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Biomedical subjects

M A García

Publications and source records attributed to M A García.

At least 19 recordsLinked to original sources
PubMed1997

On the mechanism of action of ethodin in inducing myometrium contractions.

1. Ethodin (Rivanol, 6,9-diamino-2-oxyethyl acridine lactate), has been described as an effective drug to induce uterine contractions similar to those in a physiologic labor in still-birth with uterine inertia. We investigate the mechanisms involved in the effect of this compound in contracting the smooth-muscle cells of the myometrium to improve our understanding of the processes involved in the onset of labor. 2. We conclude that the contractile effect of ethodin is mediated through the activation of uterine mast cells that release mediators able to contract the myometrium.

Animals↗
PubMed1997

CYP2D6, NAT2 and CYP2E1 genetic polymorphisms in nonagenarians.

BACKGROUND: enzymatic polymorphisms affecting the metabolic disposition of xenobiotics may modulate the rate of activation or deactivation of carcinogens and other toxic environmental chemicals. Hence, these polymorphisms may influence the risk of suffering some types of cancer and other degenerative diseases that are incompatible with extreme longevity. AIMS: to establish the distribution of three well known enzymatic polymorphisms that affect the CYP2D6, NAT-2 and CYP2E1 genes and the activity of their enzymatic gene products, involved in the disposition of many xenobiotics, in a group of nonagenarians and in much younger controls. PATIENTS: the three genotypes were determined in 41 nonagenarians (10 males, mean age 92.2 years, range 90-98) free of known malignancies or neurodegenerative diseases. The control groups comprised 217 healthy volunteers (128 males, mean age 36.3 years; SD, 12.7) for the CYP2D6 and NAT2 genotypes and 137 (116 males, mean age 32 years; SD, 18.8) for the CYP2E1 genotype. METHODS: after extraction of DNA from white blood cells, polymerase chain reaction and restriction fragment polymorphism methods were used to identify the allelic variants of the three genotypes. RESULTS: we found no qualitative or quantitative difference in the mutations underlying the three genetic polymorphisms studied, nor in the expected enzymatic phenotypes. Instead, a close parallelism exists between advanced age and younger groups. CONCLUSION: longevity does not seem to be related to any special configuration of these three polymorphic traits. Comparisons with younger controls may be adequate when studying the distribution of these polymorphisms in diseases affecting old people. No genetically determined differences in the activation of drugs metabolized by these enzymes are to be expected in very old people.

Aged↗
PubMed1997

Enhanced diltiazem deacetylase activity in pre-term and full-term rabbits compared with adult rabbits.

The in vitro metabolic activity of the esterase responsible for the hydrolysis of diltiazem (DTZ) to its deacetylated metabolite (M1) was determined in an age-dependent fashion using the rabbit as an animal model. The presence of the enzyme in several tissues (liver, lung, small intestine, and brain) and in whole blood from pre-term and full-term fetuses, full-term newborns, yound and adult rabbits was examined. To this end, DTZ was spiked to 10,000-g tissue homogenates and whole blood to yield a final concentration of 1 microgram/ml. Serial samples were withdrawn from the incubation medium up to 240 min and assayed for DTZ and M1 concentration. In all tissues examined there was a net production of M1. Chemical breakdown and stability studies confirmed the metabolic origin of the M1 formed throughout the incubation. In pre-term fetuses (25 days of gestation) the brain was found to be the most active tissue in eliminating DTZ (brain > liver > lung > small intestine). This trend changed in young and adult rabbits (lung = brain > liver > small intestine). Although an important age-dependent DTZ deacetylase activity was observed in blood, it was not included in the comparison between organs because of the unequal composition of the incubation medium. In conclusion, results showed that fetuses and newborn rabbits have a similar, and in some instances higher, DTZ deacetylase activity to that in adults (p < 0.05). In vitro findings were further confirmed by in vivo experiments.

Aging↗
PubMed1996

Transcription factor AP-2 regulates human apolipoprotein E gene expression in astrocytoma cells.

Apolipoprotein E (apoE), one of the major plasma lipoproteins, also is expressed in a variety of cell types, including the glial cells of the nervous system. apoE is involved in processes of degeneration and regeneration after nerve lesions as well as in the pathogenesis of Alzheimer's disease (AD). Glial synthesis of apoE is activated in response to injury both in the peripheral and central nervous system. We now report that the activity of the proximal apoE promoter in astrocytes is upregulated by cAMP and retinoic acid, which act synergistically. Sequence analysis of the apoE promoter indicated the presence of several AP-2 consensus sequences that could mediate the stimulatory effect of cAMP and retinoic acid. The possible functional role of AP-2 was examined by cotransfection of AP-2-deficient HepG2 cells with an apoE promoter construct and a human AP-2 expression construct. Cotransfection with AP-2 significantly elevated apoE promoter activity. DNase I footprinting technique revealed the existence of two binding sites for recombinant AP-2 in regions from -48 to -74 and from -107 to -135 of the apoE promoter. Mutations in these regions markedly impaired the trans-stimulatory effect of AP-2. These results indicate the existence of functional AP-2 sites in the promoter region of apoE that could contribute to the complex regulation of this gene in developmental, degenerative, and regenerative processess of the nervous system.

Apolipoproteins E↗
PubMed1996

Deacetylation of diltiazem by several rabbit tissues.

PURPOSE: Diltiazem (DTZ) undergoes extensive metabolism yielding several metabolites, some of which retain a certain degree of pharmacological activity. N-demethylating activity has been detected mainly in the liver. Nevertheless, the organs involved in the formation of the deacetylated metabolite of DTZ (M1) have not been fully elucidated. In order to address this issue, we have carried out in vitro studies using the blood, lung, brain, small intestine, and liver as enzyme sources. METHODS: DTZ (1,000 ng/ml) was incubated in 10,000 x g supernatant homogenates of selected tissues or in whole blood for 240 minutes at 37 degrees C. Multiple samples were withdrawn, and DTZ and its metabolite M1 were assayed by HPLC. RESULTS: The apparent degradation rate constant of DTZ was in the rank order blood > lung > brain > liver > small intestine. This trend can also be observed for the AUC and for the percentage of DTZ metabolized. In all the tissue homogenates examined there was a net production of the deacetylated metabolite. The M1 metabolite was also detected in the blood (500 ng/ml after 240 minutes of incubation). CONCLUSIONS: The widespread distribution of the DTZ deacetylase activity described in this study suggests that extrahepatic metabolism of DTZ to M1 may play a relevant role in the overall pharmacokinetics of DTZ.

Acetylation↗
PubMed1996

Penetration of enrofloxacin and ciprofloxacin into breast milk, and pharmacokinetics of the drugs in lactating rabbits and neonatal offspring.

OBJECTIVE: To determine the pharmacokinetics and milk penetration of enrofloxacin (ENR) and ciprofloxacin (CIP) in lactating rabbits and their disposition in suckling rabbits. DESIGN: Prospective cross-over study. ANIMALS: 6 lactating New Zeland White rabbits and their offspring (16 days after parturition). PROCEDURE: Serial plasma and milk samples were assayed by use of a high-performance liquid chromatography technique. In vitro protein binding in plasma and skim milk was measured by ultrafiltration. Skim-to-whole milk ratio also was determined. The time course of ENR and CIP was fitted by nonlinear least squares regression analysis, and the pharmacokinetic variables were compared. RESULTS: The time courses of ENR and CIP in plasma were similar in lactating adult rabbits (mean body clearances, 23.9 and 27.2 ml/min/kg of body weight, for ENR and CIP, respectively). Observed milk-to-plasma ratios (M/P) were determined, using the area under the milk and plasma concentration versus time profiles (ENR, 2.59; CIP, 3.61). Predicted M/P (ENR, 6.35; CIP, 3.04) were calculated from in vitro measurements. Body clearance calculated for ENR and CIP in suckling rabbit pups involved a decrease of 80 and 74%, respectively, over that found in lactating animals. CONCLUSIONS: Observed CIP M/P were correlated to predicted values, which strengthens the argument that CIP passes into the milk by nonionic diffusion. The lack of correlation between observed and predicted ENR M/P pointed out that ENR undergoes faster elimination from milk than that predicted by the diffusional model. Diminished elimination capacity observed in suckling rabbits would result in greater exposure than that predicted from concentrations alone.

Animals↗
PubMed1995

Prognostic value of S-phase cells in AML patients.

Until now, reports on the cell cycle distribution of AML patients have shown highly variable results which are probably related to the technical heterogeneity of such studies. The aim of the present paper was to analyse in 204 AML patients at diagnosis the proliferative rate (assessed by the number of S-phase cells) of peripheral blood (PB) (126 cases) and bone marrow (BM) (78 cases) cells in order to explore its relationship with disease characteristics. A strong parallelism was observed regarding the relationship between the proliferative rate of the blast cells both in PB and in BM and the disease characteristics. Cases with a high proliferative rate were associated with advanced age, high WBC counts and LDH serum levels, monocytic leukaemias (assessed both by morphological and immunophenotypic criteria) and NK-associated antigens (CD56, CD16). The proliferative activity did not influence the CR rate; in contrast, cases with a high number of S-phase cells had shorter survival. In addition, multivariate analysis showed that age, the expression of CD11b, and the S-phase counts are the only three prognostic factors displaying an independent impact on survival.

Adult↗
PubMed1995

Light scatter characteristics of blast cells in acute myeloid leukaemia: association with morphology and immunophenotype.

AIMS: To analyse the forward scatter/side scatter (FSC/SSC) distribution of acute myeloblastic leukaemia (AML) blast cells in order to assess whether it correlates with their morphology, immunophenotype, and clinical and biological disease characteristics. METHODS: FSC/SSC patterns were established upon taking into account the localisation of the residual T lymphocytes in the FSC/SSC dot plot as an internal biological standard. One hundred and seventy one newly diagnosed AML patients were analysed and five different FSC/SSC patterns were established. These five patterns could be grouped into two major categories taking into account the FSC/SSC distribution of normal cells in a bone marrow aspirate: immature patterns (1 and 2) and mature patterns (3, 4, and 5). These FSC/SSC patterns were correlated with different clinical and biological characteristics of AML patients. RESULTS: No significant associations were detected in relation to the clinical and haematological disease characteristics and the prognosis of these patients. By contrast there was a significant correlation between the FSC/SSC pattern of the AML blast cells and the FAB classification. An increased reactivity for the antigens associated with myeloid differentiation such as CD13, CD33, CD11b, CD15, CD14, CD4, CD56, and/or CD16 was detected among cases showing a mature FSC/SSC pattern (3, 4, and 5), both in the whole series and even within each of the FAB AML subtypes. By contrast, the reactivity for the CD34 precursor cell associated antigen was higher among those cases displaying an immature FSC/SSC pattern, this being observed even within each FAB subgroup. CONCLUSIONS: The FSC/SSC pattern distribution of AML blast cells not only provides an additional objective and reproductible system for the classification of these leukaemias but it may also represent a connection between the FAB morphological groups and the immunophenotypic classification of AML patients.

Acute Disease↗
PubMed1995

Selective adverse reactions to diflunisal.

BACKGROUND AND OBJECTIVE: Diflunisal is a difluorophenyl derivative of salicylic acid. We report two patients who presented immediate adverse reactions to diflunisal (Dolobid) that consisted of generalized urticaria and chest tightness. METHODS: Diflunisal was conjugated to human serum albumin in order to perform in vivo and in vitro tests (skin prick and intradermal tests, leukocyte histamine release, and RAST). The patients were challenged following a single-blind, placebo-controlled oral procedure with diflunisal and other nonsteroidal antiinflammatory drugs. RESULTS: Skin tests with diflunisal were negative as were leukocyte histamine release tests and RAST in both patients. They tolerated therapeutic doses of aspirin, salsalate, salicylamide, lysine acetylsalicylate, acetaminophen, dipyrone, and propyfenazone. The oral provocation with diflunisal elicited an immediate response at the cumulative dose of 400 mg in both patients. CONCLUSION: These are two exceptional cases of selective adverse reactions to diflunisal with good tolerance to other salicylates and nonsteroidal antiinflammatory drugs. Thus, the inhibition of cyclooxygenase does not seem to be the mechanism involved. The pathogenic mechanism implicated in the reaction remains unclear, both idiosyncratic and immunologic mechanisms could explain our patients' adverse responses.

Aged↗
PubMed1994

[Extrinsic allergic alveolitis caused by Penicillium frequentans. Review and presentation of a case].

We present a case of extrinsic allergic alveolitis due to Penicillium frequentans exposure (suberosis) at a cork factory. Diagnosis was based on clinical history, a restrictive spirometric pattern, evidence of reticular-nodular lung infiltrates on the X-ray, intradermal skin tests with dual reaction and precipitins-positive serum samples in the presence of the P. frequentans fungus. Although the patient refused to submit to a specific bronchial challenge, two natural challenges occurred when he once again happened to handle wet cork after leaving his previous job. The literature referring to this disease is reviewed.

Adult↗
PubMed1994

A comparative study of nutrient digestibility, kinetics of digestion and passage and rumen fermentation pattern in goats and sheep offered medium quality forages at the maintenance level of feeding.

The in vivo digestibility and the rates of degradation and passage of alfalfa hay (AH) and vetch straw (VS) were compared in three Granadina goats and three Segureña wethers fed at approximately maintenance level, using a change over design. The nylon bag technique was used to estimate the fractional rate of degradation of the feeds in the rumen. The fractional outflow rate of hay and straw particles was determined with chromium as a marker. No significant differences in the digestibility coefficients of nutrients between animal species were found. Nitrogen retention expressed as coefficients of both nitrogen intake and digested nitrogen was lower (P < 0.01) in goats than in sheep when VS was offered. There was no significant difference between goats and sheep in the effective degradability (measured at outflow rates in the range of 0.027 to 0.032 h-1) of dry matter (DM) for either forage. However, the effective degradabilities of the neutral detergent fibre (NDF) and crude protein (CP) of VS were lower (P < 0.01 and P < 0.001, respectively), in goats than in sheep. The degradation rates of DM, NDF and CP were not significantly different (P > 0.05) between goats and sheep. Also, the fractional rate of passage of particles from the rumen was not different (P = 0.056) between species, although there was a tendency for an increased outflow rate in goats. In a second experiment the effects of animal species, type of diet and frequency of feeding on rumen fermentation pattern were studied following a factorial design. Four goats and four wethers were used. They were randomly allocated to three dietary treatments: AH, VS or a 50:50 mixture of AH and VS (AH/VS). Rations were offered in two or three meals daily and samples of rumen content were obtained at 09.00, 11.00, 13.00, 15.00, 17.00 and 19.00 h. No difference in rumen pH was found between goats and sheep. Total volatile fatty acids and ammonia concentrations were higher (P < 0.001) in sheep than in goats. The molar proportions of acetate and isovalerate were higher (P < 0.01 and P < 0.001, respectively) in goats than in sheep, whereas the opposite was true for the molar proportion of n-butyrate. Feeding frequency had a slight effect on the rumen parameters measured. It is concluded that only minor differences in the digestive capacity and rumen activity of sheep and goats can be expected when they are fed on medium quality forages.

Animal Feed↗
PubMed1994

Dystonic storms: a practical management problem.

On rare occasions, torsion dystonia can rapidly worsen and produce life-threatening symptoms. We present reports on two children who had generalized dystonia and who demonstrate the management difficulties of "dystonic storms."

Child↗