A Randomized, Double-Blind, Placebo-Controlled Study of Gelesis100: A Novel Nonsystemic Oral Hydrogel for Weight Loss.

OBJECTIVE: This study aims to assess the efficacy and safety of Gelesis100, a novel, nonsystemic, superabsorbent hydrogel to treat overweight or obesity. METHODS: The Gelesis Loss Of Weight (GLOW) study was a 24-week, multicenter, randomized, double-blind, placebo-controlled study in patients with BMI ≥  27 and ≤ 40 kg/m2 and fasting plasma glucose ≥ 90 and ≤ 145 mg/dL. The co-primary end points were placebo-adjusted weight loss (superiority and 3% margin super-superiority) and at least 35% of patients in the Gelesis100 group achieving ≥ 5% weight loss. RESULTS: Gelesis100 treatment caused greater weight loss over placebo (6.4% vs. 4.4%, P = 0.0007), achieving 2.1% superiority but not 3% super-superiority. Importantly, 59% of Gelesis100-treated patients achieved weight loss of ≥ 5%, and 27% achieved ≥ 10% versus 42% and 15% in the placebo group, respectively. Gelesis100-treated patients had twice the odds of achieving ≥ 5% and ≥ 10% weight loss versus placebo (adjusted OR: 2.0, P = 0.0008; OR: 2.1, P = 0.0107, respectively), with 5% responders having a mean weight loss of 10.2%. Patients with prediabetes or drug-naive type 2 diabetes had six times the odds of achieving ≥ 10% weight loss. Gelesis100 treatment had no apparent increased safety risks. CONCLUSIONS: Gelesis100 is a promising new nonsystemic therapy for overweight and obesity with a highly desirable safety and tolerability profile.

Effect of a nonsystemic, orally administered hydrogel, GS100, on metformin pharmacokinetics.

Overweight and obesity are major health concerns worldwide, and are major predisposing factors for type 2 diabetes. This single-centre, Phase I, randomised, open-label, single-dose, 4-arm crossover, device-drug interaction study on 24 healthy volunteers with a body mass index of 25-40 kg/m2 tested the effect of a novel, nonsystemic, orally administered hydrogel (GS100) on the pharmacokinetics of an oral antidiabetic drug, metformin. When administered in both the fed and fasted states, the effect of GS100 on metformin pharmacokinetic characteristics was found to be similar to that of food. The type, frequency, and intensity of adverse events observed when GS100 was co-administered with metformin were similar to those observed with metformin alone. This study demonstrates that GS100 can be taken by patients receiving metformin, without altering the administration of metformin.

Age-associated changes in obstacle negotiation strategies: Does size and timing matter?

INTRODUCTION: Tripping over an obstacle is one of the most common causes of falls among older adults. However, the effects of aging, obstacle height and anticipation time on negotiation strategies have not been systematically evaluated. METHODS: Twenty older adults (ages: 77.7±3.4years; 50% women) and twenty young adults (age: 29.3±3.8years; 50% women) walked through an obstacle course while negotiating anticipated and unanticipated obstacles at heights of 25mm and 75mm. Kinect cameras captured the: (1) distance of the subject's trailing foot before the obstacles, (2) distance of the leading foot after the obstacles, (3) clearance of the leading foot above the obstacles, and (4) clearance of the trailing foot above the obstacles. Linear-mix models assessed changes between groups and conditions. RESULTS: Older adults placed their leading foot closer to the obstacle after landing, compared to young adults (p<0.001). This pattern was enhanced in high obstacles (group*height interaction, p=0.033). Older adults had lower clearance over the obstacles, compared to young adults (p=0.007). This was more pronounced during unanticipated obstacles (group*ART interaction, p=0.003). The distance of the leading foot and clearance of the trailing foot after the obstacles were correlated with motor, cognitive, and functional abilities. CONCLUSIONS: These findings suggest that there are age-related changes in obstacle crossing strategies that are dependent on the specific characteristics of the obstacle. The results have important implications for clinical practice, suggesting that functional exercise should include obstacle negotiation training with variable practice of height and available response times. Further studies are needed to better understand the effects of motor and cognitive abilities.

Imaging transporters: Transforming diagnostic and therapeutic development.

Molecular imaging allows noninvasive assessment of drug distribution across pharmacological barriers. Thus, it plays an increasingly important role in efforts to understand the interactions of molecules with membrane transporters during drug development and in clinical pharmacology. We describe established and emerging imaging modalities utilized for studying transporter expression and function. We further present examples of how molecular imaging could provide insights into the contribution of transporters to drug disposition and effects.

The role of aquaporin-1 in idiopathic and drug-induced intracranial hypertension.

Idiopathic intracranial hypertension is a common disorder affecting mainly healthy, young, overweight women. The pathogenesis of this condition is unknown, but it has been shown to follow treatment with several compounds including corticosteroids and vitamin A derivatives. This paper will offer a novel hypothesis and insight on the pathogenesis of drug induced intracranial hypertension following a review and analysis of the literature. Both corticosteroids and vitamin A derivatives have been shown to upregulate the expression of aquaporin 1, a water channel protein. Aquaporin 1 is widely distributed in the human brain and is associated with water secretion into the subarachnoid space. Aquaporin 1 was also shown to participate in the regulation of weight. Agents used for treating idiopathic intracranial hypertension reduce aquaporin 1 expression. Based on these observations, we propose that aquaporin 1 has a pathogenetic role in drug induced idiopathic intracranial hypertension. Over expression of this gene causes increased intracranial pressure, and downregulation reduces pressure and alleviates the symptomatology and complications of idiopathic intracranial hypertension.

Regional P-glycoprotein activity and inhibition at the human blood-brain barrier as imaged by positron emission tomography.

We used positron emission tomography (PET) to evaluate the contribution of P-glycoprotein (P-gp), present at the human blood-brain barrier (BBB), to regional drug distribution in the brain. Eleven healthy volunteers underwent PET imaging with [(11)C]-verapamil before and during cyclosporine A infusion. Regional P-gp inhibition was expressed as cyclosporine A-induced percentage change in the distributional clearance of verapamil (K(1)) in the brain, normalized to the regional blood flow (rCBF). K(1) estimates were similar across gray-matter regions of the brain and lower in the white matter regions, but all these estimates were considerably lower than rCBF. Normalization of K(1) by rCBF diminished the differences in estimates related to gray matter and white matter. In contrast, the K(1) for the pituitary, which is situated outside the BBB, approximated the rCBF. The magnitude of P-gp inhibition was comparable across BBB-protected brain structures. Our results indicate that P-gp and its inhibition equally affect the distribution of drugs (and therefore their neuro-efficacy and toxicity) in the various brain regions protected by the BBB.

Positron emission tomography imaging of tissue P-glycoprotein activity during pregnancy in the non-human primate.

BACKGROUND AND PURPOSE: Changes in tissue P-glycoprotein (P-gp) activity during pregnancy could affect the pharmacokinetics and thus the efficacy and toxicity of many drugs. Therefore, using positron emission tomography (PET) imaging, we tested whether gestational age affects tissue P-gp activity in the pregnant non-human primate, Macaca nemestrina. EXPERIMENTAL APPROACH: Mid-gestational (day 75 +/- 13, n= 7) and late-gestational (day 150 +/- 10, n= 5) age macaques were imaged after administration of a prototypic P-gp substrate, (11)C-verapamil (13.7-75.4 MBq.kg(-1)), before and during intravenous infusion of a P-gp inhibitor, cyclosporin A (CsA) (12 or 24 mg.kg(-1).h(-1)). Accumulation of radioactivity in the fetal liver served as a reporter of placental P-gp activity. P-gp activity was expressed as CsA-induced percent change in the ratio of the area (0-9 min) under the (11)C-radioactivity concentration-time curve in the tissue (AUC(tissue)) to that in the maternal plasma (AUC(plasma)). KEY RESULTS: The CsA-induced change in AUC(fetal liver)/AUC(maternal)(plasma) of (11)C-radioactivity significantly increased from mid- (35 +/- 25%) to late gestation (125 +/- 66%). Likewise, the CsA-induced change in AUC(maternal brain)/AUC(plasma) increased from mid- (172 +/- 80%) to late gestation (337 +/- 148%). The AUC ratio for the other maternal tissues was not significantly affected. Neither the CsA blood concentrations nor the level of circulating (11)C-verapamil metabolites were significantly affected by gestational age. CONCLUSIONS AND IMPLICATIONS: P-gp activity at the blood-brain barrier and the placental barrier in the macaque increased with gestational age. If replicated in humans, the exposure of the fetus and maternal brain to P-gp substrate drugs, and therefore their efficacy and toxicity, will change during pregnancy.

The effects of central nervous system-active valproic acid constitutional isomers, cyclopropyl analogs, and amide derivatives on neuronal growth cone behavior.

Valproic acid (VPA) is an effective antiepileptic drug with an additional activity for the treatment of bipolar disorder. It has been assumed that both activities arise from a common target. At the molecular level, VPA targets a number of distinct proteins that are involved in signal transduction. VPA inhibition of inositol synthase reduces the cellular concentration of myo-inositol, an effect common to the mood stabilizers lithium and carbamazepine. VPA inhibition of histone deacetylases activates Wnt signaling via elevated beta-catenin expression and causes teratogenicity. Given the VPA chemical structure, it may be possible to design VPA derivatives and analogs that modulate specific protein targets but leave the others unaffected. Indeed, it has been shown that some nonteratogenic VPA derivatives retain antiepileptic and inositol signaling effects. In this study, we describe a further set of VPA analogs and derivatives that separate anticonvulsant activity from effects on neuronal growth cone morphology. Lithium, carbamazepine, and VPA induce inositol-dependent spread of neuronal growth cones, providing a cell-based assay that correlates with mood-stabilizing activity. We find that two constitutional isomers of VPA, propylisopropylacetic acid and diisopropylacetic acid, but not their corresponding amides, and N-methyl-2,2,3,3-tetramethyl-cyclopropanecarboaxamide are more effective than VPA in increasing growth cone spreading. We show that these effects are associated with inositol depletion, and not changes in beta-catenin-mediated Wnt signaling. These results suggest a route to a new generation of central nervous system-active VPA analogs that specifically target bipolar disorder.

The antiepileptic and anticancer agent, valproic acid, induces P-glycoprotein in human tumour cell lines and in rat liver.

BACKGROUND AND PURPOSE: The antiepileptic drug valproic acid, a histone deacetylase (HDAC) inhibitor, is currently being tested as an anticancer agent. However, HDAC inhibitors may interact with anticancer drugs through induction of P-glycoprotein (P-gp, MDR1) expression. In this study we assessed whether valproic acid induces P-gp function in tumour cells. We also investigated effects of valproic acid on the mRNA for P-gp and the cytochrome P450, CYP3A, in rat livers. EXPERIMENTAL APPROACH: Effects of valproic acid on P-gp were assessed in three tumour cell lines, SW620, KG1a and H4IIE. Accumulation of acetylated histone H3 in rats' livers treated for two or seven days with valproic acid was evaluated using a specific antibody. Hepatic expression of the P-gp genes, mdr1a, mdr1b and mdr2, was determined by real-time polymerase chain reaction. The effects of valproic acid on CYP3A were assessed by Northern blot analysis and CYP3A activity assays. KEY RESULTS: Valproic acid (0.5-2.0 mM) induced P-gp expression and function up to 4-fold in vitro. The effect of a series of valproic acid derivatives on P-gp expression in SW620 and KG1a cells correlated with their HDAC inhibition potencies. Treatment of rats with 1 mmol kg(-1) valproic acid for two and seven days increased hepatic histone acetylation (1.3- and 3.5-fold, respectively) and the expression of mdr1a and mdr2 (2.2-4.1-fold). Valpromide (0.5-2.0 mM) did not increase histone acetylation or P-gp expression in rat livers, but induced CYP3A expression. CONCLUSIONS: Valproic acid increased P-gp expression and function in human tumour cell lines and in rat liver. The clinical significance of this increase merits further investigation.

L-Arginine improves vascular function by overcoming deleterious effects of ADMA, a novel cardiovascular risk factor.

There is abundant evidence that the endothelium plays a crucial role in the maintenance of vascular tone and structure. One of the major endothelium-derived vasoactive mediators is nitric oxide (NO), an endogenous messenger molecule formed in healthy vascular endothelium from the amino acid precursor L-arginine. Endothelial dysfunction is caused by various cardiovascular risk factors, metabolic diseases, and systemic or local inflammation. One mechanism that explains the occurrence of endothelial dysfunction is the presence of elevated blood levels of asymmetric dimethylarginine (ADMA)--an L-arginine analogue that inhibits NO formation and thereby can impair vascular function. Supplementation with L-arginine has been shown to restore vascular function and to improve the clinical symptoms of various diseases associated with vascular dysfunction.

Initial biofilm formation of Streptococcus sobrinus on various orthodontics appliances.

Biofilms accumulate on hard and soft surface in the oral cavity. Accumulation of biofilms on orthodontic appliance bear scientific and clinical interest. The objection of this study was to examine the formation of dental biofilm by Streptococcus sobrinus on different types of orthodontics appliances, using a model consisting of host and bacterial constituents. The adsorption pattern of saliva to the orthodontics appliances was determined by means of gel electrophoresis coupled with computerized densitometry techniques. The amount of salivary proteins adsorbed onto the surfaces was measured using the Bradford method. Sucrose-dependent bacterial adhesion to the saliva-coated orthodontics appliances was tested by radioactive-labelled S. sobrinus. Our results show different adsorption patterns of salivary proteins to the various orthodontic appliances as modules, brackets, springs and intra oral elastics. Modules and brackets demonstrated the most affinity to salivary proteins. A surface dependent adhesion profile was recorded, showing a high affinity of albumin and amylase to modules. Bacterial accumulation was the highest on modules compared with springs which demonstrated the least bacterial adhesion. Our study demonstrates the specificity of biofilm formation on the different orthodontic appliances. Formation of a variety of dental biofilms has a significant impact on the progression of dental diseases associated with orthodontic treatment.

Adverse drug events in hospitalized patients treated with cardiovascular drugs and anticoagulants.

PURPOSE: To evaluate the incidence of serious adverse drug events (ADEs) caused by cardiovascular drugs during hospitalization in a department of internal medicine, and to identify patients at highest risk. PATIENTS AND METHODS: All the patients treated with cardiovascular drugs and/or anticoagulants in the department between November 1999 and January 2000 were recruited into the study. During hospitalization the patients' charts were reviewed by a pharmacist and a clinician, and the occurrence of serious ADEs was assessed using the Naranjo algorithm. 'Possible' and 'doubtful' ADEs were not counted. RESULTS: Of 496 patients who were enrolled in the study, 20 (4%) had serious ADEs. Compared to patients without ADEs, patients in the ADE group were older (72 +/- 12.6 years (mean +/- SD) vs. 65 +/- 13 years, p = 0.048), their average stay in hospital was longer (7.3 +/- 5.5 days vs. 5.2 +/- 3.7 days, p = 0.018) and their mean urea levels were higher (10.8 +/- 9.3 mmol/l vs. 7.8 +/- 5.3 mmol/l, p = 0.027). The most frequent background pathologies of the 20 patients with ADEs were hypertension (in 18 (90%)) and atrial fibrillation (in nine (45%)). In 50% of the the ADE group there was a history of drug allergies. The ADEs recorded were bleeding in four (20%), arrhythmias in six (30%), orthostatic hypotension in six (30%) and skin necrosis, paranoid reaction, acute hepatitis and acute renal failure in four (20%). The causative drugs were warfarin (which accounted for 25% of the ADEs), beta-blockers (15%), propafenone (5%), amiodarone (5%), and Ca(2+)-channel blockers, nitrates and diuretics (together accounting for 50% of ADEs). Drug combinations were implicated in 50% of ADE. CONCLUSIONS: Serious ADEs were developed by 4% of hospitalized patients taking cardiovascular drugs. Those at highest risk were older, were receiving multiple drug therapy and had higher urea levels. Warfarin and beta-blockers were the drugs causing the largest number of adverse effects. ADEs are an important cause of preventable morbidity, often with serious economic implications and special attention should be given to their prevention.

Nonlinear dynamics applied to blood pressure control.

Hypertension is a very frequent disease, known to trigger a range of severe cardiovascular problems. The elucidation of its pathophysiology requires investigation of the mechanisms responsible for the maintenance of blood pressure in the normal system, and their possible failure in hypertension. Some of these control mechanisms display nonlinear features, indicating that the blood pressure signal might be characterized by nonlinear dynamics. Our aim was thus to investigate the nonlinear properties of the blood pressure signal under normal conditions, and in a cardiovascular system prone to hypertension. Blood pressure was investigated in young spontaneously hypertensive rats (SHR), versus their age-matched normotensive progenitors (WKY). The correlation dimension was computed as quantification of blood pressure control complexity. The parameters required for the calculation procedure of the correlation dimension were carefully determined. The results were tested with surrogate data statistics. assuming linear autocorrelated Gaussian noise as the null hypothesis. Non-integer correlation dimension values were found in both strains, with lower values for SHR than for WKY, in particular following alpha-blockade. In all cases, a statistically significant difference was found between the real and surrogate data. These results show that the nonlinear dynamics parameter D, can be used to detect differences in BP control between prehypertensive SHR and WKY rats as early as 6-7 weeks after birth.

Bifurcation in a simple model of the cardiovascular system.

A simple nonlinear beat-to-beat model of the human cardiovascular system has been studied. The model, introduced by DeBoer et al. was a simplified linearized version. We present a modified model which allows to investigate the nonlinear dynamics of the cardiovascular system. We found that an increase in the alpha-sympathetic gain, via a Hopf bifurcation, leads to sustained oscillations both in heart rate and blood pressure variables at about 0.1 Hz (Mayer waves). Similar oscillations were observed when increasing the beta-sympathetic gain or decreasing the vagal gain. Further changes of the gains, even beyond reasonable physiological values, did not reveal another bifurcation. The dynamics observed were thus either fixed point or limit cycle. Introducing respiration into the model showed entrainment between the respiration frequency and the Mayer waves.

The diastolic decay constant in spontaneously hypertensive rats versus WKY rats as an indicator for vasomotor control.

This research uses the diastolic decay constant (tau) to investigate the short term mechanism responsible for vasomotor control, mainly the alpha-sympathetic control system. Previous studies have shown that vasomotor control is altered in spontaneously hypertensive rats (SHR) preceding the phase of overt hypertension. The diastolic decay, according to the two element Windkessel model, displays an exponential shape with a decay constant, tau, depending on both the vascular resistance and the compliance. In our experiments, we used tau to characterize vasomotor activity and its control in the normotensive rats as well as in the spontaneously hypertensive rats (SHR) prone to hypertension. The beat to beat value of tau was evaluated from a continuous arterial blood pressure (ABP) signal, measured in the tail artery of the conscious, unrestrained rat. Four months old prehypertensive SHR were compared to their age matched normotensive controls (WKY). To study vasomotor regulation, we computed gains and delay times by investigating the compensatory response in tau to changes in mean ABP (MBP). These parameters are expected in the short term to be neurally controlled by the sympathetic system, mainly alpha-sympathetic. Our set of experiments consisted of changing MBP by performing successive injections in bolus of increasing doses of the vasoconstrictor angiotensin II. This procedure was repeated under double cardiac autonomic blockade of the vagal and beta 1 = sympathetic limbs. Our results show that, under baseline conditions, the absolute gain and delay times of tau are reduced in SHR compared to WKY. Double cardiac blockade decreases the absolute gain in both strains, while abolishing the baseline strain differences. These results reinforce our assumption that, in SHR, the alpha-sympathetic system is in a basic state of excitation even prior to the onset of overt hypertension and therefore reacting with reduced sensitivity (lower gain) to changes in MBP.

Decay constant of Doppler flow waveform as a possible indicator of ovarian malignancy.

The objectives of this study were to analyze the decay constant (tau) of the Doppler flow waveform in ovarian tumors; to determine if differences in this constant can discriminate between malignant and benign ovarian tumors; and to compare the decay constant to the known resistive index (RI), in order to determine its potential prognostic application. Patients with ovarian masses (46) were evaluated in a retrospective study; 13 had malignant tumors, 7 showed tumors with low malignant potential (LMP), 11 had benign masses, 4 had secondary ovarian metastases and 11 had functional ovarian masses. Doppler flow waves measured in the ovary before operation were analyzed from archival videotapes. The RI was calculated preoperatively, and the decay constant of the flow waveform was analyzed retrospectively. We approximated the decaying portion of the flow waveform from the systolic peak to the diastolic level to an exponential curve. Then, the decay constant associated with the flow signal was compared for different types of ovarian pathology. Ovaries with malignancies showed significantly higher mean values for the decay constant (89.7; 95% confidence interval 60.0-119.3) than those with benign tumors (41.8; 25.7-57.9) (p < 0.007), where tau is provided in pixels (in this study each pixel equals approximately 11.4 ms). The mean RI value for malignant tumors was 0.44 +/- 0.12 whereas, in benign tumors, it was 0.622 +/- 0.11. For the benign tumors, both tau and RI did not differ significantly from the measured indices in LMP tumors, metastases and functional ovarian findings. In addition, when the cutoff value of tau was set at 48, 92.3% of all malignancies were identifiable using only tau. This preliminary study indicates that the decay constant of the Doppler flow waveform is able to discriminate between malignant and benign masses and may, thus, provide substantial assistance as an additional parameter in the diagnosis of malignant ovarian tumors in postmenopausal patients.

Chronic GnRH agonist administration down-regulates platelet serotonin transporter in women undergoing assisted reproductive treatment.

The effect of pretreatment with the gonadotropin releasing hormone (GnRH) agonist D-Trp6-LHRH (Decapeptyl) on platelet serotonin transporter in women undergoing assisted reproductive treatment (ART) was investigated and compared with women treated with human menopausal gonadotropin (Pergonal). The study group (n = 10) was exposed for 12 days to 3.2 mg Decapeptyl C.R. while a comparison group (n = 9) was exposed to 11 days of human meno-pausal gonadotropin (Pergonal). All patients were assessed with the Hamilton depression and anxiety scales before and after treatment, and platelet and plasma samples were collected at the same time points. Plasma levels of estradiol, progesterone. FSH and LH were determined by radioimmunoassay (RIA). Platelet serotonin transporter was labeled using high affinity [3H]imipramine binding. The GnRH analogue induced ovarian suppression as reflected by low plasma estradiol levels, while Pergonal administration induced ovarian stimulation. An elevation in the Hamilton depression and anxiety scale scores was observed in the Decapeptyl treated group; this mood alteration was associated with a significant decrease (19%, P < 0.05) in the density (Bmax) of platelet [3H]imipramine binding sites. No significant change was observed in the Bmax of the Pergonal treated group. These results indicate that ovarian suppression (menopausal-like state) in young women is associated with depressed and anxious mood and decreased serotonin transporter density.

Prediction of binaural click lateralization by brainstem auditory evoked potentials.

A previous study by Furst et al. (1985) has shown that in healthy subjects brainstem responses evoked by binaural auditory stimuli with interaural time difference (ITD) and interaural level difference (ILD) include information about the integration of data received by both ears. A correlation was found between the first major peak of the binaural difference waveform and perception of click lateralization and fusion. We have now tested whether a similar correlation exists in patients with multiple sclerosis (MS). The ability to lateralize dichotic clicks was tested in MS patients with normal audiograms. Two kinds of psychoacoustical experiments were employed: (1) A matching experiment in which the subject was asked to match the perceived positions of two click trains, one of which consisted of dichotic clicks with ILD and the other dichotic clicks with ITD; and (2) A positional JND experiment in which the subject was asked to determine the difference in perceived position of two successive click trains. Two reference positions were tested, the head center and the side of the head near the ear, while the control was either on ITD or on ILD. According to the psychoacoustical performances, three groups of patients were identified. Group I consisted of patients who performed normally in all the psychoacoustical experiments. Group II patients were able to lateralize binaural clicks but performed abnormally in the matching experiment and in the position discrimination experiment when the control was on ITD and the reference position was the head center. The patients in Group II performed normally in the discrimination experiments when the control was on ILD, and when the control was on ITD but the reference position was the head side. Group III consisted of those who were not able to perform either one of the psychoacoustical experiments. They perceived the same binaural clicks in different positions in different times. Brainstem auditory potentials evoked by dichotic clicks with different ILDs and ITDs were measured in all the MS patients, and the corresponding binaural difference (BD) waveforms were calculated. Whenever beta, the first major peak of BD, was identified it was used to obtain a physiological matching curve. It was derived by matching an ILD on the basis of similar beta latencies. For every patient, in either Group I or II, the physiological matching curve was very similar to his psychoacoustical matching curve.