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Biomedical subjects

M Font

Publications and source records attributed to M Font.

At least 19 recordsLinked to original sources
PubMed2005

Effect of ME-3451-106, an aqueous extract of Stichaster striatus with inhibitory activity of voluntary alcohol intake, in genetically drinker rats: Isolation and identification of the active fraction.

The aqueous extract obtained from Stichaster striatus Müller & Troschel (Asteroidea, Stichasteridae) has been shown to possess activity as an alcohol appetite inhibitor after oral administration in a rat model with a genetically established excessive appetite for alcohol (Wistar rats, lineage UChB). A significant decrease in the consumption of ethanol was observed (unrelated to a possible disulfiram effect) without a change in the normal food or water intake during the experimentation period. A bio-guided fractionation of the extract was carried out in order to identify the most active fraction, in which the presence of a group of natural endogenous polyamines in undetermined proportions is suspected. Our hypothesis was to relate the activity obtained for the original ME-3451-106 extract with the presence of these polyamines in the extract in question. The activity shown by a series of commercially available polyamines (putrescine (Pu), spermidine (SPD) and spermine (SP)) in inhibiting voluntary ethanol intake lends support to our hypothesis. The extract was selected on the basis of oral tradition, which claimed that the consumption of a "soup" obtained by boiling starfish, later identified as Stichaster striatus, prevented the appearance of alcoholism in laborers on properties entrusted to the Jesuit order during the middle period of the Spanish conquest of America (17-18th century).

Alcohol Deterrents↗
PubMed2004

Two ellagitannins from the leaves of Terminalia triflora with inhibitory activity on HIV-1 reverse transcriptase.

The bioassay- guided fractionation of the aqueous extract of Terminalia triflora leaves afforded punicalin and 2-O-galloylpunicalin, isolated for the first time from this species. These compounds showed inhibitory activity on HIV-1 reverse transcriptase in a dose-dependent manner. Punicalin showed an IC(50) of 0.11 microg/ml (0.14 microM) and 2-O-galloylpunicalin an IC(50) of 0.10 microg/ml (0.11 microM).

Dose-Response Relationship, Drug↗
PubMed2002

Inhibitory effect against polymerase and ribonuclease activities of HIV-reverse transcriptase of the aqueous leaf extract of Terminalia triflora.

Dichloromethane, methanol and aqueous extracts from the leaves of Terminalia triflora were investigated for their inhibitory effect on polymerase and ribonuclease activities of HIV reverse transcriptase.The most potent activity was found in the aqueous extract, which inhibited both polymerase and ribonuclease activities of the enzyme with an IC50 of 1.6 micro g/mL and 1.8 micro g/mL respectively. The antiinfective activity of the extract was demonstrated in HLT4LacZ-IIIB cell culture with an IC50 of 1.0 micro g/mL. The extract was submitted to a purification process by extractive and chromatographic methods. The activity remained in the hydrophillic fraction. Tannins present in this active purified fraction, as determined by TLC and HPLC methods, could account for the anti HIV-RT activity found in the aqueous extract.

Anti-HIV Agents↗
PubMed2001

Double-blind olanzapine vs. haloperidol D2 dopamine receptor blockade in schizophrenic patients: a baseline-endpoint.

The aim of this study was to compare in vivo striatal D2 dopamine receptor occupancy induced by olanzapine and haloperidol in schizophrenic patients using a baseline-endpoint [(123)I]IBZM single photon computed emission tomography (SPECT) design. The relationships of striatal D2 receptor occupancy with clinical efficacy and extrapyramidal symptoms (EPS) were also assessed. Twenty-seven inpatients with schizophrenia or schizophreniform disorder were included in a 4-week prospective, randomized, double-blind, parallel and comparative clinical trial. Thirteen patients were treated with haloperidol (10 mg/day) and 14 with olanzapine (10 mg/day). Ratings of clinical status and EPS were obtained weekly. The percentage of D2 receptor occupancy was estimated by using basal ganglia (striatum)/frontal cortex IBZM uptake ratios obtained from each patient before and after 4 weeks of maintained antipsychotic treatment. Olanzapine led to a mean striatal D2 receptor occupancy of 49% (range 28-69%), which was significantly lower than that induced by haloperidol (mean 64%, range 46-90%). The baseline-endpoint SPECT design used in this study revealed lower antipsychotic D2 occupancy percentage values than those reported in the literature, using other approaches. The degree of striatal D2 receptor occupancy correlated to the EPS, which predominantly appeared in patients on haloperidol. No relationship was found between the striatal D2 receptor occupancy and clinical improvement. Olanzapine induced a lower striatal D2 occupancy than haloperidol. This low striatal D2 occupancy, together with the lower incidence of EPS in olanzapine-treated patients, contributed to confirm the atypical behavior of this new antipsychotic drug. Nevertheless, conclusions based on SPECT-estimated percentages of antipsychotic D2 occupancy should be cautious, since the SPECT design could influence the results. In this regard, SPECT studies including baseline and endpoint examinations should be encouraged.

Adult↗
PubMed2000

New antiherpetic 1,3-phenylene derivatives, inhibitors of the interaction of the HSV-1 origin binding protein (OBP) with DNA.

The synthesis of new 1,3-phenylene derivatives and their preliminary evaluation as antivirals (Herpes simplex 1, HSV-1) whose antiherpetic activity can be related with the inhibition of the interaction of the origin binding protein (OBP) with the DNA are presented. The new compounds are adjusted to a previously defined common structural model, consisting of a central aromatic system, which presents two side chains of different lengths in relative position 1, 3; these chains are made up of atomic groups characterized by the alternation of positive and negative centers, situating differently substituted rings, preferably aromatic, at the ends of both chains. Some of these derivatives, such as N,N''-(4-methoxy-1,3-phenylene)bis[N'-(4-nitrophenyl)urea] (2c) or (1,3-phenylene)bis[N-(p-tolyl)aminosulfonyl] (11b), show antiherpetic activity related to the proposed mechanism.

Animals↗
PubMed1999

Recombinant families locate the gene for non-type I cystinuria between markers C13 and D19S587 on chromosome 19q13.1.

Cystinuria is an autosomal recessive aminoaciduria in which three urinary phenotypes have been described. The gene responsible for type I, SLC3A1, encodes the amino acid transporter rBAT. This gene is not responsible for types II or III. Recently the type III locus (CSNU3) was mapped by two groups to overlapping 6-Mb regions on chromosome 19q. In the present study, we restrict the critical region for non-type I cystinuria to 2.4 Mb by recombination analysis in Italian, German, and Spanish families. For this purpose, we have used the microsatellite markers described in the region plus new microsatellites that we have developed. Our results locate the non-type I cystinuria gene in an interval flanked by the markers C13 and D19S587, which are about 2.8 cM apart.

Chromosome Mapping↗
PubMed1999

Synthesis and anti-HIV-1 activities of new pyrimido[5,4-b]indoles.

A set of new pyrimido[5,4-b]indole derivatives that are structurally related to some non-nucleside HIV-1 reverse transcriptase inhibitors were synthesized and biologically evaluated for their activity as inhibitors of wild and mutant HIV-1 RT types in an 'in vitro' recombinant HIV-1 RT screening assay, as well as anti-infectives in HLT4lacZ-1IIIB cells. Preliminary structure-activity relationships suggest that activity is promoted by simultaneous substitution in positions 2 and 4, especially when chains of alkyldiamine type are present, and by electron-releasing substituents (methoxy) in positions 7 and 8. The inactivity or the very low activity of title derivatives does not suggest interest in AIDS therapy.

Anti-HIV Agents↗
PubMed1999

Argentine plant extracts active against polymerase and ribonuclease H activities of HIV-1 reverse transcriptase.

Lipophilic and hydrophilic extracts of four Argentine plants (Gamochaeta simplicaulis Cabr. 1, Achyrocline flaccida Wein. D. C. 2, Eupatorium buniifolium H. et A. 3, and Phyllanthus sellowianus Muell. Arg. 4) were examined in vitro for their ability to inhibit the polymerase and ribonuclease H (RNase H) activities of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) (wild and Y181C mutant types). The active extracts were also examined as inhibitors of viral replication in HLT4LacZ-1IIIB cell cultures, evaluating their cytotoxicity in parallel. Infusions 2I and 4I, among the crude extracts, showed the highest activity. These extracts were refractioned into four fractions; 2I4 and 4I4 were active as inhibitors of DNA-polymerase (wild and Y181C types) and RNase H activities. These fractions were potent as inhibitors of viral replication and were not cytotoxic. Refractionation of 2I4 yielded five new fractions, two of which, 2I4-4 and 2I4-5, showed notable activity. Refractionation of 4I4 yielded for new fractions; of these, 4I4-3 and 4I4-4 were active. The marked biological activity found in the infusion of A. flaccida and P. sellowianus makes them sufficiently attractive to be considered in the combined chemotherapy of the disease.

Anti-HIV Agents↗
PubMed1999

Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (bo,+AT) of rBAT.

Cystinuria (MIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids. Mutations in SLC3A1, encoding rBAT, cause cystinuria type I (ref. 1), but not other types of cystinuria (ref. 2). A gene whose mutation causes non-type I cystinuria has been mapped by linkage analysis to 19q12-13.1 (Refs 3,4). We have identified a new transcript, encoding a protein (bo, +AT, for bo,+ amino acid transporter) belonging to a family of light subunits of amino acid transporters, expressed in kidney, liver, small intestine and placenta, and localized its gene (SLC7A9) to the non-type I cystinuria 19q locus. Co-transfection of bo,+AT and rBAT brings the latter to the plasma membrane, and results in the uptake of L-arginine in COS cells. We have found SLC7A9 mutations in Libyan-Jews, North American, Italian and Spanish non-type I cystinuria patients. The Libyan Jewish patients are homozygous for a founder missense mutation (V170M) that abolishes b o,+AT amino-acid uptake activity when co-transfected with rBAT in COS cells. We identified four missense mutations (G105R, A182T, G195R and G295R) and two frameshift (520insT and 596delTG) mutations in other patients. Our data establish that mutations in SLC7A9 cause non-type I cystinuria, and suggest that bo,+AT is the light subunit of rBAT.

Amino Acid Sequence↗
PubMed1998

The enzyme inducers 3-methylcholanthrene and phenobarbital affect the activities of glucocorticoid hormone-regulated enzymes in rat liver and kidney.

3-Methylcholanthrene, an inducer of P448-type cytochromes (mostly 1A1 and 1A2), and phenobarbital, an inducer of P450-type cytochromes (mostly 2B1 and 2B2), are prototypical for the actions of many xenobiotics. They cause endocrine disruption by affecting, among others, steroid hormone levels. Rats were treated with single bolus doses of 3-methylcholanthrene or phenobarbital, and enzyme activities that are controlled by glucocorticoids were measured in liver and kidney. The activities of the cytosolic enzymes L-alanine aminotransferase, indoleamine 2,3-dioxygenase (L-tryptophan pyrrolase), phosphoenolpyruvate carboxykinase, L-serine dehydratase and L-tyrosine aminotransferase were affected in a similar fashion: an initial activity reduction followed by two overshoots of activity 1 and 2 days after dosing. 3-Hydroxy-3-methylglutaryl coenzyme A reductase, the microsomal key enzyme of sterol synthesis, responded with a temporary reduction of activity only and evidently lost its diurnal rhythm. The time course of these changes is most likely caused by a combination of sub-physiological levels of glucocorticoids plus changes of other regulatory hormones elicited by feed intake, postprandial state, etc. A possible role for a combined action of the arylhydrocarbon (Ah) and glucocorticoid receptors in the effects of 3-methylcholanthrene is also suggested.

Animals↗
PubMed1997

Advanced HIV infection treated with zidovudine monotherapy: lifetime values of absolute cost-effectiveness as a pharmacoeconomic reference for future studies evaluating antiretroviral combination treatments. The Osservatorio SIFO sui Farmaci.

OBJECTIVE: This study was undertaken to evaluate the cost and the effectiveness of zidovudine monotherapy in patients with advanced HIV infection and to derive preliminary data on the cost-effectiveness of the triple treatment with saquinavir plus zalcitabine plus zidovudine compared with zidovudine alone. DESIGN: We used a combined method of survival analysis utilizing both the quality-adjusted time without symptoms or toxicity (Q-TWIST) method and the Gompertz approach. This combined method was applied to assess the absolute cost-effectiveness and cost-utility ratios of zidovudine monotherapy and to perform a preliminary incremental cost-effectiveness comparison of saquinavir plus zalcitabine plus zidovudine versus zidovudine alone. The clinical material used in our study was derived from two reports on the treatment of advanced HIV infection. Data of lifetime costs of HIV infection were obtained from published information. RESULTS: In patients with advanced HIV infection treated with zidovudine monotherapy, lifetime survival was 252.1 discounted person-years per 100 patients. Using an average lifetime cost of $93,000 (discounted) per individual, the absolute ratio of cost-effectiveness for zidovudine monotherapy was $36,980 per life-year, while the absolute cost-utility ratio was $47,112 per quality-adjusted life-year. In the comparative analysis of saquinavir plus zalcitabine plus zidovudine versus zidovudine alone, our calculations showed that the administration of the triple treatment can have an "average" cost-effectiveness, provided that mean lifetime survival per patient (discounted) is improved to at least 3.68 years (with an average survival gain of at least 14 mo per patient). CONCLUSIONS: The values of absolute cost-effectiveness and cost-utility ratios for zidovudine monotherapy are a useful reference point for further pharmacoeconomic studies in the area of antiretroviral drugs.

Anti-HIV Agents↗
PubMed1997

Structure-activity relationships in quinoline Reissert derivatives with HIV-1 reverse transcriptase inhibitory activity.

The relationship between the chemical structure and the HIV-1 RT inhibitory activity has been studied for a series of quinoline derivatives. Two methods were used: a standard QSAR analysis, by combining the methods of Hansch and Free-Wilson, and an analysis using quantum chemistry indices as descriptor parameters, by the semiempirical method AM1. The equations obtained lead to the proposal that the activity of the compounds increases, mainly, with the presence of electron-withdrawing substituents in position 6 of the quinoline ring that cause a decrease in the energy from the molecular orbital LUMO. In turn, this fact leads to the proposal that the most important interaction of these compounds with the HIV-1 RT is a charge transfer type interaction, with the quinoline aromatic ring acting as acceptor.

Anti-HIV Agents↗
PubMed1997

Synthesis and evaluation of new Reissert analogs as HIV-1 RT inhibitors. 2. Benzo[f]quinoline and pyridine derivatives.

The synthesis and preliminary evaluation of new benzo[f]quinoline and pyridine derivatives, obtained by application of the Reissert method and its modifications, as HIV-1 RT inhibitors and anti-infectives are presented. The most active products against HIV-1 RT wild type are the ethyl 2-cyano-1,2-dihydrobenzo[f]quinoline-1-carboxylate 2b, propyl 2-cyano-1,2-dihydrobenzo[f]quinoline-1-carboxylate 2c, and 2-cyano-1-(2'-furoyl)-1,2-dihydrobenzo[f]quinoline 2n, which maintain their activity against the mutant type P236L, resulting inactive against the Y181C type. Using the data previously obtained by our research team for analogous series derived from quinoline as reference, the compounds which have now been obtained present an increase in the cytotoxic character attributable to the introduction of a benzene ring fused with the quinoline base nucleus, as well as a decrease of the activity as HIV-1 RT inhibitors when the quinoline benzenic ring is eliminated.

Anti-HIV Agents↗
PubMed1997

Synthesis and evaluation of new Reissert analogs as HIV-1 reverse transcriptase inhibitors. 1. Quinoline and quinoxaline derivatives.

The synthesis and preliminary evaluation of new quinoline and quinoxaline derivatives (obtained by applying the original Reissert method, conveniently modified) as HIV-1 Reverse Transcriptase (RT) inhibitors are presented in this paper; likewise, the first structure-activity relationships are also proposed. Propyl 2-cyano-1(2H)-quinolin-carboxylate 2e, isopropyl 2-cyano-1 (2H)-quinolincarboxylate 2f, butyl 2-cyano-1 (2H)-quinolincarboxylate 2g and isobutyl 2-cyano-1 (2H)-quinolincarboxylate 2h have been selected as lead compounds. These compounds are active against the HIV-1 RT mutant type P236L (2f, IC50 = 1.2 microM) and present activity as anti-infective agents in HLT41acZ-1IIIB cells, showing no cytotoxicity at the active concentrations.

Anti-HIV Agents↗
PubMed1995

New indole and pyridazinoindole analogs--synthesis and study as inhibitors of phosphodiesterases and as inhibitors of blood platelet aggregation.

This paper presents the synthesis of new indole, pyridazino[4,5-b]-indole, and pyridazino[4,5-a]indole analogs as well as a study of their "in vitro" activity as inhibitors of different phosphodiesterases isolated from dog cardiac tissue, dog aorta, and bovine platelets; the study of their activity as inhibitors of platelet aggregation in guinea pig whole blood, with ADP and arachidonic acid (AA) as pro-aggregants, is also included. The selected compounds 8-benzyloxy-3,4-dihydro-1-(3,4,5-trimethoxy)benzylideneaminopyridazin o[4,5- b]indole 14g, and 8-benzyloxy-4-[(3,4-dimethyl)pyrazolyl]pyridazino[4,5-b]indo le 20 present an interesting profile as potential inodilators, with a complementary, beneficial activity as inhibitors of the aggregation, activities which could possibly be related to the inhibition of the PDE's. Among the other compounds studied, 8-benzyloxy-3,4-dihydro-1-[4-(methyl)piperazino]acetamidopyrida zino[4,5- b]indol-4-one 16c and 8-benzyloxy-3,4-dihydro-1-[4-(2- methoxyphenyl)piperazino]acetamidopyridazino[4,5-b]indol-4-o ne 16f stood out as inhibitors of platelet aggregation, with a mechanism that could possibly be related to the AA cascade.

Animals↗
PubMed1993

New 4-amino-7,8-dimethoxy-5H-pyrimido[5,4-b]indole derivatives: synthesis and studies as inhibitors of phosphodiesterases.

A series of 4-amino-7,8-dimethoxy-5H-pyrimido[5,4-b]indole derivatives has been synthesized. These compounds resemble carbazeram and other pyridazino compounds with activity in the cardiovascular system. Some of these new compounds possess inotropic activity (Table 2), with a complementary effect on the inhibition of different CGI-PDE (Table 3). The most active compounds 5, 6d, and 7 also possess activity as vasodilators (Table 4). Some of these new compounds inhibit blood platelet aggregation induced by ADP and AA and are active as inhibitors of human platelet PDEs (Tables 5 and 6).

Animals↗
PubMed1993

A novel class of cardiotonic agents: synthesis and biological evaluation of pyridazino[4,5-b]indoles with cyclic AMP phosphodiesterases inhibiting properties.

Some fused pyridazino[4,5-b]indoles (7) were synthesized. These new compounds present a planar topography and some resemblance to carbazeram, imadozan, and other pyridazino agents with cardiotonic activity. These compounds also possess a complementary effect as inhibitors of platelet aggregation. 6-(3,5-Dimethylpyrazolyl)-1,2,4-triazolo[4,3-b]pyridazino[4, 5-b]indole (7a) has a good profile as an inodilatador with antiaggregate activity due to the inhibition of phosphodiesterase.

3',5'-Cyclic-AMP Phosphodiesterases↗