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Biomedical subjects

J Pascual

Publications and source records attributed to J Pascual.

At least 109 records · Page 6Linked to original sources
PubMed2000

Structure of the PHD zinc finger from human Williams-Beuren syndrome transcription factor.

The PHD (plant homeo domain) is a approximately 50-residue motif found mainly in proteins involved in eukaryotic transcription regulation. The characteristic sequence feature is a conserved Cys(4)-HisCys(3) zinc binding motif. We have determined the solution structure of the PHD motif from the human Williams-Beuren syndrome transcription factor (WSTF) protein. The domain folds into an interleaved zinc finger which binds two Zn(2+) in a similar manner to that of the RING and FYVE domains. The structure reveals a conserved zinc-binding core, together with two variable loops that are likely candidates for interactions between the various PHD domains and their specific ligands.

Amino Acid Sequence↗
PubMed2000

Modeling cyclooxygenase inhibition. Implication of active site hydration on the selectivity of ketoprofen analogues.

Molecular modeling studies performed on the two cyclooxygenase isozymes (COXs) suggest that active site hydration is crucial for understanding inhibitor selectivity. In this work, models have been constructed considering some implicit water molecules, placed in the position suggested by GRID, that participate in the dynamic hydrogen-bonding network at the polar active site entrance together with protein residues 355, 524, 120, and 513. The selectivity observed for ketoprofen (1) and the structural analogues 2 and 3 may be rationalized in terms of such implicit hydration.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

Derivation of pharmacophore and CoMFA models for leukotriene D(4) receptor antagonists of the quinolinyl(bridged)aryl series.

The present work focuses on the study of the three-dimensional (3D) structural requirements for the leukotriene D(4) (LTD(4)) antagonistic activity of compounds having the basic quinolinyl(bridged)aryl framework. An approach combining pharmacophore mapping, molecule alignment, and CoMFA models was used to derive a hypothesis for a series of LTD(4) antagonists having the basic diaryl-bridged framework. In this compound series, the produced pharmacophore hypotheses have shown to yield molecule alignments suitable to derive valuable CoMFA models. Model selection focused on (1) obtention of coherent modeling results, (2) consistency with the available SAR data, and (3) ability to predict the activity of an independent set of congeneric molecules. This approach resulted in a combined pharmacophore and CoMFA model that can generally represent the antagonistic activity within a log unit of the measured value for compounds of the series. The resulting pharmacophore (model C) consists of an acidic or negative ionizable function (AC), a hydrogen-bond acceptor (HBA), and three hydrophobic regions (HY) and produces chemically meaningful alignments with the most active compounds of the series mapping the pharmacophore in a extended energetically favorable conformation.

Combinatorial Chemistry Techniques↗
PubMed2000

Loss of dopamine uptake sites and dopamine D2 receptors in striatonigral degeneration.

To explore the mechanisms underlying L-dopa response, we studied, by postmortem autoradiography, selective makers of dopamine presynaptic terminals, [3H]WIN 35428, and dopamine D2 receptors, [3H]nemonapride, in the putamen of four Parkinson's disease (PD) and one striatonigral degeneration (SND) neuropathologically confirmed brains as compared with six matched control brains. Dopamine uptake transporter was dramatically decreased (> 90%) both in PD and SND striatum. Dopamine D2 receptors were preserved in PD, but clearly reduced (> 76%) in the SND putamen. These data confirm that L-dopa response is closely associated with the preservation of striatal dopamine D2 receptors.

Aged↗
PubMed2000

Noninvasive assessment of cardiac risk in type I diabetic patients being evaluated for combined pancreas-kidney transplantation using dipyridamole-MIBI perfusion tomographic scintigraphy.

This study was performed to determine the value of dipyridamole-99m Tc-methoxy-isobutyl isonitrile perfusion (99mTC-MIBI) tomographic scintigraphy in the assessment of cardiac risk in patients being evaluated prior to combined pancreas-kidney transplantation (PKT). We performed perfusion tomographic scintigraphy using single photon emission computed tomography (SPECT) on 77 patients. The tomographic images did not show clinically relevant findings in 65 patients. In the remaining 12 patients, coronary arteriography was performed: 2 showed normal results, 4 showed no stenosis, and 6 showed significant stenosis ( > or = 70%). Seventy-two patients underwent PKT. During the follow-up (6-48 months), there were seven cardiac events, 4 patients with significant stenosis, and 3 with nonsignificant stenosis upon coronary arteriography, and all had pathological tomographic images. 99mTc-MIBI tomographic scintigraphy may be useful in identifying patients at low risk of incurring cardiac events after PKT and may, in a large group of patients, obviate the need for routine coronary angiography.

Adult↗
PubMed2000

Synthesis and pharmacological evaluation of new 4-2-(7-heterocyclemethoxynaftalen-2-ylmethoxy)ethylbenzoic acids as LTD(4)-antagonists.

A group of new 4-[2-(7-heterocyclemethoxynaftalen-2-ylmethoxy)ethyl]benzoic acids have been synthesized and pharmacologically evaluated as LTD(4)-antagonists. Thiazole derivatives, especially 4-[2-[7-(4-cyclobutylthiazole-2-ylmethoxyl)naphthalen- 2-ylmetho-xy]et hyl]benzoic acid, present considerable activity and improved pharmacokinetic profiles in comparison with our quinoline containing lead molecule confirming the interest of our compounds as potentially oral antiasthmatics and that the 4-alkylthiazole system can be considered as bioisosteric of the quinoline ring at least in our series of compounds.

Animals↗
PubMed2000

Alternating hemiplegia of childhood: no mutations in the familial hemiplegic migraine CACNA1A gene.

INTRODUCTION: Alternating hemiplegia of childhood (AHC) is a rare disorder mainly characterized by attacks of hemiplegia and mental retardation. It has been often associated with migraine. The CACNA1A gene on chromosome 19 is involved in familial hemiplegic migraine and other episodic cerebral disorders, but also with progressive neuronal damage. METHODS: We performed mutation analysis in this gene in four AHC patients, using single strand conformation polymorphism analysis. RESULTS: We found nine polymorphisms, but no mutations in any of the 47 exons. CONCLUSIONS: Other cerebral ion channel genes remain candidate genes for AHC.

Adult↗
PubMed2000

Comparison of rizatriptan 10 mg vs. zolmitriptan 2.5 mg in the acute treatment of migraine. Rizatriptan-Zolmitriptan Study Group.

The efficacy and tolerability of rizatriptan (MAXALT) and zolmitriptan (ZOMIG) were compared in a randomized, double-blind, double-dummy, stratified (on prior use of rizatriptan and/or zolmitriptan), placebo-controlled, single attack study in 766 patients. Rizatriptan tended to provide freedom from pain sooner than zolmitriptan (hazard ratio 1.26, P = 0.075), acting within 60 min following dosing. More patients were pain free at 2 h on rizatriptan than on zolmitriptan (43.2% vs. 35.6%, P=0.041), while headache relief at 2 h was similar (70.5% vs. 66.8%). At 2 h, fewer patients on rizatriptan had symptoms of photophobia (35.6% vs. 43.5%, P = 0.029) and nausea (25.2% vs. 32.5%, P=0.046), and more patients on rizatriptan had normal function (45.4% vs. 37.0%, P=0.025) than zolmitriptan. Headache recurred in 28% of patients taking rizatriptan, 29% taking zolmitriptan and 26% taking placebo. Both active treatments were effective compared to placebo and were well tolerated. The most common side-effects with rizatriptan were asthenia/fatigue, somnolence and dizziness, while the most common side-effects with zolmitriptan were asthenia/fatigue and dizziness.

Adult↗
PubMed2000

Consistent efficacy and tolerability of almotriptan in the acute treatment of multiple migraine attacks: results of a large, randomized, double-blind, placebo-controlled study.

In this double-blind study, the efficacy and tolerability of a single dose of almotriptan (6.25 or 12.5 mg) was compared with placebo in the treatment of three consecutive migraine attacks of moderate or severe intensity. Of 1013 randomized patients, 722 evaluable patients completed the study. The total number of attacks relieved (severe or moderate pain reduced to mild or no pain) at 2 h post-dose was significantly higher (P < 0.001) after treatment with almotriptan 6.25 or 12.5 mg compared with placebo (60% and 70% vs. 38%, respectively). Moreover, a consistent response was achieved across and within patients for almotriptan 6.25 or 12.5 mg compared with placebo (pain relief in at least two out of three attacks within 2 h for 64% and 75% vs. 36%, respectively) and less than one-third of the patients relapsed within 24 h. Almotriptan was well tolerated with no significant differences between the almotriptan and placebo treatment groups in the percentage of patients reporting adverse events. Overall, the 12.5-mg dose was associated with the most favourable efficacy/tolerability ratio and is, therefore, the recommended dose.

Acute Disease↗
PubMed2000

Antiproteinuric effect of calcium antagonists on puromycin-induced experimental nephrosis.

Calcium antagonists have a potential for beneficial effects on kidney function unrelated to their antihypertensive action. In this study we have investigated the efficacy of calcium antagonists compounds (verapamil, nifedipine and diltiazem) on reversible acute renal insufficiency, proteinuria and interstitial nephritis induced by the puromycin ammonucleoside (PAN). An increase in blood pressure (BP) was detected on day 14, with no statistical differences in the response to calcium antagonists. Serum creatinine concentration increased to 1.2 mg/dL on day 7 after PAN and decreased to 0.7 mg/dL at 14 days, calcium antagonists shortened the time required to reach baseline or control levels. Calcium antagonists also reduced proteinuria in the PAN-treated animals, in both day 7 and day 14. Differential effects of the antagonists were observed. Verapamil caused a greater reduction (p < 0.01) in proteinuria than nifedipine or diltiazem in day 7. Moreover, verapamil (p < 0.01) and nifedipine (p < 0.01) reduced the total number of interstitial infiltrating leukocytes from 690 to 120 and 425 positive cells/20 high power fields (x63) respectively, by contrast, diltiazem had no effect. We conclude that in this model of PAN nephropathy verapamil is more effective in reducing both proteinuria and the severity of acute interstitial nephritis than either nifedipine or diltiazem. The possible clinical implications of these results remain to be elucidated.

Animals↗
PubMed2000

Ergotamine in the acute treatment of migraine: a review and European consensus.

Ergotamine has been used in clinical practice for the acute treatment of migraine for over 50 years, but there has been little agreement on its place in clinical practice. An expert group from Europe reviewed the pre-clinical and clinical data on ergotamine as it relates to the treatment of migraine. From this review, specific suggestions for the patient groups and appropriate use of ergotamine have been agreed. In essence, ergotamine, from a medical perspective, is the drug of choice in a limited number of migraine sufferers who have infrequent or long duration headaches and are likely to comply with dosing restrictions. For most migraine sufferers requiring a specific anti-migraine treatment, a triptan is generally a better option from both an efficacy and side-effect perspective.

Analgesics, Non-Narcotic↗
PubMed2000

Hypertension control in the elderly with amlodipine.

Treatment of hypertension in the elderly reduces the incidence of cardiovascular events. Some classes of antihypertensive drugs, including long-acting dihydropyridine calcium channel blockers such as amlodipine, can be prescribed in the presence of comorbid conditions. The results of clinical trials support the use of long-acting dihydropyridine calcium channel blockers in the elderly; amlodipine has been shown to be effective and well tolerated in the elderly population.

Age Factors↗