Optimization of the use of collagenase in porcine islet isolation.
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Animals↗
Biomedical subjects
C Martini
Publications and source records attributed to C Martini.
1,2,3-Triazole[4,5-d]pyridazines--II. New derivatives tested on adenosine receptors.
This paper reports the synthesis and biological evaluation towards A1 and A2 adenosine receptors of new 1,2,3-triazole[4,5-d]pyridazines bearing lipophilic substituents in the 1 position. Some 1-benzyl-4-substituted amino derivatives were prepared and the cyclohexylamino-, anilino- and p-toluidino- derivatives showed an interesting moderately selective activity on the A1 receptor.
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N(6)-substituted 2-N-butyl-9-benzyl-8-azaadenines. Affinity for adenosine A1 and A2 receptors. IV.
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Adenine↗
N(6)-substituted 2-phenyl-9-benzyl-8-azaadenines. Affinity for adenosine A1 and A2 receptors. A comparison with 2-N-butyl analogous derivatives. V.
The title compounds were prepared to evaluate their affinity towards adenosine A1 and A2 receptors. Some 2-phenyl-N(6)-substituted-8-azadenines showed good binding properties and good A1 selectivity. The biological results allow us to confirm the presence in A1 receptors of a third lipophilic pocket, able to receive the substituent on N(9), and to evince increased affinity when a phenyl group on C(2) substitutes an n-butyl group. These affinity differences between analogous 2-n-butyl and 2-phenyl derivatives indicate that they arrange themselves within A1 receptors in a similar manner and suggest that this receptor is able to arrange 8-azaadenines, bearing three lipophilic substituents, in two different ways.
Adenine↗
Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. VIII-Synthesis and inhibition of benzodiazepine receptor binding of some derivatives of triazino[3,4-c]-1,4-benzothiazine and triazino[3,4-d]-1,5-benzothiazepine, two new heterocyclic ring systems.
Several series of triazino[3,4-c]-1,4-benzothiazines and triazino[3,4-d]-1,5-benzothiazepines were synthesized. Tentative syntheses performed to obtain 5H-as-triazino[3,4-c]-1,4-benzothiazin-1,2-diones and 5,6-dihydro-as-triazino[3,4-d]-1,5-benzothiazepin-1,2-diones gave rise to s-triazolo derivatives. Only in one case was the reaction successful, affording the 3,5-dihydro-as-triazino[3,4-c]-1,4-benzothiazin-1,2-dione 9a. All the final compounds were tested for their ability to displace [3H]flunitrazepam from bovine brain membranes.
Animals↗
Age-related changes in peripheral benzodiazepine receptors of human platelets.
Using 3H-PK 11195 as radioligand, the number and affinity of peripheral benzodiazepine receptors in platelets of 15 elderly healthy subjects were compared to those of 15 young subjects. The results showed that the dissociation constant (Kd) was significantly higher in the elderly than in the young subjects, while the density of binding sites did not differ. These findings suggest that the age-related changes in peripheral benzodiazepine receptors may be coupled with secondary changes in their hypothesized functions.
Adult↗
Regulation of agonist binding to A2A adenosine receptors: effects of guanine nucleotides (GDP[S] and GTP[S]) and Mg2+ ion.
Adenosine acts as a neuromodulator through at least two receptor subtypes, A1 and A2. A2 receptors have been further divided into A2A (high agonist affinity) and A2B (low agonist affinity) receptors. Both A1 and A2 receptors belong to the superfamily of guanine nucleotide-binding regulatory protein (G protein)-coupled receptors. A Gs protein couples the A2A receptor to the activation of adenylyl cyclase. In order to elucidate the mechanism of coupling between the A2A receptor and Gs, we studied the modulation by guanine nucleotides and divalent cations of agonist binding to the A2A receptor in rat striatal membranes, using [3H]CGS 21680 as a selective high-affinity agonist. We demonstrated that in rat striatal membranes agonist binding to A2A receptors was modulated by guanine nucleotides. Both GDP and GTP inhibited [3H]CGS 21680 binding to rat striatal membranes with about equal potency. The nonhydrolyzable analogs, GDP[S] and GTP[S], were equipotent inhibitors and approx. 100-times more potent than GDP and GTP. Data from competition studies with labeled and unlabeled CGS 21680 when analyzed by nonlinear regression demonstrated the presence of two binding sites in rat striatal membranes with mean values for KD of 5.6 and 343 nM and Bmax of 200 and 942 fmol/mg protein. The high-affinity binding site has the characteristics of the A2A receptor. In the presence both of (0.1 mM) GDP[S] and GTP[S], the KD values for the high-affinity site were increased severalfold, whereas the low-affinity site was no longer detected in filtration assays. Dissociation studies revealed monophasic dissociation curves both in the absence and presence of 0.1 mM GDP[S]. However the K-1 value increased in the presence of guanine nucleotide. We also showed that in bovine striatal membranes agonist binding to A2A receptors was modestly modulated by guanine nucleotides, suggesting differences of receptor Gs-protein-coupling a mechanism in different species. Divalent cations often increase agonist binding to different receptors, whereas Mg2+ ions play a role in regulating the initial steps of G-protein activation. We investigated the effects of divalent cations on [3H]CGS 21680 binding to the A2A receptor and determined the requirement of these cations to obtain the modulation of binding by guanine nucleotides. We found that millimolar concentrations of divalent cations were required to obtain an effective interaction between the A2A receptor and Gs. The high-affinity binding of [3H]CGS 21680 to the A2A receptor in rat striatal membranes was dependent on the presence of Mg2+ ions.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Conformationally restrained analogs of sympathomimetic catecholamines. Synthesis, conformational analysis, and adrenergic activity of isochroman derivatives.
In previous papers dealing with the study of the conformations and the biopharmacological activity of conformationally restrained analogs of sympathomimetic catecholamines (NE and ISO), proposals were advanced for the three-dimensional molecular models A, B, and C; these models provided information about the steric requirements for the direct activation of alpha 1, alpha 2,beta 1, and beta 2 adrenoceptors, respectively. The 1-(aminomethyl)-6,7-dihydroxyisochromans 11 and 12 and the 1-(aminomethyl)-5,6-dihydroxyisochromans 13 and 14 (1-AMDICs) are two different types of semirigid analogs of NE and ISO. The alpha 1, alpha 2, beta 1, and beta 2 adrenergic properties of the 1-AMDICs 11-14 were evaluated in vitro, both by radioligand binding assays and by functional tests on isolated preparations, and were compared with those of their parent compounds (NE and ISO). The results of a conformational study carried out by means of both 1H NMR spectrometry and theoretical calculations indicated that, in these 1-AMDICs, the presumed active groups (aryl moiety, amine nitrogen and benzylic ethereal oxygen) are in a spatial relationship corresponding to the one found for NE and ISO in their preferred conformations, which also proved to be the pharmacophoric conformation in the models A-C. By means of a comparison of the stereostructures of the 1-AMDICs 11-14 with their biopharmacological properties, it was possible to obtain a further definition of the model B with respect to the activation of the alpha 2 adrenoceptors; the superimposition of the 1-AMDICs 11 and 12 with the molecular model C made it possible to detect an area of the beta-adrenergic receptors which might hinder the fit of adrenergic drugs that are analogs of catecholamines with these receptors.
Animals↗
Studies on specific inhibition of benzodiazepine receptor binding by some C-benzoyl-1,2,3-triazole derivatives.
Certain new (1-15) or previously described (16-25) 1,2,3-triazole derivatives, characterized by a C-benzoyl substituent, were synthesized and tested for their ability to displace [3H]flunitrazepam from bovine brain membrane. Compounds 11a and 9a, bearing neutral and lipophilic substituents (phenethyl and cyclohexyl, respectively) showed the higher activity. The 5-benzoyl isomer 11b presented a lower activity, equivalent to that of the triazole acetic derivative 23, which is 4-benzyl substituted. Generally, the carboxymethyl radical in the 1-position of the triazole ring decreased the activity, probably because of intramolecular hydrogen bonding with the carbonyl function of the benzoyl substituent. The N-1 unsubstituted triazole derivatives 24 and 25 were ineffective; this result is in disagreement with our previous observations. Probably these molecules interact with the receptor site by a hydrogen bonding acceptor group and by a bulky and lipophilic portion or a hydrogen bonding donor function that is appropriately arranged.
Animals↗
Acromegalic cardiopathy: a left ventricular scintigraphic study.
In order to study "acromegalic cardiomyopathy", cardiac function was examined, using gated radionuclide ventriculography, in 18 acromegalic patients and 21 control subjects with no clinical evidence of cardiac involvement. In these acromegalic subjects, while the Ejection Fraction (EF) did not appear to be significantly different, the Peak Filling Rate (PFR) was reduced while the Time to Peak Filling Rate (TPFR) resulted significantly greater than in control subjects. These findings indicate that chronic growth hormone (GH) hypersecretion, as observed in acromegaly, deteriorate the cardiac ventricular relaxation (diastolic phase) while it has no influence on contractility (systolic phase).
Acromegaly↗
Neuropsychological and neurophysiological assessment of the central effects of interleukin-2 administration.
Neuropsychiatric disturbances may occur following interleukin-2 (IL2) administration. We studied the effects of IL2 infusion on cerebral functions in 7 patients with neuropsychological tests and event-related evoked potentials (P300). We observed a failure in the cognitive performances, an increase in latency, and a decrease in amplitude of P300. These effects followed IL2 administration and were reversible.
Adult↗
3 alpha-hydroxy-5 alpha-pregnan-20-one modulation of solubilized GABA/benzodiazepine receptor complex.
The allosteric modulation of the progesterone metabolite 3 alpha- hydroxy-5 alpha-pregnan-20-one (DHP) on [3H]Flunitrazepam and [35S]t-butylbicyclophosphorothionate (TBPS) binding was investigated on a soluble receptor preparation. Better results in the solubilization occurred by the use of the zwitterionic detergent CHAPS with the inclusion of the phospholipid asolectin: this treatment was found suitable to study the steroidal modulation on [3H]Flunitrazepam and [35S]TBPS binding. We found that DHP was able to enhance [3H]Flunitrazepam binding in the presence of Cl- ions, while [35S]TBPS binding was inhibited by DHP. Scatchard analysis of specific [35S]TBPS and [3H]Flunitrazepam binding yielded in a single straight line both in the controls and in the presence of the hormone; DHP increased the apparent affinity of [3H]Flunitrazepam binding without altering the apparent Bmax value. In the case of [35S]TBPS, DHP decreased the apparent Bmax value whereas the Kd value remained nearly the same.
Animals↗
The peripheral-type benzodiazepine receptor ligands [3H]Ro 5-4864 and [3H]PK 11195 bind to the retina of rabbit, but not of turtle.
The binding of [3H]flunitrazepam, [3H]Ro 5-4864, and [3H]PK 11195 to membrane preparations of the retina was studied in the turtle and rabbit. Only a single population of [3H]flunitrazepam binding sites was detected in the turtle, whereas two populations appeared to be present in the rabbit. No specific binding for [3H]Ro 5-4864 and [3H]PK 11195 could be detected in the turtle. In rabbit, both ligands bound with high affinity, revealing a significant population of binding sites (KD values of 24 +/- 2.3 and 2.2 +/- 0.8 nM, and Bmax values of 440 +/- 35 and 1,482 +/- 110 fmol/mg of protein, respectively). The binding was temperature- and protein-dependent. Displacement studies showed a similar rank order of potency of various unlabeled ligands against both [3H]Ro 5-4864 and [3H]PK 11195 (PK 11195 > Ro 5-4864 > flunitrazepam > flumazenil). These results suggest that peripheral-type benzodiazepine receptors are present in the retina of the rabbit, but not of the turtle.
Animals↗
Novel adenosine receptor ligands: 1,3-disubstituted[1]benzopyrano[2,3-c]pyrazol-4-ones. Synthesis and structure-activity relationships.
A series of 1,3-disubstituted[1]benzopyrano[2,3-c]pyrazol-4-ones were synthesized and tested in vitro as A1 and A2 adenosine receptor ligands. The binding results and a molecular modelling study indicated that the presence of a proton donor group in the N6-H region of adenosine and the 7-NH region of xanthine, respectively and occupancy of the A2 lipophilic area by a moiety endowed with an electrostatic effect are essential for receptor affinity and A2-selectivity.
Animals↗
[Pathology requiring admission to the neurosurgical intensive care].
A patient's admission to an ICU should benefit the patient (either short or long term). Consequently patients admitted to the ICU should be only those neurological-neurosurgical ones with one or more organ failure who need immediate or prolonged therapy with adequate monitoring and technical support not available in other wards. Normally admission depends on may other factors, the most important ones seem to be medico-legal responsibilities of the possible refusal of admission even if due to clinical reasons, organizational problems such as equipment and bed availability. There is a need for pre- and post-surgical monitoring for high risk patients. We routinely admit patients to our ICU according to the following directions: respiratory and or cardio-circulatory failure connected to the neurological pathology, impaired consciousness, neurological signs and symptoms indicating deterioration, loss of airway protective reflexes, seizured in neurological-neurosurgical patients, severe electrolyte, metabolic or nutritional disturbances which may affect the CNS; neurosurgical postoperative control, performance of complex techniques (central venous and arterial catheterization, ICP monitoring), management of multiorgan donors suitable for therapeutic transplant. The groups of pathologies observed in our ICU during 1991 where the follow-up: 442 neurological-neurosurgical patients--head trauma 141 (32%)--cerebral tumours 88 (19.9%)--vasculopathies 135 (30.6%)--others 77 (17.5%). 228 (51.5%) patients stayed for a period less than three days. According to our experience we can affirm that causes for patient's admission to neuro-ICUs are various, the legal organizational reasons have a great importance compared to the clinical ones.
Adult↗
Tricyclic heteroaromatic systems pyrazolo[1,5-a]quinoxalines: synthesis and benzodiazepine receptor activity.
The synthesis and the benzodiazepine receptor activity of some pyrazolo[1,5-a]quinoxalines bearing various substituents on the tricyclic heteroaromatic system are reported. Only one of the tested compounds showed some receptor affinity.
Animals↗
Tricyclic heteroaromatic systems 1,2,4-triazolo[1,5-a]quinoxalines: synthesis and benzodiazepine receptor activity.
The synthesis, the benzodiazepine binding activity and the "in vitro" biological effect of some 1,2,4-triazolo[1,5-a]quinoxalines, 3-aza-analogues of some previously reported pyrazolo[1,5-a]quinoxalines, are described. Molecular modelling is used to define the structural requirements of the benzodiazepine recognition site which influence the affinity and different efficacy of these rigid ligands.
Animals↗
Synthesis and benzodiazepine receptor affinity of N-(indol-3-ylglyoxylyl)-dipeptide derivatives. Structural requirements for inverse agonist/antagonist receptor interactions.
Several N-(indol-3-ylglyoxylyl)dipeptide derivatives 1-12 were synthesized and tested for their affinity at the benzodiazepine receptor in bovine cortical membranes. They proved to bind with low or no affinity at the receptor site. It was hypothesized that this result was not due to the steric hindrance of the dipeptide side chain, but to the establishment of intramolecular hydrogen bonds involving the indole N-H and/or the glyoxylyl C = O(2). Conformational analysis indicated that coiled conformations, with intramolecular hydrogen bonds, were energetically more favoured than the staggered, completely unfolded ones. Therefore, the low or no affinity of these compounds should be attributed to the unavailability of the N-H and/or C = O(2) groups for the binding, again confirming that both these groups are necessary for interaction with the receptor.
Animals↗