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javicorvi
/
pretoxtm-dataset

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PRETOX_REL
Summary of results The following compound - related or suspected compound - related findings were noted : At the low dose of 30 mg / kg COMPOUND_XXX and higher ( without dose - dependence if not otherwise mentioned ) : - increased sialorrhea , stained and encrusted mouth / snout - lower water consumption in males - slight decrease in total protein in males on day 24 - slight decrease in relative albumin in females on day 24 - slight decrease in albumin in females on days 24 and 54 ( not decreased at mid dose on day 54 ) - slight dose - dependent increase in total beta globulins in females on day 24 - slight decrease in albumin - globulin quotient in females on days 24 and 54 ( not decreased at mid dose on day 54 ) - dose - dependent decrease of N - demethylase activity in the liver in males - decrease of 7 - ethoxyresorufin deethylase activity in the liver in males in the liver of females In addition , at the mid dose of 100 mg / kg COMPOUND_XXX and higher ( without dose - dependence if not otherwise mentioned ) : - compulsive behavior ( increased frequency of cleaning behavior ) - slight decreases in reticulocyte count in males on day 25 - â € " slight decrease in total protein in females on day 24 - â € " slight dose - dependent decrease in absolute and relative weight of prostate and seminal vesicles ( without histopathological correlate ) - decrease of O - demethylase activity in the liver in males - decrease of aldrin epoxilase activity in the liver in males Additionally , at the high dose of 300 mg / kg COMPOUND_XXX : - slight decreases in red blood cell count and hemoglobin in males on day 25 - slight decrease in albumin in males on day 24 - slight increase in creatinine in males and females on day 24 - decrease of glutathione transferase activity in the liver of females Toxicokinetic evaluation revealed that exposure of female rats was about twice as much as of male rats with regard to Cmax and AUC ( 0 - 24 ) .
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NO_PRETOX_REL
There were no findings at ophthalmoscopic or electrocardiographic examinations which could be attributed to the treatment with the reference or test item .
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[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
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NO_PRETOX_REL
The toxicokinetic evaluation revealed , that systemic exposure and maximum serum concentrations of COMPOUND_XXX increased almost to the same extent as the dose increase from the mid to the high dose .
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NO_PRETOX_REL
DISCUSSION AND CONCLUSIONS Single , daily oral administration of the glucokinase activator , COMPOUND_XXX was well tolerated by rats in a four - week toxicity and toxicokinetic study at doses up to 120 mg / kg / day .
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PRETOX_REL
The relevance of the increased liver weight in high dose females at the end of the treatment period is unclear .
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PRETOX_REL
Death was likely due to an acute bacterial nephritis in the 30 mg / kg / day animal and a dosing error in the 120 mg / kg / day animal .
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PRETOX_REL
Body weight / body weight gain : e adecrease in body weight gain was observed in male and female animals at the high dose of 9.0 mg / kg COMPOUND_XXX .
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PRETOX_REL
Mean body weight was slightly decreased in 8 and 80 mg / kg / d males from day 3 to day 5 , slightly increased in 8 mg / kg / d females on days 3 and 5 and in 80 mg / kg / d females on days 2 to 5 .
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NO_PRETOX_REL
Plasma samples as well as duodenal mucosa and content samples from control animals showed no measurable COMPOUND_XXX concentrations .
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NO_PRETOX_REL
In the control group , serum concentrations after vehicle administration were below LLOQ ( 15 pg / mL ) in all but 2 samples .
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NO_PRETOX_REL
A slight accumulation was observed for the AUC 5min - 24h .
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NO_PRETOX_REL
No cause of death was determined for animal nos. 4021 and 4029 .
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NO_PRETOX_REL
In the worst case , the animals given the high dose were administered at the beginning of the study with a dose close to 273 mg / kg .
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NO_PRETOX_REL
These changes were resolved by the end of recovery .
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PRETOX_REL
CONCLUSION In conclusion , the oral administration of COMPOUND_XXX as nanocrystal dispersion ( NCD ) for 1 month to dogs at doses of 0.05 , 0.15 or 1.0 ( 1.5 ) mg / kg / day lead to early sacrifices for humane reasons in two dogs of the high dose group showing rectum prolaps or intussusception of jejunum and ileum .
[ "CONCLUSION", "In", "conclusion", ",", "the", "oral", "administration", "of", "COMPOUND_XXX", "as", "nanocrystal", "dispersion", "(", "NCD", ")", "for", "1", "month", "to", "dogs", "at", "doses", "of", "0.05", ",", "0.15", "or", "1.0", "(", "1.5", ")", "mg", "/", "kg", "/", "day", "lead", "to", "early", "sacrifices", "for", "humane", "reasons", "in", "two", "dogs", "of", "the", "high", "dose", "group", "showing", "rectum", "prolaps", "or", "intussusception", "of", "jejunum", "and", "ileum", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "B-FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "I-GROUP", "O", "B-SPECIMEN", "B-FINDING", "O", "B-FINDING", "O", "B-SPECIMEN", "O", "B-SPECIMEN", "O" ]
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PRETOX_REL
In addition , at the high dose of 20 mg / kg COMPOUND_XXX : - increased incidence of vomiting immediately after administration ; thinning of fur ; - decrease in fibrinogen and slight prolongation in thrombin time ; - acinar hypertrophy in the mandibular glands .
[ "In", "addition", ",", "at", "the", "high", "dose", "of", "20", "mg", "/", "kg", "COMPOUND_XXX", ":", "-", "increased", "incidence", "of", "vomiting", "immediately", "after", "administration", ";", "thinning", "of", "fur", ";", "-", "decrease", "in", "fibrinogen", "and", "slight", "prolongation", "in", "thrombin", "time", ";", "-", "acinar", "hypertrophy", "in", "the", "mandibular", "glands", "." ]
[ "O", "O", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "O", "B-MANIFESTATION_FINDING", "I-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O" ]
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NO_PRETOX_REL
The final stage of these processes is the complete dissolution of the microparticle depots .
[ "The", "final", "stage", "of", "these", "processes", "is", "the", "complete", "dissolution", "of", "the", "microparticle", "depots", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL
At necropsy only spontaneous alterations were observed .
[ "At", "necropsy", "only", "spontaneous", "alterations", "were", "observed", "." ]
[ "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "O" ]
[ 0, 0, 0, 8, 9, 0, 0, 0 ]
NO_PRETOX_REL
Conclusions Treatment with COMPOUND_XXX with daily i - v. doses of 0.01 , 0.07 or 0.50 mg / kg / day was well tolerated without signs of toxicity .
[ "Conclusions", "Treatment", "with", "COMPOUND_XXX", "with", "daily", "i", "-", "v.", "doses", "of", "0.01", ",", "0.07", "or", "0.50", "mg", "/", "kg", "/", "day", "was", "well", "tolerated", "without", "signs", "of", "toxicity", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O" ]
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NO_PRETOX_REL
Based on food intake , the estimated mean test item intake was about 60 , 215 , and 580 mg / kg / day for the low , mid , and high - dose level , respectively .
[ "Based", "on", "food", "intake", ",", "the", "estimated", "mean", "test", "item", "intake", "was", "about", "60", ",", "215", ",", "and", "580", "mg", "/", "kg", "/", "day", "for", "the", "low", ",", "mid", ",", "and", "high", "-", "dose", "level", ",", "respectively", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "O", "O" ]
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NO_PRETOX_REL
Body weights were taken prior to the first daily dosing on days 1 , 4 , 8 , 13 and 15 .
[ "Body", "weights", "were", "taken", "prior", "to", "the", "first", "daily", "dosing", "on", "days", "1", ",", "4", ",", "8", ",", "13", "and", "15", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL
In the kidney , mild vacuolation of the cortical tubular epithelial cells were diagnosed in females ( partly with hyaline droplets in the tubular epithelium or glomerula and intratubular casts ) .
[ "In", "the", "kidney", ",", "mild", "vacuolation", "of", "the", "cortical", "tubular", "epithelial", "cells", "were", "diagnosed", "in", "females", "(", "partly", "with", "hyaline", "droplets", "in", "the", "tubular", "epithelium", "or", "glomerula", "and", "intratubular", "casts", ")", "." ]
[ "O", "O", "B-SPECIMEN", "O", "O", "B-FINDING", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "I-SPECIMEN", "I-SPECIMEN", "O", "O", "O", "B-SEX", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "B-SPECIMEN", "O", "B-SPECIMEN", "O", "B-FINDING", "I-FINDING", "O", "O" ]
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NO_PRETOX_REL
The low dose of 20 mg salt / kg / day was well tolerated without a clear indication of toxicity .
[ "The", "low", "dose", "of", "20", "mg", "salt", "/", "kg", "/", "day", "was", "well", "tolerated", "without", "a", "clear", "indication", "of", "toxicity", "." ]
[ "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 15, 16, 0, 3, 4, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
There were no test article - related effects on body weight or food consumption .
[ "There", "were", "no", "test", "article", "-", "related", "effects", "on", "body", "weight", "or", "food", "consumption", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
Measurement of motor activity did not reveal any clear treatment - related effects .
[ "Measurement", "of", "motor", "activity", "did", "not", "reveal", "any", "clear", "treatment", "-", "related", "effects", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
The males were not affected .
[ "The", "males", "were", "not", "affected", "." ]
[ "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
Body Weight : Body weights or body weight gains were not affected by treatment with COMPOUND_XXX .
[ "Body", "Weight", ":", "Body", "weights", "or", "body", "weight", "gains", "were", "not", "affected", "by", "treatment", "with", "COMPOUND_XXX", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL
Emesis with or without feed was observed in both sexes at 150 ~ 100 mg / kg / day with increased incidence in the females .
[ "Emesis", "with", "or", "without", "feed", "was", "observed", "in", "both", "sexes", "at", "150", "~", "100", "mg", "/", "kg", "/", "day", "with", "increased", "incidence", "in", "the", "females", "." ]
[ "B-FINDING", "O", "O", "O", "O", "O", "O", "O", "B-SEX", "I-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "B-SEX", "O" ]
[ 8, 0, 0, 0, 0, 0, 0, 0, 5, 7, 0, 3, 4, 4, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 5, 0 ]
NO_PRETOX_REL
The systemic exposure increased underproportionally with increasing dose .
[ "The", "systemic", "exposure", "increased", "underproportionally", "with", "increasing", "dose", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
Some accumulation was evident at 5 mg / kg with about 2fold higher exposure on day 14 .
[ "Some", "accumulation", "was", "evident", "at", "5", "mg", "/", "kg", "with", "about", "2fold", "higher", "exposure", "on", "day", "14", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
At the start of dosing , the dogs were approximately 9 months of age , and body weights ranged from 8.6 to 10.9 kg for males and 5.9 to 8.0 kg for females .
[ "At", "the", "start", "of", "dosing", ",", "the", "dogs", "were", "approximately", "9", "months", "of", "age", ",", "and", "body", "weights", "ranged", "from", "8.6", "to", "10.9", "kg", "for", "males", "and", "5.9", "to", "8.0", "kg", "for", "females", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
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NO_PRETOX_REL
Consequently , plasma concentrations and exposure values are most likely underestimating the true exposure and reflect the minimum exposure levels obtained .
[ "Consequently", ",", "plasma", "concentrations", "and", "exposure", "values", "are", "most", "likely", "underestimating", "the", "true", "exposure", "and", "reflect", "the", "minimum", "exposure", "levels", "obtained", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
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PRETOX_REL
The finding was reversible in the mid dose group but not reversible in the high dose group Additionally at the high dose of 9.0 mg / kg COMPOUND_XXX : e diarrhea , diminished muscular tone , emaciation , ruffled fur and encrusted nose occurred in males and females .
[ "The", "finding", "was", "reversible", "in", "the", "mid", "dose", "group", "but", "not", "reversible", "in", "the", "high", "dose", "group", "Additionally", "at", "the", "high", "dose", "of", "9.0", "mg", "/", "kg", "COMPOUND_XXX", ":", "e", "diarrhea", ",", "diminished", "muscular", "tone", ",", "emaciation", ",", "ruffled", "fur", "and", "encrusted", "nose", "occurred", "in", "males", "and", "females", "." ]
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NO_PRETOX_REL
The highest concentration amounted to 6.87 ug / L ( day 1 , male ) which is approximately 400-fold lower than the lowest Cmax value of the lowest dose group ( day 1 , male , 2616 ug / L ) .
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[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
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NO_PRETOX_REL
No treatment - related changes in the skin were observed .
[ "No", "treatment", "-", "related", "changes", "in", "the", "skin", "were", "observed", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
There were no effects on food consumption .
[ "There", "were", "no", "effects", "on", "food", "consumption", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL
At 10 mg / kg , a statistically significant decrease of absolute and relative thymus weights was noted .
[ "At", "10", "mg", "/", "kg", ",", "a", "statistically", "significant", "decrease", "of", "absolute", "and", "relative", "thymus", "weights", "was", "noted", "." ]
[ "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "O", "O" ]
[ 0, 3, 4, 4, 4, 0, 0, 0, 0, 1, 0, 0, 0, 0, 10, 2, 0, 0, 0 ]
PRETOX_REL
A marked increase in ovary weights at 150 and 300 mg / kg / day and slight increases in heart weights at 75 , 150 and 300 mg / kg / day were present in females .
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[ "O", "O", "B-MANIFESTATION_FINDING", "O", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "B-SEX", "O" ]
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PRETOX_REL
Detailed examination of the bone marrow smears revealed that a shift to immaturity was observed in myeloid series cells in two animals receiving 1.0 mg / kg / occasion at the 39 week timepoint .
[ "Detailed", "examination", "of", "the", "bone", "marrow", "smears", "revealed", "that", "a", "shift", "to", "immaturity", "was", "observed", "in", "myeloid", "series", "cells", "in", "two", "animals", "receiving", "1.0", "mg", "/", "kg", "/", "occasion", "at", "the", "39", "week", "timepoint", "." ]
[ "O", "O", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "I-SPECIMEN", "O", "O", "O", "O", "O", "B-FINDING", "O", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "I-SPECIMEN", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O" ]
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NO_PRETOX_REL
Body weight and food consumption were recorded once weekly .
[ "Body", "weight", "and", "food", "consumption", "were", "recorded", "once", "weekly", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
An increase in dose from 0.15 to 1.5 mg / kg ( 1.0 mg / kg for Day 87 ) of the free base was accompanied by an increase in the plasma COMPOUND_XXX concentrations .
[ "An", "increase", "in", "dose", "from", "0.15", "to", "1.5", "mg", "/", "kg", "(", "1.0", "mg", "/", "kg", "for", "Day", "87", ")", "of", "the", "free", "base", "was", "accompanied", "by", "an", "increase", "in", "the", "plasma", "COMPOUND_XXX", "concentrations", "." ]
[ "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 3, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
At 150 ppm , there were no treatment - related changes in either sex .
[ "At", "150", "ppm", ",", "there", "were", "no", "treatment", "-", "related", "changes", "in", "either", "sex", "." ]
[ "O", "B-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 3, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
c. Feed and water intake The data for incomplete feed intake is shown in the appendix of the report .
[ "c.", "Feed", "and", "water", "intake", "The", "data", "for", "incomplete", "feed", "intake", "is", "shown", "in", "the", "appendix", "of", "the", "report", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
COMPOUND_XXX was administered by oral gavage to groups of rats ( 10 / sex / group ) for 4 weeks at dose levels of 10 , 50 , 225 and 1000 mg / kg / day .
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NO_PRETOX_REL
The individual data are listed in the raw data .
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NO_PRETOX_REL
Even though no systemic or local findings related to the compound could be observed , systemic availability , which was probably at least partly due to peroral intake of the compound , was seen at different time points .
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PRETOX_REL
The occurrence of a moderately increased M : E ratio for one high - dose female ( animal no. 4501 ) reflected a spectrum of histopathologic changes for this animal that were considered to be spontaneous and not related to COMPOUND_XXX treatment .
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PRETOX_REL
Urinalysis changes attributed to treatment with COMPOUND_XXX included decreases in specific gravity and increases in urine volume ( 75 mg / kg ) .
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PRETOX_REL
Test article - related body weight loss approximating 12 % was observed in one female at 80 mglkg / day and a slight decrease in absolute body weight gain was also evident in one male at 80 mglkg / day .
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NO_PRETOX_REL
The initiation of treatment were approximately 2.5 to 5 years of age and weighed 2.8 - 4.4 kg for males and 2.4 - 4.3 kg for females .
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PRETOX_REL
In addition to the food in the stomach at gross examination and the yellow discoloration observed in the 10 and 40 mg / kg / day groups , rats in the 180 mg / kg / day group had slight increases in reticulocyte counts and total bilirubin .
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NO_PRETOX_REL
On day 0 , the mean maximum plasma concentration ( C , , ) values of COMPOUND_XXX were 722 , 4430 , and 9900 ng / ml in females given 40 , 160 , and 400 mg / kg / day , respectively .
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PRETOX_REL
Individual dogs showed minimal to slight bile duct hyperplasia and peribiliary fibrosis .
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PRETOX_REL
Histopathologic changes were present beginning at 160 mg / kg / day and included vacuolation in a wide variety of tissues , single - cell necrosis of the liver , and m inimal skeletal muscle degeneration / regeneration ; skeletal muscle necrosis was present at 400 mg / kg / day .
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PRETOX_REL
- A diffuse hepatocellular hypertrophy of the liver was found in male and female animals associated with an increase in relative liver weights .
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NO_PRETOX_REL
The decrease was minimal to slight at 50 and 100 mg / kg and moderate at 200 and 300 mg / kg ( up to about -70 % when compared to the controls ) .
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NO_PRETOX_REL
No drug - related effects were observed in macroscopic , microscopic or organ weight data in this study .
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[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
C0062 , was dissolved in Millipore water and administered to two groups each of 20 male rats at dosages of 120 and 180 mg base / kg / day and a dosage volume of 5 mL / kg , once daily , 7 days a week , for 2 or 4 weeks .
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NO_PRETOX_REL
On completion of the study , however , it was decided to extend the histopathological evaluation to all tissues in order to fully assess all treatment - related findings .
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NO_PRETOX_REL
COMPOUND_XXX ( batch no. : XXXXX ) was administered orally by gavage as a solution in Purified Water , USP to four groups of male and female Cynomolgus monkeys ( 1 or 2 / sex ) at 0 , 10 , 37.5 and 75 ~ 50 ing / kg b.i.d. ( daily doses of 0 , 20 , 75 and 150 ~ 100 mg / kg / day ) approximately 6 hours apart for at least 2 weeks .
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NO_PRETOX_REL
Analysis of hematology , coagulation , clinical chemistry , or urinalysis parameter at the end of treatment and recovery period did not result in any findings that could be attributed to the treatment with COMPOUND_XXX .
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[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
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PRETOX_REL
Administration of the positive control resulted in dehydration , moderate body weight decreases ( 21 % ) , reduced body weight gains and food consumption decreases following 5 , 12 or 26 day treatment period .
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NO_PRETOX_REL
A NOEL ( no observed effect level ) was not determined since effects regarded as pharmacologic were seen from the lowest dose upwards .
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[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "O" ]
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PRETOX_REL
led to marked clinical findings and further affected kidneys , liver , reproductive , hematopoietic and immunologic organs as primary targets of toxicity .
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NO_PRETOX_REL
In males treated with 160 umol / kg bw .
[ "In", "males", "treated", "with", "160", "umol", "/", "kg", "bw", "." ]
[ "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]
[ 0, 0, 0, 0, 3, 4, 4, 4, 4, 0 ]
NO_PRETOX_REL
The study was designed to establish a no toxic effect level and to estimate the toxicokinetic profile .
[ "The", "study", "was", "designed", "to", "establish", "a", "no", "toxic", "effect", "level", "and", "to", "estimate", "the", "toxicokinetic", "profile", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL
Changes in the lymphoid system were related to the pharmacologic properties of the test item .
[ "Changes", "in", "the", "lymphoid", "system", "were", "related", "to", "the", "pharmacologic", "properties", "of", "the", "test", "item", "." ]
[ "B-FINDING", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 8, 0, 0, 10, 11, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
Two similarly constituted Control groups were untreated or received the vehicle alone for the same period .
[ "Two", "similarly", "constituted", "Control", "groups", "were", "untreated", "or", "received", "the", "vehicle", "alone", "for", "the", "same", "period", "." ]
[ "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 12, 13, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
In females , peak plasma concentrations varied from 152 ± 91 ng / ml at the dose 5 mg / kg / day to 392 ± 78 ng / ml at the dose 15 mg / kg / day and to 743 ± 255 ng / ml at the dose of 60 mg / kg / day .
[ "In", "females", ",", "peak", "plasma", "concentrations", "varied", "from", "152", "±", "91", "ng", "/", "ml", "at", "the", "dose", "5", "mg", "/", "kg", "/", "day", "to", "392", "±", "78", "ng", "/", "ml", "at", "the", "dose", "15", "mg", "/", "kg", "/", "day", "and", "to", "743", "±", "255", "ng", "/", "ml", "at", "the", "dose", "of", "60", "mg", "/", "kg", "/", "day", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0 ]
NO_PRETOX_REL
Female rats generally had higher AUC0_24h and Cmax values than males and plasma concentrations increased by up to 3 fold after repeated daily administration of the compound for 13 consecutive weeks .
[ "Female", "rats", "generally", "had", "higher", "AUC0_24h", "and", "Cmax", "values", "than", "males", "and", "plasma", "concentrations", "increased", "by", "up", "to", "3", "fold", "after", "repeated", "daily", "administration", "of", "the", "compound", "for", "13", "consecutive", "weeks", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
These changes were considered as due to dosing with COMPOUND_XXX .
[ "These", "changes", "were", "considered", "as", "due", "to", "dosing", "with", "COMPOUND_XXX", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
The effects were mostly pronounced in the first weeks .
[ "The", "effects", "were", "mostly", "pronounced", "in", "the", "first", "weeks", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
No difference in effect was apparent either between genders or between the two study days .
[ "No", "difference", "in", "effect", "was", "apparent", "either", "between", "genders", "or", "between", "the", "two", "study", "days", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
The gender difference was less pronounced at the 60 and 120 mg / kg / day dose groups at study day 28 , probably due to more significant accumulation of the parent compound and the metabolite in males at these dose levels .
[ "The", "gender", "difference", "was", "less", "pronounced", "at", "the", "60", "and", "120", "mg", "/", "kg", "/", "day", "dose", "groups", "at", "study", "day", "28", ",", "probably", "due", "to", "more", "significant", "accumulation", "of", "the", "parent", "compound", "and", "the", "metabolite", "in", "males", "at", "these", "dose", "levels", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 4, 4, 12, 13, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
Comparing the pre-dose values with those 24 hours post dosing on day 14 it was evident that stead - state was reached on day 14 .
[ "Comparing", "the", "pre-dose", "values", "with", "those", "24", "hours", "post", "dosing", "on", "day", "14", "it", "was", "evident", "that", "stead", "-", "state", "was", "reached", "on", "day", "14", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL
In conclusion , oral administration of COMPOUND_XXX using a Monday , Wednesday and Friday dosing schedule was not tolerated at 1.5 mg / kg / occasion due to excessive body weight loss accompanied by decreases in food consumption and faecal changes .
[ "In", "conclusion", ",", "oral", "administration", "of", "COMPOUND_XXX", "using", "a", "Monday", ",", "Wednesday", "and", "Friday", "dosing", "schedule", "was", "not", "tolerated", "at", "1.5", "mg", "/", "kg", "/", "occasion", "due", "to", "excessive", "body", "weight", "loss", "accompanied", "by", "decreases", "in", "food", "consumption", "and", "faecal", "changes", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "B-MANIFESTATION_FINDING", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-FINDING", "I-FINDING", "O" ]
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PRETOX_REL
- The bilirubin of the female controls ( week 5 ) was somewhat high .
[ "-", "The", "bilirubin", "of", "the", "female", "controls", "(", "week", "5", ")", "was", "somewhat", "high", "." ]
[ "O", "O", "B-STUDY_TESTCD", "O", "O", "B-SEX", "O", "O", "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O" ]
[ 0, 0, 2, 0, 0, 5, 0, 0, 0, 0, 0, 0, 0, 1, 0 ]
NO_PRETOX_REL
All altered parameters normalized or showed tendency towards normalization after the 4 weeks recovery period .
[ "All", "altered", "parameters", "normalized", "or", "showed", "tendency", "towards", "normalization", "after", "the", "4", "weeks", "recovery", "period", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL
Similar mammary gland effects were also recorded in males from 1.0 mg / kg / day upwards .
[ "Similar", "mammary", "gland", "effects", "were", "also", "recorded", "in", "males", "from", "1.0", "mg", "/", "kg", "/", "day", "upwards", "." ]
[ "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "B-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O" ]
[ 0, 8, 9, 9, 0, 0, 0, 0, 5, 0, 3, 4, 4, 4, 4, 4, 0, 0 ]
PRETOX_REL
Beginning at group Il , hairless , partly reddish , spots at the whole body up to a nearly complete hair loss and an increased incidence of feces with reddish / bloody , partly foamy , admixtures / mucus were observed .
[ "Beginning", "at", "group", "Il", ",", "hairless", ",", "partly", "reddish", ",", "spots", "at", "the", "whole", "body", "up", "to", "a", "nearly", "complete", "hair", "loss", "and", "an", "increased", "incidence", "of", "feces", "with", "reddish", "/", "bloody", ",", "partly", "foamy", ",", "admixtures", "/", "mucus", "were", "observed", "." ]
[ "O", "O", "B-GROUP", "I-GROUP", "O", "B-FINDING", "O", "B-FINDING", "I-FINDING", "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "B-FINDING", "I-FINDING", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O" ]
[ 0, 0, 12, 13, 0, 8, 0, 8, 9, 0, 8, 9, 9, 9, 9, 0, 0, 0, 0, 0, 8, 9, 0, 0, 8, 9, 9, 9, 0, 8, 9, 9, 0, 8, 9, 0, 8, 9, 9, 0, 0, 0 ]
NO_PRETOX_REL
Immunochemistry evaluations ( tetraiodothyronine , triiodothyronine and thyroid stimulating hormone ) were conducted on all animals once in pretest , during weeks 5 and 13 of the dosing period , and at the end of the recovery period .
[ "Immunochemistry", "evaluations", "(", "tetraiodothyronine", ",", "triiodothyronine", "and", "thyroid", "stimulating", "hormone", ")", "were", "conducted", "on", "all", "animals", "once", "in", "pretest", ",", "during", "weeks", "5", "and", "13", "of", "the", "dosing", "period", ",", "and", "at", "the", "end", "of", "the", "recovery", "period", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
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NO_PRETOX_REL
Consequently , the no - adverse - effect - level was considered to be 50 mg / kg / day in this study .
[ "Consequently", ",", "the", "no", "-", "adverse", "-", "effect", "-", "level", "was", "considered", "to", "be", "50", "mg", "/", "kg", "/", "day", "in", "this", "study", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 0 ]
NO_PRETOX_REL
Ophthalmology examinations were performed on all animals in pretest and on control and high dose animals in week 13 .
[ "Ophthalmology", "examinations", "were", "performed", "on", "all", "animals", "in", "pretest", "and", "on", "control", "and", "high", "dose", "animals", "in", "week", "13", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 15, 16, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
A treatment - related effect can not e be excluded .
[ "A", "treatment", "-", "related", "effect", "can", "not", "e", "be", "excluded", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL
Clinical pathology analysis revealed lower mean total cholesterol concentrations in both sexes ( - 58 % and -44 % in males and females , respectively ) .
[ "Clinical", "pathology", "analysis", "revealed", "lower", "mean", "total", "cholesterol", "concentrations", "in", "both", "sexes", "(", "-", "58", "%", "and", "-44", "%", "in", "males", "and", "females", ",", "respectively", ")", "." ]
[ "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "B-SEX", "I-SEX", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 1, 2, 6, 6, 0, 0, 5, 7, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
The joint effects were partially reversible following a 4 week treatment - free period , whilst the skin and stomach effects were totally reversible .
[ "The", "joint", "effects", "were", "partially", "reversible", "following", "a", "4", "week", "treatment", "-", "free", "period", ",", "whilst", "the", "skin", "and", "stomach", "effects", "were", "totally", "reversible", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
No organ toxicity was observed .
[ "No", "organ", "toxicity", "was", "observed", "." ]
[ "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
In conclusion , daily oral administration of the glucokinase activator COMPOUND_XXX to rats at doses of 30 , 60 , or 120 mg / kg / day for 4 weeks was well - tolerated .
[ "In", "conclusion", ",", "daily", "oral", "administration", "of", "the", "glucokinase", "activator", "COMPOUND_XXX", "to", "rats", "at", "doses", "of", "30", ",", "60", ",", "or", "120", "mg", "/", "kg", "/", "day", "for", "4", "weeks", "was", "well", "-", "tolerated", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O" ]
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NO_PRETOX_REL
A maximum tolerated dose level was not determined in this study .
[ "A", "maximum", "tolerated", "dose", "level", "was", "not", "determined", "in", "this", "study", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
In the absence of any microscopic correlates , these injection site findings were not considered adverse .
[ "In", "the", "absence", "of", "any", "microscopic", "correlates", ",", "these", "injection", "site", "findings", "were", "not", "considered", "adverse", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
The dosing volume for all dose groups was 5 mL / kg .
[ "The", "dosing", "volume", "for", "all", "dose", "groups", "was", "5", "mL", "/", "kg", "." ]
[ "O", "O", "O", "O", "B-GROUP", "I-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 12, 13, 13, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL
No menstrual bleeding was noted in the treatment period in one animal resulting in a decrease in frequency and incidence of the finding bloody vaginal discharge .
[ "No", "menstrual", "bleeding", "was", "noted", "in", "the", "treatment", "period", "in", "one", "animal", "resulting", "in", "a", "decrease", "in", "frequency", "and", "incidence", "of", "the", "finding", "bloody", "vaginal", "discharge", "." ]
[ "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O" ]
[ 8, 9, 9, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 8, 9, 9, 0 ]
NO_PRETOX_REL
CONCLUSION In conclusion , the oral administration of COMPOUND_XXX for 6 months to rats at doses of 0.1 , 1.0 and 7.5 mg / kg / day resulted in no treatment - related mortality .
[ "CONCLUSION", "In", "conclusion", ",", "the", "oral", "administration", "of", "COMPOUND_XXX", "for", "6", "months", "to", "rats", "at", "doses", "of", "0.1", ",", "1.0", "and", "7.5", "mg", "/", "kg", "/", "day", "resulted", "in", "no", "treatment", "-", "related", "mortality", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
In - life data collection included ; clinical observations , body weight , food consumption , ophthalmoscopy , neurological examinations , clinical pathology and electrophysiology .
[ "In", "-", "life", "data", "collection", "included", ";", "clinical", "observations", ",", "body", "weight", ",", "food", "consumption", ",", "ophthalmoscopy", ",", "neurological", "examinations", ",", "clinical", "pathology", "and", "electrophysiology", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
In conclusion , treatment with COMPOUND_XXX appeared to be well tolerated at doses of up to 1000 mg / kg / day for 7 days , with no adverse in - life findings and only minor changes in some laboratory parameters .
[ "In", "conclusion", ",", "treatment", "with", "COMPOUND_XXX", "appeared", "to", "be", "well", "tolerated", "at", "doses", "of", "up", "to", "1000", "mg", "/", "kg", "/", "day", "for", "7", "days", ",", "with", "no", "adverse", "in", "-", "life", "findings", "and", "only", "minor", "changes", "in", "some", "laboratory", "parameters", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL
Accumulation of vacuolated macrophages in the mandibular and mesenteric lymph nodes at 10 pmol / kg .
[ "Accumulation", "of", "vacuolated", "macrophages", "in", "the", "mandibular", "and", "mesenteric", "lymph", "nodes", "at", "10", "pmol", "/", "kg", "." ]
[ "B-FINDING", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "I-SPECIMEN", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]
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PRETOX_REL
Relative kidney weight was increased in both sexes .
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[ "O", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "B-MANIFESTATION_FINDING", "O", "B-SEX", "I-SEX", "O" ]
[ 0, 10, 2, 0, 1, 0, 5, 7, 0 ]
PRETOX_REL
At histopathology , this change corresponded to slight to severe atrophy of the thymus cortex with thymocyte cell loss in animals at 200 and 300 mg / kg / day .
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NO_PRETOX_REL
XXXX ) was administered intravenously , via a cephalic and / or saphenous vein , as solutions in lactate vehicle ( lN lactic acid , equivalent to that used in the highest concentration of COMPOUND_XXX , and 5 % dextrose ) to groups ( 3 or 5 / sex / group ) of male and female beagle dogs .
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[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "O" ]
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NO_PRETOX_REL
Regardless of the dose and despite the high pelvis concentration found for the parent at both doses , COMPOUND_XXX was found in pelvis in two animals only .
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[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
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