Isotretinoin 5 mg daily for low-grade adult acne vulgaris--a placebo-controlled, randomized double-blind study.

BACKGROUND: Despite acne persisting into adulthood in up to 50% of the population, very few therapeutic studies have been performed in this age group. OBJECTIVES: To assess the efficacy of 5 mg/day isotretinoin in adult acne. METHODS: An investigator initiated, industry-sponsored, randomized, double-blind, placebo-controlled, parallel-group clinical study of isotretinoin 5 mg/day in the treatment of low-grade adult acne for 16 weeks followed by an open-label phase of 16 weeks. Group 1 received 32 weeks of 5 mg isotretinoin/day; Group 2 first received 16 weeks of placebo, followed by 16 weeks open-label 5 mg isotretinoin/day. Patients were followed for a further 10 weeks off treatment. The primary end-point was the difference in acne lesion count and disability score after 16 weeks isotretinoin compared to placebo. Secondary end-points included differences in these counts/scores after 32 weeks of isotretinoin compared to baseline, and after 10 weeks off treatment, compared to end of treatment (week 32). RESULTS: There were highly significant differences (P < 0.0001) in acne lesion count, Dermatology Life Quality Index and self-assessment after 16 weeks of isotretinoin, compared to placebo (both per protocol and intention to treat). Acne lesions fell significantly, within 4 weeks of 5 mg isotretinoin/day (Group 1) and continued to fall during 32 weeks of treatment [acne lesion count (mean ± SD): 11.3 ± 8.1 (baseline), 3.6 ± 5.5 (week 16), 1.3 ± 3.1 (week 32), P < 0.0001)]. There was a similar significant reduction in acne lesion count in Group 2, but only from week 20, 4 weeks after starting open-label 5 mg isotretinoin. Adverse effects were minimal. CONCLUSIONS: Isotretinoin 5 mg/day is effective in reducing the number of acne lesions, and improving patients dermatologic quality of life, with minimal adverse effects.

A randomised trial of enteric-coated nutrient pellets to stimulate gastrointestinal peptide release and lower glycaemia in type 2 diabetes.

AIMS/HYPOTHESES: Glucagon-like peptide-1 (GLP-1), an important mediator of postprandial glycaemia, could potentially be stimulated by delivering small quantities of nutrient to a long length of distal gut. We aimed to determine whether enteric-coated pellets, releasing small amounts of lauric acid throughout the ileum and colon, could reduce glycaemic responses to meals in type 2 diabetes, associated with stimulation of GLP-1. METHODS: Eligible patients, who had type 2 diabetes controlled by diet or metformin, were each studied on two occasions in a hospital setting. After an overnight fast, patients consumed 5 g active pellets (47% lauric acid by weight) or placebo with breakfast (T = 0 min) and lunch (T = 240 min), in a crossover design with order randomised by the hospital pharmacy and allocation concealed by numbered containers. Patients and investigators making measurements were blinded to the intervention. Blood was sampled frequently for blood glucose (the primary outcome) and hormone assays. RESULTS: Eight patients were randomised (four to receive either intervention first), and all completed the study without adverse effects. Blood glucose was lower after breakfast (T = 0-240 min, area under the curve (AUC) 2,075 ± 368 vs 2,216 ± 163 mmol/l × min) and lunch (T = 240-480 min, AUC 1,916 ± 115 vs 2,088 ± 151 mmol/l × min) (p = 0.02 for each) after active pellets than after placebo. Plasma GLP-1 concentrations were higher after breakfast (p = 0.08) and lunch (p = 0.04) for active pellets. While there were no differences in insulin or glucose-dependent insulinotropic polypeptide concentrations, glucagon concentrations were higher after breakfast and lunch (p = 0.002 for each) for active pellets. CONCLUSIONS/INTERPRETATION: Delivering small amounts of nutrient to the ileum and colon can stimulate substantial endogenous GLP-1 release and attenuate postprandial glycaemia. This novel approach has therapeutic potential in type 2 diabetes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612000600842. FUNDING: The study was funded by Meyer Nutriceuticals.

Effects of variations in duodenal glucose load on glycaemic, insulin, and incretin responses in type 2 diabetes.

AIMS: Postprandial glucagon-like peptide-1 (GLP-1) secretion and the 'incretin effect' have been reported to be deficient in Type 2 diabetes, but most studies have not controlled for variations in the rate of gastric emptying. We evaluated blood glucose, and plasma insulin, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) responses to intraduodenal glucose in Type 2 diabetes, and compared these with data from healthy controls. METHODS: Eight males with well-controlled Type 2 diabetes, managed by diet alone, were studied on four occasions in single-blind, randomized order. Blood glucose, and plasma insulin, GLP-1, and GIP were measured during 120-min intraduodenal glucose infusions at 1 kcal/min (G1), 2 kcal/min (G2) and 4 kcal/min (G4) or saline control. RESULTS: Type 2 patients had higher basal (P < 0.0005) and incremental (P < 0.0005) blood glucose responses to G2 and G4, when compared with healthy controls. In both groups, the stimulation of insulin and GLP-1 by increasing glucose loads was not linear; responses to G1 and G2 were minimal, whereas responses to G4 were much greater (P < 0.005 for each) (incremental area under the GLP-1 curve 224 ± 65, 756 ± 331 and 2807 ± 473 pmol/l.min, respectively, in Type 2 patients and 373 ± 231, 505 ± 161 and 1742 ± 456 pmol/l.min, respectively, in healthy controls). The GLP-1 responses appeared comparable in the two groups. In both groups there was a load-dependent increase in plasma GIP with no difference between them. CONCLUSIONS: In patients with well-controlled Type 2 diabetes, blood glucose, insulin and GLP-1 responses are critically dependent on the small intestinal glucose load, and GLP-1 responses are not deficient.

Blood glucose concentration influences postprandial fullness in IDDM.

OBJECTIVE: Upper gastrointestinal (GI) symptoms and delayed gastric emptying both occur frequently in patients with long-standing IDDM, but the relationship between them is relatively weak. Recent studies in normal subjects have indicated that blood glucose concentration may increase the perception of sensations arising from the upper GI tract. The purpose of this study was to examine the relationships among postprandial fullness, the rate of gastric emptying, and blood glucose concentration in IDDM patients. RESEARCH DESIGN AND METHODS: We studied measurements of gastric emptying, blood glucose concentrations, cardiovascular autonomic nerve function, upper GI symptoms, and postprandial hunger and fullness in 40 IDDM patients (16 men, 24 women). ages 19-63 years. Gastric emptying of solids and liquids was measured scintigraphically, upper GI symptoms were measured by questionnaire immediately before ingestion of the test meal, and fullness and hunger were measured by visual analog scales every 15 min. Blood glucose concentrations were measured at -5, 30, 60, 90, and 120 min. RESULTS: Solid gastric emptying was delayed in 58% of the patients, and both solid and liquid gastric emptying were slower (P < 0.05) in women than in men. The score for upper GI symptoms was not significantly related to gastric emptying. In contrast, postprandial fullness, but not hunger, was related to the amount of solid (r = 0.36, P < 0.05) but not liquid in the stomach. Both before (r = 0.39, P < 0.05) and after (r = 0.47, P < 0.01) the meal, fullness was related to blood glucose concentration. Postprandial fullness was also related to autonomic nerve dysfunction (r = 0.39, P < 0.05). Multiple regression analysis confirmed that blood glucose concentration, the rate of solid gastric emptying, and autonomic nerve dysfunction were independent determinants of postprandial fullness, together accounting for 47% of the variance. CONCLUSIONS: These observations demonstrated that, in IDDM, postprandial fullness is influenced by blood glucose concentration, the rate of solid gastric emptying, and autonomic nerve function.

Predictors of delayed gastric emptying in diabetes.

OBJECTIVE: To define the predictors of the rate of gastric emptying in patients with diabetes. RESEARCH DESIGN AND METHODS: A total of 101 outpatients with diabetes (79 type 1 and 22 type 2) underwent measurements of gastric emptying of a solid/liquid meal (scintigraphy), upper gastrointestinal symptoms (questionnaire), glycemic control (blood glucose concentrations during gastric emptying measurement), and autonomic nerve function (cardiovascular reflexes). RESULTS: The gastric emptying of solid and/or liquid was delayed in 66 (65%) patients. Solid (retention at 100 min 64 +/- 3.2 vs. 50.2 +/- 3.6%, P < 0.005) and liquid (retention at 100 min 22.7 +/- 1.7 vs. 16.0 +/- 1.8%, P < 0.001) gastric emptying was slower in women than in men. Of all upper gastrointestinal symptoms (including nausea and vomiting), only abdominal bloating/fullness was associated with slower gastric emptying (P < 0.005). A multiple regression analysis demonstrated that both abdominal bloating/fullness and female sex were predictors of slower gastric emptying of both solids and liquids. CONCLUSIONS: We conclude that the presence of abdominal bloating/fullness but not any other upper gastrointestinal symptom is associated with diabetic gastroparesis and that gastric emptying is slower in diabetic women than in diabetic men.

Natural history of diabetic gastroparesis.

OBJECTIVE: The major aim of this study was to evaluate the prognosis of diabetic gastroparesis. RESEARCH DESIGN AND METHODS: Between 1984 and 1989, 86 outpatients with diabetes (66 type 1, 20 type 2; 40 male, 46 female) underwent assessment of solid and liquid gastric emptying and esophageal transit (by scintigraphy), gastrointestinal symptoms (by questionnaire), autonomic nerve function (by cardiovascular reflex tests), and glycemic control (by HbAlc and blood glucose concentrations during gastric emptying measurement). These patients were followed up in 1998. RESULTS: Of the 86 patients, solid gastric emptying (percentage of retention at 100 min) was delayed in 48 (56%) patients and liquid emptying (50% emptying time) was delayed in 24 (28%) patients. At follow-up in 1998, 62 patients were known to be alive, 21 had died, and 3 were lost to follow-up. In the group who had died, duration of diabetes (P = 0.048), score for autonomic neuropathy (P = 0.046), and esophageal transit (P = 0.032) were greater than in those patients who were alive, but there were no differences in gastric emptying between the two groups. Of the 83 patients who could be followed up, 32 of the 45 patients (71%) with delayed solid emptying and 18 of the 24 patients (75%) with delay in liquid emptying were alive. After adjustment for the effects of other factors that showed a relationship with the risk of dying, there was no significant relationship between either gastric emptying or esophageal transit and death. CONCLUSIONS: In this relatively large cohort of outpatients with diabetes, there was no evidence that gastroparesis was associated with a poor prognosis.

Effect of lipase inhibition on gastric emptying of, and the glycemic and incretin responses to, an oil/aqueous drink in type 2 diabetes mellitus.

This study examined the effects of the lipase inhibitor, orlistat, on gastric emptying of, and the glycemic and incretin hormone responses to, a drink containing oil and glucose components in patients with type 2 diabetes. Seven patients (aged 58 +/- 5 yr), managed by diet alone, consumed 60 ml olive oil (labeled with 20 MBq (99m)Tc-V-thiocyanate) and 300 ml water containing 75 g glucose (labeled with 6 MBq (67)Ga-EDTA), on two occasions, with and without 120 mg orlistat, positioned in the left lateral decubitus position with their back against a gamma camera. Venous blood samples, for measurement of blood glucose and plasma insulin, glucagon-like peptide-1 and glucose-dependent insulintropic polypeptide were obtained immediately before, and after, the drink. Gastric emptying of both oil (P < 0.001) and glucose (P < 0.0005) was faster after orlistat compared with control. Postprandial blood glucose (P < 0.001) and plasma insulin (P < 0.05) were substantially greater after orlistat compared with control. In contrast, plasma glucagon-like peptide-1 (P < 0.005) and glucose-dependent insulintropic polypeptide (P < 0.05) were less after orlistat. In conclusion, inhibition of fat digestion, by orlistat, may exacerbate postprandial glycemia, as a result of more rapid gastric emptying and a diminished incretin response.

Oral calcium suppresses biochemical markers of bone resorption in normal men.

Calcium supplementation decreases bone resorption and retards bone loss in women. There is little information about the effects of calcium supplementation in men. The effects of a 1-g oral calcium load at 0900 on bone-related biochemical variables were evaluated in 13 normal men (aged 51-70 y). Calcium administration was associated with increases in plasma ionized calcium (P < 0.001) and urinary calcium (P < 0.001), and a decrease in plasma parathyroid hormone (P < 0.001). There was a nonsignificant trend (r = -0.47, P = 0.11) for the decrease in plasma parathyroid hormone to be related to radiocalcium absorption. After the calcium load there were decreases in the urinary hydroxyproline-creatinine ratio from 11 +/- 1.1 to 7.9 +/- 0.6 (P < 0.01), the urinary deoxypyridinoline-creatinine ratio from 14.0 +/- 1.8 to 10.1 +/- 0.9 (P < 0.05), and the urinary pyridinoline-creatinine ratio from 52 +/- 5 to 40 +/- 3 (P < 0.01) between baseline and 6 h. There was no change in plasma osteocalcin. These observations indicate that a 1-g calcium load suppresses biochemical markers of bone resorption for > or = 6 h in normal men and support the concept that calcium supplementation may be useful in the prevention of bone loss in men.

Relations between calcium intake, calcitriol, polymorphisms of the vitamin D receptor gene, and calcium absorption in premenopausal women.

The relations between calcium absorption, dietary calcium intake, 1,25-dihydroxyvitamin D3 (calcitriol), and vitamin D receptor (VDR) gene polymorphisms were evaluated in 99 healthy women who were approaching menopause (mean age: 47 y, range: 43-53 y). Dietary calcium was assessed by food-frequency questionnaire and calcium absorption was measured by a single-isotope radiocalcium test. VDR alleles were classified according to the presence (b, t, a) or absence (B, T, A) of the BsmI, TaqI, and ApaI restriction enzyme cutting sites. Radiocalcium absorption was positively related to serum calcitriol (r = 0.23, P < 0.05) and inversely related to dietary calcium intake (r = -0.26, P < 0.01). There was, however, no significant relation (r = 0.10) between serum calcitriol concentrations and dietary calcium. Radiocalcium absorption was higher in the bbaaTT haplotype (P < 0.05) and the aa genotype (P < 0.05), polymorphisms said to be associated with a higher bone density. We conclude that serum calcitriol and dietary calcium are independent determinants of calcium absorption in premenopausal women and that VDR gene polymorphisms influence calcium absorption.

Interaction of insulin, glucagon-like peptide 1, gastric inhibitory polypeptide, and appetite in response to intraduodenal carbohydrate.

The relation between gastrointestinal incretin hormones in the control of insulin release and short-term satiety by intestinal carbohydrate was investigated in 8 fasted, healthy male volunteers. Insulin, gastric inhibitory polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and appetite ratings were measured during, and food intake was measured after, intraduodenal infusions of glucose or saline. Studies were conducted under hyperinsulinemic and euglycemic conditions. Raising plasma insulin with intravenous insulin infusion to concentrations slightly above usual postprandial concentrations (356.4 +/- 4.8 pmol/L) had no effect on GIP, GLP-1, or appetite ratings before the intraduodenal infusions began. Intraduodenal glucose infusion resulted in a further increase in plasma insulin to a peak of 779.4 +/- 114.0 pmol/L, caused an early increase in plasma GIP and a later increase in GLP-1 concentrations (P < 0.01), suppressed appetite (P < 0.05), and reduced energy intake (P < 0.01) compared with intraduodenal infusion of saline. There was a close association between the increase in GLP-1 and decrease in appetite. Infusion of octreotide to suppress the release of gastrointestinal hormones prevented the rise in insulin, GIP, and GLP-1 induced by intraduodenal glucose infusion and reversed the suppression of appetite and reduction in energy intake. These results suggest that 1) when infused to result in plasma concentrations slightly above usual postprandial concentrations, insulin does not inhibit its own release and 2) the effects of intraduodenal glucose on appetite may be mediated through the release of GLP-1 and not insulin.

Effects of age on concentrations of plasma cholecystokinin, glucagon-like peptide 1, and peptide YY and their relation to appetite and pyloric motility.

BACKGROUND: Aging is associated with a decrease in appetite and a slowing of gastric emptying. The gastrointestinal hormones cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), and peptide YY (PYY) may mediate these changes. OBJECTIVE: We investigated whether aging influenced the secretion of CCK, GLP-1, and PYY and their effects on appetite and pyloric motility. DESIGN: Eight healthy older (65-80 y) and 7 younger (20-34 y) men received isoenergetic (12.1 kJ/min) intraduodenal infusions of lipid and glucose for 120 min on separate days. Plasma CCK, GLP-1, and PYY concentrations were measured. RESULTS: Plasma CCK concentrations were higher in older than in younger subjects (P = 0.004) as a result of higher baseline values (4.7+/-0.2 compared with 3.2+/-0.2 pmol/L; P < 0.0001) and a greater rise during lipid infusion (increase from baseline: 7.1+/-0.5 compared with 5.3+/-0.6 pmol/L; P = 0.048). Plasma GLP-1 and PYY concentrations were not significantly different between groups. The decrease in hunger during intraduodenal lipid infusion was inversely related to the increase in CCK, GLP-1, and PYY in younger but not older subjects. During intraduodenal lipid infusion, the increase in isolated pyloric pressure wave (IPPW) frequency was positively related to GLP-1 and PYY and the increase in IPPW amplitude was positively related to CCK in older but not younger subjects, whereas the increase in IPPW amplitude and pyloric tone was negatively related to GLP-1 and PYY in younger subjects. CONCLUSIONS: Human aging is associated with increased CCK concentrations, which may contribute to the slowing of gastric emptying, mediated by increased pyloric motility. The role of increased plasma CCK concentrations in mediating the age-related decrease in appetite remains to be established.

The relation between bone density, free androgen index, and estradiol in men 60 to 70 years old.

The cause of age-related bone loss in men is poorly understood. Previous studies of the relationship between bone density and serum androgens have yielded inconsistent results, perhaps partly because age is a determinant of both. Recent studies suggest that serum estrogen levels influence bone density in adult men. In order to determine whether bone mineral density (BMD) and bone turnover are associated with serum sex steroids, we investigated 37 normal men within a narrow age range (60-70 years). Bone mineral density at the forearm, hip, and spine, testosterone, sex hormone binding globulin (SHBG), free androgen index (FAI:T/SHBG), estradiol (E), free estradiol index (FEI:E/SHBG), and markers of bone formation (alkaline phosphatase, osteocalcin, procollagen type I C-terminal extension peptide) and bone resorption (hydroxyproline/creatinine [OHPr/Cr], deoxypyridinoline/creatinine [Dpd/Cr], pyridinoline/creatinine, collagen type I cross-linked telopeptide) were measured. Bone mineral density was positively related (r > 0.35, p < 0.05 at all sites) to log FAI, whereas there was no significant relationship between BMD and either serum total testosterone, serum E, or FEI. Bone density at the spine and hip were inversely related to both OHPr/Cr (r > -0.41, p < 0.05 for all sites) and Dpd/Cr (r > -0.36, p < 0.05 for all sites). OHPr/Cr (r = -0.41, p < 0.05) and Dpd/Cr (r = -0.41, p < 0.05) were both inversely related to log FAI. We conclude that BMD and bone turnover in adult men are related to plasma free androgens.

Effects of erythromycin on gastric emptying, alcohol absorption and small intestinal transit in normal subjects.

The effects of erythromycin on gastric emptying and intragastric distribution of a mixed solid/liquid meal, alcohol absorption and small intestinal transit were examined in eight male volunteers. Each subject received, in double-blind randomized order, either erythromycin as the lactobionate (3 mg.kg-1 i.v. over 20 min) or saline immediately before the consumption of a radioisotopically labeled test meal, which consisted of 330 g minced beef and 400 ml of orange juice containing ethanol (0.5 g.kg-1 body weight) and 10 g lactulose. Erythromycin increased the rate of total stomach emptying and proximal stomach emptying of both the solid and liquid components of the meal (p < 0.001), but slowed small intestinal transit (p < 0.01). Peak blood alcohol concentrations (p < 0.01) were higher after erythromycin, with a mean increase of 40%. There was a significant inverse relationship between peak blood alcohol concentrations and the 50% emptying time for the liquid component of the meal after saline (r = -0.70, p < 0.05), but not after erythromycin (r = -0.57, p < 0.1). The total area under the venous blood alcohol concentration time curve (i.e., total absorption) was greater (p < 0.01) after erythromycin. These results suggest that: faster emptying from the proximal stomach contributes to more rapid gastric emptying induced by erythromycin, erythromycin retards small intestinal transit and that erythromycin increases the total amount of alcohol absorbed as well as the rate of alcohol absorption. These latter effects are likely to reflect more rapid delivery of alcohol to the small intestine and reduced metabolism of alcohol by the gastric mucosa.

Gastric emptying in early noninsulin-dependent diabetes mellitus.

UNLABELLED: The aims of this study were to determine in early noninsulin-dependent diabetes mellitus (NIDDM): (a) the prevalence of disordered gastric emptying of glucose; (b) the relationship between the blood glucose response to an oral glucose load and gastric emptying; and (c) the relationship between appetite and gastric emptying. METHODS: Sixteen patients (ages 39-79 yr) with recently diagnosed NIDDM consumed 350 ml water containing 75 g glucose and 99mTc-sulfur colloid while sitting in front of a gamma camera. Blood glucose concentrations were monitored immediately before and after the drink. Hunger and fullness were evaluated using visual analog scales. The results were compared to those obtained in 13 normal subjects of similar age and body mass index. All patients and control subjects were white and non-Hispanic. RESULTS: Gastric emptying was slightly slower in the NIDDM patients when compared to the control subjects (retention at 180 min 15.9 +/- 2.3% versus 3.8 +/- 1.0%, p < 0.001), but there was no significant difference in the 50% emptying time between the two groups. In the NIDDM patients, there was an inverse relationship between the magnitude of the increase in the blood glucose concentration and gastric emptying, e.g., between the area under the curve for blood glucose from 0-60 min and the intragastric retention of the drink at 60 min (r = -0.60, p < 0.05). In the NIDDM patients, fullness was greater (p < 0.005) both before and after the drink, and the score for hunger at 30 min was inversely related to the rate of gastric emptying (r = -0.52, p < 0.05). CONCLUSION: In patients with early NIDDM, gastric emptying of 75 g glucose is similar to that of normal subjects and is a significant determinant of the glycemic response.

Modification and validation of a single-isotope radiocalcium absorption test.

UNLABELLED: This study was done to establish and allow for the influence of body weight on plasma radioactivity after administering radiocalcium to measure calcium absorption. METHODS: We administered 5 microCi 45Ca in 20 mg of calcium carrier in 250 ml distilled water to 103 premenopausal volunteers over the age of 40 yr, after an overnight fast. Venous blood was withdrawn when the dose was given (to serve as a blank) and exactly 60 min later, and the counts were determined in a liquid scintillation counter. After the exclusion of three outliers, the fraction of the administered dose per liter of plasma at 60 min was a curvilinear inverse function of body weight and a positive linear function of the reciprocal of body weight, with an r value of 0.45 (p < 0.001). This latter relationship then was used to correct the plasma radioactivity to a standard body weight of 65 kg, in which the volume of distribution of the dose was assumed to be 10 liters. This yielded the estimated fraction of the dose circulating at 1 hr, which then was converted into a fractional absorption rate from our previously published equation. RESULTS: In the 100 volunteers, the mean value of the radiocalcium absorption rate (termed alpha2, to distinguish it from our original calculation) was 0.75/hr, with 98 of the 100 values falling between 0.30 and 1.20. The value alpha2 was significantly related to serum calcitriol in these 100 volunteers (r = 0.29; p = 0.003) and in 89 normal postmenopausal women (r = 0.46; p < 0.001). It also was significantly related to the 24-hr urine calcium in the same 89 women (r = 0.48; p < 0.001) and to net calcium absorption corrected for intake in balance studies on another 103 postmenopausal women (r = 0.44; p < 0.001). In most respects, alpha2 was marginally superior to alpha1 but, unlike alpha1, was independent of body weight. CONCLUSION: The modified low-carrier radiocalcium absorption test is a valid indicator of calcium absorption status over a wide range of calcium intakes and is independent of body weight.

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.

The effect of chlorothiazide on bone-related biochemical variables in normal post-menopausal women.

OBJECTIVE: To evaluate the effects of short-term administration of chlorothiazide on fasting urinary hydroxyproline, an index of bone resorption, and other bone-related biochemical parameters in normal post-menopausal women. DESIGN: Subjects served as their own control before and after chlorothiazide treatment. SETTING: Subjects were recruited by advertisement. PARTICIPANTS: Thirteen healthy post-menopausal women with a mean age of 65 years. INTERVENTION: Each subject was given chlorothiazide 500 mg bd po for 7 days. Fasting blood and urine samples were obtained immediately before the commencement of chlorothiazide (day 1) and 2 and 7 days after starting chlorothiazide. RESULTS: Chlorothiazide decreased the urinary calcium/creatinine (mean value day 1, 0.267; day 2, 0.143; day 7, 0.135; P < 0.001) and hydroxyproline/creatinine (day 1, 0.0192; day 2, 0.0145; day 7, 0.0139; P < 0.02) molar ratios. CONCLUSION: Chlorothiazide decreases fasting urinary hydroxyproline, a marker of bone resorption in post-menopausal women. This observation supports a potential role for thiazide diuretics in the prevention of osteoporosis. The observed fall in urinary hydroxyproline is of the same order as that seen after treatment with estrogen or calcium supplements.

Bone density and bone-related biochemical variables in normal men: a longitudinal study.

BACKGROUND: The objective of this study was to determine the pattern of forearm bone loss and its relationship to markers of bone turnover and sex steroids in normal men. This was a longitudinal study over a median interval of 41 months. The study was conducted in Adelaide, Australia. Study participants were 123 healthy male subjects, between the ages of 20 and 83 years. METHODS: Fat-corrected forearm bone mineral content (fcBMC), markers of bone formation (alkaline phosphatase, osteocalcin, procollagen type 1 C-terminal extension peptide) and bone resorption (collagen type I cross-linked telopeptide, hydroxyproline/creatinine, pyridinoline/creatinine, and deoxypyridinoline/creatinine), calculated serum bioavailable testosterone, and serum estradiol were measured. RESULTS: The mean time-weighted rate of change in forearm fcBMC was -0.33% +/- 0.72 (SD) per year. Bone loss commenced after 30 years of age and increased with age (p <.001), particularly after age 70 years. There was no relationship between the rate of change in fcBMC and either markers of bone turnover or serum sex steroids. CONCLUSIONS: In normal men, bone loss increases with age; there does not appear to be any relationship between this loss and either markers of bone turnover or levels of free androgen or estrogen.

Relation between gastric emptying of glucose and plasma concentrations of glucagon-like peptide-1.

Glucagon-like peptide-1 (GLP-1) may play a role in regulating gastric emptying. The aim of this study was to determine the relationship between gastric emptying of glucose and plasma concentrations of GLP-1. Gastric emptying of 75 g of glucose dissolved in 350 ml of water was measured by the use of scintigraphy in 12 normal volunteers. Venous blood samples for measurement of GLP-1 were obtained immediately before and for 180 min after ingestion of glucose. Plasma GLP-1 rose rapidly from a baseline of 8.5 +/- 1.2 pmol/l to 14.3 +/- 1.3 pmol/l at 10 min (p = 0.024), with a peak of 19.2 +/- 3.0 pmol/l at 30 min (p = 0.0006) after the glucose drink. The rate of gastric emptying was inversely related to the early rise in GLP-1, e.g., the 50% emptying time was related to the change in GLP-1 from baseline at 10 min (r = 0.57; p < 0.05). We conclude that there is an inverse relationship between gastric emptying of glucose and plasma GLP-1. This observation is consistent with the concept that GLP-1 is a determinant of, rather than determined by, the rate of gastric emptying.

Relation between calcium absorption and serum calcitriol in normal men: evidence for age-related intestinal resistance to calcitriol.

OBJECTIVE: To obtain information on the causes of age-related bone loss in men and the concomitant decline in calcium absorption. DESIGN: Cross-sectional study. SETTING: Adelaide, South Australia, Australia. SUBJECTS: A total of 95 healthy, Caucasian men (age range 27-87 y). RESULTS: Calcium absorption declined with age (r=-0.46, P<0.0001), as did 24-h urine calcium, phosphate and creatinine (r>-0.21, P<0.05 for all); serum calcitriol and 25 hydroxyvitamin D did not change with age. Calcium absorption was related to serum calcitriol (r=0.20, P=0.05). An inverse relation between the residual deviations in calcium absorption, after allowing for its dependence on calcitriol, and age (F=5.4, P<0.005) was observed. The 24-h urinary calcium, phosphate and creatinine were all related to calcium absorption (r>0.41, P<0.0001). Forearm bone density fell with age (r=-0.45, P<0.0001) but was not related to calcium absorption, or markers of bone turnover. CONCLUSIONS: In healthy Caucasian males (i) calcium absorption falls, but serum calcitriol does not change with age, (ii) the relation between calcium absorption and serum calcitriol changes with age, indicative of an intestinal resistance to calcitriol and (iii) calcium absorption is a significant determinant of 24-h urinary calcium excretion.