Angela Avila - Academia.edu (original) (raw)

Papers by Angela Avila

Research paper thumbnail of Increase in asialoganglioside- and monosialoganglioside-reactive antibodies in chronic Chagas' disease patients

The American Journal of Tropical Medicine and Hygiene, 1998

Antibodies reactive with the core glycan of asialoganglioside (GA1), monosialoganglioside (GM1), ... more Antibodies reactive with the core glycan of asialoganglioside (GA1), monosialoganglioside (GM1), and disialoganglioside (GD1a) were studied in human sera. In healthy individuals, GA1-, GM1-, and GD1a-reactive antibodies were mainly of the IgM class, but also of the IgA and IgG classes, and were present at low titers in the serum of 68%, 79%, and 91% of the individuals studied, respectively. Levels of anti-GA1 and anti-GM1 antibodies, mainly of the IgA and IgG classes, were significantly elevated (P Ͻ 0.001) in 62% and 72% of subjects, respectively, chronically infected with Trypanosoma cruzi, with no association found with the degree of myocardial damage. No significant increase in anti-GA1 and anti-GM1 antibodies was found in dilated cardiomyopathy patients. The level of anti-GD1a antibody was not significantly different between healthy controls and chronic chagasic or dilatatory cardiomyopathy patients. Since the peripheral nervous system is very rich in gangliosides, it is possible that the increases in GA1-and GM1-specific antibodies that develop during chronic T. cruzi infection are involved in the pathology of peripheral neuropathy in Chagas' disease.

Research paper thumbnail of Correlation of sinefungin susceptibility and drug-affinity for protein carboxymethyltransferase activity in American Leishmania species

Molecular and Biochemical Parasitology, 1987

Among promastigotes of 22 different American Leishmania strains, a 5000-fold variation in sinefun... more Among promastigotes of 22 different American Leishmania strains, a 5000-fold variation in sinefungin susceptibility was found, apparently independent of their taxonomic classification, although L. mexicana strains did tend to be more resistant than L. braziliensis. Protein carboxymethyltransferase (EC 2.1.1.24) and glycine N-methyltransferase (EC 2.1.1.20) activities were not substantially different in sinefungin-susceptible and -resistant American Leishmania strains. However, when [methyl-3H]methionine incorporation into total protein or gamma-glutamyl residues of leishmanial proteins was carried out in the presence or absence of sinefungin, protein carboxymethylating activity was significantly inhibited only in sinefungin-susceptible Leishmania strains. Furthermore, when protein carboxymethyltransferase activity was purified from several leishmanial strains to a state of electrophoretic homogeneity (sp. act. = 240 nmol h-1 (mg protein)-1), the enzyme from the resistant cells showed a higher inhibition constant (mean Ki 55 microM against 2 microM in susceptible cells) for sinefungin. This 28-times stronger affinity of the susceptible cell enzyme towards sinefungin despite normal protein carboxymethyltransferase specific activity seems to be a key element of the resistance mechanism of certain American Leishmania strains.

Research paper thumbnail of Differential metabolism of allopurinol and derivatives in Trypanosoma rangeli and T. cruzi culture forms

Molecular and Biochemical Parasitology, 1981

We have compared the metabolism of allopurinol (4-hydroxypyrazolo(3,4-d)pyrimidine; HPP), by Tryp... more We have compared the metabolism of allopurinol (4-hydroxypyrazolo(3,4-d)pyrimidine; HPP), by Trypanosoma rangeli, a non-pathogenic American trypanosome, and T. cruzL the causative agent of Chagas' disease. Our results indicate that T. rangeli was unable to animate allopurinol mononucleotide to 4-aminopyrazolopyrimidine (APP) mononucleotide. Radioactivity was located in the RNA, but not the DNA, only of T. cruzi. Substrate specificity studies showed T. cruzi suecino-AMP synthetase activity being 100-fold more active on HPP mononueleotide than the T. rangeli enzyme. These results possibly explain the fact that in conventional LIT medium T. rangeli growth was resistant to high concentrations of HPP. However the incubation of this hemoflageliate in an adenine-depleted LIT medium rendered it sensitive to low concentrations of APP, while remaining resistant to HIP. In contrast, and independently of the culture medium used, T. cruzi was extremely sensitive to both pyrazolopyrimidines.

Research paper thumbnail of Differential metabolism of allopurinol and derivatives in Trypanosoma rangeli and T. cruzi culture forms

Molecular and Biochemical Parasitology, 1981

We have compared the metabolism of allopurinol (4-hydroxypyrazolo(3,4-d)pyrimidine; HPP), by Tryp... more We have compared the metabolism of allopurinol (4-hydroxypyrazolo(3,4-d)pyrimidine; HPP), by Trypanosoma rangeli, a non-pathogenic American trypanosome, and T. cruzL the causative agent of Chagas' disease. Our results indicate that T. rangeli was unable to animate allopurinol mononucleotide to 4-aminopyrazolopyrimidine (APP) mononucleotide. Radioactivity was located in the RNA, but not the DNA, only of T. cruzi. Substrate specificity studies showed T. cruzi suecino-AMP synthetase activity being 100-fold more active on HPP mononueleotide than the T. rangeli enzyme. These results possibly explain the fact that in conventional LIT medium T. rangeli growth was resistant to high concentrations of HPP. However the incubation of this hemoflageliate in an adenine-depleted LIT medium rendered it sensitive to low concentrations of APP, while remaining resistant to HIP. In contrast, and independently of the culture medium used, T. cruzi was extremely sensitive to both pyrazolopyrimidines.

Research paper thumbnail of Therapy of Venezuelan patients with severe mucocutaneous or early lesions of diffuse cutaneous leishmaniasis with a vaccine containing pasteurized Leishmania promastigotes and bacillus Calmette-Guerin: preliminary report

Memórias do Instituto Oswaldo Cruz, Mar 31, 2004

Severe mucocutaneous (MCL) and diffuse (DCL) forms of American cutaneous leishmaniasis (ACL) are ... more Severe mucocutaneous (MCL) and diffuse (DCL) forms of American cutaneous leishmaniasis (ACL) are infrequent in Venezuela. Chemotherapy produces only transitory remission in DCL, and occasional treatment failures are observed in MCL. We have evaluated therapy with an experimental vaccine in patients with severe leishmaniasis. Four patients with MCL and 3 with early DCL were treated with monthly intradermal injections of a vaccine containing promastigotes of Leishmania (Viannia) braziliensis killed by pasteurization and viable Bacillus Calmette- Guerin. Clinical and immunological responses were evaluated. Integrity of protein constituents in extracts of pasteurized promastigotes was evaluated by gel electrophoresis. Complete remission of lesions occurred after 5-9 injections in patients with MCL or 7-10 injections in patients with early DCL. DCL patients developed positive skin reactions, average size 18.7 mm. All have been free of active lesions for at least 10 months. Adverse effect...

Research paper thumbnail of Therapy of Venezuelan Patients with Severe Mucocutaneous or Early Lesions of Diffuse Cutaneous Leishmaniasis with a Vaccine

Severe mucocutaneous (MCL) and diffuse (DCL) forms of American cutaneous leishmaniasis (ACL) are ... more Severe mucocutaneous (MCL) and diffuse (DCL) forms of American cutaneous leishmaniasis (ACL) are infre-quent in Venezuela. Chemotherapy produces only transitory remission in DCL, and occasional treatment failures are observed in MCL. We have evaluated therapy with an experimental vaccine in patients with severe leishmania-sis. Four patients with MCL and 3 with early DCL were treated with monthly intradermal injections of a vaccine containing promastigotes of Leishmania (Viannia) braziliensis killed by pasteurization and viable Bacillus Calmette-Guerin. Clinical and immunological responses were evaluated. Integrity of protein constituents in extracts of pasteurized promastigotes was evaluated by gel electrophoresis. Complete remission of lesions occurred after 5-9 injections in patients with MCL or 7-10 injections in patients with early DCL. DCL patients developed positive leishmanin skin reactions, average size 18.7 mm. All have been free of active lesions for at least 10 months. Ad...

Research paper thumbnail of Chemotherapy with ethidium bromide-DNA complex in established Chagas' disease

The American journal of tropical medicine and hygiene, 1979

Two different strains of mice (AKR and NMRI-IVIC) were inoculated intraperitoneally with the viru... more Two different strains of mice (AKR and NMRI-IVIC) were inoculated intraperitoneally with the virulent Y strain of Trypanosoma cruzi, and then treated with the lysosomotropic ethidium bromide-DNA complex, according to several different treatment schedules. When animals were treated 48 hours after intraperitoneal inoculation with three intraperitoneal doses of EB-DNA no parasitemia was detected, even after 11 weeks, confirming previous results. However, when infection was allowed to become fully established, that is 3-4 weeks after inoculation, and then challenged with several different treatment schedules (with varied doses and timing of administration) we failed to cure established Chagas' disease, suggesting that the claim of effectiveness for this EB-DNA complex is limited to early Chagas' disease.

Research paper thumbnail of Specific inhibitory effect of 3-deazaneplanocin A against several Leishmania mexicana and L. braziliensis strains

The American journal of tropical medicine and hygiene, 1997

The growth inhibitory effect of 3-deazaneplanocin A (c3NpcA) was tested against some pathogenic m... more The growth inhibitory effect of 3-deazaneplanocin A (c3NpcA) was tested against some pathogenic members of the family of American Trypanosomatidae. Under our culture conditions, c3NpcA displayed a strongly and uniformly leishmanistatic effect on all 23 American Leishmania (L. mexicana and L. brasiliensis) strains in the study (mean dose producing 50% inhibition compared with control parasite growth [ID50] = 96 ng/ml, 0.32 microM), but showed no inhibition against the several T. cruzi and T. rangeli strains tested with concentrations up to 10,000 ng/ml. This compound also induced a substantial expansion of the intracellular pools of both S-adenosylhomocysteine (AdoHcy) and S-adenosylmethionine (AdoMet), as well as a significant diminution of the AdoMet:AdoHcy ratio. Strong AdoHcy hydrolase activity was detected in American Leishmania promastigotes. At at a dose of 200 ng/ml, c3NpcA inhibited S-adenosyl-L-3H-methylmethionine and 3-thymidine incorporation by promastigotes after four da...

Research paper thumbnail of Inhibitory effects of sinefungin and its cyclic analog on the multiplication of Trypanosoma cruzi isolates

The American journal of tropical medicine and hygiene, 1993

Sinefungin and its cyclic analog were evaluated in vitro for activity against the multiplication ... more Sinefungin and its cyclic analog were evaluated in vitro for activity against the multiplication of Trypanosoma cruzi. When either drug was tested for eight days on twelve T. cruzi epimastigote isolates, an 800-fold difference in drug sensitivity was found. Both drugs were trypanostatics at a concentration range from 0.1 micrograms/ml to 300 micrograms/ml. The 50% effective concentration (EC50) of sinefungin and its cyclic analog at which the growth of a given isolate was inhibited was 0.38 micrograms/ml for sinefungin and 0.31 micrograms/ml for the cyclic analog against the Ma, Marin, OPS-86, Y, and Ya isolates, and > 300 micrograms/ml for sinefungin and 217 micrograms/ml for the cyclic analog against the A-35, Bertoldo, DS, EP, ES, OPS-58, and FL isolates. Incubation of drug-sensitive isolates for more than 10 days in glucose-saline (GS) medium, but not in minimal essential medium, in the presence of a 30-fold EC50 concentration of the drug induced an increase in the drug-resis...

Research paper thumbnail of Defective transport of pyrazolopyrimidine ribosides in insensitive trypanosoma cruzi wild strains is a parasite-stage specific and reversible characteristic

Comparative Biochemistry and Physiology Part B: Comparative Biochemistry, 1987

By using freshly isolated blood trypomastigotes of twelve 7". cruzi wild type strains we have fou... more By using freshly isolated blood trypomastigotes of twelve 7". cruzi wild type strains we have found eight strains sensitive to FoB and FoA, while four and one were FoA-and FoB-insensitive respectiveiy to the drug-mediated growth inhibition. 2. This was not so for APPR, to which most strains were transitory insensitive except two which were clearly sensitive. 3. AII these pyrazolopyrimidines blocked trypomastigote-amastigote transformation. 4. Incubation of pyrazolopyrimidine-insensitive wild strains with [3HIFoA, [3H]FoB and [~4C]APPR respectively indicates that insensitive cells can only accumulate low concentrations of phosphorylated metabolites. 5. This is due to a defective or impaired pyrazolopyrimidine riboside transport system in the wild type insensitive cells, as we did not detect significant variations in the levels of the various nucleoside and nucleobase metabolism enzymes studied. 6. Additional experiments suggested that FoA and FoB are incorporated by different nucleoside transport systems, as Y and ES strains were FoA-insensitive but FoB-sensitive. 7. Epimastigotes of the same T. cruzi strains were highly sensitive to low concentrations of the three pyrazoIopyrimidine ribosides studied. However, when this parasitic form was allowed to transform into trypomastigotes, these cells showed the same pyrazolopyrimidine sensitivity found before, suggesting that in T. cruzi pyrazolopyrimidine ribosideqnsensitivity is a parasite-stage specific and reversible biochemical characteristic.

Research paper thumbnail of Action of pyrazolopyrimidine derivatives on American Leishmania spp. promastigotes

Comparative Biochemistry and Physiology Part C: Comparative Pharmacology, 1986

Research paper thumbnail of Acid and Neutral Hydrolases in Trypanosoma cruzi . Characterization and Assay*

The Journal of Protozoology, 1979

Twelve acid hydrolases, 4 near-neutral hydrolases, and alkaline phosphatase were demonstrated in ... more Twelve acid hydrolases, 4 near-neutral hydrolases, and alkaline phosphatase were demonstrated in 0.34 M sucrose homogenates of Trypanosoma cruzi strain Y: p-nitrophenylphosphatase and alpha-naphthylphosphatase, with optimum pH at approximately 6.0; alpha=ga;actpsodase. beta=ga;actpsodase. beta=g;icpsodase, N-acetyl-beta-glucosaminidase, cathepsin A and peptidase I and III, with optimum pH between 5.0 and 6.0; and arylsulfatase, cathepsin D, alpha-arabinase and alpha-mannosidase with optimum pH at approximately 4.0. alpha-Glucosidase, glucose-6-phosphatase and peptidase II had optimum pH at approximately 7.0. beta-Glycerophosphatase had a broad pH-activity curve from 4,0 to 7.4, with maximum activity at pH 7.0. The main kinetic characteristics of these enzymes and their quantitative assay methods were studied. No activity was detected for alpha-fucosidase, beta-xylosidase, beta-glucuronidase, elaidate esterase, acid lipase, and alkaline phosphodiesterase.

Research paper thumbnail of Differences in allopurinol and 4-aminopyrazolo(3,4-d) pyrimidine metabolism in drug-sensitive and insensitive strains of Trypanosoma cruzi

Molecular and Biochemical Parasitology, 1984

Research paper thumbnail of Therapy of Venezuelan patients with severe mucocutaneous or early lesions of diffuse cutaneous leishmaniasis with a vaccine containing pasteurized Leishmania promastigotes and bacillus Calmette-Guerin: preliminary report

Memórias do Instituto Oswaldo Cruz, 2004

Severe mucocutaneous (MCL) and diffuse (DCL) forms of American cutaneous leishmaniasis (ACL) are ... more Severe mucocutaneous (MCL) and diffuse (DCL) forms of American cutaneous leishmaniasis (ACL) are infrequent in Venezuela. Chemotherapy produces only transitory remission in DCL, and occasional treatment failures are observed in MCL. We have evaluated therapy with an experimental vaccine in patients with severe leishmaniasis. Four patients with MCL and 3 with early DCL were treated with monthly intradermal injections of a vaccine containing promastigotes of Leishmania (Viannia) braziliensis killed by pasteurization and viable Bacillus Calmette-Guerin. Clinical and immunological responses were evaluated. Integrity of protein constituents in extracts of pasteurized promastigotes was evaluated by gel electrophoresis. Complete remission of lesions occurred after 5-9 injections in patients with MCL or 7-10 injections in patients with early DCL. DCL patients developed positive leishmanin skin reactions, average size 18.7 mm. All have been free of active lesions for at least 10 months. Adverse effects of the vaccine were limited to local reactivity to BCG at the injection sites and fever in 2 patients. Extracts of pasteurized and fresh promastigotes did not reveal differences in the integrity of protein components detectable by gel electrophoresis. Immunotherapy with this modified vaccine offers an effective, safe option for the treatment of patients who do not respond to immunotherapy with vaccine containing autoclaved parasites or to chemotherapy .

Research paper thumbnail of Trypanosoma cruzi: Allopurinol in the treatment of mice with experimental acute Chagas disease

Experimental Parasitology, 1981

Research paper thumbnail of Trypanosoma cruzi: Nucleotide and vitamin requirements of growing epimastigotes

Experimental Parasitology, 1981

Research paper thumbnail of Trypanosoma cruzi: 4-Aminopyrazolopyrimidine in the treatment of experimental Chagas' disease

Experimental Parasitology, 1983

An allopurinol metabolite, 4-aminopyrazolopyrimidine, was tested on two different strains of mice... more An allopurinol metabolite, 4-aminopyrazolopyrimidine, was tested on two different strains of mice (NMRI-IVIC and C57Bl/6J) that had been infected 4 days earlier with the virulent Ya strain of Trypanosoma cruzi. Low doses of 4-aminopyrazolopyrimidine (0.125-0.500 mg/kg body wt/day) for 10 days induced a significant reduction in parasitemia (direct counts and subinoculation experiments) and increased survival time (without any evidence of toxicity) compared with untreated animals. When tested in vitro, 4-aminopyrazolopyrimidine was sixfold more active than allopurinol as a trypanostatic drug. The low therapeutic doses of 4-aminopyrazolopyrimidine suggest that this drug may be useful in the treatment of acute Chagas' disease.

Research paper thumbnail of Trypanosoma cruzi: Defined medium for continuous cultivation of virulent parasites

Experimental Parasitology, 1979

Research paper thumbnail of Specific inhibitory effect of 3-deazaneplanocin A against several Leishmania mexicana and L. braziliensis strains

The American journal of …, 1997

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Research paper thumbnail of Diffuse cutaneous leishmaniasis responds to miltefosine but then relapses

British Journal of Dermatology, 2007

Research paper thumbnail of Increase in asialoganglioside- and monosialoganglioside-reactive antibodies in chronic Chagas' disease patients

The American Journal of Tropical Medicine and Hygiene, 1998

Antibodies reactive with the core glycan of asialoganglioside (GA1), monosialoganglioside (GM1), ... more Antibodies reactive with the core glycan of asialoganglioside (GA1), monosialoganglioside (GM1), and disialoganglioside (GD1a) were studied in human sera. In healthy individuals, GA1-, GM1-, and GD1a-reactive antibodies were mainly of the IgM class, but also of the IgA and IgG classes, and were present at low titers in the serum of 68%, 79%, and 91% of the individuals studied, respectively. Levels of anti-GA1 and anti-GM1 antibodies, mainly of the IgA and IgG classes, were significantly elevated (P Ͻ 0.001) in 62% and 72% of subjects, respectively, chronically infected with Trypanosoma cruzi, with no association found with the degree of myocardial damage. No significant increase in anti-GA1 and anti-GM1 antibodies was found in dilated cardiomyopathy patients. The level of anti-GD1a antibody was not significantly different between healthy controls and chronic chagasic or dilatatory cardiomyopathy patients. Since the peripheral nervous system is very rich in gangliosides, it is possible that the increases in GA1-and GM1-specific antibodies that develop during chronic T. cruzi infection are involved in the pathology of peripheral neuropathy in Chagas' disease.

Research paper thumbnail of Correlation of sinefungin susceptibility and drug-affinity for protein carboxymethyltransferase activity in American Leishmania species

Molecular and Biochemical Parasitology, 1987

Among promastigotes of 22 different American Leishmania strains, a 5000-fold variation in sinefun... more Among promastigotes of 22 different American Leishmania strains, a 5000-fold variation in sinefungin susceptibility was found, apparently independent of their taxonomic classification, although L. mexicana strains did tend to be more resistant than L. braziliensis. Protein carboxymethyltransferase (EC 2.1.1.24) and glycine N-methyltransferase (EC 2.1.1.20) activities were not substantially different in sinefungin-susceptible and -resistant American Leishmania strains. However, when [methyl-3H]methionine incorporation into total protein or gamma-glutamyl residues of leishmanial proteins was carried out in the presence or absence of sinefungin, protein carboxymethylating activity was significantly inhibited only in sinefungin-susceptible Leishmania strains. Furthermore, when protein carboxymethyltransferase activity was purified from several leishmanial strains to a state of electrophoretic homogeneity (sp. act. = 240 nmol h-1 (mg protein)-1), the enzyme from the resistant cells showed a higher inhibition constant (mean Ki 55 microM against 2 microM in susceptible cells) for sinefungin. This 28-times stronger affinity of the susceptible cell enzyme towards sinefungin despite normal protein carboxymethyltransferase specific activity seems to be a key element of the resistance mechanism of certain American Leishmania strains.

Research paper thumbnail of Differential metabolism of allopurinol and derivatives in Trypanosoma rangeli and T. cruzi culture forms

Molecular and Biochemical Parasitology, 1981

We have compared the metabolism of allopurinol (4-hydroxypyrazolo(3,4-d)pyrimidine; HPP), by Tryp... more We have compared the metabolism of allopurinol (4-hydroxypyrazolo(3,4-d)pyrimidine; HPP), by Trypanosoma rangeli, a non-pathogenic American trypanosome, and T. cruzL the causative agent of Chagas' disease. Our results indicate that T. rangeli was unable to animate allopurinol mononucleotide to 4-aminopyrazolopyrimidine (APP) mononucleotide. Radioactivity was located in the RNA, but not the DNA, only of T. cruzi. Substrate specificity studies showed T. cruzi suecino-AMP synthetase activity being 100-fold more active on HPP mononueleotide than the T. rangeli enzyme. These results possibly explain the fact that in conventional LIT medium T. rangeli growth was resistant to high concentrations of HPP. However the incubation of this hemoflageliate in an adenine-depleted LIT medium rendered it sensitive to low concentrations of APP, while remaining resistant to HIP. In contrast, and independently of the culture medium used, T. cruzi was extremely sensitive to both pyrazolopyrimidines.

Research paper thumbnail of Differential metabolism of allopurinol and derivatives in Trypanosoma rangeli and T. cruzi culture forms

Molecular and Biochemical Parasitology, 1981

We have compared the metabolism of allopurinol (4-hydroxypyrazolo(3,4-d)pyrimidine; HPP), by Tryp... more We have compared the metabolism of allopurinol (4-hydroxypyrazolo(3,4-d)pyrimidine; HPP), by Trypanosoma rangeli, a non-pathogenic American trypanosome, and T. cruzL the causative agent of Chagas' disease. Our results indicate that T. rangeli was unable to animate allopurinol mononucleotide to 4-aminopyrazolopyrimidine (APP) mononucleotide. Radioactivity was located in the RNA, but not the DNA, only of T. cruzi. Substrate specificity studies showed T. cruzi suecino-AMP synthetase activity being 100-fold more active on HPP mononueleotide than the T. rangeli enzyme. These results possibly explain the fact that in conventional LIT medium T. rangeli growth was resistant to high concentrations of HPP. However the incubation of this hemoflageliate in an adenine-depleted LIT medium rendered it sensitive to low concentrations of APP, while remaining resistant to HIP. In contrast, and independently of the culture medium used, T. cruzi was extremely sensitive to both pyrazolopyrimidines.

Research paper thumbnail of Therapy of Venezuelan patients with severe mucocutaneous or early lesions of diffuse cutaneous leishmaniasis with a vaccine containing pasteurized Leishmania promastigotes and bacillus Calmette-Guerin: preliminary report

Memórias do Instituto Oswaldo Cruz, Mar 31, 2004

Severe mucocutaneous (MCL) and diffuse (DCL) forms of American cutaneous leishmaniasis (ACL) are ... more Severe mucocutaneous (MCL) and diffuse (DCL) forms of American cutaneous leishmaniasis (ACL) are infrequent in Venezuela. Chemotherapy produces only transitory remission in DCL, and occasional treatment failures are observed in MCL. We have evaluated therapy with an experimental vaccine in patients with severe leishmaniasis. Four patients with MCL and 3 with early DCL were treated with monthly intradermal injections of a vaccine containing promastigotes of Leishmania (Viannia) braziliensis killed by pasteurization and viable Bacillus Calmette- Guerin. Clinical and immunological responses were evaluated. Integrity of protein constituents in extracts of pasteurized promastigotes was evaluated by gel electrophoresis. Complete remission of lesions occurred after 5-9 injections in patients with MCL or 7-10 injections in patients with early DCL. DCL patients developed positive skin reactions, average size 18.7 mm. All have been free of active lesions for at least 10 months. Adverse effect...

Research paper thumbnail of Therapy of Venezuelan Patients with Severe Mucocutaneous or Early Lesions of Diffuse Cutaneous Leishmaniasis with a Vaccine

Severe mucocutaneous (MCL) and diffuse (DCL) forms of American cutaneous leishmaniasis (ACL) are ... more Severe mucocutaneous (MCL) and diffuse (DCL) forms of American cutaneous leishmaniasis (ACL) are infre-quent in Venezuela. Chemotherapy produces only transitory remission in DCL, and occasional treatment failures are observed in MCL. We have evaluated therapy with an experimental vaccine in patients with severe leishmania-sis. Four patients with MCL and 3 with early DCL were treated with monthly intradermal injections of a vaccine containing promastigotes of Leishmania (Viannia) braziliensis killed by pasteurization and viable Bacillus Calmette-Guerin. Clinical and immunological responses were evaluated. Integrity of protein constituents in extracts of pasteurized promastigotes was evaluated by gel electrophoresis. Complete remission of lesions occurred after 5-9 injections in patients with MCL or 7-10 injections in patients with early DCL. DCL patients developed positive leishmanin skin reactions, average size 18.7 mm. All have been free of active lesions for at least 10 months. Ad...

Research paper thumbnail of Chemotherapy with ethidium bromide-DNA complex in established Chagas' disease

The American journal of tropical medicine and hygiene, 1979

Two different strains of mice (AKR and NMRI-IVIC) were inoculated intraperitoneally with the viru... more Two different strains of mice (AKR and NMRI-IVIC) were inoculated intraperitoneally with the virulent Y strain of Trypanosoma cruzi, and then treated with the lysosomotropic ethidium bromide-DNA complex, according to several different treatment schedules. When animals were treated 48 hours after intraperitoneal inoculation with three intraperitoneal doses of EB-DNA no parasitemia was detected, even after 11 weeks, confirming previous results. However, when infection was allowed to become fully established, that is 3-4 weeks after inoculation, and then challenged with several different treatment schedules (with varied doses and timing of administration) we failed to cure established Chagas' disease, suggesting that the claim of effectiveness for this EB-DNA complex is limited to early Chagas' disease.

Research paper thumbnail of Specific inhibitory effect of 3-deazaneplanocin A against several Leishmania mexicana and L. braziliensis strains

The American journal of tropical medicine and hygiene, 1997

The growth inhibitory effect of 3-deazaneplanocin A (c3NpcA) was tested against some pathogenic m... more The growth inhibitory effect of 3-deazaneplanocin A (c3NpcA) was tested against some pathogenic members of the family of American Trypanosomatidae. Under our culture conditions, c3NpcA displayed a strongly and uniformly leishmanistatic effect on all 23 American Leishmania (L. mexicana and L. brasiliensis) strains in the study (mean dose producing 50% inhibition compared with control parasite growth [ID50] = 96 ng/ml, 0.32 microM), but showed no inhibition against the several T. cruzi and T. rangeli strains tested with concentrations up to 10,000 ng/ml. This compound also induced a substantial expansion of the intracellular pools of both S-adenosylhomocysteine (AdoHcy) and S-adenosylmethionine (AdoMet), as well as a significant diminution of the AdoMet:AdoHcy ratio. Strong AdoHcy hydrolase activity was detected in American Leishmania promastigotes. At at a dose of 200 ng/ml, c3NpcA inhibited S-adenosyl-L-3H-methylmethionine and 3-thymidine incorporation by promastigotes after four da...

Research paper thumbnail of Inhibitory effects of sinefungin and its cyclic analog on the multiplication of Trypanosoma cruzi isolates

The American journal of tropical medicine and hygiene, 1993

Sinefungin and its cyclic analog were evaluated in vitro for activity against the multiplication ... more Sinefungin and its cyclic analog were evaluated in vitro for activity against the multiplication of Trypanosoma cruzi. When either drug was tested for eight days on twelve T. cruzi epimastigote isolates, an 800-fold difference in drug sensitivity was found. Both drugs were trypanostatics at a concentration range from 0.1 micrograms/ml to 300 micrograms/ml. The 50% effective concentration (EC50) of sinefungin and its cyclic analog at which the growth of a given isolate was inhibited was 0.38 micrograms/ml for sinefungin and 0.31 micrograms/ml for the cyclic analog against the Ma, Marin, OPS-86, Y, and Ya isolates, and > 300 micrograms/ml for sinefungin and 217 micrograms/ml for the cyclic analog against the A-35, Bertoldo, DS, EP, ES, OPS-58, and FL isolates. Incubation of drug-sensitive isolates for more than 10 days in glucose-saline (GS) medium, but not in minimal essential medium, in the presence of a 30-fold EC50 concentration of the drug induced an increase in the drug-resis...

Research paper thumbnail of Defective transport of pyrazolopyrimidine ribosides in insensitive trypanosoma cruzi wild strains is a parasite-stage specific and reversible characteristic

Comparative Biochemistry and Physiology Part B: Comparative Biochemistry, 1987

By using freshly isolated blood trypomastigotes of twelve 7". cruzi wild type strains we have fou... more By using freshly isolated blood trypomastigotes of twelve 7". cruzi wild type strains we have found eight strains sensitive to FoB and FoA, while four and one were FoA-and FoB-insensitive respectiveiy to the drug-mediated growth inhibition. 2. This was not so for APPR, to which most strains were transitory insensitive except two which were clearly sensitive. 3. AII these pyrazolopyrimidines blocked trypomastigote-amastigote transformation. 4. Incubation of pyrazolopyrimidine-insensitive wild strains with [3HIFoA, [3H]FoB and [~4C]APPR respectively indicates that insensitive cells can only accumulate low concentrations of phosphorylated metabolites. 5. This is due to a defective or impaired pyrazolopyrimidine riboside transport system in the wild type insensitive cells, as we did not detect significant variations in the levels of the various nucleoside and nucleobase metabolism enzymes studied. 6. Additional experiments suggested that FoA and FoB are incorporated by different nucleoside transport systems, as Y and ES strains were FoA-insensitive but FoB-sensitive. 7. Epimastigotes of the same T. cruzi strains were highly sensitive to low concentrations of the three pyrazoIopyrimidine ribosides studied. However, when this parasitic form was allowed to transform into trypomastigotes, these cells showed the same pyrazolopyrimidine sensitivity found before, suggesting that in T. cruzi pyrazolopyrimidine ribosideqnsensitivity is a parasite-stage specific and reversible biochemical characteristic.

Research paper thumbnail of Action of pyrazolopyrimidine derivatives on American Leishmania spp. promastigotes

Comparative Biochemistry and Physiology Part C: Comparative Pharmacology, 1986

Research paper thumbnail of Acid and Neutral Hydrolases in Trypanosoma cruzi . Characterization and Assay*

The Journal of Protozoology, 1979

Twelve acid hydrolases, 4 near-neutral hydrolases, and alkaline phosphatase were demonstrated in ... more Twelve acid hydrolases, 4 near-neutral hydrolases, and alkaline phosphatase were demonstrated in 0.34 M sucrose homogenates of Trypanosoma cruzi strain Y: p-nitrophenylphosphatase and alpha-naphthylphosphatase, with optimum pH at approximately 6.0; alpha=ga;actpsodase. beta=ga;actpsodase. beta=g;icpsodase, N-acetyl-beta-glucosaminidase, cathepsin A and peptidase I and III, with optimum pH between 5.0 and 6.0; and arylsulfatase, cathepsin D, alpha-arabinase and alpha-mannosidase with optimum pH at approximately 4.0. alpha-Glucosidase, glucose-6-phosphatase and peptidase II had optimum pH at approximately 7.0. beta-Glycerophosphatase had a broad pH-activity curve from 4,0 to 7.4, with maximum activity at pH 7.0. The main kinetic characteristics of these enzymes and their quantitative assay methods were studied. No activity was detected for alpha-fucosidase, beta-xylosidase, beta-glucuronidase, elaidate esterase, acid lipase, and alkaline phosphodiesterase.

Research paper thumbnail of Differences in allopurinol and 4-aminopyrazolo(3,4-d) pyrimidine metabolism in drug-sensitive and insensitive strains of Trypanosoma cruzi

Molecular and Biochemical Parasitology, 1984

Research paper thumbnail of Therapy of Venezuelan patients with severe mucocutaneous or early lesions of diffuse cutaneous leishmaniasis with a vaccine containing pasteurized Leishmania promastigotes and bacillus Calmette-Guerin: preliminary report

Memórias do Instituto Oswaldo Cruz, 2004

Severe mucocutaneous (MCL) and diffuse (DCL) forms of American cutaneous leishmaniasis (ACL) are ... more Severe mucocutaneous (MCL) and diffuse (DCL) forms of American cutaneous leishmaniasis (ACL) are infrequent in Venezuela. Chemotherapy produces only transitory remission in DCL, and occasional treatment failures are observed in MCL. We have evaluated therapy with an experimental vaccine in patients with severe leishmaniasis. Four patients with MCL and 3 with early DCL were treated with monthly intradermal injections of a vaccine containing promastigotes of Leishmania (Viannia) braziliensis killed by pasteurization and viable Bacillus Calmette-Guerin. Clinical and immunological responses were evaluated. Integrity of protein constituents in extracts of pasteurized promastigotes was evaluated by gel electrophoresis. Complete remission of lesions occurred after 5-9 injections in patients with MCL or 7-10 injections in patients with early DCL. DCL patients developed positive leishmanin skin reactions, average size 18.7 mm. All have been free of active lesions for at least 10 months. Adverse effects of the vaccine were limited to local reactivity to BCG at the injection sites and fever in 2 patients. Extracts of pasteurized and fresh promastigotes did not reveal differences in the integrity of protein components detectable by gel electrophoresis. Immunotherapy with this modified vaccine offers an effective, safe option for the treatment of patients who do not respond to immunotherapy with vaccine containing autoclaved parasites or to chemotherapy .

Research paper thumbnail of Trypanosoma cruzi: Allopurinol in the treatment of mice with experimental acute Chagas disease

Experimental Parasitology, 1981

Research paper thumbnail of Trypanosoma cruzi: Nucleotide and vitamin requirements of growing epimastigotes

Experimental Parasitology, 1981

Research paper thumbnail of Trypanosoma cruzi: 4-Aminopyrazolopyrimidine in the treatment of experimental Chagas' disease

Experimental Parasitology, 1983

An allopurinol metabolite, 4-aminopyrazolopyrimidine, was tested on two different strains of mice... more An allopurinol metabolite, 4-aminopyrazolopyrimidine, was tested on two different strains of mice (NMRI-IVIC and C57Bl/6J) that had been infected 4 days earlier with the virulent Ya strain of Trypanosoma cruzi. Low doses of 4-aminopyrazolopyrimidine (0.125-0.500 mg/kg body wt/day) for 10 days induced a significant reduction in parasitemia (direct counts and subinoculation experiments) and increased survival time (without any evidence of toxicity) compared with untreated animals. When tested in vitro, 4-aminopyrazolopyrimidine was sixfold more active than allopurinol as a trypanostatic drug. The low therapeutic doses of 4-aminopyrazolopyrimidine suggest that this drug may be useful in the treatment of acute Chagas' disease.

Research paper thumbnail of Trypanosoma cruzi: Defined medium for continuous cultivation of virulent parasites

Experimental Parasitology, 1979

Research paper thumbnail of Specific inhibitory effect of 3-deazaneplanocin A against several Leishmania mexicana and L. braziliensis strains

The American journal of …, 1997

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Research paper thumbnail of Diffuse cutaneous leishmaniasis responds to miltefosine but then relapses

British Journal of Dermatology, 2007