Search PubMed⌕ Search

Biomedical subjects

R Landgraf

Publications and source records attributed to R Landgraf.

At least 91 records · Page 5Linked to original sources
PubMed2000

Pharmacological characterisation of cortical gamma-aminobutyric acid type A (GABAA) receptors in two Wistar rat lines selectively bred for high and low anxiety-related behaviour.

Two Wistar rat lines that have been selectively bred for high-anxiety-related behaviour (HAB) and low-anxiety-related behaviour (LAB) in the elevated plusmaze test may be considered as a genetically prone animal model to study the neurochemical correlates of anxiety-related behaviour. Because there are pronounced differences between the two lines both in baseline levels of open-arm exploration in the elevated plus-maze test and in sensitivity to the anxiolytic effects of 1 mg/kg diazepam, we used these lines to investigate the pharmacology of the benzodiazepine binding site and the GABA binding site of cortical GABAA receptors. No difference in characteristics of flunitrazepam, zolpidem or muscimol binding to cortical GABAA receptors could be detected between the two lines. Although there was an increase in the brain concentration of the anxiolytic neuroactive steroid allopregnanolone, a potent positive allosteric modulator of GABAA receptors, both in HAB and LAB animals after a forced swim stress, allopregnanolone concentrations did not differ between the two lines. Moreover, plasma dehydroepiandrosterone (DHEA) concentrations were similar in HAB and LAB animals. We conclude that anxiety-related behaviour and benzodiazepine sensitivity in these rat lines are likely to be independent of the pharmacology of cortical GABAA receptors.

Animals↗
PubMed1999

Vasopressin selectively modulates the release of taurine within the septum of the rat brain.

Previous experiments have shown that arginine vasopressin (AVP) released within the septal brain area of adult male rats in response to defined stressor exposure is involved in emotionality-related behavior. We report here that a 10-min forced swimming session stimulated the release of glutamate, aspartate, arginine, gamma-aminobutyric acid (GABA) and taurine but not alanine and serine in the medio-lateral part of this brain structure. Local administration of the AVP V1 receptor antagonist d(CH2)5Tyr(Me)AVP by inverse microdialysis caused a significant increase in the concentration of taurine in microdialysates under resting conditions that was further potentiated during forced swimming. In contrast, the release of alanine, arginine, GABA and serine was unaffected by antagonist treatment. Taken together with previous data, our results suggest that the effects of intraseptally released AVP on stress-coping strategies might be mediated at least in part via its influence on the local release of taurine.

Animals↗
PubMed1999

A comparison of repaglinide and glibenclamide in the treatment of type 2 diabetic patients previously treated with sulphonylureas.

OBJECTIVE: To compare the efficacy and safety of repaglinide, a novel oral prandial glucose regulator, with that of glibenclamide, an oral hypoglycaemic agent, in the treatment of patients with type 2 diabetes. METHODS: This was a 14-week, double-blind, parallel-group trail in which a total of 195 type 2 diabetic patients treated with oral hypoglycaemic agents were randomized to receive either repaglinide, administered preprandially three times daily, or glibenclamide, given preprandially once or twice daily, as per manufacturer's recommendations. RESULTS: By the end of the study, the 2-h postprandial blood glucose values were lower in the repaglinide group than in the glibenclamide group, with the difference approaching statistical significance (repaglinide, 8.1 (0.6) mol x l(-1) vs glibenclamide, 9.1 (0.6)mmol x l(-1); P = 0.07). There was no statistically significant difference in the mean blood glucose level at the end of the study between the two groups (repaglinide, 7.1 (0.5) mmol x l(-1) vs glibenclamide, 7.4 (0.5) mmol x l(-1); P = 0.42), and baseline HbA1c values had decreased to the same degree in both the repaglinide [7.8% (0.1%) to 7.5% 0.1%)] and the glibenclamide groups [8.0 (0.1%) to 7.6 (0.1%)]. There are no significant differences between the repaglinide and glibenclamide treatment groups in the levels of fasting blood glucose, fructosamine, fasting C-peptide, insulin and proinsulin. Neither treatment group showed any clinically significant changes in blood lipid profiles. Repaglinide and glibenclamide were both well tolerated. No significant differences were observed between the two treatment groups with respect to adverse events, including hypoglycaemic episodes and weight change. No accumulation of repaglinide was apparent during the maintenance period. CONCLUSION: Repaglinide is as well tolerated as glibenclamide and is equally effective in the management of type 2 diabetes. Repaglinide may, however, offer an improvement in postprandial blood glucose control compared with glibenclamide, thereby helping to reduce the relative long-term risk of diabetic complications.

Blood Glucose↗
PubMed1999

Stress- and corticosteroid-induced modulation of the locomotor response to morphine in rats.

Stress alters the sensitivity to drugs of abuse and is, therefore, considered to be an important contributory factor to drug-seeking behaviour. There is only a limited amount of information available on stress-induced alterations in the behavioural response to opioids. We thus evaluated the influences of different stressors (restraint, handling, social defeat) on the locomotor effects induced by morphine. Further the importance of additional factors such as the number of stress events or the delay between stress and locomotor testing on stress-induced alterations were evaluated. Since these modulatory effects of stress on the locomotor effects of morphine might be mediated via the release of endogenous corticosteroids we also tested the influence of repeated intermittent and chronic administration of corticosterone (CORT) and the synthetic corticosteroid dexamethasone (DEX) on the locomotor response to morphine. Enhanced morphine-induced locomotor activity was observed in response to the repeated application (three times) of all stressors: restraint, handling and social defeat. An augmentation of the locomotor effects of a low (1 and 5 mg/kg) but not of a high dose (10 mg/kg) of morphine was seen after three, but not after one stress event. In addition, the repeated application of restraint stress (three times) resulted in an augmentation of morphine-induced locomotor stimulation 3 days, but not 1 or 10 days , after the last stress event. Similarly the repeated intermittent and chronic administration of corticosteroids, in particular of DEX, increased morphine's efficacy in stimulating locomotor activity. Our results show that stress is able to alter the locomotor stimulant effects of morphine in rats--a phenomenon called stress-induced behavioural sensitization. Moreover, these stress-induced alterations depend upon temporal factors such as number of stress events and the interval between stress and locomotor testing. Further, stress-induced CORT-release seems to be involved in stress-induced behavioural sensitization to morphine.

Adrenal Cortex Hormones↗
PubMed1999

Hyper-reactive hypothalamo-pituitary-adrenocortical axis in rats bred for high anxiety-related behaviour.

Psychiatric patients suffering from anxiety disorders or endogenous depression exhibit increased activity in their hypothalamo-pituitary-adrenocortical (HPA) axis. Recently, two Wistar rat lines, bred for high (HAB) and low (LAB) anxiety-related behaviour on the elevated plus-maze, were described as a unique psychopathological animal model (1). The present study focused on the HPA axis reactivity of HAB and LAB animals to an emotional stressor. Thus, adult male HAB and LAB animals, fitted with jugular vein catheters 5 days prior to the experiment, were exposed to an open arm of the elevated plus-maze for 5 min. Whereas basal levels of ACTH and corticosterone were similar in both lines, HAB rats showed higher plasma concentrations at 5 and 15 min following stressor exposure (both hormones and both time points: P<0.01 vs LAB). Furthermore, increased basal (P<0.05 vs LAB) and stimulated (P<0.01 vs LAB) prolactin concentrations in HAB rats were found. In contrast to ACTH, corticosterone and prolactin, plasma oxytocin and vasopressin levels did not differ between HAB and LAB animals; oxytocin, but not vasopressin, responding to open arm exposure with a significant increase in both lines (P<0.05). In conclusion, particularly due to the association between inborn anxiety and HPA axis hyper-reactivity, the HAB rat represents a promising animal model for further investigation of the relationship between emotional disturbance and neuroendocrine activity.

Adrenocorticotropic Hormone↗
PubMed1999

Emotional stress triggers intrahypothalamic but not peripheral release of oxytocin in male rats.

Previous experiments have shown that an exposure to defined stressors activates not only the 'classical' endocrine stress response but also the intrahypothalamic and peripheral release of oxytocin. In the present study we investigated the effects of an acute social defeat experience on the release of oxytocin within the hypothalamic supraoptic nucleus, just outside of the supraoptic nucleus toward the midline within the anterior ventro-lateral part of the hypothalamus, and into plasma of adult male rats. Our results demonstrate that emotional stress triggers the release of oxytocin into the extracellular fluid of both the supraoptic nucleus and the anterior ventro-lateral part of the hypothalamus (up to approximately 320% and 170%, respectively). Interestingly, oxytocin release within the latter brain area, which is likely to originate from axons forming the hypothalamo-neurohypophysial tract, was higher in absolute terms than that within the supraoptic nucleus itself, both under basal conditions and in response to social defeat. In contrast to intrahypothalamic release patterns, plasma oxytocin levels remained virtually unchanged upon stressor exposure. This demonstrates that the release of oxytocin within the hypothalamus is triggered by emotional stress. Furthermore, it indicates that under physiological conditions the release of oxytocin from the dendrites and somata upon axon terminals in the neurohypophysis is differentially regulated. Although not yet studied in detail, it may be hypothesized that the spatial and temporal release pattern of oxytocin is controlled by integrative neuronal networks at different brain levels (including hypothalamus and posterior pituitary) to ensure the appropriate involvement of this peptide in the stress response of the animal.

Aggression↗
PubMed1999

Vasopressin released within the septal brain area during swim stress modulates the behavioural stress response in rats.

The aim of the present study was to investigate the physiological significance of the neuropeptide arginine vasopressin (AVP) released within the septum, in the behavioural response of rats to stress. In the first experiment, rats were chronically implanted with a microdialysis probe aimed at the mediolateral or ventral septum to monitor the local release of AVP in response to 10 min of forced swimming in 20 degrees C warm water. Exposure to this stressor caused a significant increase in AVP release in both the mediolateral (174 +/- 21%, P < 0.01) and ventral septum (220 +/- 33%, P < 0.01). In contrast, microdialysates collected outside the mediolateral septum or in the lateral ventricle remained at prestress levels throughout the dialysis period. Furthermore, unstressed control animals failed to show significant alterations in vasopressin release in the mediolateral septum. In a second experiment, the introduction of the V1 receptor antagonist d(CH2)5Tyr(Me)AVP into the mediolateral septum via inverse microdialysis concomitant with stressor exposure caused the rats to spend an increased time floating and a reduced time swimming compared to vehicle-treated rats. This effect was acute and also detected 24 h after antagonist administration. Taken together, these findings demonstrate a significant activation of the septal vasopressinergic system in response to swim stress. Furthermore, our data support the view that AVP released within this brain area is involved in the generation of active behavioural strategies aimed at coping with new and challenging situations.

Adaptation, Psychological↗
PubMed1999

Screening of diabetic patients for microalbuminuria in primary care--The PROSIT-Project. Proteinuria Screening and Intervention.

The PROSIT (Proteinuria Screening and Intervention) Project started in 1993 in order to obtain data on the prevalence of micro- and macroalbuminuria in diabetic patients treated in primary care, to establish an easy screening programme for microalbuminuria, in which also diabetic patients can participate in self-responsibility, and to implement a specific intervention programme for incipient nephropathy. In 58 representative doctor's offices 647 diabetic patients were included, who performed at home self-tests for microalbuminuria on three days within one week using the early morning urine and a newly developed qualitative immunologic test-strip for microalbuminuria. After storage they returned the same urine samples to their doctors' offices for semiquantitative retesting with the immunologic test-strip Micral-Test II. In case of positive results the proteinuria dipstick Combur-9-Test was applied in order to exclude other causes of positive microalbuminuria (e.g. urinary tract infection). Data of 569 patients (6% Type 1, 88% Type 2 and 6% secondary diabetes) could be analysed. Both qualitative self-testing for microalbuminuria at home and semiquantitative retesting in doctors' offices were found to be feasible. Based on semiquantitative retesting the prevalences of microalbuminuria (macroalbuminuria) were 19.6% (0%) in Type 1 diabetes, 17.2% (10.8%) in Type 2 diabetes and 11.7% (7.8%) in secondary diabetes. Type 2 diabetic patients showed a clear correlation between albuminuria and diabetes duration, HbA1c, serum creatinine, triglycerides as well as micro- and macrovascular complications. 227 patients with micro- or macroalbuminuria were included into the ongoing PROSIT intervention programme.

Adult↗
PubMed1999

Approaches to the management of postprandial hyperglycaemia.

Increasing evidence suggests that tight metabolic control slows or prevents the development of diabetic complications. Various degrees of peripheral insulin resistance and inadequate glucose-induced insulin secretory profiles are seen in Type 2 diabetes. The main deficit in insulin release occurs early in the development of the disease and can be measured in association with meals, when the increase in meal-related insulin secretion is delayed and sluggish (first-peak/early-phase defect). The consequences of this are high postprandial blood glucose concentrations and overall loss of glycaemic control. Improved prandial glucose metabolism will lead to an overall improvement in glycaemic control. The new concept of prandial glucose regulation, aimed at improving or restoring meal-related insulin secretion, has led to the development of repaglinide, a carbamoylmethyl benzoic acid derivative, in the treatment of Type 2 diabetes. Patients treated with repaglinide using the concept 'one meal, one dose; no meal, no dose' experience improved insulin secretion, long-term metabolic control and quality of life and reduced postprandial hyperglycaemia. Treatment of Type 2 diabetes will be improved further through the use of combinations of drugs with different modes of action, which will prevent or reduce acute and chronic complications. New training programmes for physicians and patients must be developed to optimize the available pharmacological options for treating the extremely heterogeneous group of patients with Type 2 diabetes with a flexible oral therapeutic concept. An interdisciplinary approach to the care of these patients is urgently needed.

Diabetes Mellitus, Type 2↗
PubMed1999

Analysis of heregulin symmetry by weighted evolutionary tracing.

Heregulins are members of the protein family of EGF-like growth and differentiation factors. The primary cell-surface targets of heregulins are heterodimers of the EGF-receptor homolog HER2 with either HER3 or HER4. We used a weighted evolutionary trace analysis to identify structural features that distinguish the EGF-like domain (hrg) of heregulins from other members of the EGF family. In this analysis, each amino acid sequence is weighted according to its uniqueness and the variability in each position is assigned by an amino acid substitution matrix. Conserved residues in heregulin that are variable in other EGF-like domains are considered possible specificity-conferring residues. This analysis identifies two clusters of residues at the foot of the boot-shaped hrg domain. The residues in one cluster are recruited from the N-terminus; those in the other are from the ohm-loop region and show a weak sequence similarity to the N-terminal residues at the opposite side of the boot. The remaining residues with high conservation scores distribute themselves into these two distinct surfaces on hrg. This pseudo-twofold symmetry and the presence of two distinct interfaces may reflect the preference of hrg for heterodimeric versus homodimeric HER complexes.

Amino Acid Sequence↗
PubMed1999

Suppression of PGE(2) fever at near term: reduced thermogenesis but not enhanced vasopressin antipyresis.

Fevers are known to be suppressed near term in the mother, but the mechanism responsible for this phenomenon is not understood. We tested the hypothesis that the suppression of fever at term is a result of enhanced vasopressin-induced antipyresis. Effects of intracerebroventricular prostaglandin E(2) (PGE(2)) were examined in rats at gestational days 16-17 and 19-20 (near term) and days 1-2 postpartum. PGE(2) (50 ng) elevated body and interscapular brown adipose tissue (iBAT) temperatures and increased sympathetic nerve activity to the iBAT. PGE(2)-induced changes in iBAT temperature and nerve activity, as well as in rectal temperature, were reduced or eliminated near term, and responses were recovered in the postpartum period. Blood pressure and heart rate changes induced by central PGE(2) were also decreased at near term. Coinfusion of Manning compound, a V(1) vasopressin receptor antagonist, with PGE(2) throughout the peripartum period did not reverse the suppressed iBAT temperature and nerve activity or body temperature responses to PGE(2). Microdialysis experiments revealed unchanged terminal release of vasopressin in the ventral septal area after PGE(2) infusion in either pregnant or parturient rats. These results suggest that fever reduction at near term is not associated with enhanced vasopressin antipyresis, but may be a result of reduced sympathetic tone and in particular a reduced sympathetic drive to the iBAT. This finding may reflect a generalized reduction in autonomic output around the time of parturition.

Adipose Tissue, Brown↗
PubMed1999

A 1-year multicenter randomized double-blind comparison of repaglinide and glyburide for the treatment of type 2 diabetes. Dutch and German Repaglinide Study Group.

OBJECTIVE: Repaglinide is a newly developed oral blood glucose-lowering agent that exerts its effect by stimulating insulin secretion. This multicenter study was designed to compare the efficacy and safety of this drug with glyburide in a 1-year randomized double-blind study of outpatients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 424 subjects (154 women, 270 men) participated and had the following characteristics: age, 61 +/- 9 years; duration of diabetes. 8 years (range 0.5-35); BMI, 28.3 +/- 3.5 kg/m2; HbA1c, 7.1 +/- 1.4%; and fasting plasma glucose, 10.8 +/- 3.1 mmol/l. The majority of the subjects (91%) were previously treated with sulfonylurea, alone or in combination with metformin. The patients were randomized to a 2:1 ratio of repaglinide (0.5-4 mg t.i.d.) or glyburide (1.75-10.5 mg daily) treatment. The study protocol included a screening visit to assess patient eligibility; a titration period of 6-8 weeks, during which the dosages of repaglinide and glyburide were optimized; and a subsequent 12-month treatment period on fixed, optimal dosages. RESULTS: The trial was completed by 320 subjects, 211 (74%) in the repaglinide and 109 (78%) in the glyburide group. HbA1c initially decreased in both groups and then increased during the second half-year of the maintenance period to a similar extent in the repaglinide and glyburide subjects (0.58 and 0.45% vs. at screening, respectively). In the small group of subjects who previously controlled their condition with diet only (n = 37), a sustained improvement of metabolic control could be observed with both drugs, which was slightly better with glyburide than with repaglinide (theta HbA1c -2.4 vs. -1.0%; P < 0.05). The same trends were seen with fasting plasma glucose. There were no changes in serum lipids. Over the course of the study, 15% of the repaglinide-treated and 13% of glyburide-treated subjects withdrew due to adverse events, mostly hyperglycemia. No differences in adverse events between both drugs were reported. There were no differences in incidences of hypoglycemia. CONCLUSIONS: Repaglinide is a safe and efficacious oral blood glucose-lowering agent, with a potency similar to that of glyburide. Its rapid onset of action and hepatic clearance allows meal-related administration, including in subjects with impaired kidney function.

Adult↗
PubMed1999

Use of insulin lispro in continuous subcutaneous insulin infusion treatment. Results of a multicenter trial. German Humalog-CSII Study Group.

OBJECTIVE: Insulin lispro is an analog of human insulin with a faster onset and a shorter duration of action than regular human insulin. Efficacy and tolerability of insulin lispro in continuous subcutaneous insulin infusion (CSII) treatment were assessed in an open randomized crossover trial comparing insulin lispro and regular human insulin, both applied with insulin pumps. RESEARCH DESIGN AND METHODS: A total of 113 type 1 patients (60 male, 53 female, age [mean +/- SD] 37 +/- 12 years, duration of diabetes 19 +/- 9 years) participated in this open, randomized crossover study. Both insulins were applied for 4 months each with the appropriate intervals between the prandial insulin bolus and the meal (human insulin: 30 min; lispro: 0 min). Observation parameters were HbA1c, daily and postprandial blood glucose profiles, adverse events, rate of hypoglycemic and hyperglycemic events, number of catheter obstructions, and treatment satisfaction as assessed with an international validated questionnaire. RESULTS: The patients were well controlled with a mean HBA1c of 7.24 +/- 1.0% at baseline. HbA1c decreased in both treatment periods, but it was better during insulin lispro treatment (insulin lispro: 6.8 +/- 0.9%, regular human insulin: 6.9 +/- 1.0%, Friedman's rank-sum test: P < 0.02). In addition, the 1-h and 2-h postprandial rises in blood glucose were significantly lower (P < 0.001 for each meal) with insulin lispro, resulting in smoother daily glucose profiles as compared with regular human insulin. No significant differences were reported for the rate of hypoglycemia (mean +/- SD [median]: insulin lispro 12.4 +/- 13.9 [8], regular human insulin 11.0 +/- 11.2 [8]), for the rate of catheter obstructions (42 events in each treatment arm), and for the number and type of adverse events. No severe case of ketoacidosis was seen during insulin lispro treatment, whereas one case was reported during therapy with regular human insulin. Treatment satisfaction was better when patients were treated with insulin lispro. CONCLUSIONS: Insulin lispro is a suitable and very convenient pump insulin that may result in an improvement of long-term glucose control during CSII treatment. Its safety profile does not differ from that of regular human insulin.

Adult↗
PubMed1999

Gastrointestinal involvement in patients with diabetes mellitus: Part I (first of two parts). Epidemiology, pathophysiology, clinical findings.

In patients with type 1 or type 2 diabetes mellitus disturbances of the gastrointestinal transit are well recognized. In decreasing order of frequency, transit disturbance through the colon, stomach, small intestine and esophagus as well as altered motility of the gallbladder occur. Acute changes of blood glucose concentrations have a major, however, reversible influence on motility in various parts of the intestinal tract. Long-term hyperglycemia may influence the incidence of gastrointestinal involvement via the occurrence of neuropathic changes of the autonomic nervous system. Early satiety, nausea, vomiting, weight loss, constipation, diarrhea and epigastric pain are often reported. These symptoms and recurrent episodes of hypoglycemia or prolonged hyperglycemia can result from intestinal transit disturbances.

Autonomic Nervous System↗
PubMed1999

Gastrointestinal involvement in patients with diabetes mellitus: Part II (second of two parts). Diagnostic procedures, pharmacological and nonpharmacological therapy.

Diagnostic work-up in patients with diabetes mellitus, in whom gastrointestinal involvement is suspected comprises the assessment of gastrointestinal transit times, endoscopy, esophageal pH-metry or manometry, sonography and lactulose- or glucose-H2-breath tests. Prokinetic agents such as metoclopramide, cisapride or erythromycin and substances like loperamide, octreotide or clonidine are used to improve gastrointestinal dysfunction. Furthermore, in recent trials which aimed for the modulation of gastrointestinal transit times, cholecystokinin, proteinase inhibitors or amylin were administered in patients with diabetes mellitus. Nonpharmacological interventions include pancreas and kidney transplantation, gastric pacemakers and biofeedback training.

Diabetes Mellitus, Type 1↗
PubMed1998

Downregulation of brain mineralocorticoid and glucocorticoid receptor by antisense oligodeoxynucleotide treatment fails to alter spatial navigation in rats.

Adult male Brown Norway rats were long-term intracerebroventricularly (i.c.v.) infused with antisense oligodeoxynucleotides (18-mer, double endcapped phosphorothioate protected) targeting either mineralocorticoid or glucocorticoid receptor mRNA, or received the respective mixed bases sequence or vehicle. Mineralocorticoid receptor-mixed bases and glucocorticoid receptor-mixed bases oligodeoxynucleotide infusion (1 microg/0.5 microl/h) over a time period of seven days did not alter hippocampal mineralocorticoid receptor and glucocorticoid receptor binding when compared to vehicle treatment. In contrast, i.c.v. administration of mineralocorticoid receptor, as well as glucocorticoid receptor-antisense over the same time period resulted in a significantly reduced binding of mineralocorticoid receptor and glucocorticoid receptor in the hippocampus [mineralocorticoid receptor-antisense group approx. 72% of mineralocorticoid receptor-mixed bases and vehicle groups (100%); glucocorticoid receptor antisense group approx. 77% of glucocorticoid receptor-mixed bases and vehicle]. The specificity of these antisense effects is indicated by the finding that rats treated with mineralocorticoid receptor-antisense did not show any changes in glucocorticoid receptor and vice versa. Animals treated according to this infusion protocol and tested in the Morris water maze for their spatial navigation abilities failed to show significant differences among the groups. These data indicate that a reduction of hippocampal mineralocorticoid receptor or glucocorticoid receptor binding capacity by 20-30% does not interfere with spatial navigation.

Animals↗