A pilot study to evaluate the safety, tolerance, and efficacy of a novel stationary antral balloon (SAB) for obesity

Background: A 150 cm(3) pear-shaped gastric balloon with a 30 cm-long duodenal stem and a 7 g metallic weight at its distal end was designed and developed to facilitate weight loss by (a) delaying gastric emptying thus enhancing interprandial satiety, and (b) stimulating antral and duodenal receptors of satiation. Methods: Twenty-six patients (body mass index of 29 to 40 kg/m(2)) who failed to lose weight despite dietary intervention underwent endoscopic implantation of the balloon device. Patients were monitored for tolerance to the balloon, complications, weight loss, and compliance with a restricted caloric intake. Results: Six men and 20 women with a median body weight of 93.0kg (range, 73.5 to 119.9), median body mass index 34.3 kg/m(2) (range, 28.8 to 39.5) underwent balloon implantation for a median period of 4.0 months (range, 0.75 to 6.0). Twenty-two patients successfully complied with a 1250 to 1500 kcal daily diet restriction during the study period. Median weight reduction was 6.5 kg (range, 3.7 to 19.9). Patients with initial body weight of > 90 kg tended to loose more weight (8.1 kg) than patients weighing < 90 kg (4.5 kg) (P = 0.14). Nine patients with dwell times of 6 months lost 11.5 +/- 4.6 kg. The balloon malfunctioned in 4 patients (in I patient, the balloon leaked spontaneously but remained in the stomach and in 3 patients, the balloon migrated distally). Conclusions: Our novel balloon device may be effective in inducing weight loss by promoting compliance with a restricted caloric intake and is well tolerated due to its small size. Complications resulted from balloon rupture, which can be easily prevented by enhancements in design and use of alternative materials.

The influence of Flutter (R) VRP1 components on mucus transport of patients with bronchiectasis

Background: The Flutter (R) VRP1 combines high frequency oscillation and positive expiratory pressure (PEP). Objective: To separately evaluate the effect of the Flutter (R) VRP1 components (high frequency oscillation and PEP) on mucus transportability in patients with bronchiectasis. Methods: Eighteen patients with bronchiectasis received sessions with the Flutter (R) VRP1 or PEP for 30 min daily in a randomized, crossover study. The treatment duration was four weeks with one of the therapies, one week of a ""wash-out"" period and followed by four more weeks with the other treatment. Weekly secretion samples were collected and evaluated for mucociliary relative transport velocity (RTV), displacement in a simulated cough machine (SCM) and contact angle measurement (CAM). For the proposed comparisons, a linear regression model was used with mixed effects with a significance level of 5%. Results: The Flutter (R) VRP1 treatment resulted in greater displacement in SCM and lower CAM when comparing results from the first (9.6 +/- 3.4 cm and 29.4 +/- 5.7 degrees, respectively) and fourth weeks of treatment (12.44 +/- 10.5 cm and 23.28 +/- 6.2, respectively; p < 0.05). There was no significant difference in the RTV between the treatment weeks for either the Flutter (R) VRP1 or PEP. Conclusion: The use of the Flutter (R) VRP1 for four weeks is capable of altering the respiratory secretion transport properties, and this alteration is related to the high frequency oscillation component. (C) 2011 Elsevier Ltd. All rights reserved.

Enantioselectivity in the Pharmacokinetic Interaction Between Fluvastatin and Lercanidipine in Healthy Volunteers

Hypertension and dyslipidemia are independent risk factors for cardiovascular mortality and are frequently present in the same patient. Fluvastatin (FV), used to reduce cholesterol levels, and lercanidipine (LER), used to control blood pressured are marketed as racemic mixtures. Therapeutic activities are 30-fold higher for (+)-3R,5S-FV and 100- to 200-fold higher for S-LER compared with their respective antipodes. The present study describes the enantioselective pharmacokinetic interaction between LER and FV in healthy volunteers. A crossover randomized study was conducted in 3 phases on 8 volunteers treated with a single oral racemic dose of LER (20 mg) or FV (40 mg) or LER plus FV. Serial blood samples were collected from 0 to 24 hours. Plasma concentrations of the LER and FV enantiomers were determined by liquid chromatography/tandem mass spectrometry, and pharmacokinetic parameters were evaluated using the WinNonlin software. The Wilcoxon and Mann-Whitney tests (P < .05) were used to analyze enantiomer ratios and the pharmacokinetic drug interaction. Data are expressed as medians. In monotherapy, the kinetic disposition of both FV and LER was enantioselective. AUC values were significantly higher for (-)-3S,5R-FV than for (+)-3R,5S-FV (358.20 vs 279.68 ng.h/mL) and for S-LER compared with R-LER (13.90 vs 11.88 ng.h/mL). The pharmacokinetic parameters of FV were not enantioselective when combined with LER (AUC: (-)-3S,5R-FV: 325.21; (+)-3R,5S-FV: 316.44 ng.h/mL). There was a significant reduction in S-LER (8.06 vs 13.90 ng.h/mL) and R-LER (6.76 vs 11.88 ng.h/mL) AUC values when FV was coadministered. In conclusion, the interaction between FV-LER might be clinically relevant because AUC values of (+)-3R,5S-FV were increased when LER was coadministered, and AUC values of the 2 LER enantiomers were reduced when FV was coadministered.

Effects of acute magnesium loading on pulmonary function of stable COPD patients

Background: Magnesium (Mg) use has the potential to promote bronchodilatation and to improve lung function in obstructive diseases. IV administration of Mg during exacerbations of chronic obstructive pulmonary disease (COPD) has led to improved peak flow. This study aimed to investigate the effects of acute IV Mg loading on respiratory parameters of stable COPD patients. Material/Methods: This was a randomized, double-blind, placebo-controlled crossover study. Twenty-two male COPD patients (64 +/- 6 years old, FEV1: 49 +/- 20%) received an IV infusion of 2 g of magnesium sulfate or placebo on two distinct occasions. Spirometry and mouth maximal respiratory pressures were obtained before and 45 minutes after the infusions. Results: Mg use led to significant changes in functional respiratory capacity (-0.48 1,95% CI: -0.96, -0.01), inspiratory capacity (0.21 1,95% CI: 0.04, 0.37). The treatment was also associated with a marginally significant decrease in residual volume (-0.47 1,95% CI: -0.96, 0.02, p=0.06). Conclusions: Acute IV Mg loading in stable COPD patients was associated with a reduction in lung hyperinflation and improvement of respiratory muscle strength. The clinical potential for chronic magnesium supplementation in COPD deserves further investigation.

Albendazole-praziquantel interaction in healthy volunteers: kinetic disposition, metabolism and enantioselectivity

center dot Pharmacokinetic interactions between albendazole and praziquantel are based on plasma concentrations of the enantiomeric mixture of both drugs with contradictory data, although the antiparasitic activity arises from (-)-(R)-praziquantel and (+)-albendazole sulfoxide. WHAT THIS STUDY ADDS center dot The pharmacokinetic interaction between albendazole and praziquantel is enantioselective. Praziquantel increased the plasma concentrations of (+)-albendazole sulfoxide more than those of (-)-albendazole sulfoxide and the administration of albendazole did not change the kinetic disposition of (+)-(S)-praziquantel, but increased the plasma concentration of (-)-(R)-praziquantel. AIM This study investigated the kinetic disposition, metabolism and enantioselectivity of albendazole (ABZ) and praziquantel (PZQ) administered alone and in combination to healthy volunteers. METHODS A randomized crossover study was carried out in three phases (n = 9), in which some volunteers started in phase 1 (400 mg ABZ), others in phase 2 (1500 mg PZQ), and the remaining volunteers in phase 3 (400 mg ABZ + 1500 mg PZQ). Serial blood samples were collected from 0-48 h after drug administration. Pharmacokinetic parameters were calculated using a monocompartmental model with lag time and were analyzed using the Wilcoxon test; P < 0.05. RESULTS The administration of PZQ increased the plasma concentrations of (+)-ASOX (albendazole sulphoxide) by 264% (AUC 0.99 vs. 2.59 mu g ml-1 h), (-)-ASOX by 358% (0.14 vs. 0.50 mu g ml-1 h) and albendazole sulfone (ASON) by 187% (0.17 vs. 0.32 mu g ml-1 h). The administration of ABZ did not change the kinetic disposition of (+)-(S)-PZQ (-)-(R)-4-OHPZQ or (+)-(S)-4-OHPZQ, but increased the plasma concentration of (-)-(R)-PZQ by 64.77% (AUC 0.52 vs. 0.86 mu g ml-1 h). CONCLUSIONS The pharmacokinetic interaction between ABZ and PZQ in healthy volunteers was demonstrated by the observation of increased plasma concentrations of ASON, both ASOX enantiomers and (-)-(R)-PZQ. Clinically, the combination of ABZ and PZQ may improve the therapeutic efficacy as a consequence of higher concentration of both active drugs. On the other hand, the magnitude of this elevation may represent an increased risk of side effects, requiring, certainly, reduction of the dosage. However, further studies are necessary to evaluate the efficacy and safety of this combination.

Glutamate and the neural basis of the subjective effects of ketamine

Context: Ketamine evokes psychosislike symptoms, and its primary action is to impair N-methyl-D-aspartate glutamate receptor neurotransmission, but it also induces secondary increases in glutamate release. Objectives: To identify the sites of action of ketamine in inducing symptoms and to determine the role of increased glutamate release using the glutamate release inhibitor lamotrigine. Design: Two experiments with different participants were performed using a double-blind, placebo-controlled, randomized, crossover, counterbalanced-order design. In the first experiment, the effect of intravenous ketamine hydrochloride on regional blood oxygenation level dependent (BOLD) signal and correlated symptoms was compared with intravenous saline placebo. In the second experiment, pretreatment with lamotrigine was compared with placebo to identify which effects of ketamine are mediated by increased glutamate release. Setting: Wellcome Trust Clinical Research Facility, Manchester, England. Participants: Thirty-three healthy, right-handed men were recruited by advertisements. Interventions: In experiment 1, participants were given intravenous ketamine (1-minute bolus of 0.26 mg/ kg, followed by a maintenance infusion of 0.25 mg/ kg/ h for the remainder of the session) or placebo (0.9% saline solution). In experiment 2, participants were pretreated with 300 mg of lamotrigine or placebo and then were given the same doses of ketamine as in experiment 1. Main Outcome Measures: Regional BOLD signal changes during ketamine or placebo infusion and Brief Psychiatric Rating Scale and Clinician- Administered Dissociative States Scale scores. Results: Ketamine induced a rapid, focal, and unexpected decrease in ventromedial frontal cortex, including orbitofrontal cortex and subgenual cingulate, which strongly predicted its dissociative effects and increased activity in mid- posterior cingulate, thalamus, and temporal cortical regions (r= 0.90). Activations correlated with Brief Psychiatric Rating Scale psychosis scores. Lamotrigine pretreatment prevented many of the BOLD signal changes and the symptoms. Conclusions: These 2 changes may underpin 2 fundamental processes of psychosis: abnormal perceptual experiences and impaired cognitive- emotional evaluation of their significance. The results are compatible with the theory that the neural and subjective effects of ketamine involve increased glutamate release.

Modulation of Auditory and Visual Processing by Delta-9-Tetrahydrocannabinol and Cannabidiol: an fMRI Study

Although the effects of cannabis on perception are well documented, little is known about their neural basis or how these may contribute to the formation of psychotic symptoms. We used functional magnetic resonance imaging (fMRI) to assess the effects of Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) during visual and auditory processing in healthy volunteers. In total, 14 healthy volunteers were scanned on three occasions. Identical 10mg THC, 600mg CBD, and placebo capsules were allocated in a balanced double-blinded pseudo-randomized crossover design. Plasma levels of each substance, physiological parameters, and measures of psychopathology were taken at baseline and at regular intervals following ingestion of substances. Volunteers listened passively to words read and viewed a radial visual checkerboard in alternating blocks during fMRI scanning. Administration of THC was associated with increases in anxiety, intoxication, and positive psychotic symptoms, whereas CBD had no significant symptomatic effects. THC decreased activation relative to placebo in bilateral temporal cortices during auditory processing, and increased and decreased activation in different visual areas during visual processing. CBD was associated with activation in right temporal cortex during auditory processing, and when contrasted, THC and CBD had opposite effects in the right posterior superior temporal gyrus, the right-sided homolog to Wernicke`s area. Moreover, the attenuation of activation in this area (maximum 61, -15, -2) by THC during auditory processing was correlated with its acute effect on psychotic symptoms. Single doses of THC and CBD differently modulate brain function in areas that process auditory and visual stimuli and relate to induced psychotic symptoms. Neuropsychopharmacology (2011) 36, 1340-1348; doi:10.1038/npp.2011.17; published online 16 March 2011

Elevated progesterone concentrations enhance prostaglandin F(2 alpha) synthesis in dairy cows

The objective was to evaluate the influence of varying plasma progesterone (P(4)) concentrations throughout the luteal phase in dairy cows on PGF(2 alpha) production (assessed as plasma concentrations of 13,14-dihydro-15-keto-PGF(2 alpha); PGFM) following treatment with estradiol-17 beta (E(2)) or oxytocin (OT). In all experiments, time of ovulations was synchronized with the OvSynch protocol and Day 0 corresponded to day of second GnRH injection. In Experiment 1, non-lactating dairy cows on Day 6 remained non-treated (n = 9), received 20 mg LH (n = 7), or had ovarian follicles larger than 6 mm aspirated (n = 8). In Experiment 2, cows on Day 6 were untreated (n = 9) or received 5000 IU hCG (n = 10). In Experiments 1 and 2, all cows received 3 mg E(2) on Day 17, and blood samples were collected every 30 min from 2h before to 10h after E(2). Experiment 3 was conducted in two periods, each from Days 0 to 17 of the estrous cycle. At the end of Period 1, animals switched treatments in a crossover arrangement. Animals in Group 2/8 (n = 4) received 2 kg/d of concentrate in the first period and 8 kg/d in the second period. Animals in Group 8/2 (n = 7) received the alternate sequence. Blood was collected daily for measurement Of P(4) 4 h after concentrate feeding. On Day 17, blood was collected from 1 h before to 1 h after a 100 IU OT injection. In Experiment 1, both plasma P(4) and release Of PGF(2 alpha) were similar between LH-treated and control cows (P > 0.10). In Experiment 2, plasma P4 was elevated to a greater extent on Day 17 in cows treated with hCG (P < 0.05) and plasma PGFM was also greater in hCG-treated animals (treatment x time interaction; P < 0.05). In Experiment 3, there was a group x period interaction (P < 0.01) for plasma P(4), indicating that less concentrate feeding was associated with greater plasma P(4). Release of PGF(2 alpha) in response to OT was greater for cows receiving less concentrate (group x period interaction; P < 0.05). In conclusion, dairy cows with more elevated blood P(4) concentrations released more PGF(2 alpha) in response to E(2) or OT. (c) 2008 Elsevier B.V. All rights reserved.

Effects of Regular and Low-fluoride Dentifrices on Plaque Fluoride

Previous studies have indicated that the use of low-fluoride dentifrices could lead to proportionally higher plaque fluoride levels when compared with conventional dentifrices. This double-blind, randomized, crossover study determined the effects of placebo, low-fluoride, and conventional dentifrices on plaque fluoride concentrations ([F]) in children living in communities with 0.04, 0.72, and 3.36 ppm F in the drinking water. Children used the toothpastes twice daily, for 1 wk. Samples were collected 1 and 12 hrs after the last use of dentifrices and were analyzed for fluoride and calcium. Similar increases were found 1 hr after the children brushed with low-fluoride (ca. 1.9 mmol F/kg) and conventional (ca. 2.4 mmol F/kg) dentifrices in the 0.04- and 0.72-ppm-F communities. Despite the fact that the increases were less pronounced in the 3.36-ppm-F community, our results indicate that the use of a low-fluoride dentifrice promotes a proportionally higher increase in plaque [F] when compared with that achieved with a conventional dentifrice, based on dose-response considerations.

Pharmacokinetics of ingested fluoride: Lack of effect of chemical compound

Fluoride in drinking water may be present from natural sources or added as sodium fluoride (NaF), sodium silicofluoride (Na2SiF6) or fluorosilicic acid (H2SiF6). Results from an early study with rats suggested that, when ingested as Na2SiF6, the absorption and excretion of fluoride were greater than when ingested as NaF. Objective: The present single-blind, crossover study with 10 adults was done to determine three key pharmacokinetic parameters: the maximum plasma fluoride concentrations (C-max), the elapsed time to reach the maximum concentrations (T-max) and the 6-h areas under the time-plasma concentration curves (AUCs) after ingestion of 500 ml, of water containing 0.67 or 5.45 mg F/L present naturally or added as NaF or H2SiF6. Design: Blood was collected prior to and at nine time points during 6 h after ingestion of the test solutions. Plasma was analysed by electrode after HMDS-facilitated diffusion and the data were analysed for statistically significant differences using repeated measures ANOVA. Results: The C-max, T-max and AUC values after ingestion of the solutions containing natural fluoride, NaF or H2SiF6 did not differ significantly at either dose level. Further, the Tmax values associated with the 0.67 and SAS mg/L solutions did not differ significantly indicating that the absorption, distribution and elimination rates were not affected by the dose size. Conclusions: Considered together with published reports, the present findings support the conclusion that the major features of fluoride metabolism are not affected differently by the chemical compounds commonly used to fluoridate water nor are they affected by whether the fluoride is present naturally or added artificially. (C) 2008 Elsevier Ltd. All rights reserved.

Effect of different concentrations of fluoride in dentifrices on dentin erosion subjected or not to abrasion in situ/ex vivo

This in situ/ex vivo study assessed the effect of different concentrations of fluoride in dentifrices on dentin subjected to erosion or to erosion plus abrasion. Ten volunteers took part in this crossover and double-blind study performed in 3 phases (7 days). They wore acrylic palatal appliances containing 4 bovine dentin blocks divided in two rows: erosion and erosion plus abrasion. The blocks were subjected to erosion by immersion ex vivo in a cola drink (60 s, pH 2.6) 4 times daily. During this step, the volunteers brushed their teeth with one of three dentifrices D (5,000 ppm F, NaF, silica); C (1,100 ppm F, NaF, silica) and placebo (22 ppm F, silica). Then, the respective dentifrice slurry (1: 3) was dripped on dentin surfaces. While no further treatment was performed in one row, the other row was brushed using an electric toothbrush for 30 s ex vivo. The appliances were replaced in the mouth and the volunteers rinsed with water. Dentin loss was determined by profilometry and analyzed by 2-way ANOVA/Bonferroni test (alpha = 0.05). Dentin loss after erosive-abrasive wear was significantly greater than after erosion alone. Wear was significantly higher for the placebo than for the D and C dentifrices, which were not significantly different from each other. It can be concluded that the presence of fluoride concentrations around 1,100 ppm in dentifrices is important to reduce dentin wear by erosion and erosion + abrasion, but the protective effect does not increase with fluoride concentration. Copyright (C) 2008 S. Karger AG, Basel.

The Drop Technique: a Method to Control the Amount of Fluoride Dentifrice Used by Young Children

Purpose: The purpose of this study was to evaluate the amount of dentifrice applied to the toothbrush by school children using a liquid dentifrice (drop technique), when compared to toothpaste. Materials and Methods: A total of 178 school children (4-8 years old) from two cities in Brazil (Bauru and Bariri) participated in the present two-part crossover study. Children from Bauru received training regarding tooth-brushing techniques and use of dentifrice before data collection. In each phase, the amount of toothpaste or liquid dentifrice applied by the children to the toothbrush was measured, using a portable analytical balance (+/- 0.01 g). Data were tested by analysis of covariance (Ancova) and linear regression (p < 0.05). Results: The mean (+/- standard deviation) amounts of toothpaste and liquid dentifrice applied to the toothbrushes for children from Bauru were 0.41 +/- 0.20 g and 0.15 +/- 0.06 g, respectively. For children from Bariri, the amounts applied were and 0.48 +/- 0.24 g and 0.14 +/- 0.05 g, respectively. The amount of toothpaste applied was significantly larger than the amount of liquid dentifrice for both cities. Children from Bariri applied a significantly larger amount of toothpaste, when compared to those from Bauru. However, for the liquid dentifrice, there was no statistically significant difference between the cities. A significant correlation between the amount of toothpaste applied and the age of the children was verified, but the same was not found for the liquid dentifrice. Conclusion: The use of the drop technique reduced and standardised the amount of dentifrice applied to the toothbrush, which could reduce the risk of dental fluorosis for young children.

Factors influencing fluoride ingestion from dentifrice by children

Objective: This study assessed the percentage of the amount of dentifrice loaded onto the toothbrush that is ingested by children, taking into account age, the amount of dentifrice used during toothbrushing, and the dentifrice flavor. Methods: The sample consisted of 155 children of both genders attending public kindergartens and schools in Bauru, Brazil, divided into 5 groups (n = 30-32) of children aged 2, 3, 4, 5 and 6 years old. The dentifrices used were Sorriso(TM) (1219 ppm F, peppermint-flavored) and Tandy(TM) (959 ppm F, tutti-frutti-flavored). The assessment of fluoride intake from dentifrices was carried out six times for each child, using 0.3, 0.6, and 1.2 g of each dentifrice, following a random, crossover distribution. Brushing was performed by the children or their parents/caregivers according to the home habits and under the observation of the examiner. Fluoride present in the expectorant and on toothbrush was analyzed with an ion-specific electrode after HMDS-facilitated diffusion. Fluoride ingestion was indirectly derived. Results were analyzed by 3-way repeated-measures anova and Tukey`s tests (P < 0.05) using the percent dentifrice ingested as response variable. Results: Age and percent dentifrice ingested for both dentifrices, and the three amounts used were inversely related (P < 0.0001). Percent dentifrice ingested was significantly higher after the use of Tandy(TM) under all conditions of the study when compared with Sorriso(TM) (P < 0.0001). Significant differences were observed when brushing with 0.3 g when compared with 1.2 g, for both dentifrices tested (P < 0.05). Conclusions: The results indicate that all variables tested must be considered in preventive measures aiming to reduce the amount of fluoride ingested by young children.

Light cola drink is less erosive than the regular one: An in situ/ex vivo study

Objective: This in situ/ex vivo study assessed the erosive potential of a light cola drink when compared to a regular one. Methods: During 2 experimental 14-days crossover phases, eight volunteers wore palatal devices with 2 human enamel blocks. The groups under study were: group light, erosive challenge with light cola drink and group regular, erosive challenge with regular cola drink. During 14 days, erosive challenges were performed extraorally 3X/day. In each challenge, the device was immersed in 150 ml of light cola (group light) or regular cola (group regular) for 5 min. Erosion was analysed by surface profilometry (mu m) and surface microhardness change (%SMH). The data were statistically analyzed using paired t test (p<0.05). Results: Group light (0.6 +/- 0.2 mu m) showed significantly lesser wear than group regular (3.1 +/- 1.0 mu m). There was no significant difference between the groups for the %SMH (group light -63.9 +/- 13.9 and group regular -78.5 +/- 12.7). Conclusions: The data suggest that the light cola drink is less erosive than the regular one. (C) 2008 Elsevier Ltd. All rights reserved.

The efficacy of a highly concentrated fluoride dentifrice on bovine enamel subjected to erosion and abrasion

Background. Researchers have proposed the use of fluoride for the prevention of enamel wear; however, only limited information is available about the impact of fluoridated dentifrices. Because tooth wear is a well-recognized dental problem, the authors conducted an in situ, ex vivo study to assess the efficacy of a highly concentrated fluoride dentifrice on bovine enamel subjected to erosion and abrasion. Methods. The authors conducted a double-blind, crossover in situ study consisting of three phases (seven days each). In each phase, the authors tested one of the dentifrices (5,000 parts per million fluoride [F]; 1,100 ppm F; no F). They performed erosive challenges with the use of cola drink (60 seconds, four times per day) and abrasive challenges via toothbrushing (30 seconds, four times per day). The authors determined the enamel loss via profilometry. Results. The authors tested the data by using two-way analysis of variance (P <.05). For the erosion-plus-abrasion condition, the study results showed that enamel wear was significantly higher than that with erosion alone. The findings showed no significant differences between the dentifrices regarding enamel wear. Conclusions. Within the in situ, ex vivo conditions of this study, the authors concluded that the highly concentrated fluoride dentifrice did not have a protective effect on enamel against erosion and erosion plus toothbrushing abrasion. Clinical Implications. Patients at risk of developing enamel erosion should benefit from preventive measures other than fluoride dentifrice, because even a highly concentrated fluoride dentifrice does not appear to prevent enamel erosion.