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Biomedical subjects

P Kopelman

Publications and source records attributed to P Kopelman.

At least 19 recordsLinked to original sources
PubMed2006

Cetilistat (ATL-962), a novel lipase inhibitor: a 12-week randomized, placebo-controlled study of weight reduction in obese patients.

OBJECTIVE: To determine the efficacy, safety and tolerability of cetilistat (ATL-962), a novel inhibitor of gastrointestinal (GI) lipases, in obese patients. DESIGN: Phase II, multicentre, randomized, placebo-controlled, parallel group study. Enrolled patients (N=442) were advised a hypocaloric diet (deficient by 500 kcal per day, 30% of calories from fat) for a 2-week run-in period. Patients who satisfied the entry criteria (N=371) continued on the hypocaloric diet and were randomized to either placebo or one of three different doses of cetilistat (60 mg three times daily t.i.d., 120 mg t.i.d. and 240 mg t.i.d.) for 12 weeks, followed by a 4-week post-treatment follow-up. Safety, tolerability and body weight were assessed, together with other parameters associated with obesity. OUTCOME MEASURES: The primary outcome measure was absolute change in body weight from baseline. Secondary outcomes included the proportion of patients achieving pre-defined weight loss targets, changes from baseline in waist circumference and in blood lipids. GI tolerability criteria were specifically assessed, as was safety. RESULTS: Treatment with cetilistat reduced mean body weight to similar extents at all doses, which were statistically significant compared with placebo (60 mg t.i.d. 3.3 kg, P<0.03; 120 mg t.i.d. 3.5 kg, P=0.02; 240 mg t.i.d. 4.1 kg, P<0.001). Total serum and low-density lipoprotein cholesterol levels were likewise significantly reduced by 3-11% at all doses of cetilistat. Cetilistat was well tolerated. The frequency of withdrawal owing to treatment-emergent adverse events was similar between cetilistat-treated groups (5.3-7.6%) and placebo (7.6%). Adverse events were generally mild to moderate in intensity, occurred on only one occasion and were mostly GI in nature. The incidence of GI adverse events was increased in the cetilistat-treated groups compared to placebo. However, those GI adverse events, such as flatus with discharge and oily spotting, only occurred in 1.8-2.8% of subjects in the cetilistat-treated groups. CONCLUSIONS: Cetilistat produced a clinically and statistically significant weight loss in obese patients in this short-term 12-week study. This was accompanied by significant improvements in other obesity-related parameters. Cetilistat treatment was well tolerated. The risk-benefit demonstrated in this study in terms of weight loss vs intolerable GI adverse effects shows that cetilistat merits further evaluation for the pharmacotherapy of obesity and related disorders.

Adult↗
PubMed2004

Dietary advice for treatment of type 2 diabetes mellitus in adults.

BACKGROUND: While initial dietary management immediately after formal diagnosis is an 'accepted' cornerstone of treatment of type 2 diabetes mellitus, a formal and systematic overview of its efficacy and method of delivery is not currently available. OBJECTIVES: To assess the effect of type and frequency of different types of dietary advice to all adults with type 2 diabetes on weight, measures of diabetic control, morbidity, total mortality and quality of life. SEARCH STRATEGY: We carried out a comprehensive search of The Cochrane Library (The Cochrane Library Issue 3, 2003), MEDLINE (1966 to October Week 1, 2003), EMBASE (1980 to Week 40, 2003), CINAHL (1982 to October Week 1, 2003), AMED (1985 to October 2003), bibliographies and contacted relevant experts. SELECTION CRITERIA: All randomised controlled trials, of six months or longer, in which dietary advice was the main intervention in adults with type 2 diabetes mellitus. DATA COLLECTION AND ANALYSIS: The lead investigator performed all data extraction and quality scoring with duplication being carried out by one of the other six investigators independently with discrepancies resolved by discussion and consensus. Authors were contacted for missing data. For continuous outcomes, endpoint data were preferred to change data. MAIN RESULTS: Thirty-six articles reporting a total of eighteen trials following 1467 participants were included. Dietary approaches assessed in this review were low-fat/high-carbohydrate diets, high-fat/low-carbohydrate diets, low-calorie (1000 kcal per day) and very-low-calorie (500 kcal per day) diets and modified fat diets. Two trials compared the American Diabetes Association exchange diet with a standard reduced fat diet and five studies assessed low-fat diets versus moderate fat or low-carbohydrate diets. Two studies assessed the effect of a very-low-calorie diet versus a low-calorie diet. Six studies compared dietary advice with dietary advice plus exercise and three other studies assessed dietary advice versus dietary advice plus behavioural approaches. The studies all measured weight and measures of glycaemic control although not all studies reported these in the articles published. Other outcomes which were measured in these studies included mortality, blood pressure, serum cholesterol (including LDL and HDL cholesterol), serum triglycerides, maximal exercise capacity and compliance. The results suggest that adoption of regular exercise is a good way to promote better glycaemic control in type 2 diabetic patients, however all of these studies were at high risk of bias. REVIEWERS' CONCLUSIONS: There are no high quality data on the efficacy of the dietary treatment of type 2 diabetes, however the data available indicate that the adoption of exercise appears to improve glycated haemoglobin at six and twelve months in people with type 2 diabetes. There is an urgent need for well-designed studies which examine a range of interventions, at various points during follow-up, although there is a promising study currently underway.

Adult↗
PubMed2004

Dietary advice for treatment of type 2 diabetes mellitus in adults.

BACKGROUND: While initial dietary management immediately after formal diagnosis is an 'accepted' cornerstone of treatment of type 2 diabetes mellitus, a formal and systematic overview of its efficacy and method of delivery is not currently available. OBJECTIVES: To assess the effect of type and frequency of different types of dietary advice to all adults with type 2 diabetes on weight, measures of diabetic control, morbidity, total mortality and quality of life. SEARCH STRATEGY: We carried out a comprehensive search of The Cochrane Library (The Cochrane Library Issue 3, 2003), MEDLINE (1966 to October Week 1, 2003), EMBASE (1980 to Week 40, 2003), CINAHL (1982 to October Week 1, 2003), AMED (1985 to October 2003), bibliographies and contacted relevant experts. SELECTION CRITERIA: All randomised controlled trials, of six months or longer, in which dietary advice was the main intervention in adults with type 2 diabetes mellitus. DATA COLLECTION AND ANALYSIS: The lead investigator performed all data extraction and quality scoring with duplication being carried out by one of the other six investigators independently with discrepancies resolved by discussion and consensus. Authors were contacted for missing data. For continuous outcomes, endpoint data were preferred to change data. MAIN RESULTS: Thirty-six articles reporting a total of eighteen trials following 1467 participants were included. Dietary approaches assessed in this review were low-fat/high-carbohydrate diets, high-fat/low-carbohydrate diets, low-calorie (1000 kcal per day) and very-low-calorie (500 kcal per day) diets and modified fat diets. Two trials compared the American Diabetes Association exchange diet with a standard reduced fat diet and five studies assessed low-fat diets versus moderate fat or low-carbohydrate diets. Two studies assessed the effect of a very-low-calorie diet versus a low-calorie diet. Six studies compared dietary advice with dietary advice plus exercise and three other studies assessed dietary advice versus dietary advice plus behavioural approaches. The studies all measured weight and measures of glycaemic control although not all studies reported these in the articles published. Other outcomes which were measured in these studies included mortality, blood pressure, serum cholesterol (including LDL and HDL cholesterol), serum triglycerides, maximal exercise capacity and compliance. The results suggest that adoption of regular exercise is a good way to promote better glycaemic control in type 2 diabetic patients, however all of these studies were at high risk of bias. REVIEWERS' CONCLUSIONS: There are no high quality data on the efficacy of the dietary treatment of type 2 diabetes, however the data available indicate that the adoption of exercise appears to improve glycated haemoglobin at six and twelve months in people with type 2 diabetes. There is an urgent need for well-designed studies which examine a range of interventions, at various points during follow-up, although there is a promising study currently underway.

Adult↗
PubMed2003

Energy metabolism in Bardet-Biedl syndrome.

INTRODUCTION: Obesity is a consistent presenting feature of the Bardet-Biedl syndrome (BBS), a hereditary disorder caused by a single gene defect. This contrasts sharply with general obesity which, despite a strong hereditary component, has a multifactorial aetiology. For BBS, the phenotypic characterisation of the components of energy balance and the implications for their management remains relatively uninvestigated. OBJECTIVE: A case-control study to determine whether energy metabolism in subjects with BBS differs from matched obese controls and to inform the clinical management of these patients. METHODS: A total of 20 overweight and obese subjects with BBS (11 females, 9 males) matched for age, gender and BMI to 20 subjects without BBS. Resting metabolic rate (RMR) was measured by indirect calorimetry, physical activity by CSA accelerometry, body composition by the deuterium dilution technique and dietary intake by 7-day food records. RESULTS: There was no significant difference between BBS and control subjects in body fat (male: % fat=38, s.d. 2.8 vs 34, s.d. 9.1, female: % fat=45, s.d. 5.9 vs 44, s.d. 8.1; P=0.46] or absolute RMR (male: 6.95, s.d. 1.55 MJ/day vs 7.19, s.d. 1.28 MJ/day; P=0.6). After adjustment for gender, age, fat-free mass and fat mass, there was no significant difference in RMR between BBS and control subjects (F(1, 30)=0.91; P=0.35). A lower level of physical activity was observed in BBS subjects (median cnts/min 259, IQR=153) compared to controls (median cnts/min=306, IQR=119, P=0.02). Reported energy intake, macronutrient composition and magnitude of under-reporting were comparable in both groups. CONCLUSION: This study reveals no evidence for systematic differences in energy metabolism in subjects with BBS relative to other obese individuals, suggesting that the genetic basis of BBS is not associated with specific abnormalities in energy metabolism. This is an important finding for clinical management and supports the use of energy prescriptions based on RMR for the general obese population plus an appropriate allowance for energy expended via physical activity. Further research is needed on physical activity in BBS.

Adult↗
PubMed2001

Predictors of weight loss and maintenance during 2 years of treatment by sibutramine in obesity. Results from the European multi-centre STORM trial. Sibutramine Trial of Obesity Reduction and Maintenance.

BACKGROUND: In this report we assess pre-treatment determinants of weight loss and maintenance outcome in The Sibutramine Trial of Obesity Reduction and Maintenance (STORM), a 2 y randomized, double-blind, placebo-controlled, European multicenter study examining the effect of sibutramine (Sib) on inducing and maintaining weight loss in obese subjects. MATERIAL: A total of 605 obese patients (BMI: 30-45 kg/m2) of both gender were included from eight European centers and treated for 24 months. The patients were treated for the initial 6 months by Sib (10 mg/day) and a low-fat low-energy, individualized diet (600 kcal/day deficit). The 467 patients who achieved >5% weight loss after 6 months were randomized 3&ratio;1 to Sib (10 mg/day) (Sib/Sib) and placebo (Sib/Pla) for weight maintenance over a further 18 months. MAIN OUTCOME AND ANALYSES: Pre-treatment individual characteristics were assessed as predictors of 6 months weight loss (kg) and 24 months weight maintenance using simple and multivariate correlation and regression analyses. RESULTS: In univariate analyses, the 6 month weight loss (n=505) was positively associated with pre-treatment body weight (r=0.27), height (r=0.18), fat-free mass (r=0.21) (all P<0.001), fat mass (r=0.13, P<0.03), and resting metabolic rate (r=0.13, P<0.003). However, no relation was found with age, gender, smoking status, age at onset of obesity, or number of previous slimming attempts. The same predictors were found for weight change to endpoint in the Sib/Sib group (n=350), while no predictors were identified in the Sib/Pla (n=114). In the multivariate regression analysis only pre-treatment body weight predicted weight loss at 6 months (P<0.001). Weight change (kg) to 24 month was predicted by: 4.34+0.07*body weight (kg)-4*treatment (Sib=1, Pla=0)-0.06*age (y), (r2=8%, P<0.001). CONCLUSION: Only pre-treatment body weight seems to be an important independent predictor of 6 months weight loss and 24 month weight maintenance in this study on diet and Sib. As only 8% of the variation in 24 months weight change could be explained by the predictors, the clinical value of this information is limited.

Adolescent↗
PubMed2001

Developing an action plan for obesity education.

Obesity education has long been neglected. Medical training continues to devote little time to education on obesity and its comorbidities, and practising physicians often feel ill equipped and poorly supported when dealing with overweight and obese patients. A European action plan for obesity education is required, to act at all levels--government, education providers and trainers, media, health professionals and patients-to improve understanding of obesity as a chronic but manageable medical condition.

Congresses as Topic↗
PubMed2001

Leptin: of mice and men?

A major advance in the understanding of the control of appetite, food intake, and energy expenditure came with the discovery of leptin. Leptin concentrations correlate with adipose tissue mass, and leptin acts via the central nervous system (CNS) to reduce food intake and increase energy expenditure. A variety of different neurotransmitters have been implicated in mediating the CNS effects of leptin. In humans, leptin deficiency is unlikely to be a major cause of obesity. Most humans are not leptin deficient, but have a leptin concentration raised in proportion to their fat mass. A recent clinical trial looking at the use of recombinant leptin in treating human obesity has resulted in only variable amounts of weight loss. The role of leptin extends beyond the control of food intake and energy expenditure. Leptin reverses many of the physiological responses to starvation. It is suggested that the main role of leptin might be in response to food deprivation and not in obesity.

Animals↗
PubMed1999

An uncoupling protein 2 gene variant is associated with a raised body mass index but not Type II diabetes.

AIMS/HYPOTHESIS: Linkage between markers close to the uncoupling protein 2 and 3 genes (11q13) and resting metabolic rate and a pre-diabetic phenotype have been found. The syntenic region in mouse has been found to be linked to quantitative traits associated with obesity and diabetes. UCP2 and UCP3 could therefore have an important role in body weight regulation and susceptibility to diabetes. We investigated a recently identified variant of the UCP2 gene in exon 8 as a marker for glucose and weight homeostasis. METHODS: Length variation of the UCP2 exon 8 variant was studied by the polymerase chain reaction and agarose gel electrophoresis. Sequence variants of the UCP3 gene were sought by semi-automated DNA sequencing. RESULTS: In 453 South Indian subjects, we found an association in women between the UCP2 exon variant and body mass index (p = 0.018). These findings were replicated in a separate group of South Indian subjects (n = 143, p < 0.001) irrespective of sex. Although no association was found between the UCP2 exon 8 variant and overt obesity in British subjects, the UCP2 genotype of obese women (n = 83) correlated with fasting serum leptin concentration (p = 0.006) in the presence of extreme obesity. These observations could not be explained by tight linkage disequilibrium with a coding region variant in the region of the UCP3 gene of biological significance. Lastly, no association was found between UCP2 and Type II (non-insulin-dependent) diabetes using either a family based design (85 families) or case control study (normal glucose tolerance n = 335, impaired glucose tolerance n = 42, Type II diabetes n = 76). CONCLUSION/INTERPRETATION: We have described a UCP2 gene exon 8 variant that may affect susceptibility to weight gain by influencing regulation of leptin.

Adult↗
PubMed1999

Patient case studies.

Three contrasting cases of obese patients with type 2 diabetes mellitus are presented, which illustrate the management difficulties faced by clinicians. The first raises the issue of when to commence an oral hypoglycaemic agent in a newly diagnosed but asymptomatic obese patient; the second case addresses the problem of when to commence insulin in the face of continuing weight gain and poor glycaemic control; the final case is an example of the vicious metabolic spiral which so many patients enter, with increasing body weight, poor diabetic control and associated co-morbidities. The discussion that follows each case presentation recognises the considerable cardiovascular risk faced by such patients and provides guidance about possible management pathways including adjunctive anti-obesity pharmacotherapy.

Diabetes Complications↗
PubMed1999

Quantitative sensory and autonomic testing in male diabetic patients with erectile dysfunction.

OBJECTIVE: To correlate abnormalities of nerve fibres in the lower limbs with erectile dysfunction in male diabetic patients, using a range of quantitative sensory and autonomic function tests. PATIENTS AND METHODS: The study included 68 male diabetic patients with symptomatic erectile dysfunction and 11 matched diabetics without erectile dysfunction; none had clinical evidence of peripheral vascular disease or psychological disorder. Patients were evaluated with a symptom questionnaire based on the Michigan Neuropathy Screening Instrument questionnaire and examined clinically. Sural and peroneal nerve-conduction studies, and quantitative sensory and autonomic tests (vibration, thermal, light-touch thresholds, sensory and autonomic cutaneous axon-reflexes) were used to detect nerve abnormalities in the lower limbs, which were correlated with erectile dysfunction. RESULTS: Symptoms of neuropathy were more common in the group with male erectile dysfunction (MED), but statistically significant only for neuropathic pain (53% MED, 18% nonMED, P<0.05, chi-square test) and gastroparesis (44% MED, 0% nonMED, P<0.05). Tests of unmyelinated afferents (warming perception and capsaicin-induced sensory axon-reflex vasodilatation) were most often abnormal, sometimes with no other abnormalities on tests or neurological examination. However, abnormality of warm perception was not significantly different between groups (81% MED, 70% nonMED), suggesting that it is a poorer discriminant than abnormal sensory axon-reflex vasodilatation (89% MED, 22% nonMED, P<0.001). The only other significant test difference was decreased sural nerve action potential (70% MED, 22% non-MED, P<0.01). CONCLUSIONS: There appeared to be preferential involvement of unmyelinated sensory fibres that mediate axon-reflex vasodilatation in the limbs of diabetic patients with erectile dysfunction. This test appears to be a helpful indicator of neurological involvement in erectile dysfunction, and may be used to monitor the effect of new treatments.

Adult↗
PubMed1999

Rating the appropriateness of coronary angiography, coronary angioplasty and coronary artery bypass grafting: the ACRE study. Appropriateness of Coronary Revascularisation study.

BACKGROUND: Previous studies investigating the appropriateness of invasive management of coronary disease had not reported the internal consistency of their ratings and may now be out of date. The aim of this study was to measure the influence of clinical factors on contemporary ratings of the appropriateness of coronary angiography, percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft (CABG) in the Appropriateness of Coronary Revascularisation (ACRE) study. METHODS: The Delphi-RAND technique was used, in which an expert panel (four cardiologists, three cardiothoracic surgeons, a general physician and a general practitioner), meeting in 1995, rated mutually exclusive indications (n = 2178 for angiography, n = 995 for PTCA and n = 984 for CABG). The main outcome measures were the appropriateness category (inappropriate, uncertain or appropriate) for each of the three procedures and treatment preference. RESULTS: For revascularization, the strongest determinant of inappropriateness was coronary anatomy. The odds ratio (OR) for inappropriate PTCA was 10.6 (95 per cent confidence interval (CI) 4.8-23.5) for the effect of left main stem or three-vessel disease versus single-vessel disease, and for CABG it was 0.06 (95 per cent CI 0.03-0.15). The number of diseased vessels was strongly related to preference for medical, PTCA or CABG treatment (p for linear trend <0.001). Mild versus severe anginal symptoms were associated with inappropriate angiography (OR 2.0 (95 per cent CI 0.9-9.8), although this effect was stronger when only the cardiologists' ratings were considered (OR 10.1 (95 per cent CI 2.4-42.6)). CONCLUSION: These are the first UK ratings of appropriateness covering all three procedures. The associations with clinical factors provide evidence of the internal consistency of these ratings. Prospective validation of these ratings against clinical outcomes is under way in the ACRE study.

Aged↗
PubMed1998

Neurotrophin-3 is increased in skin in human diabetic neuropathy.

Neurotrophin-3 (NT-3), a member of the neurotrophin family, has been shown to be necessary for the development of muscle spindle and Merkel cell afferent nerve fibres in animal models. The presence of NT-3 in the suprabasal epidermis, where many unmyelinated sensory fibres terminate, has been shown for the first time. As these fibres are affected in early diabetic neuropathy and a clinical trial of recombinant human NT-3 in diabetic neuropathy is in progress, the concentrations of endogenous NT-3 in skin of 24 patients at different stages of diabetic polyneuropathy have been investigated. NT-3 concentrations, measured with a specific immunoassay, were significantly higher in affected skin biopsies from patients with diabetic neuropathy than matched control skin (diabetic skin 6.32 (1.18) pg/mg v control skin 1.28 (0.05) (mean (SEM)); p<0.004, Mann-Whitney U test), particularly in the later stages. The optical density of NT-3-immunostaining was also significantly greater in the epidermis in diabetic patients (diabetic epidermis 0.30 (0.06) v controls 0.24 (0.01); p<0.02). No correlation was found between individual quantitative sensory tests and the increase of NT-3 concentration. The increase of NT-3 seems to reflect the degree of skin denervation in diabetic neuropathy, and may represent a compensatory mechanism. The concentrations of NT-3 in other peripheral targets deserve study in diabetic neuropathy.

Adult↗
PubMed1996

Comparison of case fatality in south Asian and white patients after acute myocardial infarction: observational study.

OBJECTIVE: To compare mortality in south Asian (Indian, Pakistani, and Bangladeshi) and white patients in the six months after hospital admission for acute myocardial infarction. DESIGN: Observational study. SETTING: District general hospital in east London. PATIENTS: 149 south Asian and 313 white patients aged < 65 years admitted to the coronary care unit with acute myocardial infarction from 1 December 1988 to 31 December 1992. MAIN OUTCOME MEASURE: All cause mortality in the first six months after myocardial infarction. RESULTS: The admission rate in the south Asians was estimated to be 2.04 times that in the white patients. Most aspects of treatment were similar in the two groups, except that a higher proportion of the south Asians received thrombolytic drugs (81.2% v 73.8%). After adjustment for age, sex, previous myocardial infarction, and treatment with thrombolysis or aspirin, or both, the south Asians had a poorer survival over the six months from myocardial infarction (hazard ratio 2.02 (95% confidence interval 1.14 to 3.56), P = 0.018), but a substantially higher proportion were diabetic (38% v 11%, P < 0.001), and additional adjustment for diabetes removed much of their excess risk (adjusted hazard ratio 1.26 (0.68 to 2.33), P = 0.47). CONCLUSION: South Asian patients had a higher risk of admission with myocardial infarction and a higher risk of death over the ensuing six months than the white patients. The higher case fatality among the south Asians, largely attributable to diabetes, may contribute to the increased risk of death from coronary heart disease in south Asians living in Britain.

Adult↗
PubMed1996

The role of endogenous nerve growth factor in human diabetic neuropathy.

Nerve growth factor (NGF) is trophic to sensory and sympathetic fibers. In animal models, NGF is depleted in diabetic nerves and NGF deprivation produces hypoalgesia. Exogenous NGF can reverse some of the pathological changes in diabetic nerves and NGF excess leads to hyperalgesia. We have quantified sensory and autonomic function in early diabetic polyneuropathy and correlated changes with levels of NGF and neuropeptides in affected skin. We describe an early length-dependent dysfunction of sensory small-diameter fibers, prior to dysfunction of sympathetic fibers, with depletion of skin NGF and the sensory neuropeptide substance P. We describe a significant correlation between NGF depletion and decreased skin axon-reflex vasodilation, mediated by small sensory fibers partly via substance P release. Immunostaining shows depletion of NGF in keratinocytes in diabetic skin. We propose that a decrease in endogenous skin-derived NGF influences the presentation of diabetic polyneuropathy, although metabolic or vascular abnormalities may be the cause of the neuropathy. As loss of nociception and axon-reflex vasodilation contribute to diabetic foot ulceration, early and prolonged NGF treatment at an appropriate dose may provide rational prophylaxis for this condition.

Adolescent↗
PubMed1996

Relationships between students' clinical experiences in introductory clinical courses and their performances on an objective structured clinical examination (OSCE).

PURPOSE: To elucidate the link between the quantity and quality of clinical exposure gained by first-year clinical students in hospital settings and their performance on a subsequent comprehensive assessment of clinical skills (the objective structured clinical examination, or OSCE). METHOD: Data relating to educational activities and workload were collected for the second introductory clinical attachment undertaken by 152 (of 246) students in two British medical colleges prior to a joint comprehensive 22-station OSCE administered in May 1994. Pearson correlation coefficients were used as the main analytical tool to study the relationships between measures of clinical activity and total OSCE scores. RESULTS: In general, of 43 indices of the amount, nature, and quality of bedside, ward-based, or outpatient experience, only six correlated with OSCE scores. The strongest links were for whether students examined out-patients on their own (r = .2), whether the objectives had been made clear (r = .19) and the number of clinics attended (r = .18). Variables meeting the criteria were entered into a backwards stepwise regression analysis to predict total OSCE scores, but they explained only 23% of the variance. CONCLUSION: The association between clinical experience and educational outcomes remains poorly understood.

Clinical Competence↗