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1.
Hepatology ; 28(1): 179-91, 1998 Jul.
Article in English | MEDLINE | ID: mdl-9657111

ABSTRACT

Woodchucks were used to study the antiviral activity and toxicity of fialuridine (FIAU; 1,-2'deoxy-2'fluoro-1-beta-D-arabinofuranosyl-5-iodo-uracil). In an initial experiment, groups of six chronic woodchuck hepatitis virus (WHV) carrier woodchucks received daily doses of FIAU by intraperitoneal injection for 4 weeks. At 0.3 mg/kg/d, the antiviral effect was equivocal, but at 1.5 mg/kg/d, FIAU had significant antiviral activity. No evidence of drug toxicity was observed during the 4-week period of treatment or during posttreatment follow-up. In a second experiment, groups of nine WHV carriers or uninfected woodchucks were given 1.5 mg/kg/d of FIAU orally for 12 weeks, and the results compared with placebo-treated controls. After 4 weeks, the serum WHV-DNA concentration in the FIAU-treated carrier group was two to three logs lower than that in the placebo-treated group. After 12 weeks of FIAU treatment, serum WHV DNA was not detectable by conventional dot-blot analysis, hepatic WHV-DNA replicative intermediates (RI) had decreased 100-fold, and hepatic expression of WHV core antigen was remarkably decreased. No evidence of toxicity was observed after 4 weeks, but, after 6 to 7 weeks, food intake decreased and, after 8 weeks, the mean body weights of woodchucks treated with FIAU were significantly lower than controls. Anorexia, weight loss, muscle wasting, and lethargy became progressively severe, and all FIAU-treated woodchucks died or were euthanized 78 to 111 days after treatment began. Hepatic insufficiency (hyperbilirubinemia, decreased serum fibrinogen, elevated prothrombin time), lactic acidosis, and hepatic steatosis were characteristic findings in the final stages of FIAU toxicity in woodchucks. The syndrome of delayed toxicity in woodchucks was similar to that observed previously in humans treated with FIAU, suggesting that the woodchuck should be valuable in future investigations of the molecular mechanisms of FIAU toxicity in vivo and for preclinical toxicological evaluation of other nucleoside analogs before use in patients.


Subject(s)
Antiviral Agents/therapeutic use , Arabinofuranosyluracil/analogs & derivatives , Hepatitis B/drug therapy , Animals , Anorexia/chemically induced , Antiviral Agents/adverse effects , Arabinofuranosyluracil/adverse effects , Arabinofuranosyluracil/pharmacokinetics , Arabinofuranosyluracil/therapeutic use , Carrier State/virology , DNA, Viral/analysis , Hepatitis B/blood , Hepatitis B/pathology , Hepatitis B Core Antigens/analysis , Hepatitis B virus/genetics , Hepatitis B virus/physiology , Liver/metabolism , Liver/pathology , Marmota , Muscles/drug effects , Sleep Stages , Time Factors , Virus Replication/drug effects
3.
Antimicrob Agents Chemother ; 39(6): 1329-35, 1995 Jun.
Article in English | MEDLINE | ID: mdl-7574525

ABSTRACT

To identify the minimal structural elements necessary for biological activity, the rigid tricyclic nucleus of the known human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor tetrahydroimidazobenzodiazepinthione was subjected to systematic bond disconnection to obtain simpler structures. A rational selection and testing of modeled analogs containing these potential pharmacophoric moieties led to the discovery of a new series of nonnucleoside inhibitors of RT. The lead compound of this new PETT series of nonnucleoside RT inhibitors, N-(2-phenylethyl)-N'-(2-thiazolyl)thiourea (LY73497), was found to inhibit HIV-1 but not HIV-2 or simian immunodeficiency virus in cell culture at micromolar concentrations. This derivative was also found to inhibit HIV-1 RT. Through an integrated effort involving synthesis and molecular modeling, compounds with nanomolar potency against HIV-1 in cell culture were developed. In these studies, LY300046-HCl was identified as a potent nonnucleoside inhibitor of HIV-1 RT possessing favorable pharmacokinetic properties.


Subject(s)
HIV-1/drug effects , Intercalating Agents/pharmacology , Reverse Transcriptase Inhibitors , Thiazoles/pharmacology , Triazoles/pharmacology , Animals , Antiviral Agents/pharmacology , Base Sequence , Benzodiazepines/chemistry , Brain/metabolism , Cattle , Cells, Cultured , DNA-Directed DNA Polymerase/drug effects , DNA-Directed DNA Polymerase/metabolism , Drug Resistance, Microbial , Humans , Imidazoles/chemistry , Male , Molecular Sequence Data , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Rats, Inbred F344 , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiourea/analogs & derivatives , Thiourea/chemical synthesis , Thiourea/pharmacology
4.
Proc Natl Acad Sci U S A ; 91(25): 12003-7, 1994 Dec 06.
Article in English | MEDLINE | ID: mdl-7991573

ABSTRACT

Accumulation of the antiviral nucleoside analogue fialuridine (FIAU; 1-(2'-deoxy-2'-fluoro-beta-D-arab-inofuranosyl-5-iodouracil) in genomic DNA was examined with a modified version of a recently developed RIA for FIAU. DNA was obtained from tissues of dogs administered FIAU at 0, 1, 2, or 3 mg/kg of body weight per day for 90 days, monkeys administered FIAU at 0 or 25 mg/kg per day for 30 days, and rats administered FIAU at 0, 255, or 510 mg/kg per day for 70 days. FIAU incorporation was observed in all species. In the rat, FIAU was incorporated into DNA of all tissues examined, with highest concentrations in the liver followed by jejunum, spleen, and heart. FIAU was also incorporated into sperm DNA. Incorporation rates were as high as 11,000 pmol of FIAU per mumol of thymidine or 1 FIAU molecule per 90 thymidine molecules. In dogs and rats, the extent of incorporation was dose-dependent. Across species, FIAU concentrations in DNA were not singly dependent on the total dose administered but also may have been dependent on the duration of exposure. These studies show that FIAU accumulates to high concentrations in genomic DNA of liver as well as other tissues during chronic oral administration and suggest that net accumulation of FIAU in DNA may be a critical step in FIAU-induced toxicity.


Subject(s)
Antiviral Agents/metabolism , Arabinofuranosyluracil/analogs & derivatives , DNA/biosynthesis , Administration, Oral , Animals , Arabinofuranosyluracil/administration & dosage , Arabinofuranosyluracil/metabolism , Arabinofuranosyluracil/pharmacokinetics , Chromatography, High Pressure Liquid , DNA/isolation & purification , Dogs , Female , Hydrolysis , Macaca mulatta , Male , Muscles/metabolism , Radioimmunoassay , Rats , Rats, Inbred F344 , Sex Factors , Species Specificity , Time Factors , Tissue Distribution
5.
Carcinogenesis ; 15(2): 331-3, 1994 Feb.
Article in English | MEDLINE | ID: mdl-8313527

ABSTRACT

LY171883, a peroxisome proliferator and leukotriene D4-antagonist, induced a statistically significant increase in the number of hepatic lesions in B6C3F1 female mice in a 2 year oncogenicity study at dietary doses of 0.0225% and 0.075%. The mutation frequency and spectrum of the 61st codon of H-ras was determined for 64 independent, archived lesions from the LY171883 2 year oncogenicity study using the polymerase chain reaction (PCR), allele specific oligo hybridization (ASO) and DNA sequencing. Results showed 41 (64%) of these lesions had mutations at the 61st codon (16/21 hepatocellular carcinomas, 4/10 hepatocellular adenomas, 19/26 focal hepatocellular hyperplasias and 2/7 focal hepatocellular atypia). These mutations consisted of 18 C-A transversions, 16 A-G transitions and seven A-T transversions. Compared to the mutation frequency for spontaneously occurring archival B6C3F1 hepatic lesions (41%), the frequency of LY171883 lesions (64%) was significantly higher (P < 0.01). The frequencies of H-ras 61st codon mutations among the LY171883 lesion types (hepatocellular carcinomas 76%, hepatocellular adenomas 40%, focal hepatocellular hyperplasias 73% and hepatocellular atypia 29%) were also significantly different (P = 0.035). In contrast, spontaneous lesions showed no statistical difference in the frequencies of mutation among lesion types (P > 0.5). The mutation spectrum of the LY171883 lesions was not significantly different from the spontaneous spectra. It may be concluded that based on the similarity in mutation spectrum and the increase in mutation frequency, LY171883 may selectively promote spontaneous hepatic lesions containing H-ras 61st codon mutations. In addition, the difference in mutation frequency among lesion types does not support a linear progression of all LY171883 lesions through focal atypia, focal hepatocellular hyperplasias, hepatocellular adenomas and hepatocellular carcinomas.


Subject(s)
Acetophenones/toxicity , Carcinogens/toxicity , Codon , Genes, ras , Leukotriene D4/antagonists & inhibitors , Liver Neoplasms, Experimental/chemically induced , Tetrazoles/toxicity , Animals , Base Sequence , DNA Primers , Female , Liver Neoplasms, Experimental/genetics , Mice , Molecular Sequence Data
6.
Toxicol Pathol ; 21(6): 538-41, 1993.
Article in English | MEDLINE | ID: mdl-8052799

ABSTRACT

Three separate control lifetime studies were conducted with untreated Crl:CD-1 (ICR)BR mice using a total of 400 mice/sex maintained to 21 mo of age. Similar husbandry practices and environmental conditions were used for all 3 studies. It was noted after study initiation that the Charles River breeding facility of origin was different for each study. The aggregate range of survival and incidence of neoplasms for the combined studies was similar to that previously reported. However, these 3 groups of mice had prominent variation in survival and in the incidence of pulmonary adenomas and systemic amyloidosis in males and females, and in the incidence of hepatocellular neoplasms in males. The present studies indicate that consistent procurement of test animals is an additional variable to be considered in the establishment of a valid database within a test facility when using an outbred mouse.


Subject(s)
Mice, Inbred Strains , Neoplasms/veterinary , Rodent Diseases/epidemiology , Adenoma/veterinary , Amyloidosis/veterinary , Animals , Carcinoma/veterinary , Female , Liver Neoplasms/veterinary , Lung Neoplasms/veterinary , Male , Mice , Neoplasms/epidemiology , Neoplasms/mortality , Rodent Diseases/mortality
7.
Cancer Lett ; 71(1-3): 133-42, 1993 Jul 30.
Article in English | MEDLINE | ID: mdl-7689926

ABSTRACT

Increased message levels of testosterone-repressed prostate message-2 (TRPM-2) have been associated with programmed cell death in many tissues. To study its involvement in the apoptotic elimination of hepatocytes during liver involution and regeneration, levels of TRPM-2 message were evaluated in situ and by the ribonuclease protection assay. Although significant increases in apoptotic bodies were observed in rats 96 h following treatment with lead nitrate and ethylene dibromide, an increase in TRPM-2 message was not detected. Therefore, the expression of TRPM-2 mRNA may be a poor indicator of the extent to which apoptosis occurs during liver involution.


Subject(s)
Glycoproteins/metabolism , Liver Regeneration , Molecular Chaperones , Animals , Apoptosis , Cell Division , Clusterin , Gene Expression , Glycoproteins/genetics , In Situ Hybridization , Male , RNA/isolation & purification , Rats , Rats, Wistar , Staining and Labeling
8.
Fundam Appl Toxicol ; 19(2): 197-201, 1992 Aug.
Article in English | MEDLINE | ID: mdl-1516775

ABSTRACT

Studies were undertaken to define the subchronic toxicologic profile of ameltolide, an aminobenzamide anticonvulsant, in young adult rhesus monkeys. Daily doses of ameltolide, dissolved in 10% aqueous acacia, were administered orally via nasogastric intubation at dosages of 5, 10, 20, 45, and 100 mg/kg. Deaths occurred in two monkeys, one each at 45 and 100 mg/kg, which were directly attributable to the effects of the compound. The exact cause of death in these monkeys was not readily apparent. A third monkey (100 mg/kg) was killed moribund on Day 82 of the study due to conditions not directly related to treatment. Clinical signs in monkeys treated with 100 mg/kg included convulsions, diarrhea, weakness, inappetance, vomition, and ataxia. Plasma concentrations of the N-acetyl metabolite of ameltolide were greater than parent drug concentrations by one to two orders of magnitude. Mean area under the plasma-time curve (AUC) values for ameltolide were larger than expected at doses of 20 mg/kg or greater, while AUC values for the metabolite were less than expected at 45 and 100 mg/kg. These findings suggest a saturation of metabolism and/or excretion at the two higher doses. Similar nonlinearity was seen with mean peak concentrations for both parent and metabolite. No specific target organ toxicity was found on histological evaluation of tissue sections. Methemoglobin concentration was increased in monkeys given 45 or 100 mg ameltolide/kg. This change was not considered to be toxicologically important as there were no corroborative clinical, gross, or histopathological findings. Ameltolide administered by nasogastric intubation at doses up to 20 mg/kg/day for 3 months did not cause any toxicologically important alterations in rhesus monkeys.


Subject(s)
Anticonvulsants/toxicity , Benzamides/toxicity , Animals , Anticonvulsants/metabolism , Anticonvulsants/pharmacokinetics , Benzamides/metabolism , Benzamides/pharmacokinetics , Body Weight/drug effects , Feeding Behavior/drug effects , Female , Macaca mulatta , Male
9.
Carcinogenesis ; 13(6): 935-41, 1992 Jun.
Article in English | MEDLINE | ID: mdl-1350949

ABSTRACT

In order to better understand the molecular events in murine hepatocarcinogenesis, the frequency and types of mutations in the murine H-ras proto-oncogene isolated from 184 independent, spontaneously occurring hepatic lesions were determined. Hepatocellular foci, hyperplasias, adenomas and carcinomas were obtained from archival samples of control male (134 samples) and female (50 samples) B6C3F1 mice used in oncogenicity studies that were conducted at Lilly Research Laboratories from 1979 to 1986. The 61st codon region of the H-ras oncogene from these sections was amplified using the polymerase chain reaction. Mutation frequencies were determined by restriction fragment length polymorphism analysis. The types of mutations were characterized by allele-specific oligonucleotide hybridization and confirmed by DNA sequencing. Forty-two per cent of the carcinomas, 44% of the adenomas, 42% of the hyperplasias and 29% of the foci contained mutations at the 61 codon. The mutation spectra for the carcinomas, adenomas and hyperplasias consisted of mostly CAA-AAA transversions, followed by CAA-CGA transitions, followed by CAA-CTA transversions. These results demonstrate that: (i) the frequency of spontaneous mutations in the H-ras 61st codon is equivalent in murine hyperplasias, adenomas and carcinomas, and (ii) sex was not a determining factor in either the mutation frequency or mutation spectrum for the spontaneous lesions. If these lesions represent successive stages in the carcinogenic process, then these results suggest that mutations in the 61st codon of H-ras are early events in spontaneous murine hepatocarcinogenesis.


Subject(s)
Adenoma/genetics , Carcinoma/genetics , Codon/genetics , DNA, Neoplasm/analysis , Genes, ras/genetics , Liver Neoplasms/genetics , Liver/pathology , Amino Acid Sequence , Animals , DNA Mutational Analysis , Female , Hyperplasia/genetics , Male , Mice , Molecular Sequence Data , Polymerase Chain Reaction , Polymorphism, Restriction Fragment Length
11.
Food Chem Toxicol ; 27(5): 331-40, 1989 May.
Article in English | MEDLINE | ID: mdl-2744664

ABSTRACT

These studies evaluate the susceptibility of the Syrian hamster to the induction of renal papillary lesions after exposure to 2-bromethylamine (2-BEA), mefenamic acid, indomethacin, acetaminophen and phenylbutazone. In most cases there were 25 animals per dose group. Papillary necrosis was produced by single or multiple ip doses of 75 mg 2-BEA/kg and above, and was present within 12 hr of administration of a dose of 500 mg/kg body weight. There were lesions in the renal papilla of hamsters 10 days after a single dose of 500 mg 2-BEA/kg. The severity of papillary lesions increased up to 4 days after exposure in hamsters given a single dose of either 250 or 500 mg 2-BEA/kg. The severity of papillary lesions did not increase with the number of doses in hamsters given multiple doses (2-5) of 100 mg 2-BEA/kg. Renal papillary necrosis was observed in about 40% of hamsters given 100, 200 or 400 mg mefenamic acid/kg. Only a few of the hamsters given indomethacin had renal papillary lesions and none of those given acetaminophen (up to 400 mg/kg) or phenylbutazone (up to 600 mg/kg) developed renal papillary lesions.


Subject(s)
Cricetinae , Disease Models, Animal , Kidney Medulla/drug effects , Kidney Papillary Necrosis/chemically induced , Mesocricetus , Acetaminophen/toxicity , Animals , Ethylamines/toxicity , Indomethacin/toxicity , Kidney Medulla/pathology , Kidney Papillary Necrosis/pathology , Male , Mefenamic Acid/toxicity , Phenylbutazone/toxicity
12.
Exp Mol Pathol ; 50(2): 193-204, 1989 Apr.
Article in English | MEDLINE | ID: mdl-2707382

ABSTRACT

Rubratoxin B was given to Syrian hamsters as a single intraperitoneal dose of 0.4 mg/kg. Hamsters were killed at 1, 2, 4, and 6 hr after dosing, and the kidneys and liver were fixed by intravascular perfusion. Renal ultrastructural alterations were evident at 1 hr after treatment and were limited to the straight portion of the proximal tubule. The most prominent alterations were brush border disruption, dilation of smooth endoplasmic reticulum, mitochondrial swelling, cytoplasmic rarefaction, myelin figure formation, and swelling of basal interdigitating processes. Renal alterations were suggestive of damage to membrane structure and/or transport functions and interference with cellular bioenergetics. Hepatic alterations were not seen in the rubratoxin B-treated hamsters of this study.


Subject(s)
Kidney/drug effects , Mushroom Poisoning/pathology , Mycotoxins/toxicity , Animals , Cell Membrane/drug effects , Cell Membrane/ultrastructure , Cricetinae , Injections, Intraperitoneal , Kidney/pathology , Kidney/ultrastructure , Liver/drug effects , Liver/pathology , Liver/ultrastructure , Male , Mesocricetus , Microscopy, Electron , Mycotoxins/administration & dosage
13.
Avian Dis ; 33(2): 357-60, 1989.
Article in English | MEDLINE | ID: mdl-2751566

ABSTRACT

Corn-based diets contaminated with various concentrations of a moniliformin-producing isolate of Fusarium moniliforme var. subglutinans were found to be lethal for chicks, ducklings, and turkey poults. Ducklings appeared to be the most sensitive to the lethal effects of the toxic feed. Gross lesions were ascites, hydropericardium, and myocardial pallor. Microscopic lesions were limited to the heart and liver, and they consisted of degeneration and necrosis of the myocardium and degeneration of hepatocytes. Cardiotoxicosis was the apparent cause of death.


Subject(s)
Animal Feed/poisoning , Cyclobutanes/poisoning , Fusarium/pathogenicity , Mycotoxins/poisoning , Poultry Diseases/etiology , Animals , Chickens , Ducks , Food Microbiology , Turkeys , Zea mays/microbiology
14.
Toxicol Appl Pharmacol ; 96(1): 85-92, 1988 Oct.
Article in English | MEDLINE | ID: mdl-3188028

ABSTRACT

Studies were undertaken to determine if the toxicity and pathology of rubratoxin B, a nephrotoxic and hepatotoxic mycotoxin, could be altered by increasing or decreasing the tissue concentrations of nonprotein sulfhydryls in the liver and kidneys. Rubratoxin B dissolved in DMSO was administered ip to weanling male Syrian hamsters and Mongolian gerbils at doses of 0.4 mg/kg and 2.0 mg/kg, respectively. Rubratoxin B caused a 70% decrease in hepatic and a 60% decrease in renal cortical nonprotein sulfhydryl (NPSH) concentration, an index of tissue reduced glutathione concentration, in both species. Treatment with cysteine prior to rubratoxin B administration did not greatly alter the decreases in NPSH concentration, but did decrease the severity of renal lesions. Treatment with diethyl maleate prior to rubratoxin B administration caused an 80% reduction in hepatic and a 70% reduction in renal NPSH concentration, which was prolonged by rubratoxin B treatment. The incidence and severity of renal lesions was increased in rubratoxin B-treated hamsters and gerbils given diethyl maleate compared to animals given rubratoxin B alone. Additionally, hepatic lesions were seen in hamsters and were more frequent and severe in gerbils that were treated with diethyl maleate prior to rubratoxin B dosing compared to animals given rubratoxin B alone. Renal and hepatocellular NPSH concentration appears to decrease during rubratoxin B toxicosis in the hamster and gerbil, and appears to be contributory in lesion development, since lesions in the liver and kidneys were more severe in animals in which NPSH concentrations were reduced by treatment with diethyl maleate.


Subject(s)
Kidney/drug effects , Liver/drug effects , Mycotoxins/toxicity , Sulfhydryl Compounds/analysis , Animals , Cricetinae , Cysteine/toxicity , Gerbillinae , Kidney Tubules/drug effects , Male , Maleates/toxicity , Mesocricetus , Necrosis
15.
Food Chem Toxicol ; 26(5): 459-66, 1988 May.
Article in English | MEDLINE | ID: mdl-3391470

ABSTRACT

The LD50 for rubratoxin B dissolved in dimethylsulphoxide and administered to ICR mice by ip injection was 0.31 (0.22-0.43) mg/kg body weight. Gross alterations consisted of congestion of the liver and spleen and pallor and mottling of the kidneys. The histopathological alterations seen were hepatic and splenic congestion and renal tubular degeneration. The morphopathogenesis of lesions following a single ip LD50 dose was evaluated in a second study. Hepatic lesions were observed in mice killed between 8 and 40 hr after dosing and included diffuse sinusoidal congestion with mild sinusoidal ectasia, leucostasis, multifocal cytoplasmic vacuolation and necrosis of individual hepatocytes. Renal lesions were mild, not time-dependent, and consisted of mild degenerative changes in tubular epithelial cells of the outer stripe of the outer zone of the medulla. The activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum were increased 2 hr after dosing, peaked at 4 hr and returned to control values by the end of the test period. In a third study, rubratoxin B was administered ip daily for 1 wk at doses of 25, 50 and 75% of the ip LD50. Toxicity was dose related and cumulative with multiple doses at the highest dose. In a fourth study, rubratoxin B was administered ip at a dose of 75% of the ip LD50 daily for 1 wk. Histopathological alterations included hepatic congestion and mild sinusoidal ectasia, multifocal necrosis of hepatocytes, splenic congestion and mild renal tubular degeneration. Serum activities of AST and ALT were increased after multiple doses of rubratoxin B.


Subject(s)
Mushroom Poisoning/chemically induced , Mycotoxins/toxicity , Alanine Transaminase/blood , Animals , Aspartate Aminotransferases/blood , Dyspnea/chemically induced , Kidney/drug effects , Lethal Dose 50 , Liver/drug effects , Male , Mice , Mushroom Poisoning/pathology
17.
Food Chem Toxicol ; 25(11): 843-53, 1987 Nov.
Article in English | MEDLINE | ID: mdl-2961671

ABSTRACT

The LD50 for rubratoxin B dissolved in dimethylsulphoxide and administered to Mongolian gerbils by ip injection was 2.0 (2.26-1.77) mg/kg body weight. The gross alterations observed at autopsy were pallor and mottling of the kidneys and liver and congestion of the spleen. The histopathological alterations seen were renal tubular degeneration and necrosis, degenerative changes in hepatocytes, and congestion of the spleen. The morphopathogenesis of lesions after a single ip LD50 dose was evaluated in a second study. The histopathological alterations that were observed were focal degeneration and necrosis of hepatocytes and renal tubular degeneration and necrosis. Hepatic lesions were observed in gerbils killed between 2 and 12 hr after dosing and included multifocal cytoplasmic vacuolation and coagulative necrosis of hepatocytes. The renal lesions were first observed 2 hr after dosing and increased to maximum severity at 40 hr after dosing. Tubular regeneration accompanied ongoing tubular necrosis at the end of the test period. The activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum were increased 4 hr after dosing, peaked at 24 hr and remained elevated to the end of the test period. Serum K+ concentration was increased 16 hr after dosing and remained elevated to the end of the test period. In a third study, rubratoxin B was administered ip once daily for 7 days at doses of 25, 50 or 75% of the ip LD50. Toxicity was dose related and cumulative with multiple doses. Histopathological alterations included renal tubular degeneration and necrosis, mild tubular dilation and focal necrosis of hepatocytes. In a fourth study, rubratoxin B was administered ip at a dose of 25% of the ip LD50 once daily for 7 days. Histopathological alterations included renal tubular degeneration, mild renal tubular dilation and focal necrosis of hepatocytes. Activities of AST and ALT in serum were slightly increased after multiple doses of rubratoxin B. Results of urinalysis indicated hepatic and renal tubular damage.


Subject(s)
Mycotoxins/toxicity , Adenosine Triphosphatases/analysis , Alanine Transaminase/blood , Animals , Aspartate Aminotransferases/blood , Gerbillinae , Kidney/drug effects , Kidney/pathology , Lethal Dose 50 , Liver/drug effects , Liver/pathology , Male , Potassium/blood , Sulfhydryl Compounds/metabolism
18.
J Wildl Dis ; 23(4): 689-92, 1987 Oct.
Article in English | MEDLINE | ID: mdl-3682099

ABSTRACT

Differential pathogenesis was observed in two species of fish naturally infected with the pentastome Sebekia mississippiensis. Mosquitofish (Gambusia affinis) showed a mild inflammatory response to developing nymphs, whereas swordtails (Xiphophorus helleri) had an extensive granulomatous inflammatory reaction with accompanying hemorrhage, myositis, and myodegeneration. This suggested that certain species of tropical fish reared in the southeastern United States may be at risk to potentially harmful infections with this parasite.


Subject(s)
Cyprinodontiformes/parasitology , Fish Diseases/pathology , Parasitic Diseases, Animal , Alligators and Crocodiles/parasitology , Animals , Arthropods , Fish Diseases/parasitology , Parasitic Diseases/pathology
19.
Food Chem Toxicol ; 25(9): 685-95, 1987 Sep.
Article in English | MEDLINE | ID: mdl-3653822

ABSTRACT

The LD50 for rubratoxin B dissolved in dimethylsulphoxide and administered to Syrian golden hamsters by ip injection was 0.4 (0.2-0.8) mg/kg body weight. The greatest number of deaths occurred 6-24 hr after administration. Gross alterations consisted of congestion of the liver, spleen and kidneys and histopathological alterations involved congestion of the spleen and congestion and mild degenerative changes in hepatocytes. In a second study, rubratoxin B was administered ip daily for 1 wk at doses of 25, 50 and 75% of the ip LD50. Mortality was greatest in the 50 and 75% dose groups. Toxicity was cumulative with multiple doses. Gross alterations were similar to those found in the LD50 study. Histopathological alterations included renal tubular degeneration and necrosis and focal necrosis of hepatocytes. The morphopathogenesis of lesions following a single ip LD50 dose was evaluated in a third study. Histopathological alterations were limited to the kidney and were characterized by renal tubular degeneration and necrosis. Renal lesions were first seen at 2 hr after administration and increased in severity to a maximum at 20 hr. Tubular regeneration was first seen at 24 hr and was found to the end of the test period (72 hr). Serum activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and serum concentrations of total and indirect bilirubin were increased by 8 hr after dosing and returned to control values by the end of the test period. In a fourth study, rubratoxin B was administered ip daily for 1 wk at a dose of 25% of the ip LD50. Gross alterations were similar to those in the other studies. Histopathological alterations included progressive renal tubular degeneration and necrosis. Serum activities of AST and ALT and concentration of blood urea nitrogen (BUN) were progressively increased with increasing numbers of doses. Urinalysis indicated progressive renal tubular damage.


Subject(s)
Mushroom Poisoning/pathology , Mycotoxins/toxicity , Alanine Transaminase , Animals , Aspartate Aminotransferases/blood , Bilirubin/blood , Blood Urea Nitrogen , Cricetinae , Kidney/pathology , Kidney Tubules/pathology , Kinetics , Lethal Dose 50 , Liver/pathology , Male , Mesocricetus , Mushroom Poisoning/physiopathology , Necrosis , Spleen/pathology
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