Alzheimer's & Dementia: Translational Research & Clinical Interventions
IntroductionThis study examined the safety and pharmacodynamic effects of selective muscarinic M1... more IntroductionThis study examined the safety and pharmacodynamic effects of selective muscarinic M1 receptor orthosteric agonist HTL0018318 in 60 patients with mild‐to‐moderate Alzheimer's disease (AD) on background donepezil 10 mg/day.MethodsA randomized, double‐blind, placebo‐controlled 4‐week safety study of HTL0018318 with up‐titration and maintenance phases, observing exploratory effects on electrophysiological biomarkers and cognition.ResultsTreatment‐emergent adverse events (TEAEs) were mild and less frequently reported during maintenance versus titration. Headache was most commonly reported (7–21%); 0 to 13% reported cholinergic TEAEs (abdominal pain, diarrhea, fatigue, nausea) and two patients discontinued due to TEAEs. At 1 to 2 hours post‐dose, HTL0018318‐related mean maximum elevations in systolic and diastolic blood pressure of 5 to 10 mmHg above placebo were observed during up‐titration but not maintenance. Postive effects of HTL0018318 were found on specific attenti...
AimsTo explore the safety, tolerability, pharmacokinetics and pharmacodynamics (PD) of GSK2646264... more AimsTo explore the safety, tolerability, pharmacokinetics and pharmacodynamics (PD) of GSK2646264 using skin challenge models.MethodsHealthy volunteers (HV) with a positive allergen skin prick test received GSK2646264 (0.5% or 1% ww) and placebo creams on up to 10% body surface area (BSA). Cold (ColdU) or chronic spontaneous (CSU) urticaria patients received 1% GSK2646264 or placebo on up to 10% BSA. PD assessments included weal characteristics after skin allergen challenge, critical temperature threshold (CTT) in ColdU patients and defined area urticaria activity score in CSU patients.ResultsThirty‐four patients were randomised (17 HV, 12 ColdU, 5 CSU). Topical application of GSK2646264 and placebo was well tolerated. Systemic pharmacokinetics (AUC [0–24] h*ng/mL) was similar between HVs (Geomean 97.9 [%CV 37]) and ColdU patients (Geomean 68.2 [%CV 14; 3.5% BSA] or 167 [%CV 120; 10% BSA]). Whilst in HVs a similar reduction in skin allergen challenge weal area was observed following...
e20567 Background: Patients are the most integral resource of clinical trials in oncology. Howeve... more e20567 Background: Patients are the most integral resource of clinical trials in oncology. However, we rarely ask them formally about their experiences of clinical trial participation. The purpose ...
Human Psychopharmacology: Clinical and Experimental, 2019
ObjectiveThis double‐blind, randomised, placebo‐controlled, two‐part study assessed the impact of... more ObjectiveThis double‐blind, randomised, placebo‐controlled, two‐part study assessed the impact of GSK2981710, a medium‐chain triglyceride (MCT) that liberates ketone bodies, on cognitive function, safety, and tolerability in healthy older adults.MethodsPart 1 was a four‐period dose‐selection study (n = 8 complete). Part 2 was a two‐period crossover study (n = 80 complete) assessing the acute (Day 1) and prolonged (Day 15) effects of GSK2981710 on cognition and memory‐related neuronal activity. Safety and tolerability of MCT supplementation were monitored in both parts of the study.ResultsThe most common adverse event was diarrhoea (100% and 75% of participants in Parts 1 and 2, respectively). Most adverse events were mild to moderate, and 11% participants were withdrawn due to one or more adverse events. Although GSK2981710 (30 g/day) resulted in increased peak plasma β‐hydroxybutyrate (BHB) concentrations, no significant improvements in cognitive function or memory‐related neuronal...
Background: Body composition in children is generally measured by 2-component (2C) models, which ... more Background: Body composition in children is generally measured by 2-component (2C) models, which are subject to error arising from variation in fat-free mass (FFM) composition. The 4-component (4C) model, which divides body weight into fat, water, mineral, and protein, can overcome these limitations. Objective: The aims of our study were to 1) describe 4C model data for children aged 8-12 y; 2) evaluate interindividual variability in the hydration, bone mineral content, and density of FFM; 3) evaluate the success with which 2C models and bedside techniques measure body composition in this age group with use of the 4C model as a reference. Design: Dual-energy X-ray absorptiometry, underwater weighing, deuterium dilution, bioelectrical impedance analysis, and anthropometry were used to determine body composition in 30 children. The contribution of methodologic error to the observed variability in the hydration and density of FFM was evaluated by using propagation of error. Results: Mean (±SD) FFM density and hydration were 1.0864 ± 0.0074 kg/L and 75.3 ± 2.2%, respectively, and were significantly different from adult values (P < 0.02). Relative to the 4C model, deuterium dilution and dual-energy X-ray absorptiometry showed no mean bias for fatness, whereas underwater weighing underestimated fatness (P < 0.025). Fatness determined by using skinfold-thickness and bioelectrical impedance analysis measurements along with published equations showed poor agreement with 4C model data. Conclusions: Biological variability and methodologic error contribute equally to the variability of FFM composition. Our findings have major implications for bedside prediction methods used for children, traditionally developed in relation to underwater weighing.
Background: The gut hormone motilin stimulates gastrointestinal motility by inducing gastric phas... more Background: The gut hormone motilin stimulates gastrointestinal motility by inducing gastric phase III of the migrating motor complex (MMC) and enhancing the rate of gastric emptying. Camicinal (GSK962040), a small molecule motilin receptor agonist, has been shown to increase gastrointestinal motility. Methods: In this proof of concept study the effects of camicinal on MMC activity, esophageal and gastric pH was evaluated in eight healthy volunteers as a secondary endpoint. Doses of 50 and 150 mg were compared to placebo for a period of 24 hours in a double-blinded randomized crossover trial.
A proportion of patients with foregut dysmotility fail to respond to standard interventions. Moti... more A proportion of patients with foregut dysmotility fail to respond to standard interventions. Motilin agonists may be beneficial in this group. We aimed to determine the effect of camicinal, a novel motilin agonist, on gastrointestinal physiology in healthy volunteers.
1. This study aimed to investigate the possible role of leptin in post-traumatic anorexia by maki... more 1. This study aimed to investigate the possible role of leptin in post-traumatic anorexia by making pre- and post-operative (0–8 days) measurements of circulating leptin concentrations in six patients undergoing elective total hip replacement for osteoarthritis. 2. Mean daily hunger rating (four categories) and food intake (assessed by food record charts) were measured pre-operatively, as well as post-operatively for the first 5 days (days 0–5). Leptin concentrations, circulating metabolites [glucose, non-esterified fatty acids, glutamine and 3-hydroxy-butyrate] and insulin and cortisol concentrations were measured pre-operatively (day 0) and post-operatively (days 1, 2, 3, 5 and 8). 3. Mean leptin concentrations were significantly increased only on day 1 (56% increase compared with pre-operative values, P < 0.009), whereas food intake (only 0.6 MJ on day 0) and hunger (5/6 patients ‘not hungry’ on day 0) only gradually improved over the next few days. (The energy intake over the...
The study was designed to evaluate a noninvasive breath test using naturally I3C-rich corn (maize... more The study was designed to evaluate a noninvasive breath test using naturally I3C-rich corn (maize) as substrate to provide quantitative information about the digestion of starch by children in health and disease. The variability of background I3C:l2C of young British children was investigated by collecting breath samples over 6 h from 17 healthy children, 6-35 mo old, and from seven children with cystic fibrosis, 25-48 mo old, in their homes. Background "C enrichment was-26.6 and-25.4 d per mil in the healthy and cystic fibrosis groups, respectively (p < 0.01), and varied little during the day (SD = 0.4 d per mil). Eight healthy children and five with cystic fibrosis were given a test breakfast of corn starch cooked in milk with sugar. The cystic fibrosis group repeated the test with the addition of an enzyme supplement containing a-amylase. Subjects accepted variable amounts of starch (range 0.2-2.8 g/kg body wt). The percentage of ingested I3C recovered during the 6 h after the meal increased with age in the healthy children (range 15-53%). Three children with cystic fibrosis had negligible I3C recoveries, and the other two had lower recoveries than expected for their age. The addition of enzymes did not consistently improve I3C recovery. We conclude that the I3C breath test based on corn has potential for investigating starch digestion in young children. Initial results suggest that starch digestion is impaired in some children with cystic fibrosis and that enzyme supplements do not improve digestion consistently or completely. (Pediatr Res 32: 45-49, 1992) Children with cystic fibrosis have decreased activity of pancreatic amylase (I), the major enzyme involved in the intraluminal hydrolysis of starch. As a consequence, most children with cystic fibrosis receive pancreatic enzyme supplements containing a-amylase (2). Although starch is the principal complex carbohydrate in the diet during early life and represents about 20% of the total energy intake at 2 y of age in children in Europe (3,4), information about the digestion of this carbohydrate in young children with cystic fibrosis is limited (5). In addition, the effect of enzyme supplements on the digestion of starch has not been clearly established in children. Noninvasive breath tests, which involve substrates that are naturally or artificially labeled with I3C, the stable isotope of carbon, have been used to make quantitative measurements of the digestion of complex carbohydrates in healthy infants and adults (6,7) and in those with pancreatic insufficiency (8). When
SUBJECTS AN D METHODS evaluate the potenti al role of breast-milk amylase in digestion of food ca... more SUBJECTS AN D METHODS evaluate the potenti al role of breast-milk amylase in digestion of food carbo hydrate given in complement of breast-feedin g. The object of our study was to measure breast-milk am ylase activity in two different groups of women practicing prolonged lactati on: mothers living in an affiuent city of England, and less privileged mothers living in a rural village of Th e Gambia, West Africa, whose children are at a high risk for malnutrition. Th e results demonstrated that am ylase is secreted into breast milk throu ghout 2 y of lactation in quantities of potentially valuable digestive capacity and that the activity of this enzyme is rema rkably similar in the breast milk of English and Gambian women. T he results brought out the great differences in breast-milk amylase activity amo ng mothers living in the same community. Within-subj ect variations. Before the main studies, a detailed investigation of within-subject variations in amylase activity was cond ucted on English and Gambian subjects, to develop a sampling protoco\' Within-feed and diurn al variations, and consistency within indi viduals were examined in five English and five Gambian mothers. The English mothers provided a small sample of milk from both breasts by manual expression, just before and after each feed duri ng a single 24 h period. Th e mothers were 27-to 32-y-old, parity 1-3, and were at vario us stages oflactatio n ranging from 4 to 13 wk of lactation. Th e feed frequency per day was 6-7. The Ga mbian moth ers provided a small sample of mil k from both breasts by ma nual expression at 0800 , 1200, 1500, 1800, and 2100 h on 3 con secuti ve days. The moth ers were 27to 33-y-old, parity 6-8, an d were at 5-6 wk of lactati on. In addition , to stud y within-subject variations du ring exclusive breast-feedi ng, a longitudinal stud y was conducted in a group of seven mot hers who were recru ited in the lactation clinic of the Helena Venizelos Maternity Hospital, Athens, Gree ce, where it is clinic policy to recommend exclusive breast-feeding for 6 mo. The mot hers were 20-to 37-y-old, parity 1-4, and were exclusively breast-feeding throughout the study. The moth ers provided small sam ples of transiti onal milk (3-1 1 d postpartum) and sequential sampl es of mature milk at approxima tely monthl y inte rvals for 6 mo from both breasts. Milk collection. On the strength of the results of these studies (detailed later) a sim ple samp ling procedu re was adopted for the further studies: amylase was measured in a small sample « 1 mL) of milk obta ined from both breasts on one occasion, irrespective of the suckling pattern, and milk samp les from left and right breast were pooled before analysis. Stu dy comm unities. Breast-milk am ylase was measured in two cross-sectional groups of English and Gambian mothe rs. Th e English subjects lived in the Cambridge area and were recruited th rough local lactation support groups. Fifty-eight mothers par-502
Objective: Tinnitus is a common symptom that demonstrates a significant comorbidity with anxiety ... more Objective: Tinnitus is a common symptom that demonstrates a significant comorbidity with anxiety and depression. The novel neurokinin-1 receptor antagonist, vestipitant, has anxiolytic properties and a good safety profile. Vestipitant was investigated for potential effect against chronic tinnitus as a standalone treatment and in conjunction with a selective serotonin reuptake inhibitor, paroxetine. Study Design: Randomized, double-blind, crossover study. Setting: Tertiary neurotologic and audiologic center with additional referrals from a secondary university hospital center. Patients: Twenty-four adult patients with tinnitus were randomized into the study. Main Outcome Measures: Visual analogue scale (VAS) measurements of tinnitus loudness (intensity), pitch and distress, VAS measurements of arousal/anxiety, Tinnitus Handicap Inventory, Quick Inventory of Depressive Symptomatology, and plasma concentrations of trial drugs. Results: No statistically significant treatment benefit effect was detected for tinnitus (intensity, pitch, and distress) VAS scores, arousal-anxiety VAS scores, Tinnitus Handicap Inventory, or tinnitus aggravation scores assessed on Days 1 and 14. However, a statistically significant worsening of tinnitus intensity and distress scores was observed after vestipitant compared with placebo for the mean data collected over the treatment period. No relevant differences in vestipitant plasma concentrations were observed between the subjects given the combination with paroxetine and those receiving vestipitant alone. No specific relationships were observed between tinnitus intensity and vestipitant plasma concentrations. Conclusion: Although well-tolerated vestipitant, alone or in combination with paroxetine, was not effective in ameliorating tinnitus in this patient group.
Visceral hypersensitivity is important in the pathophysiology of irritable bowel syndrome and thu... more Visceral hypersensitivity is important in the pathophysiology of irritable bowel syndrome and thus a target for modulation in drug development. Neurokinin (NK) receptors, including NK 3 receptors, are expressed in the motor and sensory systems of the digestive tract. The aim of this study was to compare the effects of two different doses (25 and 100 mg) of the NK 3 receptor antagonist, talnetant (SB223412) with placebo on rectal sensory function and compliance in healthy volunteers studied at two centres. Rectal barostat tests were performed on 102 healthy volunteers, randomized to receive either oral talnetant 25 or 100 mg or placebo over 14-17 days. Studies were performed on three occasions: day 1 immediately prior to 1st dose, day 1 4 h postdose, and after 14-to17-day therapy. Compliance, and pressure thresholds for first sensation, urgency, discomfort and pain were measured using ascending method of limits, and sensory intensity ratings for gas, urgency, discomfort and pain determined during four random phasic distensions (12, 24, 36 and 48 mmHg). Talnetant had no effect on rectal compliance, sensory thresholds or intensity ratings compared with placebo. In general, the results obtained at the two centres differed minimally, with intensity scores at one centre consistently somewhat lower. At the doses tested, talnetant has no effect on rectal compliance or distension-induced rectal sensation in healthy participants.
Journal of Pediatric Gastroenterology and Nutrition, 1989
The influence of diet and maternal parity on the fatty acid composition of mature breast milk hav... more The influence of diet and maternal parity on the fatty acid composition of mature breast milk have been studied in 23 rural Gambian mothers. The subjects&amp;amp;#39; habitual diet was low in fat (16% total energy), groundnuts (peanuts) constituting the principal fat source. The high abundance of oleic and linoleic acids in groundnut fat were reflected in the proportions of these fatty acids in breast milk (47.0 +/- 1.5 and 13.0 +/- 0.3 g/100 g fat, respectively), which were elevated compared with mothers in other African communities. Estimates of daily breast-milk fatty acid secretion indicated that there was little risk of essential fatty acid deficiency in Gambian infants. The proportions of fatty acids synthesized de novo (10:0, 12:0, 14:0) were less than expected from published studies of mothers consuming low-fat diets, averaging 16.8 +/- 1.4 g/100 g fat. As the study was conducted at a time of food shortage and high energy expenditure, it is argued that mobilisation of body fat during negative energy balance increased the availability of long-chain fatty acids to the breast. The proportion of endogenous fatty acids was markedly reduced in the milk of mothers of very high parity (parity 1 = 19.3 +/- 1.6 g/100 g fat; parities 10 + = 11.4 +/- 1.5 g/100 g fat; p less than 0.01). It is hypothesised that this represents an impairment of the ability to synthesise breast-milk fatty acids de novo in these mothers.
Human Psychopharmacology: Clinical and Experimental, 2011
ObjectivesTo identify tasks that were sensitive to a temporary decline in cognitive performance a... more ObjectivesTo identify tasks that were sensitive to a temporary decline in cognitive performance after sleep deprivation and to investigate the ability of the acetylcholinesterase inhibitor donepezil to reverse any sleep deprivation‐induced impairment.MethodsThirty healthy volunteers were administered either a 5‐mg daily dose of donepezil or placebo for 14–17 days, in a double‐blind parallel group design, then underwent either 24 h sleep deprivation or a normal night of sleep in non‐blinded crossover, and were subsequently tested on a battery of cognitive tasks designed to measure different components of memory and executive function.ResultsSleep deprivation selectively impaired performance on several memory tasks whilst also impairing non‐memory function on these tasks. Performance on other tasks was spared. Despite partially reversing the decline in subjective alertness associated with sleep deprivation, treatment with donepezil failed to significantly reverse the decline in cognit...
Alzheimer's & Dementia: Translational Research & Clinical Interventions
IntroductionThis study examined the safety and pharmacodynamic effects of selective muscarinic M1... more IntroductionThis study examined the safety and pharmacodynamic effects of selective muscarinic M1 receptor orthosteric agonist HTL0018318 in 60 patients with mild‐to‐moderate Alzheimer's disease (AD) on background donepezil 10 mg/day.MethodsA randomized, double‐blind, placebo‐controlled 4‐week safety study of HTL0018318 with up‐titration and maintenance phases, observing exploratory effects on electrophysiological biomarkers and cognition.ResultsTreatment‐emergent adverse events (TEAEs) were mild and less frequently reported during maintenance versus titration. Headache was most commonly reported (7–21%); 0 to 13% reported cholinergic TEAEs (abdominal pain, diarrhea, fatigue, nausea) and two patients discontinued due to TEAEs. At 1 to 2 hours post‐dose, HTL0018318‐related mean maximum elevations in systolic and diastolic blood pressure of 5 to 10 mmHg above placebo were observed during up‐titration but not maintenance. Postive effects of HTL0018318 were found on specific attenti...
AimsTo explore the safety, tolerability, pharmacokinetics and pharmacodynamics (PD) of GSK2646264... more AimsTo explore the safety, tolerability, pharmacokinetics and pharmacodynamics (PD) of GSK2646264 using skin challenge models.MethodsHealthy volunteers (HV) with a positive allergen skin prick test received GSK2646264 (0.5% or 1% ww) and placebo creams on up to 10% body surface area (BSA). Cold (ColdU) or chronic spontaneous (CSU) urticaria patients received 1% GSK2646264 or placebo on up to 10% BSA. PD assessments included weal characteristics after skin allergen challenge, critical temperature threshold (CTT) in ColdU patients and defined area urticaria activity score in CSU patients.ResultsThirty‐four patients were randomised (17 HV, 12 ColdU, 5 CSU). Topical application of GSK2646264 and placebo was well tolerated. Systemic pharmacokinetics (AUC [0–24] h*ng/mL) was similar between HVs (Geomean 97.9 [%CV 37]) and ColdU patients (Geomean 68.2 [%CV 14; 3.5% BSA] or 167 [%CV 120; 10% BSA]). Whilst in HVs a similar reduction in skin allergen challenge weal area was observed following...
e20567 Background: Patients are the most integral resource of clinical trials in oncology. Howeve... more e20567 Background: Patients are the most integral resource of clinical trials in oncology. However, we rarely ask them formally about their experiences of clinical trial participation. The purpose ...
Human Psychopharmacology: Clinical and Experimental, 2019
ObjectiveThis double‐blind, randomised, placebo‐controlled, two‐part study assessed the impact of... more ObjectiveThis double‐blind, randomised, placebo‐controlled, two‐part study assessed the impact of GSK2981710, a medium‐chain triglyceride (MCT) that liberates ketone bodies, on cognitive function, safety, and tolerability in healthy older adults.MethodsPart 1 was a four‐period dose‐selection study (n = 8 complete). Part 2 was a two‐period crossover study (n = 80 complete) assessing the acute (Day 1) and prolonged (Day 15) effects of GSK2981710 on cognition and memory‐related neuronal activity. Safety and tolerability of MCT supplementation were monitored in both parts of the study.ResultsThe most common adverse event was diarrhoea (100% and 75% of participants in Parts 1 and 2, respectively). Most adverse events were mild to moderate, and 11% participants were withdrawn due to one or more adverse events. Although GSK2981710 (30 g/day) resulted in increased peak plasma β‐hydroxybutyrate (BHB) concentrations, no significant improvements in cognitive function or memory‐related neuronal...
Background: Body composition in children is generally measured by 2-component (2C) models, which ... more Background: Body composition in children is generally measured by 2-component (2C) models, which are subject to error arising from variation in fat-free mass (FFM) composition. The 4-component (4C) model, which divides body weight into fat, water, mineral, and protein, can overcome these limitations. Objective: The aims of our study were to 1) describe 4C model data for children aged 8-12 y; 2) evaluate interindividual variability in the hydration, bone mineral content, and density of FFM; 3) evaluate the success with which 2C models and bedside techniques measure body composition in this age group with use of the 4C model as a reference. Design: Dual-energy X-ray absorptiometry, underwater weighing, deuterium dilution, bioelectrical impedance analysis, and anthropometry were used to determine body composition in 30 children. The contribution of methodologic error to the observed variability in the hydration and density of FFM was evaluated by using propagation of error. Results: Mean (±SD) FFM density and hydration were 1.0864 ± 0.0074 kg/L and 75.3 ± 2.2%, respectively, and were significantly different from adult values (P < 0.02). Relative to the 4C model, deuterium dilution and dual-energy X-ray absorptiometry showed no mean bias for fatness, whereas underwater weighing underestimated fatness (P < 0.025). Fatness determined by using skinfold-thickness and bioelectrical impedance analysis measurements along with published equations showed poor agreement with 4C model data. Conclusions: Biological variability and methodologic error contribute equally to the variability of FFM composition. Our findings have major implications for bedside prediction methods used for children, traditionally developed in relation to underwater weighing.
Background: The gut hormone motilin stimulates gastrointestinal motility by inducing gastric phas... more Background: The gut hormone motilin stimulates gastrointestinal motility by inducing gastric phase III of the migrating motor complex (MMC) and enhancing the rate of gastric emptying. Camicinal (GSK962040), a small molecule motilin receptor agonist, has been shown to increase gastrointestinal motility. Methods: In this proof of concept study the effects of camicinal on MMC activity, esophageal and gastric pH was evaluated in eight healthy volunteers as a secondary endpoint. Doses of 50 and 150 mg were compared to placebo for a period of 24 hours in a double-blinded randomized crossover trial.
A proportion of patients with foregut dysmotility fail to respond to standard interventions. Moti... more A proportion of patients with foregut dysmotility fail to respond to standard interventions. Motilin agonists may be beneficial in this group. We aimed to determine the effect of camicinal, a novel motilin agonist, on gastrointestinal physiology in healthy volunteers.
1. This study aimed to investigate the possible role of leptin in post-traumatic anorexia by maki... more 1. This study aimed to investigate the possible role of leptin in post-traumatic anorexia by making pre- and post-operative (0–8 days) measurements of circulating leptin concentrations in six patients undergoing elective total hip replacement for osteoarthritis. 2. Mean daily hunger rating (four categories) and food intake (assessed by food record charts) were measured pre-operatively, as well as post-operatively for the first 5 days (days 0–5). Leptin concentrations, circulating metabolites [glucose, non-esterified fatty acids, glutamine and 3-hydroxy-butyrate] and insulin and cortisol concentrations were measured pre-operatively (day 0) and post-operatively (days 1, 2, 3, 5 and 8). 3. Mean leptin concentrations were significantly increased only on day 1 (56% increase compared with pre-operative values, P < 0.009), whereas food intake (only 0.6 MJ on day 0) and hunger (5/6 patients ‘not hungry’ on day 0) only gradually improved over the next few days. (The energy intake over the...
The study was designed to evaluate a noninvasive breath test using naturally I3C-rich corn (maize... more The study was designed to evaluate a noninvasive breath test using naturally I3C-rich corn (maize) as substrate to provide quantitative information about the digestion of starch by children in health and disease. The variability of background I3C:l2C of young British children was investigated by collecting breath samples over 6 h from 17 healthy children, 6-35 mo old, and from seven children with cystic fibrosis, 25-48 mo old, in their homes. Background "C enrichment was-26.6 and-25.4 d per mil in the healthy and cystic fibrosis groups, respectively (p < 0.01), and varied little during the day (SD = 0.4 d per mil). Eight healthy children and five with cystic fibrosis were given a test breakfast of corn starch cooked in milk with sugar. The cystic fibrosis group repeated the test with the addition of an enzyme supplement containing a-amylase. Subjects accepted variable amounts of starch (range 0.2-2.8 g/kg body wt). The percentage of ingested I3C recovered during the 6 h after the meal increased with age in the healthy children (range 15-53%). Three children with cystic fibrosis had negligible I3C recoveries, and the other two had lower recoveries than expected for their age. The addition of enzymes did not consistently improve I3C recovery. We conclude that the I3C breath test based on corn has potential for investigating starch digestion in young children. Initial results suggest that starch digestion is impaired in some children with cystic fibrosis and that enzyme supplements do not improve digestion consistently or completely. (Pediatr Res 32: 45-49, 1992) Children with cystic fibrosis have decreased activity of pancreatic amylase (I), the major enzyme involved in the intraluminal hydrolysis of starch. As a consequence, most children with cystic fibrosis receive pancreatic enzyme supplements containing a-amylase (2). Although starch is the principal complex carbohydrate in the diet during early life and represents about 20% of the total energy intake at 2 y of age in children in Europe (3,4), information about the digestion of this carbohydrate in young children with cystic fibrosis is limited (5). In addition, the effect of enzyme supplements on the digestion of starch has not been clearly established in children. Noninvasive breath tests, which involve substrates that are naturally or artificially labeled with I3C, the stable isotope of carbon, have been used to make quantitative measurements of the digestion of complex carbohydrates in healthy infants and adults (6,7) and in those with pancreatic insufficiency (8). When
SUBJECTS AN D METHODS evaluate the potenti al role of breast-milk amylase in digestion of food ca... more SUBJECTS AN D METHODS evaluate the potenti al role of breast-milk amylase in digestion of food carbo hydrate given in complement of breast-feedin g. The object of our study was to measure breast-milk am ylase activity in two different groups of women practicing prolonged lactati on: mothers living in an affiuent city of England, and less privileged mothers living in a rural village of Th e Gambia, West Africa, whose children are at a high risk for malnutrition. Th e results demonstrated that am ylase is secreted into breast milk throu ghout 2 y of lactation in quantities of potentially valuable digestive capacity and that the activity of this enzyme is rema rkably similar in the breast milk of English and Gambian women. T he results brought out the great differences in breast-milk amylase activity amo ng mothers living in the same community. Within-subj ect variations. Before the main studies, a detailed investigation of within-subject variations in amylase activity was cond ucted on English and Gambian subjects, to develop a sampling protoco\' Within-feed and diurn al variations, and consistency within indi viduals were examined in five English and five Gambian mothers. The English mothers provided a small sample of milk from both breasts by manual expression, just before and after each feed duri ng a single 24 h period. Th e mothers were 27-to 32-y-old, parity 1-3, and were at vario us stages oflactatio n ranging from 4 to 13 wk of lactation. Th e feed frequency per day was 6-7. The Ga mbian moth ers provided a small sample of mil k from both breasts by ma nual expression at 0800 , 1200, 1500, 1800, and 2100 h on 3 con secuti ve days. The moth ers were 27to 33-y-old, parity 6-8, an d were at 5-6 wk of lactati on. In addition , to stud y within-subject variations du ring exclusive breast-feedi ng, a longitudinal stud y was conducted in a group of seven mot hers who were recru ited in the lactation clinic of the Helena Venizelos Maternity Hospital, Athens, Gree ce, where it is clinic policy to recommend exclusive breast-feeding for 6 mo. The mot hers were 20-to 37-y-old, parity 1-4, and were exclusively breast-feeding throughout the study. The moth ers provided small sam ples of transiti onal milk (3-1 1 d postpartum) and sequential sampl es of mature milk at approxima tely monthl y inte rvals for 6 mo from both breasts. Milk collection. On the strength of the results of these studies (detailed later) a sim ple samp ling procedu re was adopted for the further studies: amylase was measured in a small sample « 1 mL) of milk obta ined from both breasts on one occasion, irrespective of the suckling pattern, and milk samp les from left and right breast were pooled before analysis. Stu dy comm unities. Breast-milk am ylase was measured in two cross-sectional groups of English and Gambian mothe rs. Th e English subjects lived in the Cambridge area and were recruited th rough local lactation support groups. Fifty-eight mothers par-502
Objective: Tinnitus is a common symptom that demonstrates a significant comorbidity with anxiety ... more Objective: Tinnitus is a common symptom that demonstrates a significant comorbidity with anxiety and depression. The novel neurokinin-1 receptor antagonist, vestipitant, has anxiolytic properties and a good safety profile. Vestipitant was investigated for potential effect against chronic tinnitus as a standalone treatment and in conjunction with a selective serotonin reuptake inhibitor, paroxetine. Study Design: Randomized, double-blind, crossover study. Setting: Tertiary neurotologic and audiologic center with additional referrals from a secondary university hospital center. Patients: Twenty-four adult patients with tinnitus were randomized into the study. Main Outcome Measures: Visual analogue scale (VAS) measurements of tinnitus loudness (intensity), pitch and distress, VAS measurements of arousal/anxiety, Tinnitus Handicap Inventory, Quick Inventory of Depressive Symptomatology, and plasma concentrations of trial drugs. Results: No statistically significant treatment benefit effect was detected for tinnitus (intensity, pitch, and distress) VAS scores, arousal-anxiety VAS scores, Tinnitus Handicap Inventory, or tinnitus aggravation scores assessed on Days 1 and 14. However, a statistically significant worsening of tinnitus intensity and distress scores was observed after vestipitant compared with placebo for the mean data collected over the treatment period. No relevant differences in vestipitant plasma concentrations were observed between the subjects given the combination with paroxetine and those receiving vestipitant alone. No specific relationships were observed between tinnitus intensity and vestipitant plasma concentrations. Conclusion: Although well-tolerated vestipitant, alone or in combination with paroxetine, was not effective in ameliorating tinnitus in this patient group.
Visceral hypersensitivity is important in the pathophysiology of irritable bowel syndrome and thu... more Visceral hypersensitivity is important in the pathophysiology of irritable bowel syndrome and thus a target for modulation in drug development. Neurokinin (NK) receptors, including NK 3 receptors, are expressed in the motor and sensory systems of the digestive tract. The aim of this study was to compare the effects of two different doses (25 and 100 mg) of the NK 3 receptor antagonist, talnetant (SB223412) with placebo on rectal sensory function and compliance in healthy volunteers studied at two centres. Rectal barostat tests were performed on 102 healthy volunteers, randomized to receive either oral talnetant 25 or 100 mg or placebo over 14-17 days. Studies were performed on three occasions: day 1 immediately prior to 1st dose, day 1 4 h postdose, and after 14-to17-day therapy. Compliance, and pressure thresholds for first sensation, urgency, discomfort and pain were measured using ascending method of limits, and sensory intensity ratings for gas, urgency, discomfort and pain determined during four random phasic distensions (12, 24, 36 and 48 mmHg). Talnetant had no effect on rectal compliance, sensory thresholds or intensity ratings compared with placebo. In general, the results obtained at the two centres differed minimally, with intensity scores at one centre consistently somewhat lower. At the doses tested, talnetant has no effect on rectal compliance or distension-induced rectal sensation in healthy participants.
Journal of Pediatric Gastroenterology and Nutrition, 1989
The influence of diet and maternal parity on the fatty acid composition of mature breast milk hav... more The influence of diet and maternal parity on the fatty acid composition of mature breast milk have been studied in 23 rural Gambian mothers. The subjects&amp;amp;#39; habitual diet was low in fat (16% total energy), groundnuts (peanuts) constituting the principal fat source. The high abundance of oleic and linoleic acids in groundnut fat were reflected in the proportions of these fatty acids in breast milk (47.0 +/- 1.5 and 13.0 +/- 0.3 g/100 g fat, respectively), which were elevated compared with mothers in other African communities. Estimates of daily breast-milk fatty acid secretion indicated that there was little risk of essential fatty acid deficiency in Gambian infants. The proportions of fatty acids synthesized de novo (10:0, 12:0, 14:0) were less than expected from published studies of mothers consuming low-fat diets, averaging 16.8 +/- 1.4 g/100 g fat. As the study was conducted at a time of food shortage and high energy expenditure, it is argued that mobilisation of body fat during negative energy balance increased the availability of long-chain fatty acids to the breast. The proportion of endogenous fatty acids was markedly reduced in the milk of mothers of very high parity (parity 1 = 19.3 +/- 1.6 g/100 g fat; parities 10 + = 11.4 +/- 1.5 g/100 g fat; p less than 0.01). It is hypothesised that this represents an impairment of the ability to synthesise breast-milk fatty acids de novo in these mothers.
Human Psychopharmacology: Clinical and Experimental, 2011
ObjectivesTo identify tasks that were sensitive to a temporary decline in cognitive performance a... more ObjectivesTo identify tasks that were sensitive to a temporary decline in cognitive performance after sleep deprivation and to investigate the ability of the acetylcholinesterase inhibitor donepezil to reverse any sleep deprivation‐induced impairment.MethodsThirty healthy volunteers were administered either a 5‐mg daily dose of donepezil or placebo for 14–17 days, in a double‐blind parallel group design, then underwent either 24 h sleep deprivation or a normal night of sleep in non‐blinded crossover, and were subsequently tested on a battery of cognitive tasks designed to measure different components of memory and executive function.ResultsSleep deprivation selectively impaired performance on several memory tasks whilst also impairing non‐memory function on these tasks. Performance on other tasks was spared. Despite partially reversing the decline in subjective alertness associated with sleep deprivation, treatment with donepezil failed to significantly reverse the decline in cognit...
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Papers by Odile Dewit