Biomedical subjects

B Ebert

Publications and source records attributed to B Ebert.

At least 73 records · Page 4Linked to original sources

PubMed1995

Ketobemidone, methadone and pethidine are non-competitive N-methyl-D-aspartate (NMDA) antagonists in the rat cortex and spinal cord.

The opiate agonists, ketobemidone, methadone and pethidine, were evaluated as N-methyl-D-aspartate (NMDA) receptor antagonists using the rat cortical wedge preparation and the neonatal rat spinal cord preparation for electrophysiological studies and [3H](RS)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-im ine ([3H]MK-801) binding experiments using rat forebrain homogenates. Ketobemidone, methadone and pethidine were inhibitors of [3H]MK-801 binding with Ki values of 26 microM, 0.85 microM and 47 microM, respectively. In the cortex, 1 mM ketobemidone and 1 mM methadone reduced NMDA responses, but not (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA) or kainate responses in an use-dependent manner, whereas 1 mM pethidine was devoid of antagonist activity. In the spinal cord preparation, the activities of ketobemidone and methadone were weaker than in cortex. In contrast, pethidine was equipotent with ketobemidone in the spinal cord. These results suggest that ketobemidone and methadone may be useful therapeutic agents in conditions where a combined opiate agonist and NMDA antagonist treatment is desired.

Analgesics, Opioid↗

PubMed1995

[Quantification of variations in arm perfusion after plexus anesthesia with color doppler sonography].

The axillary brachial plexus block is a well-known technique for intra- and postoperative analgesia and sympathetic blockade in hand and microsurgery. The aim of this study was to show the influence of the axillary brachial plexus block on the blood flow as a side effect. METHODS. We used a colour-coded sonography unit (Toshiba) with a 7.5-MHz transducer. A total of 12 patients with no clinical signs of vascular diseases were enrolled in this study. We measured the peak blood flow velocity and the peak flow at the bifurcation of the brachial artery and vein and the proximal and distal radial artery before and after the plexus block. In addition, we were able to take the morphological aspects of the analysed vessels into consideration as we also used conventional sonography. This was done to detect any early signs of vascular malformation or arteriosclerosis, either of which might have affected the measurements. RESULTS. The average arterial peak blood flow after the plexus block was 1.9 times that before. On the venous side, the block effect caused an average increase of the blood flow to 8.6 times than before the block. In general, an additional and immediate effect of the block was a significant rise in blood flow velocity with an increase in cross-section area. CONCLUSIONS. The brachial plexus block combines two advantages: pain relief and pain management plus temporary sympathectomy. In conclusion, it prevents vasospasms and improves the circulation of the hand in patients undergoing reimplantation of limbs and those with nutritional disorders.

Adolescent↗

PubMed1995

Excitatory amino acid receptor ligands: asymmetric synthesis, absolute stereochemistry and pharmacology of (R)- and (S)-homoibotenic acid.

The (R)- and (S)-forms of 2-amino-3-(3-hydroxyisoxazol-5-yl)propionic acid (homoibotenic acid, HIBO) were synthesized, using (S)-BOC-phenylalanine as a chiral auxiliary and their absolute stereochemistry correlated with that of (R)-Br-HIBO. The enantiomeric excesses for (R)-HIBO (1) (> 99.5%) and (S)-HIBO (2) (99.5%) were determined using chiral HPLC. Whereas compounds 1 and 2 were equipotent inhibitors of the binding of [3H]glutamic acid in the presence of calcium chloride, 2 showed AMPA agonist activity and 1 very weak NMDA agonist activity.

Animals↗

PubMed1995

[Unilateral, paramedian spinal contusion after athletic injury with complete recovery].

The acute injury of the spinal column and the spinal cord asks for immediate diagnostic techniques and adequate therapeutical intensive care in order to secure the possibility of a maximum of neurologic recovery. An impact trauma of the spinal cord in sports accidents can cause an incomplete paraplegia. In some cases, morphologic lesions of the myelon cannot be detected. We present an exceptional and striking case of a 15-year old young woman who suffered from a contusio spinalis after high jump with the clinical signs of an incomplete, sensomotoric paraplegia which showed a strictly unilateral and paramedian border at the right side of her body for about two weeks. Additionally, the diagnostic possibilities of physical examination, magnetic resonance imaging, computed tomography and neurophysiologic diagnostic techniques in detecting spinal cord injuries are demonstrated.

Adolescent↗

PubMed1995

[Lyme borreliosis in hand surgery. A case report].

The clinical courses of Borrelia burgdorferi infections may show such variety, that diagnostic problems arise. On the other hand, early antibiotic therapy is necessary in order to prevent late-term complications. In this article, we present an exceptional case of a long-term documentation of Lyme-disease which was not diagnosed until an acrodermatitis chronica atrophicans had developed. Whether the manifestation of bilateral carpal tunnel syndrome is connected with Lyme borreliosis is yet to be clarified.

Acrodermatitis↗

PubMed1994

Synthesis and structure-activity studies on acidic amino acids and related diacids as NMDA receptor ligands.

The 3-isoxazolol amino acids (S)-2-amino-3-(3-hydroxy-5-methyl-4- isoxazolyl)propionic acid [(S)-AMPA, 2] and (R,S)-2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid (AMAA, 5a) (Figure 1) are potent and specific agonists at the AMPA and N-methyl-D-aspartic acid (NMDA) subtypes, respectively, of (S)-glutamic acid (1) receptors. A number of amino acids and diacids structurally related to AMAA were synthesized and tested electrophysiologically and in receptor-binding assays. The hydroxymethyl analogue 7c of AMAA was an NMDA agonist approximately equipotent with AMAA in the [3H]CPP-binding assay (IC50 = 7 +/- 3 microM) and electropharmacologically in the rat cortical wedge model (EC50 = 8 +/- 2 microM). In contrast to this, the tertbutyl analogue 7a of AMAA turned out to be an antagonist at NMDA and AMPA receptors. The conformational characteristics of AMAA and 7a, c were studied by molecular mechanics calculations. Compound 7a possesses extra steric bulk and shows significant restriction of conformational flexibility compared to AMAA and 7c, which may be determining factors for the observed differences in biological activity. Although the nitrogen atom of quinolinic acid (6) has very weak basic character, 6 is a, perhaps subtype-selective, NMDA receptor agonist and a potent neurotoxic agent. These aspects prompted us to synthesize and test the diacids 8a, b, in which the amino group of AMAA has been replaced by a methylthio and methoxy group, respectively. Neither compound showed significant affinity for nor depolarizing effects at NMDA receptors. The hydroxymethyl AMPA analogue 3c showed no interaction with NMDA receptors and only weak AMPA agonist effects.

Acetates↗

PubMed1994

Resolution, absolute stereochemistry, and pharmacology of the S-(+)- and R-(-)-isomers of the apparent partial AMPA receptor agonist (R,S)-2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid [(R,S)-APPA].

(R,S)-2-Amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid ((R,S)-APPA) is the only partial agonist at the (R,S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) subtype of excitatory amino acid receptors so far described. In light of the pharmacological interest in partial agonists, we have now accomplished the resolution of (R,S)-APPA. (S)-(+)-APPA (5) and (R)-(-)-APPA (6) were obtained in high enantiomeric purity using (R)-(+)- and (S)-(-)-1-phenylethylamine, respectively, as resolving agents. The absolute stereochemistry of 6 was established by X-ray analysis of 6.HCl.0.25H2O. Compounds 5 and 6 were tested electropharmacologically using the rat cortical wedge preparation and in receptor-binding assays using [3H]-AMPA, [3H]kainic acid, and the N-methyl-D-aspartic acid (NMDA) receptor ligands [3H]CPP, [3H]MK-801, and [3H]glycine. Whereas 6 did not significantly affect the binding of any of these ligands (IC50 > 100 microM), compound 5 revealed affinity for only the [3H]AMPA-binding site (IC50 = 6 microM). In electropharmacological tests, 5 showed full AMPA receptor agonism (EC50 = 230 microM). This effect of 5 was insensitive to the NMDA antagonist CPP but was inhibited competitively by the non-NMDA antagonist NBQX (pKi = 6.30). Compound 6, on the other hand, turned out to be a non-NMDA receptor antagonist, inhibiting competitively depolarizations induced by AMPA (pKi = 3.54), kainic acid (pKi = 3.07), and 5 (pKi = 3.57).

Alanine↗

PubMed1994

Molecular pharmacology of the AMPA agonist, (S)-2-amino-3-(3-hydroxy-5-phenyl-4-isoxazolyl)propionic acid [(S)-APPA] and the AMPA antagonist, (R)-APPA.

The heterocyclic analogue of (S)-glutamic acid, (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid [(S)-AMPA] is a potent and selective AMPA receptor agonist, whereas the enantiomeric compound, (R)-AMPA, is virtually inactive. We have previously characterized (RS)-2-amino-3-(3-hydroxy-5-phenyl-4-isoxazolyl)propionic acid [(RS)-APPA] as a partial AMPA receptor agonist showing about 60% of the efficacy of (RS)-AMPA. This partial agonism produced by (RS)-APPA is, however, only apparent, since resolution of (RS)-APPA has now been shown to provide the full AMPA receptor agonist, (S)-APPA, whereas (R)-APPA is a non-N-methyl-D-aspartic acid (non-NMDA) receptor antagonist showing preferential AMPA blocking effects. In agreement with classical theories for competitive interaction between agonists and antagonists, the efficacy of depolarizations produced by (S)-APPA in the rat cortical wedge preparation was shown to be progressively reduced with increasing molar ratios of (R)-APPA/(S)-APPA. These compounds and the competitive antagonists (RS)-2-amino-3-(3-carboxymethoxy-5-methyl-4-isoxazolyl)propionic acid [(RS)-AMOA], 6-cyano-7-nitroquinoxalin-2,3-dione (CNQX) and 6-nitro-7-sulfamoylbenzo(f)quinoxalin-2,3-dione (NBQX) were also tested in [3H]AMPA and [3H]CNQX binding systems, the latter ligand being used in the absence or presence of thiocyanate ions. On the basis of these studies it is suggested that (RS)-AMPA and the AMPA agonist (S)-APPA interact with a high-affinity receptor conformation, whereas the competitive antagonists (RS)-AMOA and (R)-APPA, derived from these agonists, preferentially bind to a low-affinity AMPA receptor conformation.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1994

Modulation of AMPA receptor function in relation to glutamatergic abnormalities in Alzheimer's disease.

Abnormalities in the excitatory glutamate neurotransmitter system appear to be a prominent factor in Alzheimer's disease (AD). Whereas hypoactivity of this system is observed in some areas of Alzheimer brains, hyperactivity may play a role in the degenerative processes in other brain areas. This apparently paradoxical situation makes therapeutic intervention in the glutamatergic system in AD difficult and demands the development of unique therapeutic approaches. The involvement of the (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) subtype of glutamate receptors in AD brain dysfunctions seems to be important, and compounds showing different modulatory activity at AMPA receptors are discussed in relation to therapeutic possibilities. Compounds enhancing excitatory activity at AMPA receptors may have beneficial effects on the learning and memory deficits observed in AD, whereas agents showing antagonistic or partial agonist profiles may block or delay the progressive neurodegeneration, which is a key phenomenon in AD. In vitro experiments with compounds capable of enhancing AMPA receptor activity have been performed. Such compounds without excitatory activity on their own may not show the excitotoxic properties characteristic of glutamate agonists. Another possibility for therapeutic intervention is the use of a partial agonist. The concept of "functional partial agonism" at the AMPA receptors is described with a specific example.

Alzheimer Disease↗

PubMed1994

[C-reactive protein as infection parameter in clinically suspected postoperative infection after trauma surgery and orthopedic interventions. 2].

Prospectively the levels of C-reactive protein (CRP) of 40 patients were studied twice within 6-12 hours in case of a suspected infection after different osteosynthetic and orthopedic procedures and compared with the levels of the erythrocyte sedimentation rate (ESR). 16 patients showed an increase of CRP in relation to a wound infection, hematoma or effusion in all but one case. 6 patients showed an increase of ESR, which also could be cleared in all but one case. Those patients with a proved wound infection demonstrated a CRP-rise in 8 cases, a CRP-plateau in 4 cases and no CRP-decrease. The same patients showed an ESR-rise in 3, an ESR-plateau in 7 and an ESR-decrease in even 2 cases. This study indicates that the determination of two CRP-levels with a short interval in case of a clinically suspected infection is another, meaningful criterion in making a decision for an operative revision.

Blood Sedimentation↗

PubMed1994

[Variability of the length and joint angle proportions of the distal radius].

The anatomical proportions of length and degree of joint-angles on the distal end of the radius and ulna show an wide variety in our population. 926 x-rays of "normal" and injured wrist-joints performed during 1984-89 were exactly measured and compared in respect to length and joint-angles of radius and ulna. Comparing the results with earlier reports in the literature it can be demonstrated that apparently there has been a remarkable change of the anatomical proportions in this region in the course of time and generations. The knowledge of the anatomical conditions is essential in acute traumatology as well as in corrections of posttraumatic wrist-deformities by osteotomy, bone grafting and internal fixation in regard to a posttraumatic restricted joint-function.

Adult↗

PubMed1994

Molecular pharmacology of gamma-aminobutyric acid type A receptor agonists and partial agonists in oocytes injected with different alpha, beta, and gamma receptor subunit combinations.

Using systematic combination of alpha 1, alpha 3, and alpha 5 with beta 1, beta 2, and beta 3, together with gamma 1, gamma 2, and gamma 3, we have investigated the contributions of the various alpha, beta, and gamma subunits to the pharmacology of gamma-aminobutyric acid (GABA)A agonists. We have characterized GABA, (RS)-dihydromuscimol, piperidine-4-sulfonic acid, and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol with recombinant human GABAA receptors expressed in Xenopus oocytes. Our observations indicate that the alpha subunit is the major determinant of efficacy for partial GABAA agonists. When alpha 1 and alpha 3 or alpha 1 and alpha 5 are coexpressed, the alpha 1 subunit determines the maximum efficacy, whereas the affinity is determined by the entire combination of subunits. Thus, the results of the present study demonstrate that the pharmacology of GABAA agonists is dependent on the subunit composition of the GABAA receptor complex. Functional GABAA receptors containing two different alpha subunits show pharmacological profiles distinctly different from those of receptors containing a single alpha subtype, indicating that two different alpha subunits can be coexpressed in one functional GABAA receptor complex.

Animals↗

PubMed1993

[Eponyms of distal radius fractures. Colles-Pouteau, Smith-Goyrand and Barton fractures and their importance in the trauma surgery patient sample].

Fractures at the distal end of the radius are quite common. So, these fractures are well known to represent consequences of industrial accidents leading to temporary unfitness for work, too. Eponym descriptions of fractures may mislead authors and readers as well if used in a non-uniform way in medical literature. Using the original articles of the first describing authors a clear distinction of eponyms concerning fractures near to the wrist joint is given. The authors of this feature report of the clinical experience in treatment and results of distal radius fractures in combination with aspects of expert opinions on these fractures.

Accidents, Occupational↗

PubMed1993

The non-depolarizing D-form of bromohomoibotenic acid enhances depolarizations evoked by the L-form or quisqualate.

The D-enantiomer of bromohomoibotenic acid (Br-HIBO) was inactive in electrophysiological experiments when administered alone, but enhanced depolarizations evoked by L-Br-HIBO or quisqualate when co-administered with these agonists. In addition, quisqualate induced a long-lasting (> 120 min) sensitization of cortical wedge neurons to D-Br-HIBO. This latter effect of D-Br-HIBO was similar to, but significantly more potent and selective, than the earlier observed quisqualate-induced sensitization of cortical neurones to depolarization by (S)-2-amino-4-phosphonobutyric acid (L-AP4).

Aminobutyrates↗

PubMed1993

Optimization of a recombinant von Willebrand factor fragment as an antagonist of the platelet glycoprotein Ib receptor.

The binding of von Willebrand factor (vWF) to platelet glycoprotein (GP) Ib receptor is one of the initial events in thrombus formation. Previous studies have shown that RG12986, a reduced and alkylated recombinant fragment of vWF (Ser445-Val733), can inhibit binding of native vWF to GP Ib and offers potential as an anti-thrombotic agent. We have now evaluated a series of deletion mutants of RG12986 and found that reduced and alkylated rvWF508-704 is close to the minimal sequence with optimal RG12986-like activity (IC50 for inhibition of GP Ib-dependent platelet aggregation in the absence of modulators: 0.022 microM +/- 0.01, n = 3) and that it too binds directly to GP Ib. Under in vitro conditions, with no exogenous modulators present and in the absence of shear stress, oxidized rvWF508-704 (containing a disulfide bond between Cys508 and Cys659) is approximately 5-fold less active than reduced and alkylated rvWF508-704; the two fragments, however, display comparable activity in the presence of the modulator botrocetin. The smaller rvWF508-704 fragment offers distinct advantages over RG 12986. In particular, removal of non-active NH2 and COOH terminal sequences may reduce the risk of antigenicity and may contribute to rendering the molecule mostly monomeric in solution, as opposed to the monomer-dimer equilibrium previously described for RG12986.

Chromatography, High Pressure Liquid↗

PubMed1993

Conformational aspects of the muscarinic receptor interactions of bicyclic isoxazole ester bioisosteres of arecoline.

3-Methoxy-4,5,6,7-tetrahydroisoxazolo [4,5-c]pyridine (O-Me-THPO) and O,5-di-Me-THPO are conformationally restricted bioisosteres of the muscarinic agonists norarecoline and arecoline, respectively, showing partial agonist effects at muscarinic acetylcholine receptors. The 7-membered ring analogue of O-Me-THPO, 3-methoxy-5,6,7,8-tetrahydro-4H-isoxazolo[4,5-c]azepine (O-Me-THAO), shows higher affinity for muscarinic receptor sites than O-Me-THPO or O,5-di-Me-THPO. Similarly, O-Et-THAO binds much more tightly to muscarinic receptor sites than its 6-membered ring analogues, O-Et-THPO and O-Et-5-Me-THPO. Based on receptor binding data, O-Me-THPO and O-Me-THAO, and O-Et-THPO and O-Et-THAO, respectively, show similar degrees of partial agonism. They also show similar relative affinities for muscarinic M1 and M2 receptor sites. Using the semiempirical quantum mechanics programme, AM1, and the molecular mechanics programme, SYBYL, we have studied the conformational flexibility of the O-alkyl-THPO and O-alkyl-THAO ring systems. As expected, the 7-membered ring of the latter system was shown to be markedly more flexible than the piperidine rings of O-alkyl-THPO analogues. On the basis of this analysis, a common pharmacophore for these two classes of compounds was constructed.

Arecoline↗

PubMed1992

Excitatory amino acid receptor ligands. Synthesis and biological activity of 3-isoxazolol amino acids structurally related to homoibotenic acid.

The 3-isoxazolol amino acid (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA, 2) and the isomeric compound (RS)-2-amino-3-(3-hydroxy-4-methylisoxazol-5-yl)propionic acid (4-methylhomoibotenic acid, 4a) are potent agonists at the AMPA subtype of central excitatory amino acid receptors. Using 4a as a lead structure, the amino acids 4c-e, in which the 4-methyl group of 4a is replaced by substituents of different size and polarity, were synthesized. Attempts to synthesize 4-(bromomethyl)homoibotenic acid (4f), a potential receptor alkylating agent, were unsuccessful. 4-Butylhomoibotenic acid (4c) and 4-(2-hydroxyethyl)homoibotenic acid (4e) were equipotent as inhibitors of [3H]AMPA binding (IC50 = 2 microM) and showed similar excitatory activity in the rat cortical slice preparation. 4d did not show significant affinity for AMPA receptor sites, but turned out to be a weak N-methyl-D-aspartic acid (NMDA) receptor antagonist. However, like 4c,e, 4d did not significantly affect the binding of the competitive NMDA antagonist, [3H]CPP, or the noncompetitive NMDA antagonist, [3H]MK-801. None of the amino acids 4c-e showed detectable affinity for [3H]kainic acid binding sites. Like the parent compound 4a (IC50 = 0.18 microM), 4c (IC50 = 0.18 microM), 4e (IC50 = 0.14 microM), and in particular 4d (IC50 = 0.02 microM) were effective inhibitors of calcium chloride-dependent [3H]glutamic acid binding, whereas AMPA is inactive (IC50 greater than 100 microM) in this binding assay. Thus, 4d is an effective and highly selective inhibitor of calcium chloride-dependent [3H]glutamic acid binding and may be a useful tool for studies of the physiological relevance and pharmacological importance of this binding affinity.

Animals↗

PubMed1991

Identification of a novel NMDA receptor in rat cerebellum.

Specific binding sites for the noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, [3H]MK-801, were identified in synaptic membranes isolated from rat cerebellum. The density of these sites (0.61 pmol/mg protein), derived from linear Scatchard plots, was lower than those measured in a number of forebrain regions (0.81-2.96 pmol/mg protein). The Kd value for cerebellar [3H]MK-801 binding sites (37.7 nM) was markedly higher than those (1.53-1.82 nM) detected in rat forebrain regions. Experiments were carried out in the presence of 30 microM L-glutamic acid and 1 microM glycine, and after a 210 min incubation [3H]MK-801 binding was maximally stimulated. The pharmacology of these cerebellar [3H]MK-801 binding sites was markedly different from that of [3H]MK-801 sites in the rat cortex. These data have highlighted a novel population of NMDA receptors, which are functionally coupled to an ion channel but exhibit remarkably weak affinity for MK-801.

Animals↗