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A Badia

Publications and source records attributed to A Badia.

At least 37 records · Page 2Linked to original sources
PubMed2000

New tacrine-huperzine A hybrids (huprines): highly potent tight-binding acetylcholinesterase inhibitors of interest for the treatment of Alzheimer's disease.

Several new 12-amino-6,7,10,11-tetrahydro-7, 11-methanocycloocta[b]quinoline derivatives (tacrine-huperzine A hybrids, huprines) have been synthesized and tested as acetylcholinesterase (AChE) inhibitors. All of the new compounds contain either a methyl or ethyl group at position 9 and one or two (chloro, fluoro, or methyl) substituents at positions 1, 2, or 3. Among the monosubstituted derivatives, the more active are those substituted at position 3, their activity following the order 3-chloro > 3-fluoro > 3-methyl > 3-hydrogen. For the 1,3-difluoro and 1,3-dimethyl derivatives, the effect of the substituents is roughly additive. No significant differences were observed for the inhibitory activity of 9-methyl vs 9-ethyl derivatives mono- or disubstituted at positions 1 and/or 3. The levorotatory enantiomers of these hybrid compounds are much more active (eutomers) than the dextrorotatory forms (distomers) as AChE inhibitors. Compounds rac-20, (-)-20, rac-26, (-)-26, rac-30, (-)-30, and rac-31 showed human AChE inhibitory activities up to 28.5-fold higher than for the corresponding bovine enzyme. Also, rac-19, (-)-20, (-)-30, and rac-31 were very selective for human AChE vs butyrylcholinesterase (BChE), the AChE inhibitory activities being 438-871-fold higher than for BChE. Several hybrid compounds, specially (-)-20 and (-)-30, exhibited tight-binding character, showing higher activity after incubation of the enzyme with the inhibitor than without incubation, though the reversible nature of the enzyme-inhibitor interaction was demonstrated by dialysis. The results of the ex vivo experiments also supported the tight-binding character of compounds (-)-20 and (-)-30 and showed their ability to cross the blood-brain barrier. Molecular modeling simulations of the AChE-inhibitor complex provided a basis to explain the differences in inhibitory activity of these compounds.

Acetylcholinesterase↗
PubMed2000

Presynaptic effect of 7-OH-DPAT on evoked [3H]-acetylcholine release in rat striatal synaptosomes.

The objective of the present experiments was to study the presynaptic effect of 7-hydroxy-N,N-di-n-propyl-2-aminotetraline (7-OH-DPAT, a D(2)-like dopamine receptor agonist) on [3H]-acetylcholine ([3H]-ACh) release induced by potassium (15 mM, 25 mM and 60 mM), potassium channel-blockers (4-aminopyridine, 4-AP; tetraethylammonium, TEA and quinine) and veratridine to gain insight into the mechanisms involved in the activation of the D(2) dopamine-receptor subtype located at striatal cholinergic nerve terminals. 7-OH-DPAT (1 microM) inhibited the evoked [3H]-ACh release induced by K(+) 15 mM in a similar percentage than that obtained during basal conditions (30% and 27%, respectively). Nevertheless, in the presence of 25 mM and 60 mM of K(+) the inhibitory effect of 7-OH-DPAT was completely abolished. 4-AP (1-100 microM) and TEA (1 and 5 mM) significantly enhanced [3H]-ACh release, showing 69.32%+/-7.60% (P<0.001) and 52.27%+/-5.64% (P<0.001), respectively, at the highest concentrations tested. In these conditions, 7-OH-DPAT (1 microM) inhibited the release induced by potassium channel-blockers approximately 25-27%. Quinine (0.1-1 microM) did not alter [3H]-ACh release either in the presence or absence of 7-OH-DPAT. Veratridine 10 microM evoked [3H]-ACh release in the presence of a low-calcium medium, but in such conditions 7-OH-DPAT (1 microM) did not modify the neurotransmitter release in the absence or presence of veratridine. Present data indicate that activation of the presynaptic D(2) dopamine receptor inhibits the [3H]-ACh release by increasing K(+) conductance, as high K(+) concentrations abolished the inhibitory control of 7-OH-DPAT on [3H]-ACh release. This effect could be mediated by potassium channels different from those sensitive to 4-AP, TEA and quinine. In addition, the presynaptic D(2) dopamine-receptor activation seems to not involve changes in intracellular Ca(2+).

4-Aminopyridine↗
PubMed2000

Role of calcium on the modulation of spontaneous acetylcholine efflux by the D2 dopamine receptor subtype in rat striatal synaptosomes.

The role of calcium in the modulation of spontaneous [3H]acetylcholine ([3H]ACh) efflux through presynaptic D2 dopamine hetero-receptors was investigated in rat striatal synaptosomes. The kinetic studies of [3H]ACh efflux in the presence or absence of Ca2+ were carried out in nonstimulating conditions. When Ca2+ was omitted from the superfusion medium, a notable and significant (P<0.001) decrease of tritium efflux (39%) was obtained. While [3H]ACh efflux was insensitive to tetrodotoxin (TTX) 1 microM, cadmium (10 microM), a nonselective antagonist of calcium channels, significantly reduced the tritium efflux by 24% (P<0.001), while the L-type calcium antagonist, nifedipine, (30 microM) inhibited the tritium efflux by only 10% (P<0.02). 2-(4-Fenylpiperidine)cyclohexanol (vesamicol), an inhibitor of the vesicular [3H]ACh carrier, significantly depressed the spontaneous tritium efflux in the presence of Ca2+ (60%; P<0.001) and in a low-calcium medium (20%; P<0.001). Although 1 microM of 7-hydroxy-N,N-di-n-propyl-2-aminotetraline (7-OH-DPAT) inhibited spontaneous [3H]ACh efflux in the presence of calcium, this dopaminergic agonist did not modify the neurotransmitter release in either the low-Ca2+ medium or in the presence of vesamicol. These results suggest that the spontaneous [3H]ACh efflux is a process involving a Ca2+-dependent component (39%), sensitive to calcium channel-blockers and vesamicol, in rat striatal synaptosomes. In addition, activation of the D2 dopamine hetero-receptor only modulates the calcium-dependent component of spontaneous [3H]ACh efflux.

Acetylcholine↗
PubMed2000

N-Benzylpiperidine derivatives of 1,2,4-thiadiazolidinone as new acetylcholinesterase inhibitors.

A new family of 1,2,4-thiadiazolidinone derivatives containing the N-benzylpiperidine fragment has been synthesised. The acetylcholinesterase (AChE) inhibitory activity of all compounds was measured using Ellman's method and some of them turned out to be as potent as tacrine. Furthermore, compound 13 was as active as tacrine in reversing the blockade induced by tubocurarine at rat neuromuscular junction. Additionally, receptor binding studies provided new lead compounds for further development of alpha2-adrenergic and sigma-receptor antagonists. Molecular dynamic simulation using X-ray crystal structure of AChE from Torpedo californica was used to explain the possible binding mode of these new compounds.

Acetylcholinesterase↗
PubMed2000

A dynamic view of self-assembled monolayers.

In this Account, we discuss the dynamic features of self-assembled monolayers (SAMs) on both planar and nonplanar substrates. Our focus is on organothiol and organic acid-based monolayers. Results from variable-temperature electrochemical, calorimetric, vibrational, and solid-state NMR spectroscopic measurements lead to a convergent description of SAM dynamics.

Acids↗
PubMed2000

Arthroscopic resection of dorsal wrist ganglia and treatment of recurrences.

From 1995 to 1998, 30 patients with dorsal wrist ganglia and four with recurrent dorsal ganglia underwent arthroscopic resection. At a mean follow-up of 16 months, no complications were seen, but minimal pain persisted in three patients. Two recurrences were seen after arthroscopic resection of primary ganglia.

Adolescent↗
PubMed1999

Synthesis, in vitro pharmacology, and molecular modeling of very potent tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease.

Eleven new 12-amino-6,7,10,11-tetrahydro-7, 11-methanocycloocta[b]quinoline derivatives [tacrine (THA)-huperzine A hybrids, rac-21-31] have been synthesized as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. For derivatives unsubstituted at the benzene ring, the highest activity was obtained for the 9-ethyl derivative rac-20, previously prepared by our group. More bulky substituents at position 9 led to less active compounds, although some of them [9-isopropyl (rac-22), 9-allyl (rac-23), and 9-phenyl (rac-26)] show activities similar to that of THA. Substitution at position 1 or 3 with methyl or fluorine atoms always led to more active compounds. Among them, the highest activity was observed for the 3-fluoro-9-methyl derivative rac-28 [about 15-fold more active than THA and about 9-fold more active than (-)-huperzine A]. The activity of some THA-huperzine A hybrids (rac-19, rac-20, rac-28, and rac-30), which were separated into their enantiomers by chiral medium-pressure liquid chromatography (chiral MPLC), using microcrystalline cellulose triacetate as the chiral stationary phase, showed the eutomer to be always the levorotatory enantiomer, their activity being roughly double that of the corresponding racemic mixture, the distomer being much less active. Also, the activity of some of these compounds inhibiting butyrylcholinesterase (BChE) was tested. Most of them [rac-27-31, (-)-28, and (-)-30], which are more active than (-)-huperzine A as AChE inhibitors, turned out to be quite selective for AChE, although not so selective as (-)-huperzine A. Most of the tested compounds 19-31 proved to be much more active than THA in reversing the neuromuscular blockade induced by d-tubocurarine. Molecular modeling of the interaction of these compounds with AChE from Torpedo californica showed them to interact as truly THA-huperzine A hybrids: the 4-aminoquinoline subunit of (-)-19 occupies the same position of the corresponding subunit in THA, while its bicyclo[3.3.1]nonadiene substructure roughly occupies the same position of the corresponding substructure in (-)-huperzine A, in agreement with the absolute configurations of (-)-19 and (-)-huperzine A.

Acetylcholinesterase↗
PubMed1999

Adrenergic and purinergic components in bisected vas deferens from spontaneously hypertensive rats.

1. Purinergic and adrenergic components of the contractile response to electrical field stimulation (EFS) have been investigated in epididymal and prostatic portions of Wystar Kyoto (WKY) and spontaneously hypertensive rat (SHR) vas deferens. 2. In both halves of SHR and WKY vas deferens, EFS (40 V, 0.5 ms for 30 s, 0.5-32 Hz) evoked frequency-related contractions. The neurogenic responses were biphasic, consisting of a rapid non-adrenergic response, dominant in the prostatic portion, followed by a slow tonic adrenergic component, dominant in the epididymal half. 3. Phasic and tonic components of the frequency-response curves evoked by EFS were significantly higher in the epididymal but not in the prostatic portion of vas deferens from SHR compared to WKY rats. 4. The alpha1-adrenoceptor antagonist prazosin (0.1 microM) was more effective against both components of the contractile response in the epididymal end of SHR than in WKY rats. 5. Inhibition by alpha, beta-methylene adenosine 5'-triphosphate (alpha,beta-meATP 3 and 30 microM) was higher in both components of the contractile responses in WKY preparations than in SHR. 6. Combined alpha1-adrenoceptor and P2x-purinoceptor antagonism virtually abolished the EFS-evoked contractile response in both strains. The degree of inhibition by prazosin (0.1 microM) after P2x-purinoceptor blockade was higher in SHR than in WKY rats. 7. These results demonstrate a modification in the purinergic and noradrenergic contribution to neurogenic responses in SHR and WKY animals besides a co-participation of ATP and noradrenaline in both contractile components of the response to EFS.

Adenosine Triphosphate↗
PubMed1999

Randomized clinical trial of adjuvant mitomycin plus tegafur in patients with resected stage III gastric cancer.

PURPOSE: The efficacy of adjuvant chemotherapy in gastric cancer is controversial. We conducted a phase III, randomized, multicentric clinical trial with the goal of assessing the efficacy of the combination of mitomycin plus tegafur in prolonging the disease-free survival and overall survival of patients with resected stage III gastric cancer. PATIENTS AND METHODS: Patients with resected stage III gastric adenocarcinoma were randomly assigned, using sealed envelopes, to receive either chemotherapy or no further treatment. Chemotherapy was started within 28 days after surgery according to the following schedule: mitomycin 20 mg/m(2) intravenously (bolus) at day 1 of chemotherapy; 30 days later, oral tegafur at 400 mg bid daily for 3 months. Disease-free survival and overall survival were estimated using the Kaplan-Meier analysis and the Cox proportional hazards model. RESULTS: Between January 1988 and September 1994, 148 patients from 10 hospitals in Catalonia, Spain, were included in the study. The median follow-up period was 37 months. The tolerability of the treatment was excellent. The overall survival and disease-free survival were higher in the group of patients treated with chemotherapy (P =.04 for survival and P =.01 for disease-free survival in the log-rank test). The overall 5-year survival rate and the 5-year disease-free survival rate were, respectively, 56% and 51% in the treatment group and 36% and 31% in the control group. CONCLUSION: Our positive results are consistent with the results of recent studies; which conclude that there is a potential benefit from adjuvant chemotherapy in resected gastric cancer.

Aged↗
PubMed1998

Synthesis and evaluation of tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease.

Seventeen polycyclic compounds related to tacrine and huperzine A have been prepared as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. The conjunctive pharmacomodulation of huperzine A (carbobicyclic substructure) and tacrine (4-aminoquinoline substructure) led to compound 7jy, 2.5 times less active than tacrine as AChE inhibitor, but much more active than its (Z)-stereoisomer (7iy). Derivatives 7dy and 7ey, lacking the ethylidene substituent, showed to be more active than tacrine. Many other structural modifications of 7jy led to less active compounds. Compounds 7dy and 7ey also showed to be much more active than tacrine in reversing the partial neuromuscular blockade induced by d-tubocurarine.

Acetylcholinesterase↗
PubMed1998

Colonic volvulus and ulcerative jejunoileitis due to occult celiac sprue.

Colonic volvulus is a rare complication of celiac disease. A case is reported of a 46-year-old man with a long-standing history of diarrhea and abdominal distention with a diagnosis of irritable bowel syndrome. After an elective inguinal hernia repair, a cecal volvulus and an ulcerative jejunoileitis developed in the patient that required an extensive intestinal resection. Short bowel syndrome developed and was treated with total parenteral and enteral nutrition. The patient had a poor course after reinitiation of oral diet. Subsequently, celiac sprue was diagnosed and the patient improved with a gluten-free diet.

Celiac Disease↗
PubMed1998

[Complicated liver hydatid: experience at one center].

The object of the present paper is to show four patients treated at the "Ricardo Gutiérrez" Children's Hospital, with diagnosis of complicated liver hydatid disease, since april 1977 until january 1997. The four patients were previously healthy, and were admitted with acute symptomatology, which varied depending on the kind of complication. They were all studied before surgery, except for one patient, with simple x-ray, abdominal ultrasonography, and in some cases with computerized tomography; in addition blood serologic analysis were performed, which allowed us 100% effectiveness in the diagnosis. The observed complications were two intrabiliary rupture of the hydatid cyst, one infection of the cyst, and one intra abdominal rupture. All patients underwent surgery, which confirmed the diagnosis, and an uneventful follow up of 20 years in the first child. In spite of the infrequent presentation of the complicated hydatid disease, in an endemic region it is not impossible for it to be seen. In this case it will require a well trained team of specialists, to solve not only the problems that the diagnosis and treatment mean, but also the possibility of a correct follow-up, with the resolution of the possible obstacle that might show-up for the disease itself, and from the changes that the surgery produces.

Adolescent↗
PubMed1997

Use of the operational model of agonism and [3H]prazosin binding to assess altered responsiveness of alpha1-adrenoceptors in the vas deferens of spontaneously hypertensive rat.

Changes in functional responsiveness to alpha1-adrenoceptor activation with noradrenaline and in [3H]prazosin binding in the epididymal portion of vas deferens from normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) were investigated. The operational model fitting and the nested hyperbolic method were used to analyze the effects of irreversible receptor alkylation by phenoxybenzamine (0.1 microM) on the alpha1-adrenoceptor mediated contractile responses to noradrenaline of vasa deferentia from SHR and WKY rats. Saturation isotherms for [3H]prazosin revealed a significant increase (P < 0.05) in the Bmax in SHR vas deferens (145 +/- 19 fmol/mg protein) compared with vas deferens from normotensive controls (75 +/- 12 fmol/mg protein) without changes in the K(D). No differences in the proportion of high and low affinity binding sites for WB-4101 and 5-methylurapidil were observed. The maximum contractile response, alpha, (P < 0.001) and the pEC50 (P < 0.05) values for noradrenaline were greater for SHR than for WKY rat tissues. The apparent affinity (pK(A)) determined by the nested hyperbolic method and by the operational model of agonism was found to be similar in the two strains. In agreement with relative pEC50, the efficacy (tau) value for SHR was greater than for WKY rats. However, the difference in the tau estimates did not reach statistical significance. In summary, in the epididymal portion of SHR vas deferens, the increased maximum contractile response to noradrenaline is due to an increase of Em. Taken together, the tau values and the results from binding experiments lead to the assumption that the transducer constant K(E) must be greater in SHR than in WKY rats, suggesting a deterioration in the transduction of the stimulus provided by the agonist in hypertensive animals.

Adrenergic alpha-Agonists↗
PubMed1997

Correlation of wrist ligamentotaxis with carpal distraction: implications for external fixation.

Cadaver forearms were tested to measure carpal bone separation and wrist ligament tension in response to MTS-based incremental wrist distraction. Distraction of 2 mm separated the proximal carpal row from the radius and transmitted an average tension of 8 N. The mid-carpal joint also began to widen at this level of distraction. Distraction of 4 mm resulted in an average tension of 20 N. At this level of distraction, radioscaphoid separation started to exceed radiolunate separation. A transition from low- to high-stiffness response was observed over a range of 4-8 mm distraction for the 12 specimens tested, with an average tension of 80 N associated with 8 mm distraction. Average values of carpal height ratio, revised carpal height ratio, and carpal height index were found to be poor indicators of distraction, owing to their high variability between specimens.

Cadaver↗
PubMed1997

Vegetable and fruit intake and the risk of lung cancer in women in Barcelona, Spain.

A case-control study on women was carried out in Barcelona, Spain, to investigate the relationship of lung cancer with the intake of vegetables, fruits and some foods of animal origin. The study included 103 cases and 206 controls matched by age and residence. Diet intake was assessed by means of a food frequency questionnaire. A reduction in risk, adjusted for smoking habit, was found for the intake of yellow/orange vegetables (mainly carrots) and tomatoes. The odds ratio (OR) and 95% confidence interval (CI) for the highest versus lowest tertile of intake were 0.37 (0.19-0.74) for yellow/orange vegetables and 0.45 (0.22-0.91) for tomatoes; both had a significant inverse trend. A tendency to a reduction in risk of lung cancer with increased intake was observed for all vegetables, leafy green vegetables, dark green vegetables and cruciferous, but these associations did not reach statistical significance. No association with lung cancer was found for the intake of fruits or foods of animal origin rich in retinol. Similar patterns were observed for women who never smoked and when the analysis was restricted to adenocarcinoma.

Adenocarcinoma↗
PubMed1997

D2 dopamine receptors and modulation of spontaneous acetylcholine (ACh) release from rat striatal synaptosomes.

1. The effect of two D3/2 dopamine receptor agonists, LY-171555 (quinpirole) and 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) on spontaneous [3H]-acetylcholine ([3H]-ACh) release were investigated in rat striatal synaptosomes. 2. Quinpirole and 7-OH-DPAT inhibited in a concentration-dependent manner the basal efflux of [3H]-ACh with similar Emax (maximal inhibitory effect) values (29.95 +/- 2.91% and 33.19 +/- 1.21%, respectively). Significant differences were obtained between the pEC50 (-log of molar concentration) of quinpirole (7.87 +/- 0.12) and 7-OH-DPAT (7.21 +/- 0.17; P < 0.01). 3. Different concentrations (0.3-10 nM) of haloperidol (D2/3 dopamine receptor antagonist) shifted to the right the concentration-response curves elicited by quinpirole and 7-OH-DPAT, without modifications in the Emax. 4. Slopes of a Schild plot obtained with haloperidol in the presence of quinpirole and 7-OH-DPAT were not significantly different from unity (0.85 +/- 0.05 and 1.17 +/- 0.11, respectively) and consequently haloperidol interacted with a homogeneous receptor population. The pKB values of haloperidol obtained from Schild regression were 9.96 +/- 0.15 (in presence of quinpirole) and 9.90 +/- 0.09 (in presence of 7-OH-DPAT). 5. Specific binding of [3H]-YM-09151-2 to membranes of striatal synaptosomes and cells expressing D2 and D3 dopamine receptors was inhibited by haloperidol. Analysis of competition curves revealed the existence of a single population of receptors. There were no differences between the estimated pKi (-log of molar concentration) values for synaptosomes (8.96 +/- 0.02) and cells expressing D2 receptors (8.81 +/- 0.05), but the pKi value from cells expressing D3 dopamine receptors differed significantly (8.48 +/- 0.06; P < 0.01). 6. In conclusion, the data obtained in the present study indicate that quinpirole and 7-OH-DPAT, two D3/2 dopamine receptor agonists, inhibit the spontaneous [3H]-ACh efflux and this effect is competitively antagonized by haloperidol and probably mediated through dopamine D2 receptors.

Acetylcholine↗
PubMed1996

Possible involvement of alpha 1-adrenoceptors in the modulation of [3H]noradrenaline release in rat brain cortical and hippocampal synaptosomes.

Nerve terminals obtained from rat brain cortex and hippocampus, were labelled with 0.04 microM of [3H]noradrenaline ([3H]NA). Thereafter the basal release of [3H]NA was measured in a Brandel superfusion apparatus, in the presence of alpha 1-adrenoceptor agonists (phenylephrine or noradrenaline) or these alpha 1-adrenoceptor agonists along with prazosin, an alpha 1-adrenoceptor antagonist. In cortical synaptosomes both alpha 1-adrenoceptor agonists increased the basal release of [3H]NA in a concentration-dependent manner (EC50 = 0.15 microM for phenylephrine and 12.6 microM for noradrenaline). Effects were reversed by 0.01 microM prazosin (EC50 = 2.46 and 130.1 microM, respectively). In synaptosomes from rat brain hippocampus, phenylephrine (EC50 = 1.28 microM) and noradrenaline (EC50 = 33.7 microM) also increased the [3H]NA release and prazosin (0.01 microM) shifted the corresponding concentration-response curves to the right (EC50 = 7.38 and 264.0 microM, respectively). Events produced by noradrenaline acting as alpha 1-adrenoceptor agonist did not show Ca2+ dependence. These results suggest (1) the presence of functional alpha 1-adrenoceptors in nerve terminals from rat brain cortex and hippocampus, (2) that these receptors seem to play a role in the presynaptic modulation of [3H]NA release, and (3) that intraterminal Ca2+ may be involved.

Adrenergic alpha-Agonists↗