Neopterin derivatives to activate NF-kappa B.
Explore the source record for details and available documents.
Biopterins↗
Biomedical subjects
G Hoffmann
Publications and source records attributed to G Hoffmann.
Effect of inhaled nitric oxide on endotoxin-induced hypoxaemia in rabbits.
In five mechanically ventilated rabbits, we studied the property of inhaled nitric oxide in helping to treat hypoxaemia which was induced by intravenous endotoxin (Escherichia coli-derived lipopolysaccharide, serotype 0111: B4). We used measurements of arterial partial pressure of oxygen to check a therapeutic nitric oxide benefit. Pulmonary artery pressure was continuously monitored. Furthermore, we determined the single-breath diffusing capacity for nitric oxide. Measurements of plasma nitrite/nitrate concentration served as an indicator of endogenous nitric oxide output. The first infusion of endotoxin led to a transient pulmonary vasoconstriction, whereas arterial partial pressure of oxygen was permanently reduced by 30 +/- 10 mmHg (mean +/- SD), attaining minimal values of 48 +/- 3.4 mmHg due to additional endotoxin. Single-breath diffusing capacity for nitric oxide declined by 20 +/- 5.5% of baseline values until the experiments were concluded. Endotoxin induced an increase in plasma nitrite/nitrate concentration in the five rabbits as well as in the control animals (four rabbits) without exogenous nitric oxide supply. During the 25 inhalations of nitric oxide (3-50 ppm), arterial oxygenation did not change significantly. Thus endotoxin permanently impaired pulmonary gas exchange without inducing pulmonary hypertension. Inhaled nitric oxide did not improve arterial oxygenation during endotoxaemia.
Administration, Inhalation↗
On the problems of switching from intravenous to oral administration in drug treatment of endogenous depression--a placebo-controlled double-blind trial with doxepin.
In the treatment of depressive disorders the onset of action can be accelerated if the antidepressant drug is initially administered by intravenous infusion. It is not clear whether this effect is due to pharmacological or to psychological effects of the infusion setting. The necessary switch to oral administration may be problematic. Uncontrolled observations indicate that it could be associated with a remarkable deterioration in the course of the disease. This randomized double-blind placebo-controlled study on doxepin is the first investigation of the effect of the switch from parenteral to oral administration on symptoms of endogenous depression. The hypothesis to be tested, that there is a significant worsening of treatment response during the switch, must be rejected on the basis of objective and subjective psychometric tests. There was in fact a continuous improvement. Precondition was a selection of patients with typical "endogenous" depressions and maintenance of at least constant plasma levels of the active antidepressants. In patients under the age of 65 years this can generally be achieved by switching in a ratio of 125 mg i.v. to 250 per os in the case of doxepin. Individual case studies indicated that a worsening in the patient's progress after switching was correlated with a decreasing plasma level of the active drug. Low plasma level already during the infusion period, insufficient response, and questionable compliance on oral medication were associated. Due to large interindividual differences of plasma levels by a factor of 10, measurements before and after switching are required.
Administration, Oral↗
Nitric oxide donors inhibit spontaneous depolarizations by L-type Ca2+ currents in alveolar epithelial cells.
L2 cells, a cloned pneumocyte-derived cell line, express voltage-dependent L-type Ca2+ channels, causing transient depolarizing spikes of the membrane potential (Vm) [P. Dietl, T. Haller, B. Wirleitner, H. Völkl, F. Friedrich, and J. Striessing. Am. J. Physiol. 269 (Lung Cell. Mol. Physiol. 13): L873-L883, 1995]. In this study, we examined the effect of nitric oxide (NO)- and guanosine 3',5'-cyclic monophosphate (cGMP)-dependent cell signaling on the activity of L-type Ca2+ channels. Using conventional microelectrodes, spontaneous depolarizations (SD) of Vm by activation of these channels are regularly seen in the presence of 10 mM bath Sr2+. The NO donors sodium nitroprusside (SNP; 1 mM), 3-morpholinosydnonimine (SIN-1; 100 microM), as well as S-nitroso-N-acetyl-D,L-penicillamine (SNAP; 10 microM) caused a significant reduction of the frequency of Sr(2+)-induced SD. These effects were completely reversed by 6-anilino-5,8-quinolinequinone (10 microM), an inhibitor of the soluble guanylyl cyclase, and could be mimicked by 8-bromoguanosine 3'5'-cyclic monophosphate (8-BrcGMP; 100 microM). Perforated patch-clamp experiments revealed that 8-BrcGMP exerted a significant decrease of the depolarization-induced L-type Sr2+ current in the majority of tested cells. Consistent with the dependency of these NO-mediated effects on cGMP, incubation of L2 cells with SNP, SIN-1, and SNAP lead to a pronounced increase of cellular cGMP concentration. We conclude that the NO donors inhibit the activity of L-type Ca2+ channels in L2 cells via a cGMP-dependent pathway. In the alveoli, this might occur under conditions associated with the release of NO.
Aminoquinolines↗
Sleep anomalies in the chronic fatigue syndrome. A comorbidity study.
Polysomnographic findings were compared between a group of patients with the chronic fatigue syndrome (CFS; n = 49) and a matched healthy control (HC) group (n = 20). Sleep initiation and sleep maintenance disturbances were observed in the CFS group. The percentage of stage 4 was significantly lower in the CFS group. A discriminant analysis allowed a high level of correct classification of CFS subjects and HC. Sleep-onset latency and the number of stage shifts/hour contributed significantly to the discriminant function. The presence of these anomalies as well as the decrease in stage 4 sleep were not limited to the patients also diagnosed with fibromyalgia or with a psychiatric disorder. No association was found between sleep disorders and the degree of functional status impairment. The mean REM latency and the percentage of subjects with a shortened REM latency were similar in CFS and HC.
Adult↗
Sleep in detoxified alcoholics: impairment of most standard sleep parameters and increased risk for sleep apnea, but not for myoclonias--a controlled study.
OBJECTIVE: To assess recently alcohol-abstinent chronic alcoholic patients for selected parameters indicative of sleep quality. METHOD: Patients (n = 24, 14 male), abstinent 3-6 weeks, and healthy controls (n = 20) were admitted to a clinical sleep unit. Measurements included sleep respiratory events and periodic limb movements, using strict methodology. RESULTS: Clear signs of sleep deterioration and a high prevalence of apneic/hypopneic episodes were observed. Apneas were found at the same frequency for men and women; this has not been described before. No periodic limb movement was found. CONCLUSIONS: Considering the high degree of morbidity and mortality observed in sleep apneic syndrome, systematic screening for sleep apneas is recommended for alcoholics seeking help.
Adult↗
[Sleep apnea and nocturnal ventilatory assistance (nCPAP): 5-year experience in the conventional system].
The reimbursement of nasal continuous positive airway pressure (nCPAP) by the Belgian social security, via a conventional system, has made since 1991 this treatment available to an increasing number of patients having moderate to severe sleep apnoea hypopnoea syndrome (SAHS). We have reviewed our experience in prescribing domiciliary nCPAP from 1991 to 1995. Three hundred twenty-five subjects with SAHS, predominantly male (89%) and/or obese (77%) subjects, have benefited. Mean use of nCPAP machine, assessed by reading the time counter, amounted 4.7 h per 24 h, with only 23% of non-compliant patients (use < 3 h per 24 h). In 205 patients nCPAP was effective in controlling SAHS-related symptoms. Cure, with successful weaning from nCPAP, was obtained in 16 patients, as a result of marked weight loss in 13 of them. Forty-six non-compliant subjects were not allowed by the physician to go on, and 40 subjects left nCPAP because of intolerance. Finally, 10 patients abandoned nCPAP because of inefficacy, ascribed to some associated condition, being predominant, and 8 patients died. Our results suggest that domiciliary nCPAP is an effective treatment for SAHS in a majority of subjects, but that this kind of treatment is prescribed lifelong, unless there is a marked weight loss. The Belgian conventional system, as it requires a regular follow-up, contributes to keep non-compliance within acceptable limits.
Adult↗
Erythropoietin response is blunted in critically ill patients.
Explore the source record for details and available documents.
Critical Illness↗
Erythropoietin response and cytokines in critically ill patients.
Explore the source record for details and available documents.
Anemia, Iron-Deficiency↗
Genetic diversity in Proteus penneri.
DNA of thirteen Proteus penneri strains derived from four European countries (nine strains from Germany, two strains from United Kingdom, one strain from Turkey, one strain from Hungary) was examined by random amplified polymorphic DNA-PCR (RAPD-PCR) method. RAPD with primer AACGCGCAAC gave different patterns, which suggests a DNA sequence microdiversity within this species. The method provides a fast, economical and reproducible means for typing P. penneri.
Genetic Variation↗
Neopterin and 7,8-dihydroneopterin induce apoptosis in the rat alveolar epithelial cell line L2.
The neopterin derivatives, neopterin and 7,8-dihydroneopterin, modulate the cellular oxidant-antioxidant balance as well as the expression of the inducible nitric oxide synthase (iNOS) gene. Since apoptosis can be induced by reactive oxygen intermediates and nitric oxide (NO) we investigated whether these neopterin derivatives induce apoptotic cell death. As model we selected the rat alveolar epithelial cell line L2. 24 h incubation of neopterin (1-1000 microM) as well as 7,8-dihydroneopterin (1-1000 microM) resulted in a significant increase of percent apoptotic cells (measured by FACS analysis). Coincubation of both pteridines with the cytomix (interferon-gamma plus tumor necrosis factor-alpha) led to a significantly higher apoptosis than the cytomix alone. In contrast to the cytomix, no iNOS gene expression and no NO release could be detected after incubation with neopterin or 7,8-dihydroneopterin. We conclude that neopterin and 7,8-dihydroneopterin are per se inducers of apoptosis which is not mediated by nitric oxide. This may be of importance in inflammatory pulmonary diseases associated with an activation of the cellular immune system.
Animals↗
Neopterin activates transcription factor nuclear factor-kappa B in vascular smooth muscle cells.
We have previously shown that the pteridine compound neopterin stimulates inducible nitric oxide synthase (iNOS) gene expression in vascular smooth muscle cells in vitro. The mechanisms whereby neopterin exhibits these effects remained unclear. The present study demonstrates that neopterin induces the translocation of the transcription factor nuclear factor-kappa B (NF-kappa B) to the nucleus. Pretreatment of cells with the antioxidant pyrrolidine dithiocarbamate completely suppressed the effects of neopterin on NF-kappa B activation, iNOS gene expression, and nitric oxide release. From these data we conclude that neopterin activates the translocation of NF-kappa B subunits to the nucleus by modulating the intracellular redox state. This is one possible explanation for the impact of neopterin on iNOS gene expression.
Animals↗
Nitric oxide donors suppress erythropoietin production in vitro.
Many inflammatory diseases are associated with a hypoproliferative anaemia. Patients with this anaemia often present with serum erythropoietin (EPO) concentrations that are too low for the degree of their anaemia. Proinflammatory cytokines, in addition to their inhibitory effects on proliferation of erythroid progenitors, could contribute to the pathogenesis of this anaemia by reducing EPO production. Because several cytokines stimulate nitric oxide (NO) synthase we propose that nitric oxide might mediate the suppression of EPO production during inflammation. In order to test this hypothesis we investigated the effects of NO donors on 24-h hypoxia-induced EPO production in the hepatocellular carcinoma cell line HepG2. Following application of the NO donors sodium nitroprusside (SNP), 3-morpholinosydnonimine (SIN-1), and S-nitroso-N-acetyl-D,L-penicillamine (SNAP), EPO production was dose-dependently reduced: compared to the untreated control EPO production was lowered by 89% with SNP (1000 microM), by 66% with SIN-1 (1000 microM), and by 72% with SNAP (500 microM). In contrast, 8-bromo-cGMP did not inhibit EPO formation. Since pyrogallol (300 microM) and H2O2 (250 microM) showed a comparable suppression of EPO synthesis, we propose that NO might affect EPO production either by a similar direct influence on the cellular redox state or via increasing the cellular content of reactive oxygen species.
Carcinoma, Hepatocellular↗
[Circadian blood serotonin and melatonin level in anorexia nervosa patients in comparison with normally menstruating women].
Day and night rhythms of melatonin and serotonin were measured in four female anorexia nervosa patients and for comparison in a control group with normal 28-day menstrual cycle. In the anorexia nervosa group the levels of gonadotropins and sexual steroids were distinctly lowered. In the LHRH test the hormonal profile showed pubertal to prepubertal patterns of secretion with an only moderate increase of LH and distinct shifting of the LH/FSH ratio in direction of FSH. For both groups the 24-hour profiles of melatonin and serotonin showed a normal cycle, i.e. melatonin had its maximum by night, whereas serotonin in contrast displayed its highest values by day. However, in the group of patients with anorexia nervosa the maximum of melatonin was on the average 2.1 fold higher than that found in the control group, whereas that of serotonin was 1.4 fold higher. A close functional coherence between the neurotransmitters melatonin and serotonin and the hypothalamic secretion of LHRH is being discussed.
Adolescent↗
Cognitive functioning in patients with chronic fatigue syndrome.
A comprehensive battery of neuropsychological tests was administered to 35 outpatients suffering from Chronic Fatigue Syndrome (CFS). They were compared to 33 normal controls matched for age, gender, intelligence, and education. The patients displayed psychomotor slowing and impaired attention. The learning rate of verbal and visual material for patients with CFS was slower, and delayed recall of verbal and visual information was impaired. Because there was a high variability in cognitive impairment within the CFS group, it would be inappropriate to generalize results to the entire CFS population. Two neuropsychological variables indicating aspects of psychomotor performance and verbal memory were found to discriminate best between patients and controls.
Adult↗
[Long-term observations of the extent and reversibility of bone demineralization after leuprorelin acetate depot therapy].
Therapy of endometriosis with a GnRH-agonist (Leuprorelin) demonstrated a good therapeutical efficiency. As a side effect it had a significant negative impact on trabecular bone mass (non significant on cortical bone) as measured by DXA. Rising levels of Osteocalcin indicated the stimulation of bone remodelling. Three years after the end of the therapy a long term follow up control was able to detect the complete recovery of the mean density values in the extremities with even higher values in some patients compared with the initial measurement. In the spine half of the patients reached or surpassed the initial values. Regarding the patients history the differences in the recovery were obviously due to a different lifestyle especially body exercise, and not due to a different reaction to the GnRH-agonist therapy. Without being able to predict the individual bone loss due to a GnRH agonist therapy the results of this study indicate that the transient oestrogen deficiency does not result in a relevant long term bone loss or an elevated risk of osteoporosis. On the other hand in case of known risk factors or of a prolonged or repeated GnRH-agonist therapy the individual bone density and the individual bone loss should be controlled by DXA. Those patients with a significant negative impact on their bone mass then can be treated directly.
Adolescent↗
[Results of long-term follow-up in treatment of endometriosis with the GnRH agonist leuprorelin acetate depot (Enantone-Gyn monthly depot)].
In a previous study 198 patients with histologically confirmed endometriosis underwent a "three-step" therapy, where surgical removal of endometriosis implants was followed by a 6 months treatment with 3.75 mg leuprorelinacetate depot as monthly subcutaneous injections and a second look laparoscopy with removal of residuals. In the following report long-term follow-up data generated in 112 of the above 198 patients on the post-treatment effect in respect to symptoms and pregnancy outcome in infertility are reported. For this purpose a special questionnaire was used. The follow-up period was up to 60 months with a median time of 33.5 months. Out of 112 patients 91 complained of infertility. 43 out of these 91 (47.3 %) became pregnant during the follow-up period, resulting in 55 pregnancies and 36 newborns. More than half of these patients conceived spontaneously, whereas in the rest stimulation programs became necessary. Recurrence of dysmenorrhoea, dyspareunia and pelvic pain was defined as recurrence of disease. During the follow-up period 70/112 (62.5 %) of the patients complained recurrence of symptoms with median first onset at 11 months. In two third symptoms were still less severe than at admission and classified as mild and moderate. The r-AFS score at first and second look laparoscopy did not differ in patients with and without recurrence of disease (p = 0.311 and 0.750). Only 28.6 % (20/70) of patients required an additional medical or surgical treatment. A subgroup of 51 patients could be evaluated in respect to quality of life and improvement of subjective conditions. Regain of quality of life and improvement of subjective conditions were reported in 54.9 % (28/51) and 52.9 % (27/51) respectively. The study results suggest that although the physiological effects of leuprorelin acetate treatment as suppression of ovarian function is rapidly reversible, the therapeutic effects linger, as evidenced by ongoing reduction of symptoms from baseline, leaving many patients asymptomatic or much improved longer than 1 year after treatment has ended. Besides long term relief and/or sustained reduction in symptom severity, the high pregnancy rate in infertility, as well as regain of quality of life and well being favour this therapeutic approach in endometriosis.
Adult↗
[Isolated respiratory insufficiency in Arnold-Chiari malformation].
We report on a 45-year old woman with daytime sleepiness, polycythemia, hypoxemia and hypercapnia, admitted to hospital on three occasions in a 10 month period for acute respiratory failure. Polysomnography demonstrated apneas of central type, testing of the respiratory drive suggested central alveolar hypoventilation and magnetic resonance imaging showed an Arnold-Chiari malformation with syringomyelia. The originality of this case is the absence of any neurologic sign, respiratory failure being the sole manifestation of the Arnold-Chiari malformation.
Acute Disease↗