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Biomedical subjects

A R Fernández

Publications and source records attributed to A R Fernández.

12 recordsLinked to original sources
PubMed2005

Trypanosoma cruzi: chemotherapeutic effects of clomipramine in mice infected with an isolate obtained from an endemic area.

The susceptibility of Trypanosoma cruzi strains to nifurtimox and benznidazole has been investigated and resistant strains have been described. Some tricyclic drugs are lethal for trypomastigote and epimastigote forms of T. cruzi (Tulahuen strain) and prevent the disease in mice. We investigated whether clomipramine, a tricyclic antidepressant drug with anti-trypanothione reductase and anti-calmodulin effects, could be effective in treating Albino Swiss mice infected with trypomastigotes of a new T. cruzi isolate from a chronic patient from an endemic area of Argentina in two different treatment schedules. Both treatment schedules were effective in reducing electrocardiographic changes and preventing myocardial structural damage. The cardiac beta-receptors low affinity was compensated for by an increment in their density. This probably maintained cardiac function since 70% of the mice survived for more than 2 years even though anti-cruzipain titers remained high. These results demonstrate that clomipramine, clinically used as a neuroleptic, could be a promising trypanocidal agent for the treatment of Chagas' disease.

Animals↗
PubMed2004

Thioridazine treatment prevents cardiopathy in Trypanosoma cruzi infected mice.

Trypanosoma cruzi trypanothione reductase is an enzyme that has been identified as a potential target for chemotherapy. Thioridazine inhibits it and prevented cardiopathy in mice infected with T. cruzi Tulahuen strain. As not all T. cruzi strains respond to treatment in the same way, an isolate from a chronic patient (SGO Z12) was used; parasitaemias were studied along with, survival, serology, electrocardiography, histology and cardiac beta receptor function. Parasitaemia in thioridazine (80 mg/(kg day) for 3 days) treated mice was less and lasted for a shorter period (P < 0.01), there were reduced electrocardiographic and histological alterations and significantly improved survival (80% of non-treated died). Treated mice had lower receptor affinity and higher density as a compensatory mechanism, modifying the course of T. cruzi infection (SGO Z12 isolate) and preventing the consequent cardiopathy.

Animals↗
PubMed2001

Uterus inferior segment compression as a clinical test for diagnosing nuchal cord.

To investigate sensitivity, specificity, positive and negative predictive values and accuracy of uterus inferior segment compression (UISC) as clinical test for diagnosing nuchal cord. This test is used empirically. The clinical test was applied to 214 pregnant women in the first phase of delivery with single cephalic fetuses. The main observation was deceleration of the fetal heart rate by performing the clinical test in the presence of nuchal cord. Statistic analysis was done by chi2-test. The results were: sensitivity 35.7%, specificity 84.8%, positive predictive value 45.4%, negative predictive value 78.8% and accuracy 71.9% (chi2=10.66, p=0.0011). The UISC could be used as a tool in the initial exploration of the term pregnant woman in labor without complications to rule out the presence of nuchal cord. When the UISC test is positive, close vigilance is recommended along with the availability of an emergency team in case of fetal distress.

Adolescent↗
PubMed1999

Trypanosoma cruzi: increased 5'-nucleotidase activity associated with dysfunction of adrenergic receptors in acutely infected albino Swiss mice.

Adenosine, derived from hydrolysis of 5'-AMP by 5'-nucleotidase activity, may be involved in coupling coronary blood flow to cardiac function and metabolism; it has been postulated as a cardioprotective substance in ischemic myocardium. The stimulation of beta-adrenergic receptors produces an increase in adenosine by 5'-AMP hydrolysis. In addition, it has been demonstrated that in Chagas' disease there is decreased cardiac perfusion. We show in this paper by histochemical and densitometric procedures that ecto-5'-nucleotidase activity increases in ventricles of acutely Trypanosoma cruzi-infected mice and that the density of beta-adrenergic receptors is significantly diminished with affinity similar to controls, showing that a compensatory mechanism was absent. The increase of ecto-5'-nucleotidase in heart myocytes from infected mice may produce cardioprotective adenosine that may be independent of beta-adrenergic function, based on the hypoperfusion conditions of acute chagasic cardiomyopathy.

5'-Nucleotidase↗
PubMed1999

Thioridazine treatment modifies the evolution of Trypanosoma cruzi infection in mice.

Thioridazine, a tricyclic drug, is known to have a direct effect on Trypanosoma cruzi, disrupting the parasites' mitochondria and kinetoplasts. In the present study, the drug was used orally, at 80 mg/kg.day for 3 days, to treat mice inoculated with low numbers of T. cruzi. The drug caused no apparent toxicity in the host. It cleared trypomastigotes from the bloodstream, prevented the histological and functional alterations of the heart normally observed in the chronic phase of the experimental disease, and greatly reduced the mortality rate compared with that in untreated, infected controls. When checked 135 days post-infection, the density of cardiac beta receptors and the cardiac histology of the treated mice were indistinguishable from those of uninfected, untreated controls. The drug is already used to treat humans, as a neuroleptic drug. It appears to be able to prevent acute infection with T. cruzi evolving into chronic disease, at least in mice, and may be a useful base from which to design new agents for the treatment of Chagas disease.

Animals↗
PubMed1998

Structural, ultrastructural studies and evolution of Trypanosoma cruzi-infected mice treated with thioridazine.

Thioridazine (THI) is a tricyclic drug that belongs to the phenothiazine series. THI had a lethal effect upon epimastigotes in culture medium in a concentration of 0.5 microM. Trypanocidal effect upon trypomastigotes of Trypanosoma cruzi was observed above 0.5 mM of THI. Ultrastructural studies showed intracellular vacuoles in both parasite forms and mitochondrion reorganization. To analyze the use of THI as a therapy, male mice were inoculated with 7.10(4) trypomastigotes of T. cruzi, Tulahuen strain, and treated with THI for 3 days, with 80 mg/kg/day. Survival and parasitemia of mice treated with lower doses were similar to those observed in the control group (14 days postinfection). THI treatment modified parasitemia levels. They were negative by day 20 p.i. Hearts from control untreated mice presented typical chagasic myocarditis. Hearts from THI-treated mice sacrificed by day 30 p.i. showed inflammatory infiltrates without amastigote nests. Three months postinfection a mild infiltrate located in the interventricular septum was observed. Survival of this group was 9 months. Present results show that THI had a direct effect upon parasitemia, improved survival of treated mice, and modified the evolution of experimental Chagas disease.

Animals↗
PubMed1998

Automated peritoneal dialysis: a Spanish multicentre study.

BACKGROUND: A prospective sequential study on continuous ambulatory peritoneal dialysis (CAPD) and three techniques of automated peritoneal dialysis (APD) was conducted to assess peritoneal clearances, the influence of peritoneal permeability on nocturnal APD clearances and the suitability of the peritoneal equilibration test (PET) for predicting clearances on APD. METHODS: After performing a PET, a series of clinical, biochemical and dialysis adequacy markers were evaluated after 2 months on CAPD, continuous cycling peritoneal dialysis (CCPD) and tidal volume peritoneal dialysis (TPD) with 50% and 25% tidal volumes. Forty five patients participated and 33 completed the study. RESULTS: Serum urea and creatinine decreased significantly whereas haemoglobin and glucose increased. Mean peritoneal urea clearance (1/week) was 55.40+/-8.76 on CAPD, 74.82+/-12.62 on CCPD, 69.20+/-14.63 on TPD (tidal 50%) and 66.89+/-13.23 on TPD (tidal 25%); mean creatinine clearance (1/week/1.73 m2) was 42.80 +/- 9.95, 52.19 +/- 11.11, 51.31 +/- 13.3 and 49.17 +/- 11.83, respectively. Both clearances were significantly lower on CAPD than on APD (P<0.001). CCPD was the automated technique that provided the best nocturnal urea clearance (P<0.01). Nocturnal creatinine clearance did not show significant differences between CCPD and TPD (tidal 50%), being better with both techniques than with TPD (tidal 25%). There were statistically significant differences between nocturnal dialysate to plasma (D/P) ratios and those corresponding to the nearest times in the PET. The urea D/P ratio at 180 min and the creatinine D/P ratio at 240 min of the PET were the parameters that better estimated nocturnal clearances on APD. CONCLUSIONS: This study confirms that TPD does not improve the results of CCPD. Significant differences between D/P ratios during actual nocturnal cycles and PETs were observed.

Aged↗
PubMed1997

Trypanocidal effects of promethazine.

Promethazine is currently used for its antipsychotic and ansiolytic effects. It is a phenothiazine with anticalmodulin action, not toxic for human beings at therapeutic doses. The present results show that promethazine has trypanocidal effect on both epimastigote and trypomastigote stages of T. cruzi; two hundred microM inhibited epimastigote growth in culture medium and 2 microM immobilized and killed bloodstream trypomastigotes. When promethazine (55 mg/Kg/day) was used as treatment of T. cruzi infected mice, it proved effective in reducing parasitemia and it increased the survival of treated animals. Ultrastructural studies suggest that the lethal effect of this phenothiazine is related to a detergent effect that disrupts T. cruzi cell membrane.

Animals↗
PubMed1996

Cardiac beta receptors' density or affinity modified by different Trypanosoma cruzi amount.

Chagas' disease presents complex physiopathogenic mechanism, many of them poorly understood, that in our country generally produce cardiac lesions. The acute phase related with the presence of the parasite is usually asymptomatic. This report studies if the amount of T. cruzi that induced acute infection could modify the myocardiopathy evolution. Previous works have shown that Albino Swiss mice inoculated with 45 tripomastigotes (AcL) presented alterations in the cardiac pharmacological response to adrenergic agonist and antagonist studied at 30 days post-infection (p.i). Mice inoculated with 7 x 10(4) parasites/animal showed similar behaviour at 7 days p.i. We studied the involvement of the affinity and density of cardiac beta receptors in both acute groups by binding with 3H/DHA. The AcH group presented less cardiac beta receptors number (p < 0.001), but their affinity was conserved. The AcL model presented significantly less affinity (p < 0.01) but density was not different from non infected animals. beta receptors' affinity of both infected groups were similar, but AcH density was significantly diminished when compared with AcL. These studies demonstrates that the amount of T. cruzi received by the host determines and acelerates the evolution of the chagasic myocardiopathy.

Acute Disease↗
PubMed1992

Isometric developed tension and histopathology of myocardium of chagasic mice. II.

In a preceding paper we reported the evolution of chagasic cardiopathy in mice inoculated with low number of T. cruzi from 2 days to 75 days post-infection (p.i.). The present work analyzed the contractility, pharmacological response and histopathology of myocardium isolated from chronic chagasic mice from 90 days until 180 days. p.i. Myocardium contractile force reached values similar to controls until 165 days p.i. From this to the end contractility was significantly lower. At 90 days p.i. NE provoked negative inotropic effect or had no effect in 13% of the cases tested. The others had a reactivity to NE similar to normal ventricles. From 105 days until 180 days p.i. NE induced to a positive inotropic effect significantly lower than in normal. ACh effect was significantly smaller from 165 days to the end. Previously ACh ventricles responses were as control. The effects of dibenamine, propranolol and atropine (10-6M) on chagasic ventricles were similar to those observed in normal tissues. At 90 days p.i. the histopathology showed focalized inflammatory infiltrates. At 180 days p.i. fibers fragmentations and loss of typical striated characteristic of cardiac tissue. The abnormal pharmacological response described could be attributed to alterations in cardiac beta and muscarinic receptors probably due to a lower oxygen support. The present paper shows that during chronic Chagas' disease myocardial function and pharmacological reactivity are seriously and definitively compromised.

Acetylcholine↗
PubMedDate not supplied

Effects of clomipramine on Trypanosoma cruzi infection in mice.

Trypanosoma cruzi, widely distributed in Latin American countries, provokes Chagas disease, characterized by cardiomyopathy and mega-viscera. The drugs used currently for treatment of acute Chagas disease are highly toxic; the side-effects are undesirable and patients may abandon treatment. We have previously demonstrated that clomipramine (CLO) exerts trypanocidal effects upon epimastigotes and trypomastigotes in vitro with anticalmodulin activity. The present study analyses the effectiveness of CLO treatment in mice infected with a low number of T. cruzi, an animal model that reproduces acute, indeterminate and chronic phases of this trypanosomiasis. In this work, our results demonstrated that CLO 5 mg/kg daily for 30 days, or 2 doses of CLO 40 mg/kg given intraperitoneally at 1 h and 7 days after infection, was not toxic for the host, but was effective against the parasite in that parasitaemias became negative and only mild heart structural and electrocardiographic alterations were detected in the chronic phase in the group treated with CLO 5 mg/kg. In mice treated with CLO 40 mg/kg, none of these alterations was detected. Cardiac beta receptor density and affinity returned to normal in the chronic stage in both experimental groups. T. cruzi enzymes such as calmodulin and trypanothione reductase represent potential drug targets. It has been reported that both can be inhibited by CLO, a tricyclic drug used in clinical therapeutics. We have shown that CLO strongly decreased the mortality rate and electrocardiographic alterations; in addition cardiac beta receptor density and heart histology returned to, or close to, normality 135 days post infection. These results clearly demonstrated that CLO treatment modified significantly the natural evolution of T. cruzi infection.

Animals↗