Prolactin and thyrotropin responses to thyrotropin-releasing hormone and metoclopramide in men with chronic alcoholism.

To investigate whether anterior pituitary function is disturbed in chronic alcoholic men after a period of alcoholic abuse, TSH and PRL secretagogues were given to such patients in the acute and late withdrawal states (1 and 8 days after admission to hospital, respectively). The TSH and PRL responses were compared with those obtained in a group of control patients without a history of alcohol abuse. Twenty five micrograms of TRH, injected iv in six alcoholic men during acute withdrawal, raised TSH by 1.6 +/- 0.8 (SEM) microU/ml and PRL by 18 +/- 7 ng/ml. In the seven control patients the corresponding responses were significantly larger (7.8 +/- 1.4 microU/ml, P less than 0.01; and 56 +/- 10 ng/ml, P less than 0.02, respectively). When the alcoholics were reinvestigated in the late withdrawal state their TSH and PRL responses increased significantly to 2.9 +/- 1.1 microU/ml (P less than 0.05) and 41 +/- 9 ng/ml (P less than 0.05), respectively. To determine whether dopaminergic inhibition contributed to the reduced TSH and PRL responsiveness in the acute withdrawal state, six additional chronic alcoholic men were tested with oral metoclopramide. This drug, which has dopamine D2-receptor blocking properties, induced similar PRL responses (7- to 8-fold PRL increments) in the acute and late withdrawal states but did not alter TSH. Furthermore, TRH, injected 90 min after oral priming with metoclopramide in six additional alcoholics, elicited TSH and PRL increments in the acute withdrawal state which did not differ significantly from those obtained in the late withdrawal state (TSH, 3.5 +/- 0.9 vs. 4.1 +/- 1.2 microU/ml; PRL, 27 +/- 3 vs. 24 +/- 6 ng/ml). These findings suggest that dopaminergic inhibition of the thyrotrophs and lactotrophs may be responsible for the blunted TSH and PRL responses to TRH during the acute withdrawal period in chronic alcoholic patients.

The influence of indomethacin, theophylline, and propranolol on ethanol augmentation of glucose-induced insulin secretion.

The effect of indomethacin, theophylline, and propranolol on ethanol augmentation of insulin secretion after intravenous glucose stimulation was studied. Intravenous glucose tolerance tests were performed with and without pretreatment with oral ethanol. The role of indomethacin was evaluated in six healthy subjects; the effect of theophylline and propranolol on ethanol augmentation in insulin secretion was studied in five and six subjects, respectively. Ethanol pretreatment was followed by increased insulin (P < .01) and C-peptide areas (P < .01) after intravenous glucose (Area, 0 to 20 minutes). Indomethacin suppressed the ability of ethanol to augment insulin (P < .01) and C-peptide (P < .01) responses. Neither theophylline nor propranolol affected ethanol augmentation of insulin secretion. In conclusion, indomethacin probably interferes with the mechanism for ethanol augmentation of glucose-induced insulin secretion. It is suggested that inositol phospholipids take part in the effect of ethanol to augment insulin secretion, and that indomethacin interferes with the metabolism of inositol phospholipids.

Insulin uptake by the human alcoholic cirrhotic liver.

Insulin uptake by the human cirrhotic liver was studied in six patients with Laennec's cirrhosis, and the result was compared with that found in ten control patients with varying diseases affecting the biliary system. All patients had portal catheters for diagnostic purposes. The fractional hepatic uptake of insulin was calculated from the clearance rates for insulin obtained after a constant rate infusion into a peripheral vein and the portal vein in each patient. The fractional hepatic extraction of insulin was 13% +/- 5 in cirrhotic patients and differed significantly from the fractional hepatic extraction found in controls (51% +/- 5;P less than 0.001).

Inhibition of melatonin secretion by ethanol in man.

To determine whether ethanol inhibits nocturnal melatonin (MT) secretion, three experiments (A, B, and C) were performed in seven normal subjects. In A, ethanol at a dose of 0.34 g/kg was administered orally at 6:00, 8:00, and 10:00 PM. Each dose was increased to 0.52 g/kg in B. In C, water was substituted for ethanol. Blood samples for determination of serum MT levels were drawn every second hour between 6:00 PM and 8:00 AM. Urinary excretion of MT during the night was also determined. In A, serum ethanol reached a maximal level of 13 +/- 1 mmol/L at 12 midnight. In B, the corresponding maximum was 25 +/- 1 mmol/L. The higher alcohol dose inhibited nocturnal MT secretion by 20% +/- 5% (P < .01), whereas the lower dose lacked such effect. Urinary excretion of MT was left unaffected by alcohol at both doses. Five additional normal subjects were given alcohol as described above at a dose of 0.52 g/kg (experiment D). This induced mild nocturnal hypoglycemia as evidenced by a glucose decremental area (5.9 +/- 1.8 mmol/L.h) that differed significantly from zero (P < .05). To determine whether a reduced glucose delivery to pinealocytes might contribute to the decreased MT secretion in alcohol-intoxicated subjects, two experiments (E and F) were performed in eight healthy individuals. In E, ethanol was given orally as in B; three small oral doses of glucose were also given at 8:00 PM, 10:00 PM, and 12 midnight. In F, water was substituted for ethanol and glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of naloxone, atropine, and metoclopramide on ethanol augmentation of insulin secretion after intravenous glucose stimulation.

The effect of naloxone (opiate antagonist), atropine (muscarinic antagonist), and metoclopramide (dopamine antagonist) upon ethanol augmentation of insulin secretion after intravenous glucose stimulation was studied in 19 young healthy subjects. Intravenous glucose tolerance tests were performed with and without pretreatment with oral ethanol. The effect of naloxone, atropine, and metoclopramide on insulin secretion was investigated in six, six, and seven subjects, respectively. Ethanol pretreatment was followed by increased insulin (p less than 0.001) and C-peptide areas (p less than 0.01) after intravenous glucose (0-10 min), indicating that ethanol augments insulin secretion. Neither antagonism with naloxone nor with atropine or metoclopramide was able to suppress the ethanol augmentation of insulin secretion. The decline in glucagon concentration normally seen after intravenous glucose administration was partially prevented by ethanol pretreatment.

The ethanol augmentation of glucose-induced insulin secretion is abolished by calcium antagonism with nifedipine: no evidence for a role of glucagon-like peptide-1 (GLP-1).

We studied the effect of ethanol and calcium antagonism (nifedipine) on insulin- (n = 8) and glucagon-like peptide-1 (GLP-1) (n = 6) secretion in healthy subjects. Four experiments in random order were performed (control, ethanol, nifedipine, and combination). Intravenous glucose tolerance tests were performed with and without pretreatment with oral ethanol and nifedipine. Ethanol pretreatment was followed by increased insulin (ethanol vs. control; p < 0.01) and C-peptide (ethanol vs. control; p < 0.05) areas after intravenous glucose (0-20 min), indicating that ethanol augments insulin secretion. Calcium antagonism with nifedipine abolished the ethanol augmentation of insulin secretion (insulin area 0-20 min, ethanol vs. combination, p < 0.05; and C-peptide area 0-20 min, ethanol vs. combination, p < 0.01). The GLP-1 response (area 0-90 min) was not significantly affected by ethanol.

Biological responses of sheep treated with endotoxin-contaminated superoxide dismutase and endotoxin preparations.

The purpose of this study was to evaluate the biological response of sheep to different doses of endotoxin and endotoxin-contaminated enzyme preparations. The enzyme used in this experiment was superoxide dismutase (SOD), as it is currently being used in many different experiments and because several preparations were found to be heavily contaminated with endotoxin. A group of ewes were injected intravenously with a variety of different treatments. Peripheral blood was used to determine the total number of leukocytes, a differential cell count to find out the numbers of polymorphonucleocytes (PMN) and monocytes (M), and to measure the concentration of 15-ketodihydro-PGF2 alpha. In addition, rectal temperature was recorded. Treatments included saline (control), Pharmacia-Chiron's Cu/Zn-SOD (r-hSOD, 8 mg/kg), Sigma's bovine SOD (bSOD, 8 mg/kg), Grünenthal's bSOD (8 mg/kg), various doses of Salmonella typhimurium endotoxin (1000, 200, 100, 50, 20, 10, 5, and 1 ng/kg), and a mixture of endotoxin (200 ng/kg) plus r-hSOD (8 mg/kg). Results indicate that sheep react to endotoxin-contaminated SOD preparations with an endotoxemia which is similar to that seen in animals receiving endotoxin alone. This endotoxemia includes, among other things, a rise in rectal temperature, a peak in the PGF2 alpha metabolite, and an increased PMN/M ratio. Endotoxin administered at doses of 50 to 200 ng/kg also caused the expected signs of endotoxemia. At 1000 ng/kg endotoxin actually led to a decreased rectal temperature. This may be due to a type of endotoxemic shock, resulting in a decrease in peripheral blood circulation. Low doses of endotoxin (10, 5, and 1 ng/kg) caused a leukocytosis via increases in PMN; no greater changes in rectal temperature or the PGF2 alpha metabolite were noted. The combination of r-hSOD with 200 ng/kg of endotoxin caused an endotoxemia similar to that caused by 200 ng/kg of endotoxin alone. In conclusion, if an endotoxin-contaminated SOD-preparation was used to study the efficacy of SOD, there would be a serious risk of interaction by the endotoxins. In such a case it would be impossible to distinguish the effects of the endotoxin from those of the preparation itself. It is therefore important that researchers are alert to the problem of endotoxin contamination.

Primary hyperparathyroidism in pregnancy: a diagnostic and therapeutic challenge.

The risk of severe complications arising from primary hyperparathyroidism (pHPT) is increased during pregnancy. Gestational pHPT often goes undiagnosed, and by the time it is diagnosed, a majority of women have endured one or more failed pregnancies. During pregnancy, active transport of calcium ions from the mother to the fetus leads to suppression of the fetal parathyroids. When the prenatal pool of calcium is depleted, the newborn may develop neonatal hypocalcemic tetany. The mother, in turn, may suffer from worsening hypercalcemia and a hypercalcemic crisis after delivery. Awareness and confirmation of the diagnosis may be crucial for the outcome. The only definitive treatment of pHPT is parathyroidectomy, which should be recommended in most cases. Our two cases illustrate both the importance of and the difficulty in detecting pHPT during pregnancy, as well as some of the serious complications that may occur during pregnancy and after delivery.

Insulin sensitivity in alcoholics in a withdrawal state.

Insulin sensitivity in non-diabetic alcoholics in a withdrawal state was investigated using a euglycaemic clamp technique on two occasions with an interval of 1 week. Insulin was infused at a rate of 40 mU m-2 min-1 (n = 9) and 20 mU m-2 min-1 (n = 9). Hepatic glucose production was estimated with tritiated glucose in six subjects. The fasting glucose level at the first examination, 5.1 +/- 0.2 mmol l-1, exceeded that found at the second examination, 4.7 +/- 0.1 mmol l-1 (P less than 0.05), although the C-peptide concentration was higher at the first examination (2.7 +/- 0.3 vs. 1.6 +/- 0.2 ng ml-1; P less than 0.001). Both glucose uptake (5.0 +/- 0.6 vs 6.2 +/- 0.7 mg kg-1 min-1; P less than 0.05) and tissue sensitivity (M/I; 0.08 +/- 0.02 vs. 0.1 +/- 0.02 mg kg-1 min-1/mU l-1; P less than 0.05) increased between the first and second euglycaemic clamp (40 mU m-2 min-1). At the low insulin infusion rate (20 mU m-2 min-1), the tissue sensitivity to insulin increased (0.09 +/- 0.01 vs. 0.13 +/- 0.02 mg kg-1 min-1/mU l-1; P less than 0.05). Hepatic glucose production did not change during the examination period (2.2 +/- 0.2 vs. 2.3 +/- 0.1 mg kg-1 min-1), neither was there a change in the suppression of hepatic glucose output during hyperinsulinaemia (40 mU m-2 min-1). Our findings indicate that, in non-diabetic alcoholics, insulin sensitivity in peripheral tissues is decreased during the early part of a withdrawal period.

Insulin secretion in alcoholics in a withdrawal state.

Insulin secretion was studied after stimulation with oral glucose and intravenous glucagon in 23 chronic alcoholics in a withdrawal state. Each subject was studied twice at one week's interval between the examinations. The insulin and C-peptide responses to glucagon were lower in the early withdrawal state. Moreover, the insulin and C-peptide increments were, when related to the magnitude of the glycemic stimulus, lower in the early than in the late withdrawal state. The fasting values of blood glucose, insulin and C-peptide and the blood glucose and C-peptide levels after oral glucose were higher in the early withdrawal state. These findings indicate that glucose metabolism in alcoholics in a withdrawal state can be disturbed by impaired insulin secretion and insulin resistance.

Insulin effect in chronic alcoholics during alcohol withdrawal.

Insulin effect was investigated in 20 chronic alcoholics by use of an insulin and glucose infusion which suppressed endogenous insulin secretion. It was found that the effect of insulin was lower during the first week than the second week of alcohol withdrawal.

Persons with insulin-dependent diabetes mellitus: acceptance and coping ability.

AIMS: The purposes of this study were to describe how persons with insulin-dependent diabetes mellitus (IDDM) accept their disease and what sense of coherence they have, in order to determine whether a person's acceptance of the disease is related to his or her sense of coherence. Whether acceptance of the disease and sense of coherence are related to the disease duration, complications of the disease, metabolic control and demographic data would also be determined. DESIGN: One hundred and seven, randomly selected, insulin-dependent, diabetic subjects (47 men and 60 women) participated in the study. The Acceptance of Disability Scale Modified (ADM scale), the Sense of Coherence Scale (SOC scale), a study-specific questionnaire and the patients records were used to collect the data. BACKGROUND: IDDM implies a major change in way of life. Ingrained procedures and patterns of behaviour must be adapted to the disease and its treatment. RESULTS: The results of the present study show that educational level seems to be an important factor for how well a person accepts the disease and the sense of coherence. Persons with higher scores on the ADM and the SOC scales had higher levels of education. Moreover, they also had a better metabolic control. Individuals with a poor metabolic control had more disease-related complications. A significant correlation between the ADM and the SOC scores was found, indicating that persons with a high degree of acceptance of the IDDM also had a high coping capability. CONCLUSIONS: It is important to individualize the care of subjects with IDDM and to identify the persons with low acceptance of their disease and a low sense of coherence.

Use of two-dimensional gas chromatography with electron-capture detection for the measurement of lipopolysaccharides in peritoneal fluid and plasma from rats with induced peritonitis.

The content of 3-hydroxymyristic acid from Escherichia coli lipopolysaccharide in peritoneal fluid and plasma from rats was determined by two-dimensional gas chromatography with electron-capture detection of the 3-O-pentafluorobenzoyl methyl ester derivative. The detection limit of lipopolysaccharide in peritoneal fluid was 3 ng/ml. An experimental model of E. coli peritonitis in the rat was used, with and without coinjection of bile. The concentrations of lipopolysaccharide were highest in both peritoneal fluid and plasma samples from rats injected with E. coli and bile, reaching a maximum 1 h after injection by the gas chromatographic method. Corresponding Limulus assay results for peritoneal samples showed a small increase of lipopolysaccharide concentrations during the first 4 h after injection, followed by a substantial increase. The results indicate that bile salts cause an increased release of lipopolysaccharide from gram-negative bacterial cells in vivo and that this may be responsible for the high mortality caused by peritonitis. In contrast to the Limulus assay, gas chromatography enables the total amount of lipopolysaccharide in a clinical sample to be determined.

Collaborative study of a control standard endotoxin using the Limulus amebocyte (gel-clot) test.

A collaborative study was undertaken to determine the potency in endotoxin Units (EU) and International Units (IU) of a control standard endotoxin, LIF-1. Five laboratories from the Swedish Pharmaceutical Industry participated in the study. As reference preparations, two official standards, USP reference standard endotoxin, EC-5 (expressed in EU) and WHOs international standard endotoxin (expressed in IU), were used. The study was performed using the Limulus Amebocyte Lysate (LAL), gel-clot test. The test protocol included dilutions of the endotoxin in steps of 1:1.25 instead of the conventional 1:2 step dilution method. This gave more precise and standardized results. The content of one vial of LIF-1 (CSE) was calculated to be 22 EU and 16 IU which indicates that 1 EU (USP) corresponds to 0.7 IU (WHO).

Pharmacokinetics of human tick-borne encephalitis virus antibody levels after injection with human tick-borne encephalitis immunoglobulin, solvent/detergent treated, FSME-BULIN S/D in healthy volunteers.

This study assessed tick-borne encephalitis virus (TBEV) neutralizing antibody levels after injection of FSME-BULIN S/D (human tick-borne encephalitis immunoglobulin; 0.2 ml/kg body weight) in healthy volunteers. After screening of 18 volunteers for TBEV antibody titers, 12 healthy volunteers with TBEV antibody titers < 5 were entered into the pharmacokinetic part of the study. TBEV antibody titers were analyzed before injection and after 24 h, 48 h, 3 d, 4 d and 8 d. Vital signs, adverse events and laboratory tests for safety were analyzed after intramuscular injection with the immunoglobulin at 4 sites in the gluteal muscles. Injection with 0.2 ml/kg of FSME-BULIN S/D induced a fast increase in, and sustained titers of, neutralizing antibody levels against TBEV. The injections were well tolerated and the safety profile of the product was fully acceptable.

Tetanus antibody levels of female volunteers after injection with solvent/detergent-treated human tetanus immunoglobulin (Tetabulin S/D).

BACKGROUND AND OBJECTIVES: The aim of this study was to analyse the increase of antitetanus titre in volunteers following injection with human tetanus immunoglobulin (HTI). MATERIALS AND METHODS: Twelve females with tetanus antibody titres of < or = 0.05 international units (IU)/ml were injected with 500 IU of human tetanus immunoglobulin (Tetabulin S/D). The tetanus antibody titres were determined before injection, and after 30 h, 48 h and 4 days. RESULTS: A fast and sustained increase of protective tetanus antibody levels was observed in 10 of 12 volunteers. No adverse events related to the study drug were reported. CONCLUSIONS: HTI confers rapid and effective immunity to tetanus.

Prandial subcutaneous injections of glucagon-like peptide-1 cause weight loss in obese human subjects.

Recombinant glucagon-like peptide-1 (7-36)amide (rGLP-1) was recently shown to cause significant weight loss in type 2 diabetics when administered for 6 weeks as a continuous subcutaneous infusion. The mechanisms responsible for the weight loss are not clarified. In the present study, rGLP-1 was given for 5 d by prandial subcutaneous injections (PSI) (76 nmol 30 min before meals, four times daily; a total of 302.4 nmol/24 h) or by continuous subcutaneous infusion (CSI) (12.7 nmol/h; a total of 304.8 nmol/24 h). This was performed in nineteen healthy obese subjects (mean age 44.2 (sem 2.5) years; BMI 39.0 (sem 1.2) kg/m(2)) in a prospective randomised, double-blind, placebo-controlled, cross-over study. Compared with the placebo, rGLP-1 administered as PSI and by CSI generated a 15 % reduction in mean food intake per meal (P=0.02) after 5 d treatment. A weight loss of 0.55 (sem 0.2) kg (P<0.05) was registered after 5 d with PSI of rGLP-1. Gastric emptying rate was reduced during both PSI (P<0.001) and CSI (P<0.05) treatment, but more rapidly and to a greater extent with PSI of rGLP-1. To conclude, a 5 d treatment of rGLP-1 at high doses by PSI, but not CSI, promptly slowed gastric emptying as a probable mechanism of action of increased satiety, decreased hunger and, hence, reduced food intake with an ensuing weight loss.

Antidiabetogenic action of glucagon-like peptide-1 related to administration relative to meal intake in subjects with type 2 diabetes.

OBJECTIVE: To establish the antidiabetogenic effect of glucagon-like peptide-1 (GLP-1) when differently administered relative to meal intake in subjects with type 2 diabetes. DESIGN: The study was a placebo-controlled comparison with random assignment to treatment sequence. A 3-h stepwise infusion of GLP-1 (17 nmol) was started either at the onset of a standard meal (550 kCal) (A) or at 30 min (B) or 60 min (C) after the start of the meal. SETTING: The study was conducted at a university hospital. SUBJECTS: Eight patients with type 2 diabetes (four women and four men), age 62 +/- 3.9 years (range 47-74 years), weight 79.8 +/- 5.4 kg (range 62-104 kg), BMI 26.2 +/- 1.3 kg m(-2) (range 21-31 kg m(-2)), diabetes duration 10.5 +/- 2.0 years (range 3-19 years) and HbA1c levels 6.1 +/- 0.3% (range 4.7-7.7%) participated in the study. All patients were treated with oral sulphonylureas. RESULTS: Glucagon-like peptide-1 significantly lowered postprandial glycaemia by a similar degree in all three situations versus the control meal (P < 0.05). Postprandial insulin levels were not different in the four experimental series, whereas the postprandial glucagon levels were significantly lowered by GLP-1 in (A) and (B) (P < 0.03) but not in (C). Gastric emptying, as determined by the paracetamol test, was retarded by GLP-1 only in (A) (P < 0.01), but not affected in (B) or (C). CONCLUSIONS: GLP-1 reduced postprandial hyperglycaemia in subjects with type 2 diabetes regardless of administration at the onset of meal intake or at 30 or 60 min after start of meal intake, although the mechanism of the antidiabetogenic action of GLP-1 depended on administration versus meal intake. Thus, when administered at the start of a meal, GLP-1 was antidiabetogenic mainly through retarding gastric emptying, whereas when given at 30 or 60 min after meal ingestion, changes in islet hormone secretion seem to be predominant.