Patient preference for sustained-release versus standard paracetamol (acetaminophen): a multicentre, randomized, open-label, two-way crossover study in subjects with knee osteoarthritis.

Guidelines for osteoarthritis (OA) management recommend paracetamol (acetaminophen) as the most appropriate first-line analgesic for mild to moderate pain. Standard paracetamol requires four times daily dosing. Drug compliance and convenience are inversely related to daily dose frequency. Compliance is a pivotal component of the successful management of OA pain and is influenced by patient preferences or beliefs. The added convenience of three times daily dosing may enhance compliance and, therefore, pain relief. This multicentre, randomized, open-label, two-way crossover, phase IV study is the first to evaluate patient preference with a sustained-release paracetamol tablet formulation designed for three times daily dosing. Compared with standard paracetamol tablets dosed four times daily, the sustained-release formulation was preferred in a 2:1 ratio, provided better overall joint pain relief, resulted in higher levels of satisfaction in subjects with OA of the knee and has the potential to improve patient compliance and, therefore, pain control.

Apolipoprotein E4 is associated with reduced calcaneal quantitative ultrasound measurements and bone mineral density in elderly women.

Some studies have reported an association between the apolipoprotein E4 (APOE4) allele and reduced bone density and increased propensity to fracture, but this remains controversial as other studies have not found an association between APOE4 and bone density or fracture. No information is available concerning the effect of the APOE4 allele on quantitative ultrasound (QUS) parameters. We therefore examined this issue in a population-based study of 1332 healthy elderly women, examining the effect of the APOE4 allele on QUS parameters at the calcaneus and comparing this to dual-energy X-ray absorptiometry (DEXA) bone mineral density (BMD) at the hip. In addition, we examined the effect of the APOE4 allele on fracture. Subjects who had at least one APOE4 allele (n = 308) had lower calcaneal QUS parameters and lower hip BMD at the total hip, trochanter, and intertrochanter, but not the femoral neck, compared to subjects without an APOE4 allele (n = 1024) after adjustment for age, body mass index (BMI), and smoking. The decrement in QUS parameters and BMD was approximately 2%. Those subjects having an APOE4 allele were also more likely to fall into a low bone density group, defined by a T score of <1 SD below the young normal range (odds ratio [OR] 1.55, 95% confidence interval [CI] 1.08-2.22). We compared both prevalent and incident nontraumatic fractures over 2 years in the APOE4-present group compared with the APOE4-absent group. There were 354 subjects who entered the study with a history of one or more prevalent fractures, and 104 subjects sustained a nontraumatic fracture during the study. These fractures were not associated with the presence of the APOE4 allele, but a 2% decrement in BMD was unlikely to be associated with a statistically observable increase in fractures in this study. The APOE4 allele was not associated with a difference in any biochemical measures of bone formation or resorption, or in estrogen concentration, nor was it associated with a difference in BMI. Therefore, we conclude that the APOE4 allele is associated with a consistent decrease in both QUS parameters at the calcaneus and BMD at the clinically important hip site, and that this is not associated with differences in biochemical measures of bone formation or resorption.

Effect of prolonged hyperinsulinaemia on adipocyte insulin binding and action in normal man.

Prolonged moderate insulinaemia over 20 h in normal humans produces a significant reduction of in vivo insulin action. To examine the effects in man of such moderate hyperinsulinaemia on in vitro glucose metabolism, insulin-receptor binding, glucose transport and incorporation of glucose into lipid were determined in adipocytes isolated from paired gluteal fat biopsies, taken from six normal human volunteers before and 1 h after 20 h of exogenous hyperinsulinaemia (plasma insulin 38 +/- 3 mU/l). Specific binding of insulin to isolated adipocytes was not altered (6.7 +/- 0.7 versus 7.6 +/- 1.5% per 10(5) cells). Basal glucose transport of 3-O-[14C]methylglucose in the absence of insulin was reduced after hyperinsulinaemia (5.2 +/- 1.1 versus post 4.3 +/- 1.3 pmol/7 s per 10(5) cells, 0.1 less than P greater than 0.05; or expressed as percent of maximal response: 60 +/- 5 versus post 49 +/- 1%, P less than 0.05), but maximal transport (9.2 +/- 1.5 versus post 8.7 +/- 1.5 pmol/7 s per 10(5) cells) and ED50 (87 +/- 17 versus 67 +/- 15 pmol/l) were unchanged. Conversion of glucose into lipid, using 3-D-[3H]glucose, was unchanged basally, at maximal response or ED50 of the dose response curve. In conclusion, moderate 20 h in vivo hyperinsulinaemia in normal humans induces only a small change in basal vitro adipocyte glucose transport, and no change in insulin-receptor binding or in vitro incorporation of glucose into lipid. These data suggest that the adipocyte does not contribute to the impaired insulin action produced by in vivo moderate hyperinsulinaemia in man.

Effects of short-term pulsatile and continuous insulin delivery on glucagon secretion and insulin secretion and action.

In six normal nonobese subjects, hyperinsulinemic euglycemic clamps were performed during paired sequential two-hour intravenous (IV) insulin infusions separated by an hour washout period. Each infusion was either 32 mU/kg/h of continuous insulin (CI) or 75% of this dose as 40-second pulses delivered every 13 minutes (PI). Six studies were performed with each of the following sequences in random order: PI-CI, CI-PI, and CI-CI. Based on the initial infusions, the insulin-dependent fractional glucose disappearance rate (X) during pulsatile insulin delivery (3.0 +/- 0.4 min-1 X 10(2), n = 6) was 73% of that of the continuous infusions (4.1 +/- 0.3 min-1 X 10(2), n = 12). This ratio was similar to that of the measured time-averaged plasma insulin areas (PI = 24.7 +/- 3.8 v CI = 31.4 +/- 3.5 mU/L). There was an average 23% enhancement of insulin's hypoglycemic effect during the second 12 CI infusions compared with the 12 initial CI infusions (X = 5.1 +/- 0.5 v 4.1 +/- 0.3 min-1 X 10(2), P less than .05). There was no significant difference between the enhancing effects of PI and CI infusions on insulin action in the subsequent CI's (X = 4.9 +/- 0.9 for PI-CI v X = 5.3 +/- 0.2 min-1 X 10(2) for CI-CI). First infusion PI significantly (P less than .05) decreased plasma C-peptide levels (0.34 +/- 0.05 to 0.20 +/- 0.06 mumol/L), whereas CI did not (0.33 +/- 0.02 to 0.32 +/- 0.07).(ABSTRACT TRUNCATED AT 250 WORDS)

Hormonal effects of norepinephrine on acute glucose disposal in humans: a minimal model analysis.

It is not known whether circulating norepinephrine (NE) has a direct hormonal influence on glucose disposal. This study examines whether moderate elevation of NE alters the disposal of an acute intravenous (IV) glucose load, as analysed by the minimal model of Bergman. Eight healthy normal subjects were infused with either 25 ng/kg/min NE (plasma NE 1,284 +/- 259 pg/mL) or normal saline (plasma NE 314 +/- 86 pg/mL), 30 minutes prior to and during an IV glucose tolerance test (GTT). There was a small but significant rise (P less than .05) in basal blood glucose levels during the initial 30-minute NE infusion which was accompanied by a 40% increase (0.39 +/- .02 to 0.59 +/- .07 nmol/L, P less than .01) in nonesterified fatty acid levels (NEFA). Insulin, C-peptide, and glucagon levels did not change. NE impaired the rate of acute glucose disposal (Kg 1.74 +/- 0.24 v 2.10 +/- 0.23 (min-1, P less than .05). Minimal model analysis revealed a corresponding 35% decrease in insulin sensitivity (SI 4.85 +/- 1.51 v 7.28 +/- 1.16 min-1 microU-1 mL-1 x 10(4), P less than .05) but no significant differences between glucose-mediated glucose disposal or pancreatic B-cell responsiveness. The glucose disposition index (si* phi2), a direct measure of an individual's overall insulin- mediated glucose disposal, was reduced by 70% in the NE-infussed subjects (si* phi2 69 +/-22 v 223 +/- 76 mg-1 ml-1 min-3 x 10(2), p< .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic consequences of prolonged hyperinsulinemia in humans. Evidence for induction of insulin insensitivity.

Hyperinsulinemia is frequently associated with a variety of insulin-resistant states and has been implicated causally in the development of insulin resistance. This study examines the metabolic consequences of prolonged hyperinsulinemia in humans. Basally and 1 h after cessation of a 20-h infusion of insulin (0.5 mU X kg-1 X min-1, aimed at elevating plasma insulin levels to approximately 30 mU/L) or normal saline, subjects were assessed for glucose turnover with 3-[3H]glucose; insulin sensitivity, as measured by either the euglycemic glucose-clamp technique or the intravenous glucose tolerance test (IVGTT) minimal model method of Bergman; and monocyte insulin-receptor binding. Hepatic glucose production (Ra) was suppressed by greater than 95% during each euglycemic clamp and during the 20-h insulin infusion. After the insulin infusion, Ra and glucose utilization rate returned to the initial basal level within 1 h, as did insulin levels. At that time, insulin sensitivity was significantly decreased, as measured by the "insulin action" parameter during the 40- to 80-min phase of the clamp (0.049 +/- 0.003 vs. 0.035 +/- 0.007 min-1, P less than .05) and during the 80- to 120-min phase (0.047 +/- 0.005 vs. 0.039 +/- 0.007 min-1, .05 less than P less than .1).(ABSTRACT TRUNCATED AT 250 WORDS)