Variability in fasting lipid and glycogen contents in hepatic and skeletal muscle tissue in subjects with and without type 2 diabetes: a 1H and 13C MRS study.

The measurement of tissue lipid and glycogen contents and the establishment of normal levels of variability are important when assessing changes caused by pathology or treatment. We measured hepatic and skeletal muscle lipid and glycogen levels using (1)H and (13)C MRS at 3 T in groups of subjects with and without type 2 diabetes. Within-visit reproducibility, due to repositioning and instrument errors was determined from repeat measurements made over 1 h. Natural variability was assessed from separate measurements made on three occasions over 1 month. Hepatic lipid content was greater in subjects with diabetes relative to healthy subjects (p = 0.03), whereas levels of hepatic and skeletal muscle glycogen, and of intra- and extra-myocellular lipid, were similar. The single-session reproducibility values (coefficient of variation, CV) for hepatic lipid content were 12% and 7% in groups of subjects with and without diabetes, respectively. The variability of hepatic lipid content over 1 month was greater than the reproducibility, with CV = 22% (p = 0.08) and CV = 44% (p = 0.004) in subjects with and without diabetes, respectively. Similarly, levels of variation in basal hepatic glycogen concentrations (subjects with diabetes, CV = 38%; healthy volunteers, CV = 35%) were significantly larger than single-session reproducibility values (CV = 17%, p = 0.02 and CV = 13%, p = 0.05, respectively), indicating substantial biological changes in basal concentrations over 1 month. There was a decreasing correlation in measurements of both hepatic lipid and glycogen content with increasing time between scans. Levels of variability in intra- and extra-myocellular lipid in the soleus muscle, and glycogen concentrations in the gastrocnemius muscle, tended to be larger than expected from single-session reproducibility, although these did not reach significance.

Pharmacokinetic and pharmacodynamic assessment of a five-probe metabolic cocktail for CYPs 1A2, 3A4, 2C9, 2D6 and 2E1.

AIMS: The primary objectives of the present study were to establish whether there was a pharmacokinetic or pharmacodynamic interaction between the probe drugs caffeine (CYP1A2), tolbutamide (CYP2C9), debrisoquine (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A4), when administered in combination as a cocktail. Furthermore, the tolerability of these probe drugs, both alone and in combination as a cocktail was assessed. METHODS: Twelve healthy volunteer subjects (age range 22-48 years) were entered into an open, fixed sequence, 6-limb, single centre study. The randomization was such that all drugs were given individually followed by the full "cocktail" as the last treatment limb. The phenotypic index used to assess the intrinsic activity of the CYP isoforms included metabolite/parent ratios in plasma and urine (CYPs 1A2, 2E1 & 2C9), parent/metabolite ratios in urine (CYP2D6) and plasma AUClast (CYP3A4). Blood pressure and blood glucose measurements were used to assess pharmacodynamic interactions. Tolerability was assessed through reporting of adverse events RESULTS: Overall, there was little evidence that the probe drugs interacted metabolically when co-administered as the cocktail. The ratio of the geometric mean (and 90% confidence interval) of the phenotypic index, obtained after administration of the probe as part of the cocktail and when given alone were: caffeine, 0.86 (0.67-1.10), midazolam, 0.96 (0.74-1.24), tolbutamide, 0.86 (0.72-1.03), debrisoquine 1.04 (0.97-1.12) and chlorzoxazone, 0.95 (0.86-1.05). There was no difference in blood pressure and blood glucose concentrations following the cocktail and dosing of the individual probes. There was no effect on ECG recordings at any time-point. The adverse events reported for individual drug administrations were mild, transient and expected. Overall no more adverse events were reported on the cocktail study days than on the days when the drugs were administered alone. CONCLUSIONS: The five probe drugs when coadministered, in this dosing regimen, demonstrated no evidence of either a metabolic or pharmacodynamic interaction that might confound the conclusions drawn during a cocktail study. The present cocktail methodology has the potential to become a useful tool to aid the detection of clinically important drug-drug interactions during drug development.

Evaluation of a pharmacokinetic interaction between remacemide hydrochloride and phenobarbitone in healthy males.

AIMS: To determine whether there is a pharmacokinetic interaction between the antiepileptic drugs remacemide and phenobarbitone. METHODS: In a group of 12 healthy adult male volunteers, the single dose and steady-state kinetics of remacemide were each determined twice, once in the absence and once in the presence of phenobarbitone. The effect of 7 days remacemide intake on initial steady-state plasma phenobarbitone concentrations was also investigated. RESULTS: Apparent remacemide clearance (CL/F) and elimination half-life values were unchanged after 7 days intake of the drug in the absence of phenobarbitone (1.25 +/- 0.32 vs 1.18 +/- 0.22 l kg(-1) h(-1) and 3.29 +/- 0.68 vs 3.62 +/- 0.85 h, respectively). Concomitant administration of remacemide with phenobarbitone resulted in an increase in the estimated CL/F of remacemide (1.25 +/- 0.32 vs 2.09 +/-0.53 l kg-1 h-1), and a decreased remacemide half-life (3.29 +/- 0.68 vs 2.69 +/- 0.33 h). The elimination of the desglycinyl metabolite of remacemide also appeared to be increased after the phenobarbitone intake (half-life 14.72 +/- 2.82 vs 9.61 +/- 5.51 h, AUC 1532 +/- 258 vs 533 +/- 281 ng ml(-1) h). Mean plasma phenobarbitone concentrations rose after 7 days of continuing remacemide intake (12.67 +/- 1.31 vs 13.86 +/- 1.81 microgram ml(-1)). CONCLUSIONS: Phenobarbitone induced the metabolism of remacemide and that of its desglycinyl metabolite. Remacemide did not induce its own metabolism, but had a modest inhibitory effect on the clearance of phenobarbitone.

The degree of day-to-day variation in food intake in diabetic patients.

A prospective study of food intake using 7 day food diaries was undertaken in 92 diabetic men and women aged 17-81 years. The median individual day-to-day coefficients of variation for energy intake were: in insulin treated patients 12.0%, in non-insulin treated patients 13.7%; for carbohydrate intake 14.5% and 13.8% and for fat 20.7% and 20.8%, respectively. The median individual differences between the minimum and maximum daily intake of energy in insulin treated patients was 787 kcal, in non-insulin treated patients 649 kcal, for carbohydrate intake 89g and 77g and fat 50g and 43g, respectively. Only 39% patients ate within 20% of their prescribed carbohydrate diet. In non-insulin treated patients on prescribed calorie controlled diets, calorie consumption was on average 46% in excess of that prescribed. Although the variation in dietary intake in diabetic patients is large, it is smaller than that reported in non-diabetic subjects in the UK. This variation is likely to make the manipulation of other antidiabetic therapy both difficult and somewhat arbitrary.

Ethnic differences in risk markers for heart disease in Bradford and implications for preventive strategies.

OBJECTIVES: To assess and compare the prevalence of established risk markers for ischaemic heart disease in a sample of Asian and non-Asian men and to relate these observations to preventive strategies. SETTING: Two factories in the textile industry in Bradford, West Yorkshire, UK. Subjects--288 male manual workers aged 20 to 65 years. DESIGN: Cross sectional study within one occupational/social class stratum. MEASUREMENTS AND MAIN RESULTS: Age, body mass index, plasma lipids, fibrinogen and serum insulin values, blood pressure, smoking habits, alcohol consumption, and exercise routines were recorded. Plasma total cholesterol concentrations were significantly lower in Asian than non-Asian men (5.3 mmol/l v 5.8 mmol/l respectively, p < 0.0001), as were low density lipoprotein cholesterol concentrations (3.4 mmol/l v 3.7 mmol/l, p = 0.0150), and high density lipoprotein (HDL) cholesterol (1.1 mmol/l v 1.3 mmol/l, p < 0.0001). Hypercholesterolaemia (concentration > 6.5mM) was present in nearly one quarter of non-Asians but less than one eighth of Asian men. Triglyceride values were not significantly higher in Asians. Smoking rates were high in non-Asians (43.8%) and only slightly lower in Asians (39.1%). Asian smokers smoked fewer cigarettes per day on average (9.3 v 16.1, p = 0.0001). Almost a quarter of non-Asian men (23.1%) and 26.6% of Asian men had raised blood pressure. Systolic pressures were higher in non-Asian men (138.3 mmHg v 133.0 mmHg, p = 0.0070), but diastolic pressures showed no ethnic differences. Diabetes was more prevalent in Asian men (10.9% v 4.4% p < 0.05), who also showed higher serum insulin concentrations after glucose loading (22.3 mU/l v 10.2 mU/l, p < 0.0001). Plasma fibrinogen values were higher in non-Asian men (2.9 g/l v 2.6 g/l, p < 0.0001) and these were associated with smoking. Nearly all non-Asians (92.5%) consumed alcohol at some time whereas 62.5% of Asians habitually abstained from alcohol consumption. Among the drinkers, non-Asian men consumed on average, 23.9 units per week and Asian men 18.4 units per week (p = 0.083). The mean body mass index for Asian men was 24.5 kg/m2 which was not significantly different to the mean in non-Asian men (25.2 kg/m2). The frequency of exercise in leisure time was low in both groups with 44.4% of non-Asian and 21.1% of Asian men taking moderate exercise weekly, and even fewer, regular strenuous exercise (16.3% and 8.6% respectively). CONCLUSIONS: The plasma cholesterol and fibrinogen concentrations, prevalence of hypertension, smoking habits, alcohol intakes, and infrequency of exercise in leisure time in these non-Asian men in Bradford were consistent with an increased risk of heart disease. The pattern of risk markers was clearly different in Asian men. Only their lower HDL cholesterol concentrations, marginally higher triglyceride values, higher prevalence of diabetes, and very low frequency of exercise in leisure time would be consistent with a higher risk of heart disease compared with non-Asians. The implications of these observations for heart disease preventive strategies are discussed.

Insulin resistance, diabetes, and risk markers for ischaemic heart disease in Asian men and non-Asian in Bradford.

OBJECTIVE: To examine the hypothesis, in a community not studied before, that insulin resistance associated with centralised adiposity is the mechanism underlying the predisposition of Asian immigrant communities to both ischaemic heart disease and diabetes mellitus. DESIGN: Cross sectional study within one socioeconomic stratum. SETTING: Two factories in the textile sector in Bradford, West Yorkshire. SUBJECTS: Male manual workers of Asian (110) and non-Asian origin (156) aged 20-65 years. RESULTS: Diabetes was almost three times more prevalent in the Asian group. Two hours after an oral glucose load Asian men had double the serum insulin concentrations of non-Asian men (p < 0.0001). Asian men also had significantly lower concentrations of plasma total cholesterol (p < 0.03), high density lipoprotein cholesterol (HDL) (HDL2, p < 0.0001; HDL3, p < 0.0001), and apolipoprotein AI (p < 0.0001). Fasting plasma triglyceride concentrations were slightly higher (p = 0.072) in the Asian men; thus the ratio of triglyceride cholesterol was higher (p = 0.006). The inter-relation between serum insulin and plasma lipid concentrations indicated metabolic differences between the ethnic groups. Insulin concentrations were associated with cholesterol concentrations in the Asian men only and there was a lack of association between triglyceride, low density lipoprotein cholesterol, and HDL cholesterol in this group. The risk marker profile in the Asian men was therefore quite different to that of their non-Asian counterparts and was associated with a greater tendency to centralised adiposity. CONCLUSION: These data support the insulin resistance hypothesis and thus have important implications for strategies for the prevention of heart disease in Asian communities in the United Kingdom.

Diabetic diets and nutritional recommendations: what happens in real life?

Prospective 7-day estimated weight food records were computer analysed in 92 diabetic patients, 45 men and 47 women, 25 with Type 1 and 67 Type 2 diabetes, attending a hospital-based diabetic clinic. The nutrient intakes were compared with a national survey in non-diabetic British adults (OPCS) and the current EASD recommendations for the diabetic diet. Only three diabetic patients achieved the recommended 50-60% energy intake as carbohydrate, four achieved less than 30% energy as fat, one patient less than 10% saturated fat and 20 ate greater than 30 g fibre per day. The overall nutrient intakes of these diabetic patients reflected those of non-diabetic subjects except for a greater intake of protein and smaller intakes of sugar and alcohol. These findings reinforce the problems currently faced in achieving the present recommendations for the diabetic diet.

Fatal Pasteurella multocida septicaemia following a cat bite in a man without liver disease.

We report a fatal case of septicaemia caused by Pasteurella multocida that followed a cat bite. The patient, a man aged 54 years, was not suffering from disease of the liver but had a history of ischaemic heart disease, non-insulin-dependent diabetes mellitus and rheumatoid arthritis which had been treated with steroids for 13 years.

A retrospective study of thirty-two patients with small-cell bronchogenic carcinoma and inappropriate secretion of antidiuretic hormone.

Thirty-two patients with inappropriate secretion of antidiuretic hormone (ADH) complicating small-cell carcinoma of the bronchus were identified from a total of 226 patients with small-cell carcinoma of the bronchus treated at the Christie Hospital, Manchester, between 1978 and 1984. Basic data were collected from patients' files concerning the extent of the tumour, symptoms of inappopriate secretion of antidiuretic hormone, biochemical findings, treatment, the course of the inappropriate secretion of ADH and that of the underlying tumour. The data were then analysed and compared with results of previous studies. The response of the inappropriate secretion of ADH to treatment was found to be a significant prognostic factor. Further data were collected to determine the reason for this but it was difficult to drawn any firm conclusions.