Effect of somatostatin-14 on gastric emptying and on gastrin and insulin release after ingestion of a mixed solid-liquid meal in man

The effect of somatostatin-14 on gastric emptying, as well as on serum concentrations of gastrin, insulin, glucose, calcium, and phosphorus after ingestion of a mixed solid-liquid meal was examined in seven healthy men in a double-blind placebo-controlled study. An i.v. bolus injection of 61 nmol somatostatin was followed by 244 nmol infused at a constant rate over 90 minutes. Gastric emptying of a radiolabelled meal was surveyed with the use of a gamma camera. A weak delaying effect of somatostatin on gastric emptying of a solid meal did not prove to be statistically significant. Somatostatin decreased significantly the postprandial gastrin release: the area under the gastrin curve, AUC0-90, 9954 +/- 2287 ng.l-1 min (placebo) vs 5327 +/- 718 ng.l-1 min (somatostatin), p less than 0.05. At the same time suppression of the postprandial insulin release by somatostatin was observed--area under the insulin curve, AUC0-90, 1450 +/- 161 mU.l-1 min (placebo) vs 501 +/- 60 mU.l-1 min (somatostatin), p less than 0.002. The postprandial increase in serum glucose concentration was initially attenuated, and shifted towards the end of somatostatin infusion, when referred to the placebo situation. Somatostatin did not change significantly the serum calcium or phosphorus concentrations. The results obtained indicate that somatostatin's effect on gastric evacuation is less pronounced in contrast to the significant inhibitory influence of somatostatin on release of gastrointestinal hormones.     

A comparative study on gastric emptying and secretory status in the early postoperative period after truncal vagotomy with two pyloroplasty variants performed for peptic ulcer disease. II. Heineke-Mikulicz pyloroplasty and comparison with the cassimally routine

In 14 peptic ulcer patients undergoing truncal vagotomy with Heineke-Mikulicz pyloroplasty (VTP-HM), gastric emptying of a radiolabeled solid meal, gastric acid secretion and gastrin release was examined within a median of 14 days (range; 10 to 63 days) following the operation, and compared with the results obtained in 14 patients subjected to vagotomy and Cassimally pyloroplasty (VTP-Cas). VTP-HM markedly disturbed gastric emptying in 10 out of 14 patients (71%), four of which (28%) had extremely rapid, and six (43%) exhibited abnormally delayed gastric emptying. Due to a wide inter-subject variability, no significant differences between VTP-HM and VTP-Cas were found for any of the gastric emptying parameters considered. The basal acid output was significantly lower after VTP-Cas than VTP-HM: 2.4 +/- 0.8 vs 5.8 +/- 1.0mmol.h-1, (p less than 0.02). The difference in pentagastrin-stimulated gastric acid secretion: 9.4 +/- 1.4 vs 12.0 +/- 1.8 mmol.h-1 for VTP-Cas vs VTP-HM, respectively, was not statistically significant. Higher fasting serum gastrin concentration (102.0 +/- 21.1 vs 63.3 +/- 8.3 ng.l-1), and greater postprandial gastrin release (AUC0-120: 16690 +/- 2648 vs 10654 +/- 1283 ng.l-1 min) were observed after VTP-HM than after VTP-Cas. The respective differences did not, however, reach the level of statistical significance, the possible clinical relevance of the differences between the two pyloroplasty procedures with respect to their effect on gastric evacuatory and secretory functions is discussed.     

Metabolic effects of lacidipine: a placebo-controlled study using the euglycaemic hyperinsulinaemic clamp.

1. Twelve healthy male volunteers received lacidipine 4 mg and matching placebo, each for 2 weeks, in a randomised, double-blind crossover study, and attended on 4 study days to evaluate the effects of single and multiple dosing using the euglycaemic hyperinsulinaemic 'clamp'. 2. On each study day, a primed constant-rate infusion of soluble insulin (1.5 mu kg-1 min-1) was administered for 180 min with a variable-rate infusion of 20% dextrose to maintain euglycaemia (5.2 mmol l-1). Whole-body insulin sensitivity was calculated during the past 40 min of the 'clamp'. At frequent intervals, measurements of BP and HR were recorded and venous blood samples collected for serum insulin, C-peptide, potassium, triglyceride (TG) and plasma noradrenaline concentrations. 3. Lacidipine was generally well tolerated and there were no adverse biochemical events. Mean values for insulin sensitivity +/- s.d. were 8.9 +/- 1.6 and 9.1 +/- 2.0 mg kg-1 min-1 after single doses of lacidipine and placebo respectively (95% CI, -1.0, 1.3), and correspondingly 9.6 +/- 2.1 and 9.7 +/- 1.5 mg kg-1 min-1 after 2 weeks (95% CI, -1.0, 1.3). 4. There was a significant reduction in fasting serum TG concentrations after 2 weeks of lacidipine: 0.7 +/- 0.3 mmol l-1 vs 0.9 +/- 0.6 (P < 0.001). However, changes in serum TG and potassium concentrations during the 'clamp' were not significantly different between the 4 study days. 5. Thus, in 'insulin sensitive' volunteers, lacidipine reduces fasting serum TG concentrations but has no effect on insulin-stimulated uptake of glucose, potassium and TG under euglycaemic hyperinsulinaemic conditions.     

Effect of anti-obesity drugs promoting energy expenditure, yohimbine and ephedrine, on gastric emptying in obese patients

The effect of ephedrine, a non-selective adrenoreceptor agonist, and yohimbine, a selective alpha 2-adrenolytic drug, on gastric emptying of a radiolabelled solid meal was examined in groups of 8 (all women) and 15 (4 men and 11 women) obese patients, respectively. Patients were given orally, double-blind in random order, placebo or 50 mg ephedrine in the first group, and placebo or 15 mg yohimbine in the second group, 1.5 h prior to the gastric emptying measurement performed with the use of a gamma camera. Yohimbine did not significantly affect gastric emptying--the fraction of the meal retained within the stomach at the end of the examination (that is after 90 min), F90, amounted to 71.0 +/- 3.8% (placebo) and 66.8 +/- 4.1% (yohimbine); the gastric emptying index, Ix, was 0.737 +/- 0.106 min-1 x 10(-2) (placebo) and 0.885 +/- 0.128 min-1 x 10(-2) (yohimbine). A significant delay in gastric emptying was observed after administration of ephedrine: F90 increased from 70.3 +/- 5.1% after placebo to 80.9 +/- 3.0% after ephedrine, P less than 0.02, and Ix decreased from 0.747 +/- 0.142 min-1 x 10(-2) to 0.461 +/- 0.080 min-1 x 10(-2) after ephedrine, P less than 0.02. We conclude that the inhibitory influence of ephedrine on gastric emptying, and thus possibly on satiety, makes it a candidate for trial as pharmacological support of a low-energy diet treatment of obesity.     

A comparative study on gastric emptying and secretory status in the early postoperative period after truncal vagotomy with two pyloroplasty variants performed for peptic ulcer disease. I. Cassimally pyloroplasty

Gastric emptying (GE) of a radiolabeled solid meal, gastric acid secretion and gastrin release were examined within a median of 15.5 days (range: 9 to 66) after surgery in 14 peptic ulcer patients subjected to truncal vagotomy with Cassimally pyloroplasty (VTP-Cas). A significant delay in GE was observed after VTP-Cas; the median slope of GE curves, K, decreased from 14.65 (range: 2.56 to 21.86) before to 4.05 (range: 0 to 11.67) min-1.10-3 after the operation (p less than 0.002). The postoperative GE was significantly slower than in a group of 41 healthy controls (median K = 9.09, range: 3.72 to 28.66 min-1.10(-3), p less than 0.01 vs the VTP-Cas-operated patients), and was characterized by a biphasic pattern with a slowed second phase. VTP-Cas resulted in a reduction of the basal acid secretion by an average of 87% (from 9.5 +/- 3.4 to 1.2 +/- 0.2 mmol.h-1, p less than 0.05), and the pentagastrin-stimulated acid output by 72% (from 30.8 +/- 7.2 to 8.6 +/- 1.6 mmol.h-1, p less than 0.05). The fasting serum gastrin concentration remained unchanged after VTP-Cas (68.2 +/- 10.8 pre- vs 67.3 +/- 9.4 ng.1-1 post-operatively), whereas a slight and statistically insignificant increase in the meal-induced gastrin release was found following the VTP-Cas-AUC0-120: 10002 +/- 1298 pre- vs 11234 +/- 1422 ng.1-1 min postoperatively.     

Pharmacokinetics and pharmacodynamics of roxatidine in patients with renal insufficiency.

1. Roxatidine acetate, a new histamine H2-receptor antagonist, was administered in the evening (75 mg p.o.) to eight patients with renal insufficiency (CLCR 8-17 ml min-1) for 12 days and plasma drug concentrations were measured. 2. Ambulatory intragastric pH was monitored following the last dose and values were compared with those on day 1 when all patients received a placebo. 3. The terminal elimination half-life (mean +/- s.d.) of roxatidine was 10.8 +/- 2.4 h and its oral clearance was 178 +/- 43 ml min-1. 4. During roxatidine treatment gastrin levels increased slightly (median 189 vs 289 ng l-1) and the hyperparathyroid status of the patients was almost normalized (parathyroid hormone levels: median 199 vs 132 ng l-1). 5. The mean latency to a gastric pH of at least 4 was 4.3 +/- 1.4 h. The duration of action (intragastric pH > 4) was 10.6 +/- 3.9 h. 6. As in a pilot study with six patients (CLCR < or = 17 ml min-1) the recommended dosage regimen (75 mg 48 h-1) was unable to maintain gastric pH > 4 for more than 6 h, daily nocturnal intake of 75 mg roxatidine acetate appears appropriate to elevate gastric pH > 4 for a sufficient period of time.     

Calcitonin suppresses gastric emptying of a radiolabelled solid meal in humans.

The effects on gastric emptying of calcitonin/i.v. 1.5 i.u. kg-1 body mass bolus or 10 i.u. followed by infusion to overall 1.5 i.u. kg-1 body mass dose vs placebo were studied in four healthy volunteers and in four patients with an active peptic ulcer. Gastric emptying of a radiolabelled solid meal was surveyed. Pronounced delay in gastric emptying was observed in all studied subjects, mean transit time MTT90 calcitonin 39.2 +/- 0.85 min vs placebo 32.8 +/- 1.31 min, P less than 0.001.     

Double-blind, randomized, placebo-controlled study to evaluate the effects of tegaserod on gastric motor, sensory and myoelectric function in healthy volunteers

BACKGROUND: The effects of tegaserod on gastric accommodation and postprandial satiety remain unclear. AIM: To compare the effects of tegaserod 6 mg twice daily vs. placebo on gastric volumes, postprandial symptoms, gastric emptying, small bowel transit and the surface electrogastrogram in female and male healthy volunteers. METHODS: Randomized, double-blind, placebo-controlled study evaluated gastric function before and after 7 days of tegaserod 6 mg twice daily (n = 21) vs. placebo (n = 20) in healthy volunteers. Validated methods were used to study gastric emptying, myoelectrical activity, volumes and satiation postnutrient challenge. RESULTS: There were no significant effects of tegaserod on the primary endpoints assessing gastric function: emptying of solids or liquids, total gastric volumes or myoelectrical activity. Maximum tolerated volume and aggregate symptom score with nutrient challenge on placebo were 1,035 mL (+/-44) and 130 (+/-15) vs. 989 mL (+/-43) and 117 (+/-15) during tegaserod, respectively (all P = N.S.). Postprandial change in proximal gastric volume by single photon emission-computed tomography was decreased in females on tegaserod (246 +/- 30) vs. placebo (358 +/- 32) (P = 0.015). Proximal fasting volumes in females were increased on tegaserod (126 +/- 12) vs. placebo (92 +/- 13) (P = 0.066). CONCLUSIONS: While tegaserod decreased proximal gastric volume change after a meal, it does not appear to have significant effects on gastric motor and sensory function in healthy individuals. Further studies are required in patients with disturbances of gastric motor and sensory function.     

Preventive effects of octreotide (SMS 201-995) on diabetic ketogenesis during insulin withdrawal.

1. Exogenous somatostatin inhibits glucagon secretion and prevents ketoacidosis in diabetic patients, but has the therapeutic disadvantage of requiring continuous intravenous infusion to exhibit these effects. 2. Consequently, we examined the effect of subcutaneous administration of the long-acting somatostatin analogue octreotide (SMS 201-995) on early ketogenesis in diabetic ketoacidosis. On two separate occasions insulin was withdrawn over a period of 9 h from seven type I diabetic patients. On the second occasion the patients were given 50 micrograms octreotide s.c. before the insulin withdrawal and every 3 h during insulin withdrawal. 3. Differences in integrated free fatty acid responses (4706 +/- 1227 mumol l-1 h vs 3026 +/- 835 mumol l-1 h, AUC, P = NS) were not significant, but the peak increments of acetoacetate (1413 +/- 354 mumol l-1 vs 612 +/- 176 mumol l-1, P less than 0.05), beta-hydroxybutyrate (2180 +/- 475 mumol l-1 vs 922 +/- 246 mumol l-1, P less than 0.01) and the decrements in plasma bicarbonate (-8 +/- 1 mumol l-1 vs -4 +/- 1 mumol l-1, P less than 0.05) and pH (-0.07 +/- 0.01 vs -0.03 +/- 0.01, P less than 0.05) were significantly less with octreotide. 4. At the same time peak increments of glucagon were lower with octreotide treatment (329 +/- 206 pg ml-1 vs 39 +/- 30 pg ml-1, P less than 0.05). 5. We conclude that, despite accelerated lipolysis and provision of substrate for ketogenesis during insulin withdrawal, this somatostatin analogue significantly reduces ketogenesis resulting from insulin deprivation, probably secondary to decreasing glucagon secretion. This drug may be useful in short term prophylactic treatment of diabetic patients during periods of increased risk for ketoacidosis.     

Effects of fedotozine on gastric emptying and upper gastrointestinal symptoms in diabetic gastroparesis

BACKGROUND: Delayed gastric emptying and upper gastrointestinal symptoms occur frequently in patients with diabetes mellitus. AIM: To evaluate the effects of fedotozine on gastric emptying and gastrointestinal symptoms in diabetic gastroparesis. METHODS: Thirty-one diabetic patients (20 type 1, 11 type 2) with gastroparesis were randomized to receive fedotozine (30 mg as the tartrate) or placebo t.d.s. Measurements of gastric emptying (100 g ground beef labelled with 20 MBq 99mTc-sulphur colloid chicken liver and 150 mL 10% dextrose labelled with 10 MBq 113mIn-DTPA) and gastrointestinal symptoms were performed before and after 12-16 days of treatment. Data are the mean +/- s.d. RESULTS: Of the 31 patients enrolled, two were excluded from analysis. Data from the remaining 29 patients (18 type 1, 11 type 2; 22 female, seven male), aged 42.7 +/- 11.1 years (of whom 14 were randomized to fedotozine and 15 to placebo), were analysed. Fedotozine had no effect on either gastric emptying (solid retention at 100 min; fedotozine: baseline, 84 +/- 15%; treatment, 73 +/- 23% vs. placebo: baseline, 83 +/- 10%; treatment, 70 +/- 20%) or liquid 50% emptying time (fedotozine: baseline, 59 +/- 32 min; treatment, 58 +/- 38 min vs. placebo: baseline, 44 +/- 9 min; treatment, 43 +/- 21 min) or gastrointestinal symptoms (fedotozine: baseline, 4.4 +/- 2.9; treatment, 4.1 +/- 3.9 vs. placebo: baseline, 4.9 +/- 4.2; treatment, 4.8 +/- 3.9). CONCLUSIONS: Fedotozine has no effect on gastric emptying in patients with diabetic gastroparesis.     

Influence of ghrelin on gastric emptying and meal-related symptoms in idiopathic gastroparesis

BACKGROUND: Ghrelin, the endogenous ligand of the growth hormone secretagogue receptor, is released from the stomach. Animal studies suggest that ghrelin stimulates gastrointestinal motor activity. AIM: To investigate the influence of ghrelin on gastric emptying rate and meal-related symptoms in idiopathic gastroparesis. METHODS: In six patients with idiopathic gastroparesis, a breath test was used to measure gastric emptying rates (t(1/2)) for solids and liquids after administration of saline or ghrelin 40 microg/30 min in a double-blind, randomized fashion. At each breath sampling, the patient was asked to grade the intensity of six different symptoms (epigastric pain, bloating, postprandial fullness, nausea, belching and epigastric burning) and these were added to obtain meal-related symptom severity score. RESULTS: Ghrelin significantly enhanced liquid emptying (t(1/2): 86 +/- 7 vs. 53 +/- 6 min, P = 0.02) and tended to enhance solid emptying (144 +/- 45 vs. 98 +/- 15 min, P = 0.06). Ghrelin pre-treatment significantly decreased cumulative meal-related symptom score (196 +/- 30 vs. 136 +/- 23, P = 0.04) and individual scores for fullness (55 +/- 8 vs. 39 +/- 8, P = 0.02), and for pain (40 +/- 8 vs. 16 +/- 5, P < 0.05). CONCLUSIONS: In idiopathic gastroparesis, administration of ghrelin enhances gastric emptying and improves meal-related symptoms. These observations suggest a potential for ghrelin receptor agonists in the treatment of gastroparesis.     

Long-term cisapride treatment improves diabetic gastroparesis but not glycaemic control

BACKGROUND: In patients with diabetic gastroparesis, delayed food delivery to the intestine may become a major obstacle to post-prandial glycaemic control. AIM: To investigate whether cisapride accelerates gastric emptying in the long term or improves diabetes control in patients with diabetic gastroparesis. METHODS: Eighty-five patients with long-standing insulin-dependent diabetes mellitus (glycosylated haemoglobin (HbA1c) > 7.0%), dyspepsia and diabetic neuropathy were tested for impaired gastric emptying of solids by the 13C-octanoate breath test. Nineteen of these patients with severe diabetic gastroparesis (i.e. t1/2 > 170 min) were randomly treated with 10 mg cisapride t.d.s. (n=9) or placebo (n=10) for 12 months. Thereafter, the breath test, dyspeptic symptoms and HbA1c values were reassessed. RESULTS: Half emptying times in nine patients with diabetic gastroparesis were significantly shortened by cisapride (175 +/- 46 min vs. 227 +/- 40 min; P < 0.03). Half emptying times in the 10 patients taking placebo did not change (205 +/- 37 min vs. 211 +/- 36 min, P=0.54). Cisapride significantly reduced dyspepsia (score: 4.1 +/- 1.6 vs. 2.0 +/- 0.5, P=0.002). HbA1c values after 12 months of treatment were not different (cisapride: 7.7 +/- 0.4% vs. 7.6 +/- 0.9%, P=0.76; placebo: 7.5 +/- 0.6% vs. 7.6 +/- 1.5%, P=0.89). CONCLUSIONS: Prokinetic treatment with cisapride accelerates gastric emptying of solids and improves dyspeptic symptoms in diabetic gastroparesis. Glycaemic control, however, is not affected by cisapride.     

Impact of gastric emptying on the pharmacokinetics of ethanol as influenced by cisapride

AIMS: To examine the influence of cisapride on the pharmacokinetics of ethanol and the impact of gastric emptying monitored by the paracetamol absorption test. METHODS: Ten healthy male volunteers took part in a cross-over design experiment. They drank a moderate dose of ethanol 0.30 g kg-1 body weight exactly 1 h after eating breakfast either without any prior drug treatment or after taking cisapride (10 mg three times daily) for 4 consecutive days. In a separate study, the same dose of ethanol was ingested on an empty stomach (overnight fast). Paracetamol (1.5 g) was administered before consumption of ethanol to monitor gastric emptying. Venous blood was obtained at 5-10 min intervals for determination of ethanol by headspace gas chromatography and paracetamol was analysed in serum by high performance liquid chromatography (h.p.l.c.). Results The maximum blood-ethanol concentration (Cmax ) increased from 3.8+/-1.7 to 5.6+/-2.3 mmol l-1 (+/-s.d.) after treatment with cisapride (95% confidence interval CI on mean difference 0.28-3.28 mmol l-1 ). The area under the blood-ethanol curve (AUC) increased from 6.3+/-3.5 to 7.9+/-2.6 mmol l-1 h after cisapride (95% CI -0. 74-3.9 mmol l-1 h). The mean blood ethanol curves in the cisapride and no-drug sessions converged at approximately 2 h after the start of drinking. Both Cmax and AUC were highest when the ethanol was ingested on an empty stomach (Cmax 9.5+/-1.7 mmol l-1 and AUC 14. 6+/-1.9 mmol l-1 h), compared with drinking 1 h after a meal and regardless of pretreatment with cisapride. CONCLUSIONS: A small but statistically significant increase in Cmax occurred after treatment with cisapride owing to faster gastric emptying rate as shown by the paracetamol absorption test. However, the rate of absorption of ethanol, as reflected in Cmax and AUC, was greatest after drinking the alcohol on an empty stomach. The cisapride-ethanol interaction probably lacks any clinical or forensic significance.     

Influence of intrapyloric botulinum toxin injection on gastric emptying and meal-related symptoms in gastroparesis patients

BACKGROUND: Recent observations in limited numbers of patients suggest a potential benefit of intrapyloric injection of botulinum toxin in the treatment of gastroparesis. AIM: To characterize the effect of botulinum toxin on solid and liquid gastric emptying and on meal-related symptoms. METHODS: In 20 gastroparesis patients (17 women, mean age 37 +/- 3 years, three diabetic and 17 idiopathic), gastric emptying for solids and liquids was measured before and one month after intrapyloric botulinum toxin 4 x 25 units. Before the meal and at 15-min intervals up to 240 min postprandially, the patient graded the intensity of six gastroparesis symptoms, and a meal-related severity score was obtained by adding all intensities. Data (mean +/- S.E.M.) were compared using paired Student's t-test. RESULTS: Treatment with botulinum toxin significantly enhanced solid (t(1/2) 132 +/- 16 vs. 204 +/- 35 min, P < 0.05) but not liquid (92 +/- 10 vs. 104 +/- 11 min, N.S.) emptying. This was accompanied by a significant decrease in cumulative meal-related symptom score (73.5 +/- 16.3 vs. 103 +/- 17.1 baseline, P = 0.01) as well as individual severity scores for postprandial fullness, bloating, nausea and belching (all P < 0.001, two-way anova). CONCLUSIONS: Botulinum toxin improves solid but not liquid gastric emptying in gastroparesis, and this is accompanied by significant improvement of several meal-related symptoms.     

The pharmacokinetics and pharmacodynamics of quinidine and 3-hydroxyquinidine.

1. The pharmacokinetics and pharmacodynamics of quinidine and 3-hydroxyquinidine based upon measurements of total and unbound serum concentrations were determined after a single dose (400 mg) and at steady state (200 mg every 6 h). 2. The oral clearance (7.6 +/- 1.9 vs 4.8 +/- 2.0 ml min-1 kg-1; P less than 0.05) and renal clearance (1.2 +/- 0.3 vs 0.63 +/- 0.25 ml min-1 kg-1; P less than 0.005) or quinidine were lower during steady state than after the single dose. 3. The area under the serum concentration vs time curve (AUC) of 3-hydroxyquinidine was greater at steady state than after the single dose (2.0 +/- 0.7 vs 3.0 +/- 0.6 mg l-1 h; P less than 0.05) and its renal clearance was less (3.0 +/- 1.1 vs 1.54 +/- 0.38 ml min-1 kg-1; P less than 0.05). 4. The slope of the relationship between quinidine concentration and change in QTc interval was greater at steady state (40.1 +/- 21.7 vs 72.2 +/- 41.7 ms/(mg l-1); P less than 0.05).     

静注卡介苗建立免疫性胰岛素抵抗模型

目的建立并考察卡介苗诱导的胰岛素抵抗动物模型。方法用正糖钳实验方法及其他生化检验方法测定卡介苗每鼠10 mg iv后大鼠血糖、葡萄糖耐量、血清TNF-α、胰岛素刺激的葡萄糖代谢速率及其他生化指标的变化。结果卡介苗iv后第2,4及8周,动物的葡萄糖耐量均受到损伤,胰岛素刺激的葡萄糖代谢速率显著下降,血清TNF-α含量升高。结论卡介苗iv可造成稳定的胰岛素抵抗模型,其造模机理可能与升高大鼠血清TNF-α含量有关。     

Effects of effervescent ranitidine on gastric pH: comparison with almagate and placebo in fasting and postprandial conditions

AIM: To compare the effect of effervescent ranitidine, almagate (magnesium carbonate-aluminium hydroxide) and placebo on gastric pH, in fasting and postprandial conditions. METHODS: Twelve healthy volunteers underwent a gastro-oesophageal pH monitoring on three different occasions after the administration of each of the following randomly allocated treatments: almagate, effervescent ranitidine and placebo. Treatment effects were assessed in fasting and postprandial conditions. Onset and duration of alkalinization, percentage of time with pH > 4 and median gastric pH after treatments were calculated in both periods. RESULTS: Onset of action of effervescent ranitidine was similar to almagate in fasting [median 1.2 min (IQR: 0.6-12.7) vs. 2.9 min (0.4-227.6)] and postprandial conditions [1.4 min (0.5-4.9) vs. 4.1 min (1.3-63.8)] and both were significantly faster than placebo [fasting 211.1 min (2.7-240); postprandial 240 min (175.6-240)]. The duration of action of effervescent ranitidine was statistically significant longer than almagate in fasting [235 min (105.2-239.4) vs. 19.4 min (6.7-38.8)] and postprandial conditions [171.8 min (133.2-239.5) vs. 61.3 min (44.7-91.9)]. Effervescent ranitidine was more effective than almagate in increasing the percentage of time with a pH > 4 both in fasting (73.9% vs. 7.3%) and postprandial (59.1% vs. 21.3%). CONCLUSIONS: Effervescent ranitidine shows an effect on gastric pH as fast as almagate but provides a duration of alkalinization longer than almagate, in both fasting and postprandial conditions.     

C-peptide has no effect on forearm blood flow during local hyperinsulinaemia in healthy humans

BACKGROUND: C-peptide increases forearm blood flow (FBF) in patients with Type 1 diabetes, probably by interaction with insulin, but not in healthy subjects. It is unclear if the vasodilating effect is sealed at normal fasting insulin concentrations. METHODS: The effects of C-peptide alone and during local hyperinsulinaemia were studied in healthy young men. Subjects received intra-arterial insulin at 6 pmol min-1 (low dose) or placebo for 60 min with subsequent coinfusion of C-peptide at increasing doses of 2-60 pmol min-1 in a double-blind crossover study (n = 8). In control experiments insulin at 30 pmol min-1 (high dose) was coinfused with C-peptide (n = 3). FBF was measured by strain-gauge plethysmography. RESULTS: Placebo had no effect on FBF (mean percentage change from baseline at 50 min -3.1%, 95% confidence interval [CI]-14.9, + 8.7). Insulin infusion slightly enhanced FBF by + 10.2% (95% CI -6.8, + 27.2; low dose) and + 17.6% (95% CI -38.8, + 74.0; high dose), respectively. The mean individual difference of the change in FBF between low-dose insulin and placebo was + 13.3% (95% CI -6.0, + 32.7; P = NS). Infusion of C-peptide increased local C-peptide concentrations from 1.8 +/- 0.1 ng ml-1 to 6.1 +/- 2.8 ng ml-1, but had no effect on FBF during placebo or hyperinsulinaemia (mean difference vs low dose insulin -16.0%, 95% CI -38.9, + 6.9). CONCLUSION: The vasodilating effect of C-peptide seen in Type 1 diabetes is not detectable during fasting or hyperinsulinaemia in the forearm vasculature of healthy subjects. This suggests saturation of its vasodilating potency at insulin concentrations within the normal or in the supraphysiological range.     

Influence of delaying gastric emptying on meal-related symptoms in healthy subjects

BACKGROUND: Although delayed gastric emptying is often found in functional dyspepsia, a causal role for delayed emptying in inducing symptoms has not been demonstrated. AIM: To investigate the influence of delaying gastric emptying rate in healthy volunteers on the occurrence of meal-related symptoms. METHODS: Fourteen healthy subjects (six men, mean age 23 +/- 1) underwent gastric emptying studies twice using the 14C octanoic acid and 13C glycin breath test after pre-treatment with saline or sumatriptan 6 mg s.c. Breath samples were taken before meal and at 15-min intervals for a period of 360 min postprandially. At each breath sampling, the subject was asked to grade the intensity (0-6) of four dyspeptic symptoms. RESULTS: Sumatriptan pre-treatment significantly delayed solid but not liquid gastric emptying (t1/2 respectively 159 +/- 11 vs. 112 +/- 9 min, P < 0.005 and 134 +/- 11 vs. 116 +/- 12 min, N.S.). Sumatriptan significantly decreased the mean cumulative symptom score (21.3 +/- 5.5 vs. 8.0 +/- 2.6, P = 0.01), as well as scores for each individual symptom. CONCLUSION: A moderate delay in gastric emptying in health is not associated with an increase of meal-related symptoms. This observation argues against a causal role for delayed gastric emptying in the pathogenesis of dyspeptic symptoms.     

Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus.

PURPOSE: The pharmacology and tolerability of exenatide in patients with type 2 diabetes mellitus were studied. METHODS: Two randomized, single-blind, placebo-controlled studies were conducted. Treatment with oral antidiabetic agents was stopped 14 days before study initiation. In the first study (study A), eight subjects received placebo, 0.1-, 0.2-, 0.3-, and either 0.4-microg/kg exenatide or placebo five minutes before a meal combined with liquid acetaminophen (to assess the rate of gastric emptying) on days 1, 3, 5, 7, and 9. In the second study (study B), subjects received a single s.c. dose of exenatide or placebo on consecutive days. Part 1 of study B used exenatide doses of 0.01 and 0.1 microg/ kg; 0.02-, 0.05-, and 0.1-microg/kg doses were given in part 2. After an overnight fast, the study drug was injected 15 minutes before a meal (part 1) and before a meal and acetaminophen (part 2). Parts 1 and 2 of study B enrolled six and eight patients, respectively. RESULTS: In both studies, plasma exenatide pharmacokinetic profiles appeared dose proportional. Exenatide doses of 0.02-0.2 microg/kg dose-dependently lowered postprandial glucose excursions. Exenatide suppressed postprandial plasma glucagon and slowed gastric emptying. There were no serious adverse events and no patient withdrawals related to treatment. Nausea and vomiting were the most common adverse events and were mild to moderate in severity at doses ranging from 0.02 to 0.2 microg/kg. CONCLUSION: Administration of preprandial exenatide by s.c. injection resulted in dose-proportional exenatide pharmacokinetics and antidiabetic pharmacodynamic activity. At doses ranging from 0.02 to 0.2 microg/kg, exenatide dose-dependently reduced postprandial plasma glucose excursion by insulinotropism, suppression of plasma glucagon, and slowing of gastric emptying.