allosteric agonist, on ataxia in patients with spinocerebellar degeneration. Fifteen Japanese ataxic patients enrolled in a 14-day single-blind trial of d-cycloserine (daily oral dose of 50 mg) following a 14-day single-blind placebo phase. At the end of the d-cycloserine administration, there was a significant reduction in the posture, gait and total score of the international cooperative ataxia rating scale and in the time for walking and speech tasks. d-Cycloserine was well-tolerated and no adverse effect was observed. d-Cycloserine may have therapeutic efficacy for spinocerebellar ataxia.

Can we eliminate placebo in ALS clinical trials?

BACKGROUND: Previous studies concluded that the decline in strength in patients with amyotrophic lateral sclerosis (ALS) is a linear function. If so, a patient's natural history might serve as the control, instead of placebo, in a clinical trial.METHODS: A placebo‐controlled ALS clinical trial included a natural history phase, followed by a 6‐month treatment phase. Each patient's forced vital capacity (FVC) score and maximal voluntary isometric contraction (MVIC) raw scores were measured monthly, standardized, and averaged into megascores. For 138 patients, the arm, leg, FVC, arm+leg combination, and arm+leg+FVC combination megascore slopes during the natural history phase and during the placebo phase were compared.RESULTS: The mean slope of megascores during the natural history phase and the mean slope during the placebo phase were not different for the arm, leg, and arm+leg megascores, but were different for the FVC and arm+leg+FVC combination megascores.CONCLUSIONS: Natural history controls may be useful in ALS exploratory trials that use arm megascore slope as the primary outcome measure. However, there are distinct limitations to the use of natural history controls, so that Phase 3 ALS clinical trials require placebo controls.