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Biomedical subjects

E Alvarez

Publications and source records attributed to E Alvarez.

At least 91 records · Page 5Linked to original sources
PubMed2000

Peripheral versus central effects of glucagon-like peptide-1 receptor agonists on satiety and body weight loss in Zucker obese rats.

The present study explores the potential utility of peripheral versus central administration of glucagon-like peptide-1 (GLP-1) receptor agonists in the regulation of feeding behavior in Wistar and Zucker obese rats. Acute central (intracerebroventricular [i.c.v.]) and peripheral (subcutaneous [s.c.]) administration of both GLP-1 (7-36) amide and exendin-4 resulted in a reduction in food intake for at least 4 hours, exendin-4 being much more potent than GLP-1 (7-36) amide, especially after peripheral administration. Both Zucker obese rats (fa/fa) and their lean littermates (Fa/-) responded to acute central and peripheral administration of exendin-4. Moreover, in situ hybridization revealed specific labeling for the mRNA for GLP-1 receptors in several brain areas of both the obese and lean rats. The presence of this receptor was also detected by affinity cross-linking assays. Long-term s.c. administration of exendin-4 (1 single injection per day, 1 hour prior to the onset of the dark phase of the cycle) decreased daily food intake and practically blocked weight gain in obese rats. In contrast to previous studies, these findings show that peripheral (s.c.) administration of both GLP-1 receptor agonists also induces satiety and weight loss in rats, and suggest the potential usefulness of exendin-4 as a therapeutic tool for the treatment of diabetes and/or obesity.

Amines↗
PubMed2000

Cost-effectiveness of fluoxetine plus pindolol in patients with major depressive disorder: results from a randomized, double-blind clinical trial.

Some preliminary studies have suggested that the beta-adrenoceptor 5-HT1A antagonist pindolol (PIN) could increase the effect of selective serotonin reuptake inhibitors (SSRIs). We prospectively estimated the cost-effectiveness of fluoxetine and pindolol versus fluoxetine plus placebo, using results from the first double-blind randomized clinical trial comparing both treatments. Efficacy and medical care resource utilization were collected prospectively in a parallel, randomized, double-blind clinical trial conducted in a single centre in Spain. Average cost-effectiveness (cost/% response and cost/% remission) as well as the incremental cost-effectiveness were calculated for both treatments. A 'bootstrap' method was used to calculate confidence limits around the incremental cost-effectiveness ratio. A significantly greater percentage of patients (one-tailed P < 0.05) in the fluoxetine FLX + PIN group than in the FLX + PLA group had experienced a therapeutic response (74.5% versus 58.97%) at 6 weeks. Direct medical costs were lower in the FLX + PIN group (mean 2508 pesetas per patient) than in the FLX + PLA group (mean 31870 pesetas per patient). Hospital admissions due to worsening of depressive symptoms were significantly lower (P < 0.05) in the FLX + PIN group (0/55) than in the FLX + PLA group (4/56). The observed differences in average costs and percentage response in the study were -29362 pesetas (< 0) and 15.6% (> 0), respectively, and the resulting cost-effectiveness ratio was negative. These outcomes indicate that the FLX + PIN option completely dominates FLX + PLA. These results suggest that, over a course of 6 weeks of treatment, the combination of fluoxetine and pindolol incurs lower direct medical costs than treatment with fluoxetine placebo. Despite their limitations, economic assessments in addition to clinical trials allow a 'dynamic assessment' on the potential success of the drug, both from a clinical and an economic point of view, allowing decisions on priorities to be made earlier.

Adult↗
PubMed2000

Personal-computer-based system for three-dimensional anatomic-physiological correlations during stereotactic and functional neurosurgery.

This paper describes the automatic three-dimensional (3D) graphic possibilities that are supplied by the Neurosurgical Deep Recording System (NDRS) to facilitate anatomic-physiological targeting during stereotactic and functional neurosurgery using depth recording. This software has been developed to substitute the complex electronic equipment ordinarily used for deep brain electrical recording, display and processing by a personal computer. It may also help to improve on-line graphic analysis, automatic management of the recorded information and flexibility to implement different forms of signal analysis. It can automatically show a 2D or 3D representation of the electrode track, with the electrophysiological findings superimposed as well as the corresponding sagittal, coronal and axial views of a brain atlas using automatic scaling. The NDRS has already successfully been applied during more than 300 neurosurgeries in Spain and Cuba, enabling improved targeting accuracy and safety.

Brain Mapping↗
PubMed2000

Effects of policosanol on postmenopausal women with type II hypercholesterolemia.

This randomized, double-blind, placebo-controlled study was conducted to investigate the efficacy, safety and tolerability of policosanol, a cholesterol-lowering drug purified from sugar-cane wax, in postmenopausal women with type II hypercholesterolemia. A total of 244 women who had experienced the menopause and showed elevated serum total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels despite 6 weeks on a standard lipid-lowering diet were randomized to receive placebo or policosanol 5 mg/day for 12 weeks, after which the dose was doubled to 10 mg/day for the next 12 weeks. Policosanol (5 and 10 mg/day) significantly lowered LDL-C levels (17.7% and 25.2%, respectively) and total cholesterol (12.6% and 16.7%, respectively), as well as the ratios of LDL-C to high-density lipoprotein cholesterol (HDL-C) (17.0% and 29.3%, respectively) and total cholesterol to HDL-C (16.7% and 27.2%, respectively), compared to the baseline and placebo; at the same time, policosanol significantly raised HDL-C levels by 16.5% and 29.3%, respectively. The drug was safe and well tolerated. No drug-related adverse events were observed, and even the extent of adverse events was less in the policosanol group than in the placebo group. Four serious adverse events occurred in the placebo group (one myocardial infarction, two cases of hypertensive status and one surgical intervention) compared to none in the policosanol group. In conclusion, policosanol is effective, safe and well tolerated in hypercholesterolemic postmenopausal women.

Aged↗
PubMed2000

Transforming growth factor-beta and response to anticancer therapies in human liver and gastric tumors in vitro and in vivo.

Liver cancer and gastric cancer are the most common solid tumors worldwide. Transforming growth factor-beta (TGF-beta) production and lack of response to TGF-beta growth inhibitory effects have been associated with tumor progression and therapeutic resistance. HepG2, Hep3B, and SK-HEP-1 human liver cancer lines produce 3, 5.7, and 2.5 ng TGF-beta1; 1.4, 2, and 4 ng TGF-beta2 and 0.15, 0.2 and 0.22 ng TGF-beta3 per 107 cells (24 h). Expression of the TGF-beta type I receptor is 20x, 1x, and 0.6x the level in mink lung MvLu1 cells in the HepG2, Hep3B, and SK-HEP-1 cells, respectively. HepG2 and Hep3B cells do not express the TGF-beta type II receptor while SK-HEP-1 cells express 7x the level found in mink lung MvLu1 cells. Hs 746T, KATO III, RF-1, and RF-48 human gastric cancer cell lines produce 12. 5, 0.35, 0.4, and 0.4 ng TGF-beta1; 2.6, 0.95, 0.5, and 0.52 ng TGF-beta2 and 0.42, 0.17, 0.12, and 0.14 ng TGF-beta3 per 107 cells (24 h). Expression of TGF-beta type I receptor is 0.7x, 0.7x, 0.8x, 0.6x the level in mink lung MvLu1 cells in the Hs 746T, KATO III, RF-1 and RF-48 cells, respectively. KATO III cells are lacking in the TGF-beta type II receptor while Hs 746T, RF-1 and RF-48 cells express 10x, 0.8x, and 1x the levels in mink lung MvLu1 cells. The IC50 for TGF-beta1 is >>10 ng/ml in all of these lines except RF-48 where TGF-beta1 is mitogenic. The response of the cell lines to radiation, doxorubicin, mitomycin C, cisplatin, 5-fluorouracil, methotrexate, and gemcitabine showed that SK-HEP-1 was the most drug resistant liver cancer cell line and KATO III was the most drug resistant gastric cancer cell line. Overall, there was no correlation between TGF-beta secretion in cell culture and sensitivity of the cells to anticancer agents. Increased TGF-beta1 levels were detectable in the plasma of nude mice bearing Hep3B and Hs 746T xenografts. Those tumors which secreted greater amounts of TGF-beta were more therapeutically resistant in vivo.

Activin Receptors, Type I↗
PubMed2000

SB-253514 and analogues; novel inhibitors of lipoprotein-associated phospholipase A2 produced by Pseudomonas fluorescens DSM 11579. I. Fermentation of producing strain, isolation and biological activity.

Two new classes of inhibitors of LpPLA2 have been identified in fermentations of Pseudomonas fluorescens. The two structurally isomeric series differ in the geometry of closure of the bicyclic carbamate and comprise a range of compounds varying only in length of their lipophilic sidechain. The most abundant species were extracted from the cells and purified by silica and C18 chromatography. Members of the more stable class were shown to be potent and selective competitive inhibitors of LpPLA2.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2000

[Percutaneous intrahepatic portosystemic shunting in the treatment of veno-occlusive disease of the liver after bone marrow transplantation].

Veno-occlusive disease of the liver is a frequent cause of morbidity and mortality after bone-marrow transplantation. Its clinical manifestations are primarily related to the development of portal hypertension and sinusoidal congestion. The efficacy of the different therapeutic options used is controversial. We present a 22-year-old woman with veno-occlusive liver disease histologically confirmed after autologous bone-marrow transplantation, with progressive alteration in liver biochemistry and ascites. She was treated by percutaneous intrahepatic portosystemic shunting. After the procedure there was a marked improvement in ascites and an increase in diuresis with liver function progressively returning to normal. The safety and efficacy of this approach in the treatment of patients with veno-occlusive liver disease should be evaluated in controlled studies.

Adult↗
PubMed2000

[Differential binding of hyaluronic acid in 2 CD44+ sublines. Relationship with tumor infiltration].

We have established and characterized a cell line (LBL) from a spontaneous murine T lymphoma LB. Histopathological analysis has demonstrated LB primary tumor infiltration in spleen, lymph nodes, liver, thymus, bone marrow and lung. However LBL cells infiltrated all these organs except lung. Two sublines with different growth behavior were derived from LBL cell line. One of them grew in suspension as clusters (LBLc) while the other one grew as adherent monolayers (LBLa). Growth rate, response to mitogenic stimuli and apoptosis induction were different among the parental cell line and the derived sublines. CD44 was expressed constitutively in LBL and LBLa cells. In contrast LBLc cells only expressed similar levels of this molecule when stimulated with PMA. LBLa cells showed hyaluronic acid (HA) binding properties, while LBL and LBLc cells were not able to bind HA even when activated with PMA. We postulate that differences in HA binding could be related with different infiltration behaviors.

Adjuvants, Immunologic↗
PubMed1999

Synthesis of novel polyethers in a geometrically precise conformation.

[reaction: see text] A convergent design for the preparation of a polyoxyethylene-based channel molecule is presented, and the synthesis of the key unit 2 required for the projected construction is described. The essential elements of the design included face to face oriented macrorings spaced by rigid trans-fused oxanes. The strategy combines conformational predictability of C-linked oxanyl systems and ring-closing metathesis for the synthesis of crown ethers with engineerable ion-binding abilities.

Journal Article↗
PubMed1999

Pretreatment platelet 5-HT concentration predicts the short-term response to paroxetine in major depression. Grupo de Trastornos Afectivos.

BACKGROUND: A previous retrospective study revealed that a high pretreatment platelet serotonin (5-HT) concentration was associated with a low response to serotonergic antidepressants in drug-free major depressives. We have examined such a relationship in depressive patients treated with paroxetine. METHODS: Seventy-four drug-free major depressives (DSM-IV) were admitted to the study. Clinical ratings were performed and blood was drawn prior to the initiation of treatment and after 4 weeks of paroxetine (20 mg/day). The concentrations of 5-HT, 5-hydroxyindoleacetic acid, and tryptophan were determined in plasma and blood. RESULTS: Paroxetine treatment reduced platelet 5-HT to 17% of baseline after 4 weeks of treatment. Responder patients had a pretreatment platelet 5-HT concentration 22% lower than nonresponders (p < .035). Admission HAMD scores, plasma paroxetine concentration, or platelet 5-HT concentration at endpoint did not differ between responders and nonresponders. Yet, the response rate was 11% in patients with high pretreatment platelet 5-HT (> 900 ng/10(9) platelets) and 50% in those below that value (p < .004). CONCLUSIONS: These findings support that depressed patients with a high pretreatment platelet 5-HT concentration have a poor therapeutic outcome after treatment with a standard paroxetine dose. These differences may be related to the existence of molecular differences in the 5-HT transporter.

Adolescent↗
PubMed1999

Mechanism of inhibition of DNA (cytosine C5)-methyltransferases by oligodeoxyribonucleotides containing 5,6-dihydro-5-azacytosine.

A key step in the predicted mechanism of enzymatic transfer of methyl groups from S-adenosyl-l-methionine (AdoMet) to cytosine residues in DNA is the transient formation of a dihydrocytosine intermediate covalently linked to cysteine in the active site of a DNA (cytosine C5)-methyltransferase (DNA C5-MTase). Crystallographic analysis of complexes formed by HhaI methyltransferase (M.HhaI), AdoMet and a target oligodeoxyribonucleotide containing 5-fluorocytosine confirmed the existence of this dihydrocytosine intermediate. Based on the premise that 5,6-dihydro-5-azacytosine (DZCyt), a cytosine analog with an sp3-hybridized carbon (CH2) at position 6 and an NH group at position 5, could mimic the non-aromatic character of the cytosine ring in this transition state, we synthesized a series of synthetic substrates for DNA C5-MTase containing DZCyt. Substitution of DZCyt for target cytosines in C-G dinucleotides of single-stranded or double-stranded oligodeoxyribonucleotide substrates led to complete inhibition of methylation by murine DNA C5-MTase. Substitution of DZCyt for the target cytosine in G-C-G-C sites in double-stranded oligodeoxyribonucleotides had a similar effect on methylation by M. HhaI. Oligodeoxyribonucleotides containing DZCyt formed a tight but reversible complex with M.HhaI, and were consistently more potent as inhibitors of DNA methylation than oligodeoxyribonucleotides identical in sequence containing 5-fluorocytosine. Crystallographic analysis of a ternary complex involving M.HhaI, S-adenosyl-l-homocysteine and a double-stranded 13-mer oligodeoxyribonucleotide containing DZCyt at the target position showed that the analog is flipped out of the DNA helix in the same manner as cytosine, 5-methylcytosine, and 5-fluorocytosine. However, no formation of a covalent bond was detected between the sulfur atom of the catalytic site nucleophile, cysteine 81, and the pyrimidine C6 carbon. These results indicate that DZCyt can occupy the active site of M.HhaI as a transition state mimic and, because of the high degree of affinity of its interaction with the enzyme, it can act as a potent inhibitor of methylation.

Animals↗
PubMed1999

A double-blind, randomized, placebo-controlled trial of pindolol augmentation in depressive patients resistant to serotonin reuptake inhibitors. Grup de Recerca en Trastorns Afectius.

BACKGROUND: Pindolol has been reported to hasten the antidepressant action of selective serotonin reuptake inhibitors in open-label and placebo-controlled trials. Pilot studies also suggested that pindolol could augment the antidepressant response in unresponsive patients. We investigated whether the addition of pindolol can induce a rapid response in treatment-resistant patients. METHODS: After a single-blind lead-in placebo phase of 5 days to exclude placebo responders, 80 outpatients with major depression who did not respond to a minimum of 6 weeks of treatment with clomipramine hydrochloride, 150 mg/d; fluoxetine hydrochloride, 40 mg/d; fluvoxamine maleate, 200 mg/d; or paroxetine hydrochloride, 40 mg/d, were randomly assigned to additionally receive placebo (3 times daily) or pindolol (2.5 mg 3 times daily) for 10 days. The median number of ineffective treatments in the current episode was 2 (range, 1-4). Hamilton Rating Scale for Depression and Montgomery-Asberg Scale for Depression scores were used as primary measures of efficacy. RESULTS: At end point, the Hamilton and Montgomery-Asberg scores and change from baseline in Hamilton score were not significantly different in patients taking placebo or pindolol. The response rate was equal in both groups (12.5%). No differences in the clinical outcome were found when the various pretreatment subgroups were considered. At end point, the plasma concentration of pindolol was 9.9+/-5.1 ng/mL (mean +/- SD; n = 40). CONCLUSIONS: Although pindolol can accelerate the antidepressant action of selective serotonin reuptake inhibitors in previously untreated patients, it does not elicit a rapid clinical response in treatment-resistant patients within a 10-day period.

Adult↗
PubMed1999

Respiratory chain enzyme activities in spermatozoa from untreated Parkinson's disease patients.

We studied respiratory chain enzyme activities in spermatozoa homogenates from 12 untreated Parkinson's disease (PD) male patients and from 23 age matched healthy male controls. When compared with controls, PD patients showed significantly lower specific activities for complexes I+ III, II+III, and IV. However, citrate synthase corrected activities were similar in patients and controls. Values for enzyme activities in the PD group did not correlate with age at onset, duration, scores of the Unified Parkinson's Disease Rating Scales and Hoehn and Yahr staging. These results suggest that this tissue cannot be used to develop a diagnostic test for PD.

Aged↗
PubMed1999

Enzymatic rationale and preclinical support for a potent protein kinase C beta inhibitor in cancer therapy.

The macrocyclic bisindolylmaleimide, LY333531, selectively inhibits protein kinase C beta 1 and beta 2 isoforms with an approximate IC50 of 5 nanomolar. The efficacy of LY333531 administered alone and in combination with cytotoxic cancer therapies in models of non-small cell lung carcinoma and brain tumors was determined in vivo. In the Lewis lung carcinoma, administration of LY333531 enhanced the activity of paclitaxel and fractionated radiation and, to a lesser degree, carboplatin and gemcitabine. In the human T98G glioblastoma multiforme xenograft, the addition of LY333531 to treatment with carmustine (BCNU) resulted in enhanced tumor response in a nodule grown subcutaneously and increased life-span in animals bearing an intracranial tumor from 37 days in the control animals to 64 days in the BCNU treated animals, and to 104 days in the LY333531 plus BCNU treated animals with 4 out of 5 animals being long-term survivors.

Animals↗
PubMed1999

Short-term cyclosporine induces a remission of autoimmune hepatitis in children.

BACKGROUND/AIMS: The current immunosuppressive treatment of patients with autoimmune hepatitis consists of prednisone and azathioprine. High doses of prednisone used to obtain the remission of the disease are associated with serious adverse effects. To avoid harmful consequences of prednisone therapy, we proposed to treat patients with oral cyclosporine to obtain the remission of the inflammatory process. METHODS: This is a pilot, multinational, multicenter, clinical trial involving children with autoimmune hepatitis. Thirty-two children were recruited, who according to international criteria were considered as having definite autoimmune hepatitis. Cyclosporine alone was administered for 6 months, followed by combined low doses of prednisone and azathioprine for 1 month, after which cyclosporine was discontinued. Biochemical remission of the disease was established by the follow-up of serum transaminase activity levels. Growth parameters and adverse effects of the treatment were recorded. RESULTS: Two patients were withdrawn from the study: one for non-compliance and the other for liver failure which did not improve with cyclosporine. Of the 30 remaining patients, 25 normalized alanine aminotransferase activity levels by 6 months and all the patients by 1 year of treatment. Z-scores for height showed a trend towards improvement during treatment. Adverse effects of cyclosporine were mild and disappeared during weaning off the medication. CONCLUSIONS: Cyclosporine induced the biochemical remission of the hepatic inflammatory/necrotic process in children with autoimmune hepatitis, with few and well-tolerated adverse effects.

Adolescent↗
PubMed1999

Phase III trial of cyclophosphamide, epirubicin, fluorouracil (CEF) versus cyclophosphamide, mitoxantrone, fluorouracil (CNF) in women with metastatic breast cancer.

BACKGROUND: The mitoxantrone combination CNF and the epirubicin combination CEF have shown similar activity and less toxicity than the standard CAF combination in metastatic breast cancer (MBC). A prospective randomised study was started to compare safety and activity between CEF and CNF administered using a classical chemotherapeutic schedule in MBC. PATIENTS AND METHODS: From December 1987 to June 1993, 151 patients were randomised to receive cyclophosphamide (C) 100 mg m(-2) p.o. days 1-14, fluorouracil (F) 500 mg m(-2) i.v. days 1 and 8, and epirubicin (E) 30 mg m(-2) i.v. days 1 and 8, or mitoxantrone (N) 6 mg m(-2) i.v. days 1 and 8, every 4 weeks. Seventy-three patients were eligible for CEF and 72 for CNF. RESULTS: Objective responses were observed in 61.6% of the CEF group and 44.4% in CNF group (p = 0.004). The median duration of response was 64 weeks in CEF and 50 weeks in CNF group (p = 0.02) and median time to progression was 51 and 33 weeks, respectively (p = 0.0004). At the time of analysis, all except six patients (one in CNF and five in CEF) had died and the median survival time in the CEF group was longer than in CNF (74.4 weeks vs 51.4 weeks; log-rank chi2 test p = 0.015). CNF produced more hematologic toxicity than CEF (WHO scale; grades 2-4); leucopenia 84% vs 68% (p = 0.03) and thrombocytopenia 17% vs 4.5% (p = 0.01); CEF caused more grade 2 and 3 alopecia: 93% vs 70% (p = 0.001). CONCLUSION: The combination CEF using this schedule and dosage in metastatic breast cancer is more effective with less toxicity than CNF, except for alopecia, and was associated with longer survival.

Aged↗
PubMed1999

Coexpression of glucagon-like peptide-1 (GLP-1) receptor, vasopressin, and oxytocin mRNAs in neurons of the rat hypothalamic supraoptic and paraventricular nuclei: effect of GLP-1(7-36)amide on vasopressin and oxytocin release.

This study was designed to gain better insight into the relationship between glucagon-like peptide-1 (GLP-1) (7-36) amide and vasopressin (AVP) and oxytocin (OX). In situ hybridization histochemistry revealed colocalization of the mRNAs for GLP-1 receptor, AVP, and OX in neurons of the hypothalamic supraoptic and paraventricular nuclei. To determine whether GLP-1(7-36)amide alters AVP and/or OX release, both in vivo and in vitro experimental study designs were used. In vivo, intravenous administration of 1 microg of GLP-1(7-36)amide into the jugular vein significantly decreased plasma AVP and OX concentrations. In vitro incubation of the neurohypophysis with either 0.1 or 1 microg of GLP-1(7-36)amide did not modify the release of AVP. However, addition of 1 microg of GLP-1(7-36)amide to the incubation medium increased slightly the secretion of OX. The coexpression of GLP-1 receptor and AVP mRNAs in hypothalamic supraoptic and paraventricular nuclei gives further support to the already reported central effects of GLP-1 (7-36)amide on AVP. Our findings also suggest a dual secretory response of AVP and OX to the effect of GLP-1 (7-36)amide, which most likely is related to the amount and/or the route of peptide administration.

Animals↗