Biomedical subjects

J A Castro

Publications and source records attributed to J A Castro.

At least 127 records · Page 7Linked to original sources

PubMed1988

Toxic effects of nifurtimox and benznidazole, two drugs used against American trypanosomiasis (Chagas' disease).

American trypanosomiasis (Chagas' disease) is an endemic parasitic disease afflicting more than 20 million persons in Latin America. Two drugs are currently being used for treatment of the acute phase of Chagas' disease: 4-[(5-nitrofurfurylidene)amino-3-methylthiomorpholine-1,1-di oxide] (Nifurtimox; Nfx) and (N-benzl-2-nitro-1-imidazole acetamide) (Benznidazole; Bz). Nfx and Bz have serious undesirable effects, which have been reported during their clinical use, including anorexia and weight loss, nausea and vomiting, nervous excitation, insomnia, psyche depressions, convulsions, vertigo, headache, sleepiness, myalgias, arthralgias, loss of balance, disorientation, forgetfulness, paresthesias, adynamia, acoustic phenomena, peripheral neuropathies, gastralgia, mucosal edema, hepatic intolerance, skin manifestations, and intolerance to drinking alcohol. Effects in the central and peripheral nervous system of Nfx were also reproduced in animals. Signs of testicular and ovarian injury were reported for both Nfx and Bz, the effects of Bz being in general less intense than those of Nfx. Both drugs evidenced mutagenicity. In light of the present knowledge about the toxicity of Nfx and Bz, further studies on the mutagenic, teratogenic, carcinogenic, and reproductive effects of both drugs are recommended. Lack of information is particularly serious for Bz. Studies on Nfx and Bz biotransformation, activation to reactive metabolites, and potential mechanisms for their toxic effects were analyzed. Risk-benefit considerations of the use of Nfx and Bz were made and an analysis of the need for research on Chagas' disease chemotherapy was also performed.

Chagas Disease↗

PubMed1988

Glutathione (GSH) content in livers from control and carbon tetrachloride poisoned rats treated with the calmodulin inhibitors thioridazine, imipramine or chlorpromazine.

Administration to rats of the calmodulin (CaM) inhibitors Thioridazine (TDZ) or Imipramine (IMP) (50 mg/kg ip) or Chlorpromazine (CPZ) at a dose of 25 mg/kg, ip 6 hr after olive oil or CCl4 (1 ml/kg, ip as a 20% olive oil solution) significantly increased the GSH content in liver of CCl4 poisoned animals but not in controls. The analysis of present observations and past results with Trifluoperazine, suggest that increases in GSH content in CCl4 poisoned animals treated with protective anticalmodulins are a consequence of prevention and not the cause of their preventive effects.

Animals↗

PubMed1987

Early biochemical alterations in liver mitochondria from carbon tetrachloride poisoned rats.

Covalent binding of reactive metabolites of 14CCl4 were found 1 or 3 h after treatment with the solvent in the lipid and protein fractions of highly purified liver mitochondrial of rats. Most of the label was found in the phospholipid (PL) fraction, much less in cholesterol esters (ChE), and only minor quantities in other lipids. The reactive metabolites of 14CCl4 activated by isolated mitochondria interact mostly with ChE and far less with PL and other fractions. Both in vivo and in vitro covalent binding to PL is decreasing in the following order: phosphatidylethanolamine greater than diphosphatidylglycerol greater than phosphatidylcholine greater than sphingomyelin greater than lysophosphatidyl choline. No evidence of lipid peroxidation was found in liver mitochondrial lipids in the first 6 h and only a slight tendency of decrease in arachidonic acid concentration at 24 h. The incorporation of [14C] leucine in mitochondrial, microsomal or cytosolic proteins decreased as early as 1 h after treatment. These results, in agreement with previous reports suggest the existence of multiple sites in liver cells for the activation of CCl4. The transport of altered phospholipids and proteins and the inhibition of protein synthesis might contribute to the propagation of damage from the endoplasmic reticulum to other organelles.

Animals↗

PubMed1987

Effects of carbon tetrachloride on the liver of chickens. Early biochemical and ultrastructural alterations in the absence of detectable lipid peroxidation.

Administration of CCl4 i.p. to Leghorn chickens did not promote lipid peroxidation of liver microsomal lipids, as evidenced by either increased diene conjugation or by decreased arachidonic acid content. The hepatotoxin did not produce liver necrosis 24 h after dosing, but decreased the cytochrome P-450 content, and aminopyrine N-demethylase and glucose 6 phosphatase activities at 1, 3, 6 and 24 h. CCl4 administration produced dilation of the rough endoplasmic reticulum and detachment of ribosomes from their membranes. These observations suggest that lipid peroxidation is not the key event in the production of these biochemical and ultrastructural alterations, elicited by CCl4.

Aminopyrine N-Demethylase↗

PubMed1987

Liver microsomal benznidazole and nifurtimox nitroreductase activity in male rats of different age.

Nifurtimox (Nfx) and Benznidazole (Bz) are 2 drugs used in the chemotherapy of Chagas' disease, a sickness afflicting millions of Latin Americans. Their toxicity is related to nitroreductive activation. Nfx and Bz nitroreductase activity in liver microsomes from male rats is already present at low levels in the newborn and reaches full adult activity in 28 days. This suggests a better therapeutic approach by starting the treatment of transplacentally acquired Chagas' disease immediately after birth.

Aging↗

PubMed1987

Species and sex differences in the liver microsomal nitroreductive biotransformation of nifurtimox and benznidazole.

Nifurtimox (NFX) and Benznidazole (Bz) are two drugs effective against acute Chagas' disease. Both have considerable toxic side effects related to nitroreductive biotransformation. In this work, we studied the species and sex differences in liver microsomal NFX (NFX-ase) and Bz nitroreductase activity (Bz-ase). Animal species tested were rats, mice, hamsters and guinea-pigs. Bz-ase is significantly higher in male rats and hamsters than in females. No significant sex difference was observed in mice or guinea-pigs. Bz-ase in the males is: hamsters greater than mice greater than guinea-pig approximately equal to rat and in females it is: mice approximately equal to guinea-pig approximately equal to hamster greater than rat. NFX-ase is higher in either male rats or female mice than in either female rats or male mice. No sex difference was observed in the other species. In males NFX-ase is: hamsters approximately equal to mice greater than rat approximately equal to guinea-pig, while in females it is mice approximately equal to hamsters greater than guinea-pig approximately equal to rat. Results suggest that hamsters and mice might be the most suitable species to study toxic effects related to their liver microsomal nitroreductive biotransformation. This might be of particular relevance for carcinogenicity studies.

Animals↗

PubMed1986

Imipramine prevention of carbon tetrachloride-induced liver necrosis at late states of the intoxication process.

Imipramine administration (50 mg kg-1, i.p.) to Sprague-Dawley male rats (240-290 g) 6 or 10 h after CCl4 (1 ml kg-1, i.p.) partially prevents liver necrosis induced by the hepatotoxin. When imipramine is given 30 min before CCl4, it inhibits in part the CCl4-induced lipid peroxidation and the covalent interactions of reactive metabolites with microsomal lipids or proteins and partially prevents CCl4-induced cytochrome P-450 destruction, but not glucose 6 phosphatase activity depression. Imipramine administration prior to CCl4 does not modify levels of the hepatotoxin reaching the liver or the body temperature of CCl4 treated animals. Early preventive effects of imipramine on cytochrome P-450, might be attributed to inhibition of covalent interactions of reactive metabolites. The hypothesis that imipramine exerted late preventive effects by interfering with calcium deleterious effects or by modulation of protein and phospholipid synthesis or degradation is analyzed.

Animals↗

PubMed1986

Effect of inhibitors of the FAD-containing monooxygenase system from rat liver microsomes on monomethylhydrazine metabolism and activation to reactive metabolites.

Several inhibitors of the FAD-containing monooxygenase (FAD-MO) system from rat liver microsomes (imipramine, chlorpromazine, mercaptoethylamine, dithiothreitol, naphthylthiourea, phenylthiocarbamide) and one inhibitor of the liver microsomal cytochrome P-450 (P-450)-mediated biotransformations (SKF 525 A), were tested as possible inhibitors of monomethylhydrazine (MMH) biotransformation to CO2 and to reactive metabolites that bind covalently to nucleic acids and proteins. Results confirm previous suggestions that both FAD-MO and P-450 are involved in MMH metabolism to CO2 and suggest a similar participation of both systems for production of reactive metabolites interacting with macromolecules.

Animals↗

PubMed1986

Effects of nifurtimox or benznidazole administration on rat testes: ultrastructural observations and biochemical studies.

Ultrastructural and biochemical alterations in testes of Sprague-Dawley rats receiving either nifurtimox (Nfx) or benznidazole (Bz) (both 100 mg/kg po) were studied. Nfx produced intense deleterious effects on Steroli cells consisting of dilatation of endoplasmic reticulum and perinuclear membrane, alterations in shape and size of mitochondria, increased lysosomal activity, detachment of ribosomes, and alterations in shape and configuration of spermatids and mature spermatozoa. Bz induced alterations were similar in nature but far less intense and observable only in some cells or preparations or animals but not in others. Testicular Nfx but not Bz nitroreductase activity was detected in microsomal and cytosolic fractions. Microsomal Nfx nitroreductase activity was not inhibited by CO. The cytosolic activity in the presence of hypoxanthine was inhibited by allopurinol and that in the presence of N-methylnicotinamide was inhibited by menadione. All these enzymatic activities were inhibitable by oxygen except the cytosolic one in the presence of N-methylnicotinamide. No evidence for lipid peroxidation was found in testes from Nfx treated animals. Covalent binding of Bz reductive metabolites to testicular proteins and phospholipids was found. Toxicological and pharmacological implications for patients suffering Chagas' disease and receiving these drugs were analyzed.

Animals↗

PubMed1986

Late preventive effects of trifluoperazine on carbon tetrachloride-induced hepatic necrosis.

As a very preliminary test for a possible role of calmodulin in CCl4-induced hepatic injury, we studied the effects of the anticalmodulin drug trifluoperazine (TFP) on several deleterious actions of CCl4 on the liver. TFP administrated 30 min before or 6 or 10 hr after CCl4 significantly prevented hepatic necrosis induced by the hepatotoxin at 24 hr but not at 72 hr. TFP did not modify the CCl4 concentrations reaching the liver, or the intensity of the covalent binding of CCl4-reactive metabolites to hepatic microsomal proteins or lipids or the CCl4-induced cytochrome P-450 and glucose 6 phosphatase destruction. TFP administration decreased body temperature between 0 and 1 degree C in controls and between 1.2 and 3.5 degrees C in CCl4-treated animals during the 24-hr observation period. When TFP-treated CCl4-poisoned animals were kept normothermic, protective effects were eliminated. One possibility is that the protective effect of TFP might be due to a nonspecific action related to decreased body temperature. Alternatively, prevention might result from TFP inhibition of a late-occurring process critical for CCl4-induced cell necrosis requiring calmodulin participation. If this alternative were in operation, protective consequences of this inhibitory effect of TFP should be either canceled or counteracted in the normothermic TFP + CCl4-treated animal.

Animals↗

PubMed1986

Effect of chlorpromazine on protein, phospholipid and RNA synthesis or degradation in rat liver.

Chlorpromazine (CPZ) administration to rats (25 mg/kg ip) significantly stimulated (14C)-leucine incorporation to liver microsomal proteins, (14C)-orotic acid incorporation to liver RNA and (32P) incorporation to liver microsomal lipids. CPZ administration did not modify the decay of radioactivity of liver microsomal lipids prelabeled with (32P) or that of microsomal proteins prelabeled with [(14C)-guanidino]-arginine. Results suggest that CPZ administration stimulates protein, phospholipids and RNA synthesis but does not affect their degradation. The relation of these findings with CPZ preventive effects on CCl4-induced liver injury is discussed.

Animals↗

PubMed1986

Administration of N-nitrosodimethylamine, N-nitrosopyrrolidine, or N'-nitrosonornicotine to nursing rats: their interactions with liver and kidney nucleic acids from sucklings.

When nursing Sprague-Dawley rats were treated with [14C]N-nitrosodimethylamine [(NDMA) CAS: 62-75-9], N-nitrosopyrrolidine (CAS:930-55-2), or N'-nitrosonornicotine (CAS: 16543-55-8), the liver and kidney DNA from their 14-day-old offspring that had been nursed over a 24-hour period became labeled. Upon analysis, liver DNA from sucklings whose nursing mothers were treated with [14C]NDMA showed N7-methylguanine- and O6-methylguanine-altered bases. The results suggest that these nitrosamines, which are present in food, tobacco smoke, and in different environmental sources, are a risk not only for lactating mothers but also for the nursing infants.

Alkylation↗

PubMed1986

Standard dose 131I therapy for toxic multinodular goiter in an endemic goiter region.

1. The effect of the standard 15 mCi dose of 131I on the thyroid function of 25 patients from an endemic goiter region with toxic multinodular goiter of different sizes was determined. 2. The patients were followed for 1 to 5 years and 7 months (mean: 2 years and 10 months). Eighteen patients were treated with the antithyroid drugs propylthiouracil or methimazole before 131I and seven only received 131I. 3. All but three patients achieved euthyroidism after a single dose of 131I. Two patients in the antithyroid treatment group became hypothyroid 2 months and 2 years after the isotope therapy, respectively. Pretreatment with antithyroid drugs did not significantly modify the effectiveness of 131I treatment. 4. This simplified dose regimen of 131I was effective in the treatment of hyperthyroidism caused by multinodular goiter in an endemic region, and the efficacy was independent of the size of the goiter.

Adult↗

PubMed1986

Effect of the pretreatment with pyrazole, cystamine or diphenyl-P-phenylenediamine (DPPD) on the CCl4-promoted pentane evolution in rats.

CCl4 administration to Sprague-Dawley male rats promotes pentane evolution which is an index of lipid peroxidation (LP) occurrence in vivo. Pyrazole (150 mg/kg, ip) or cystamine (600 mg/kg, po) pretreatment do not prevent CCl4-induced increases in pentane evolution, while the prior administration of the powerful antioxidant DPPD (600 mg/kg, ip at 48, 24 and 10 minutes before CCl4) prevents most of it. Since previous studies evidenced that pyrazole and cystamine but not DPPD prevent several early effects of CCl4 and diminish the intensity of the covalent binding of CCl4 reactive metabolites to cellular constituents (CB), results suggest that CB and LP might be related to those deleterious effects of CCl4 on the liver.

Animals↗

PubMed1986

Interaction of benznidazole reactive metabolites with rat liver deoxyribonucleic acid and nuclear proteins.

Benznidazole (Bz) (N-benzyl-2-nitro-1-imidazole acetamide) is one of the drugs used in the chemotherapy of Chagas' disease. Microsomal suspensions anaerobically activated Bz in the presence or absence of NADPH to metabolites that covalently bind to proteins or to DNA incorporated into the incubation mixture. At high Bz concentrations (0.2 mM) NADPH enhanced the intensity of the process while at low Bz concentrations (0.02 mM) it decreased it. Nuclear preparations were also able to anaerobically activate Bz to reactive metabolites that bind covalently their DNA and proteins. The process was enzymatic and required NADPH. Most of the interaction between Bz metabolites and nuclear proteins involved the acidic non-histone proteins and those from the nuclear sap. A minor part of the interaction was with basic deoxyribonucleoproteins, acidic ribonucleoproteins and residual fractions. Almost no interaction with histones was observed. Potential toxicological implications of the observed interactions are analyzed.

Animals↗

PubMed1986

Increased glutathione (GSH) content in livers of control and carbon tetrachloride poisoned rats treated with the anticalmodulin drug trifluoperazine (TFP).

TFP administration to rats (50 mg/kg, ip) 6 hr after olive oil or CCl4 (1 mg/kg, ip as a 20% olive oil solution) significantly increases the GSH content in liver at 24 hr. The role of GSH increases in the late preventive effects against CCl4 hepatotoxicity is discussed. A link between the calcium/calmodulin (CaM) system and the GSH status in liver is postulated.

Animals↗

PubMed1985

Studies on pentane evolution by rats treated with nifurtimox or benznidazole.

Sprague-Dawley male rats were treated with either 100 mg/kg Nifurtimox or Benznidazole p.o. and pentane evolution was measured at different periods of time. No significant increase in pentane evolution was observed in animals treated with Benznidazole during periods of time up to 10 h. In animals treated with Nifurtimox, a significant increase in pentane evolution was observed at 10 h but not at 3 or 6 h. The pentane evolution effect of Nifurtimox was compared to that of carbon tetrachloride. The latter was very intense up to 1 h and ceased thereafter. The possible participation of lipid peroxidation in the unwanted toxic side effects of Nifurtimox and Benznidazole is discussed.

Animals↗

PubMed1985

Micronucleus formation in bone marrow of mice treated with nifurtimox or benznidazole.

A single nifurtimox administration to male mice orally (p.o.) (600 - 2000 mg/kg) but not intraperitoneally (i.p.) was able to increase micronucleus formation in bone marrow significantly. No significant increase in micronucleus formation in the bone marrow of mice treated with benznidazole at dosages up to 2000 mg/kg, either p.o. or i.p., was observed. The potential mutagenic risk of nifurtimox treatment in patients suffering from Chagas' disease is analyzed.

Animals↗