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javicorvi
/
pretoxtm-dataset

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PRETOX_REL
Metaphyseal hyperostosis , growth plate thickening and / or synovial cell hyperplasia were also observed with a lower incidence and severity in rats from the low dose group .
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[ "B-FINDING", "I-FINDING", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "I-GROUP", "O" ]
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NO_PRETOX_REL
No macroscopic findings were noted at necropsy .
[ "No", "macroscopic", "findings", "were", "noted", "at", "necropsy", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
There were no changes in nerve conductance in COMPOUND_XXX treated rats nor histopathological findings .
[ "There", "were", "no", "changes", "in", "nerve", "conductance", "in", "COMPOUND_XXX", "treated", "rats", "nor", "histopathological", "findings", "." ]
[ "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
Summary COMPOUND_XXX ( GK4 ) is a glucokinase activator which is being developed for the treatment of non-insulin dependent diabetes mellitus ( NIDDM ) .
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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" ]
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PRETOX_REL
Administration of COMPOUND_XXX was associated with reductions in white blood cell parameters including decreases in white blood cell and lymphocyte counts at doses ≥ 0.3 mg / kg in males and ≥ 1.0 mg / kg in females ; decreases in neutrophil , eosinophil and basophil counts at 3.0 mg / kg , and reductions in red cell parameters ( red blood cell counts , hemoglobin , hematocrit ) and platelet counts , and increases in reticulocyte counts and red cell distribution at doses at doses ≥ 1.0 mg / kg .
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PRETOX_REL
â € " As can be seen from the table , animal H 073 / control group and H 062 / group | showed a reduced health status at the end of the study with strengthened breathing in animal H 062 .
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[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "O", "O" ]
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NO_PRETOX_REL
The pharmacokinetic evaluation of the present study indicates an about linear pharmacokinetic behavior of the drug after i.v. administration of 0.01 , 0.07 or 0.5 mg / kg COMPOUND_XXX in female Cynomolgus monkeys , i.e. the increase of systemic exposure and observed maximum concentrations was about proportional to the dose increase .
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NO_PRETOX_REL
In the control group , no plasma levels of 89 Y could be detected .
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[ "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
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NO_PRETOX_REL
Evaluation of hematology , coagulation , clinical chemistry and urinalysis parameters at the end of the treatment and recovery period did not reveal any treatment related findings .
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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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PRETOX_REL
Compound - related changes in thyroid hormones measured at the end of the dosing period consisted of slight reductions in thyroid stimulating hormone ( decreased by 13.2 and 14.6 % for females at 1.0 and 3.0 mg / kg respectively ) , slight increases in tetraiodothyronine ( T4 ) ( increased by 21.9 and 18.3 % for females at 1.0 and 3.0 mg / kg respectively ) , and slight increases in T3 levels ( increased by 26 and 19 % respectively for males at 1.0 and 3.0 mg / kg , respectively ) , relative to concurrent controls .
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NO_PRETOX_REL
These changes were seen in all treatment groups , including the control group .
[ "These", "changes", "were", "seen", "in", "all", "treatment", "groups", ",", "including", "the", "control", "group", "." ]
[ "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "I-GROUP", "O", "O", "O", "B-GROUP", "I-GROUP", "O" ]
[ 0, 0, 0, 0, 0, 12, 13, 13, 0, 0, 0, 12, 13, 0 ]
NO_PRETOX_REL
Discussion and Conclusions Daily treatment of animals over 4 weeks with COMPOUND_XXX at 15 μmol Gd / kg bw .
[ "Discussion", "and", "Conclusions", "Daily", "treatment", "of", "animals", "over", "4", "weeks", "with", "COMPOUND_XXX", "at", "15", "μmol", "Gd", "/", "kg", "bw", "." ]
[ "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" ]
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NO_PRETOX_REL
The dose solution concentration was -6.6 to +9.9 % of target .
[ "The", "dose", "solution", "concentration", "was", "-6.6", "to", "+9.9", "%", "of", "target", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL
Clinical Chemistry : Dose - related decreases in glucose levels were observed in males given ≥ 300 mg / kg / day and in females given ≥ 100 mg / kg / day .
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[ "O", "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "B-SEX", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "B-SEX", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]
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NO_PRETOX_REL
Approximately 1.0 gram tissue samples were collected from liver , heart , kidney , skeleton muscle , bone marrow ( from the opposite leg where samples are collected for histopathology examination ) and duodenum of non-recovery animals for toxicokinetic analyses .
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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" ]
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NO_PRETOX_REL
CONCLUSION The oral administration of COMPOUND_XXX the tosylate salt , up to the dose of 1000 mg base / kg over 26 weeks in male Wistar rats did not lead to any overt toxicity and , in particular , there was no change in serum glucose concentration .
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[ "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", "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
The gall bladder and kidney changes were no longer present at the end of the 4 - week recovery period indicating complete recovery while Kupffer cell hypertrophy and bile duct proliferation , both of minimal severity , were present in the two high - dose recovery females suggesting partial reversibility .
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PRETOX_REL
Tubular necrosis was accompanying regeneration and mineralization in the animal with macroscopically detectable gravel in the urinary bladder .
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[ "B-FINDING", "I-FINDING", "O", "O", "O", "O", "B-FINDING", "O", "O", "O", "O", "O", "O", "B-FINDING", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O" ]
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NO_PRETOX_REL
All the other changes , highlighted by data statistical analyses , were considered not toxicologically relevant , since they were without dose - relationship or minimal in degree or devoid of pathological meaning .
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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" ]
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PRETOX_REL
A minimal increase in absolute segmented neutrophils was observed in males given 500 mg / kg / day of NS and OS .
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[ "O", "B-MANIFESTATION_FINDING", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "B-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O" ]
[ 0, 1, 1, 0, 2, 6, 6, 0, 0, 0, 5, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
The mean plasma levels of the compound in males at study termination were 1.3 , 9.1 and 104.8 ng / ml whilst those in females were 1.4 , 5.9 and 85.7 ng / ml at the low , mid and high dose levels , respectively .
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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", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "O", "O", "O" ]
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NO_PRETOX_REL
The data for the clinical findings recorded during the study are presented in the appendix of the report .
[ "The", "data", "for", "the", "clinical", "findings", "recorded", "during", "the", "study", "are", "presented", "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" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL
Intraperitoneal injections were only necessary ( due to swollen tails ) in most of the animals of group IV during the last week .
[ "Intraperitoneal", "injections", "were", "only", "necessary", "(", "due", "to", "swollen", "tails", ")", "in", "most", "of", "the", "animals", "of", "group", "IV", "during", "the", "last", "week", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 8, 9, 0, 0, 0, 0, 0, 0, 0, 12, 13, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
The test item did not induce any noteworthy transcriptional changes in heart or skeletal muscle and electron microscopic evaluation of heart tissue of treated animals generally showed the same ultra-morphology of all cellular organelles as the corresponding control animals .
[ "The", "test", "item", "did", "not", "induce", "any", "noteworthy", "transcriptional", "changes", "in", "heart", "or", "skeletal", "muscle", "and", "electron", "microscopic", "evaluation", "of", "heart", "tissue", "of", "treated", "animals", "generally", "showed", "the", "same", "ultra-morphology", "of", "all", "cellular", "organelles", "as", "the", "corresponding", "control", "animals", "." ]
[ "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" ]
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PRETOX_REL
Exudate and synovial cell changes appeared to be completely reversible , although fibroplasia was only partiaiiy reversible .
[ "Exudate", "and", "synovial", "cell", "changes", "appeared", "to", "be", "completely", "reversible", ",", "although", "fibroplasia", "was", "only", "partiaiiy", "reversible", "." ]
[ "B-FINDING", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "O", "O", "O", "O", "O" ]
[ 8, 0, 8, 9, 9, 0, 0, 0, 0, 0, 0, 0, 8, 0, 0, 0, 0, 0 ]
PRETOX_REL
Only male rats were used in this study as effects on heart weight with COMPOUND_XXX were noted in both sexes .
[ "Only", "male", "rats", "were", "used", "in", "this", "study", "as", "effects", "on", "heart", "weight", "with", "COMPOUND_XXX", "were", "noted", "in", "both", "sexes", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "O", "O", "O", "O", "B-SEX", "I-SEX", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 10, 2, 0, 0, 0, 0, 0, 5, 7, 0 ]
PRETOX_REL
After the 8 - week recovery period , the alterations were no longer apparent ( gall bladder , small and large intestine , lymphatic tissues , bone marrow ) or were present at a lower frequency / severity ( male and female reproductive system , pancreas and pigment deposition in various organs / tissues ) .
[ "After", "the", "8", "-", "week", "recovery", "period", ",", "the", "alterations", "were", "no", "longer", "apparent", "(", "gall", "bladder", ",", "small", "and", "large", "intestine", ",", "lymphatic", "tissues", ",", "bone", "marrow", ")", "or", "were", "present", "at", "a", "lower", "frequency", "/", "severity", "(", "male", "and", "female", "reproductive", "system", ",", "pancreas", "and", "pigment", "deposition", "in", "various", "organs", "/", "tissues", ")", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "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-MANIFESTATION_FINDING", "O", "O", "O", "O", "B-SEX", "I-SEX", "B-SPECIMEN", "I-SPECIMEN", "I-SPECIMEN", "O", "B-SPECIMEN", "O", "B-FINDING", "I-FINDING", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "B-SPECIMEN", "O", "O" ]
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NO_PRETOX_REL
The findings determined at necropsy and the findings of the histopathological a investigations including the incidence of the alterations found are presented in the pathology report in the appendix of the report .
[ "The", "findings", "determined", "at", "necropsy", "and", "the", "findings", "of", "the", "histopathological", "a", "investigations", "including", "the", "incidence", "of", "the", "alterations", "found", "are", "presented", "in", "the", "pathology", "report", "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", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
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PRETOX_REL
Prior to sacrifice , this animal displayed persistent and severe signs of inappetence , and emetic and fecal changes as well as an approximate 15 % loss in body weight .
[ "Prior", "to", "sacrifice", ",", "this", "animal", "displayed", "persistent", "and", "severe", "signs", "of", "inappetence", ",", "and", "emetic", "and", "fecal", "changes", "as", "well", "as", "an", "approximate", "15", "%", "loss", "in", "body", "weight", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "O", "O", "B-FINDING", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O" ]
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PRETOX_REL
The changes recorded at 7.5 mg / kg / day were partially ( mammary gland changes in females , bone marrow changes , prostate changes , increased levels of ALT in males and ALP in females ) or completely reversible ( all remaining changes ) .
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[ "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "B-FINDING", "O", "B-SEX", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "B-SPECIMEN", "B-FINDING", "O", "B-MANIFESTATION_FINDING", "O", "O", "B-STUDY_TESTCD", "O", "B-SEX", "O", "B-STUDY_TESTCD", "O", "B-SEX", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
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NO_PRETOX_REL
The treatment period was extended for a further nine days during which the dose concentration for animals which had received 0.1 mg / ml was increased to 0 3 mg / ml ; the Controls and animals receiving 0.2 mg / ml were treated as before .
[ "The", "treatment", "period", "was", "extended", "for", "a", "further", "nine", "days", "during", "which", "the", "dose", "concentration", "for", "animals", "which", "had", "received", "0.1", "mg", "/", "ml", "was", "increased", "to", "0", "3", "mg", "/", "ml", ";", "the", "Controls", "and", "animals", "receiving", "0.2", "mg", "/", "ml", "were", "treated", "as", "before", "." ]
[ "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", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O" ]
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NO_PRETOX_REL
At 150 ppm : No treatment - related effects were observed in either sex .
[ "At", "150", "ppm", ":", "No", "treatment", "-", "related", "effects", "were", "observed", "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
After the 26th week of treatment , the maximal concentrations and the areas under the curves of COMPOUND_XXX were proportional to the dose .
[ "After", "the", "26th", "week", "of", "treatment", ",", "the", "maximal", "concentrations", "and", "the", "areas", "under", "the", "curves", "of", "COMPOUND_XXX", "were", "proportional", "to", "the", "dose", "." ]
[ "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
No clinical signs were observed in other animals treated at the same or lower doses .
[ "No", "clinical", "signs", "were", "observed", "in", "other", "animals", "treated", "at", "the", "same", "or", "lower", "doses", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 15, 16, 0 ]
NO_PRETOX_REL
The evaluation of blood pressure ( for individual and mean values see appendix of the report ) showed no adverse effects up to and including group Ill. .
[ "The", "evaluation", "of", "blood", "pressure", "(", "for", "individual", "and", "mean", "values", "see", "appendix", "of", "the", "report", ")", "showed", "no", "adverse", "effects", "up", "to", "and", "including", "group", "Ill.", "." ]
[ "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", "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, 12, 13, 0 ]
PRETOX_REL
There was a higher variation in PAG concentrations than for COMPOUND_XXX in the jejunal content , especially at 60 mg / kg / day with higher values around noon or in the afternoon ( at 11:00 , 14:00 and 17:00 ) than at the other time points .
[ "There", "was", "a", "higher", "variation", "in", "PAG", "concentrations", "than", "for", "COMPOUND_XXX", "in", "the", "jejunal", "content", ",", "especially", "at", "60", "mg", "/", "kg", "/", "day", "with", "higher", "values", "around", "noon", "or", "in", "the", "afternoon", "(", "at", "11:00", ",", "14:00", "and", "17:00", ")", "than", "at", "the", "other", "time", "points", "." ]
[ "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "B-SPECIMEN", "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", "O", "O", "O", "O" ]
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PRETOX_REL
There were several gross pathology findings which were considered to be test - article related in the daily - dosed 200 and 270 mg / kg rats ( Groups 3 and 4 ) , consisting of flaking and scabbing in the treated skin sections .
[ "There", "were", "several", "gross", "pathology", "findings", "which", "were", "considered", "to", "be", "test", "-", "article", "related", "in", "the", "daily", "-", "dosed", "200", "and", "270", "mg", "/", "kg", "rats", "(", "Groups", "3", "and", "4", ")", ",", "consisting", "of", "flaking", "and", "scabbing", "in", "the", "treated", "skin", "sections", "." ]
[ "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "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", "B-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "O", "O", "O", "O", "B-FINDING", "O", "B-FINDING", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "O" ]
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NO_PRETOX_REL
In conclusion , administration of 212 - 713 to the Charles River CD rats was well tolerated at the dose levels used in this study .
[ "In", "conclusion", ",", "administration", "of", "212", "-", "713", "to", "the", "Charles", "River", "CD", "rats", "was", "well", "tolerated", "at", "the", "dose", "levels", "used", "in", "this", "study", "." ]
[ "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
Abnormalities of the growth plate / metaphyseal junction were also seen at 1000 mg / kg / day , which were not fully reversible following 4 weeks recovery .
[ "Abnormalities", "of", "the", "growth", "plate", "/", "metaphyseal", "junction", "were", "also", "seen", "at", "1000", "mg", "/", "kg", "/", "day", ",", "which", "were", "not", "fully", "reversible", "following", "4", "weeks", "recovery", "." ]
[ "B-FINDING", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "B-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", "O", "O", "O", "O", "O" ]
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NO_PRETOX_REL
There were no treatment - related mortalities .
[ "There", "were", "no", "treatment", "-", "related", "mortalities", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
XXXXX ) suspended in 0.5 % ( w / v ) hydroxyethylcellulose ( Natrosol ) instead of suspension in Klucel .
[ "XXXXX", ")", "suspended", "in", "0.5", "%", "(", "w", "/", "v", ")", "hydroxyethylcellulose", "(", "Natrosol", ")", "instead", "of", "suspension", "in", "Klucel", "." ]
[ "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 following investigations were performed ; clinical observations , body weight , food consumption , ophthalmoscopy , electrocardiography , toxicokinetics , haematology , clinical chemistry , thyroid function , urinalysis , troponin analysis , pathology and histopathology .
[ "The", "following", "investigations", "were", "performed", ";", "clinical", "observations", ",", "body", "weight", ",", "food", "consumption", ",", "ophthalmoscopy", ",", "electrocardiography", ",", "toxicokinetics", ",", "haematology", ",", "clinical", "chemistry", ",", "thyroid", "function", ",", "urinalysis", ",", "troponin", "analysis", ",", "pathology", "and", "histopathology", "." ]
[ "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
Mean body weights and food consumption values remained comparable throughout the study .
[ "Mean", "body", "weights", "and", "food", "consumption", "values", "remained", "comparable", "throughout", "the", "study", "." ]
[ "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 ]
PRETOX_REL
In conclusion , the oral in - feed administration of COMPOUND_XXX to male rats for 13 weeks at 180 mg salt / kg / day caused a reduced body weight gain and food intake , and minimal to slight mucosal hyperplasia in the jejunum and to a lesser extent in the ileum .
[ "In", "conclusion", ",", "the", "oral", "in", "-", "feed", "administration", "of", "COMPOUND_XXX", "to", "male", "rats", "for", "13", "weeks", "at", "180", "mg", "salt", "/", "kg", "/", "day", "caused", "a", "reduced", "body", "weight", "gain", "and", "food", "intake", ",", "and", "minimal", "to", "slight", "mucosal", "hyperplasia", "in", "the", "jejunum", "and", "to", "a", "lesser", "extent", "in", "the", "ileum", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-SEX", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "B-MANIFESTATION_FINDING", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "O", "O", "O", "O", "O", "O", "O", "B-SPECIMEN", "O" ]
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NO_PRETOX_REL
From a daily dose of 40 μmol / kg bw .
[ "From", "a", "daily", "dose", "of", "40", "μmol", "/", "kg", "bw", "." ]
[ "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]
[ 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 0 ]
PRETOX_REL
Consistent with the hepatic findings under microscopic examination , group 3 animals also had prominent hepatic lobular markings on gross examination , and increases in ALT as well as total cholesterol levels at various occasions ante-mortem .
[ "Consistent", "with", "the", "hepatic", "findings", "under", "microscopic", "examination", ",", "group", "3", "animals", "also", "had", "prominent", "hepatic", "lobular", "markings", "on", "gross", "examination", ",", "and", "increases", "in", "ALT", "as", "well", "as", "total", "cholesterol", "levels", "at", "various", "occasions", "ante-mortem", "." ]
[ "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "O", "O", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "O", "O", "O" ]
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NO_PRETOX_REL
The dose volume was 2 mL / kg .
[ "The", "dose", "volume", "was", "2", "mL", "/", "kg", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL
At 100 and 1000 mg / kg / day body weight development , food consumption , general health conditions including body temperature were affected by the test compound .
[ "At", "100", "and", "1000", "mg", "/", "kg", "/", "day", "body", "weight", "development", ",", "food", "consumption", ",", "general", "health", "conditions", "including", "body", "temperature", "were", "affected", "by", "the", "test", "compound", "." ]
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PRETOX_REL
Mid-dose animals in Group 3 also showed the hepatic lesions identified for low - dose animals , albeit with greater incidence and severity .
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[ "B-DOSE_QUALIFICATION", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
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PRETOX_REL
Dose levels of 60 and 180 mg / kg / day were selected based on data from a previous 2 year carcinogenicity study in rats , however , at 180 mg / kg / day , adverse clinical signs of subdued behavior , hunched posture , piloerection and red secretions around the eyes , the nose and the perineal were observed in some animals towards the end of the fourth week of dosing and in a couple of animals as early as the end of the second week of dosing .
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NO_PRETOX_REL
No correlation with changes in urinalysis , serum clinical chemistry parameters , or histopathological changes in the urinary tract were observed .
[ "No", "correlation", "with", "changes", "in", "urinalysis", ",", "serum", "clinical", "chemistry", "parameters", ",", "or", "histopathological", "changes", "in", "the", "urinary", "tract", "were", "observed", "." ]
[ "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
Clinical observations , body weight and food consumption determinations were performed on all groups .
[ "Clinical", "observations", ",", "body", "weight", "and", "food", "consumption", "determinations", "were", "performed", "on", "all", "groups", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 0 ]
PRETOX_REL
In serum of treated dogs , antibodies reacting with the nucleoli of hepatocytes and , to a lesser extent , of bile duct epithelial cells were detected immunohistochemically .
[ "In", "serum", "of", "treated", "dogs", ",", "antibodies", "reacting", "with", "the", "nucleoli", "of", "hepatocytes", "and", ",", "to", "a", "lesser", "extent", ",", "of", "bile", "duct", "epithelial", "cells", "were", "detected", "immunohistochemically", "." ]
[ "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "I-SPECIMEN", "I-SPECIMEN", "O", "O", "O", "O" ]
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PRETOX_REL
This incident was considered not to prevent from meeting the study objectives , because first , clear toxic effects were noted at this high dose level already starting from the mid dose level , and second , increased systemic exposure of the animals to the unchanged test substance was shown at the high dose level .
[ "This", "incident", "was", "considered", "not", "to", "prevent", "from", "meeting", "the", "study", "objectives", ",", "because", "first", ",", "clear", "toxic", "effects", "were", "noted", "at", "this", "high", "dose", "level", "already", "starting", "from", "the", "mid", "dose", "level", ",", "and", "second", ",", "increased", "systemic", "exposure", "of", "the", "animals", "to", "the", "unchanged", "test", "substance", "was", "shown", "at", "the", "high", "dose", "level", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "O", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "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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NO_PRETOX_REL
These data support the contention that the neurodegenerative change in sciatic nerve after treatment with glucokinase activators is due to prolonged hypoglycemia , and is not relevant for the treatment of the hyperglycemic diabetic population .
[ "These", "data", "support", "the", "contention", "that", "the", "neurodegenerative", "change", "in", "sciatic", "nerve", "after", "treatment", "with", "glucokinase", "activators", "is", "due", "to", "prolonged", "hypoglycemia", ",", "and", "is", "not", "relevant", "for", "the", "treatment", "of", "the", "hyperglycemic", "diabetic", "population", "." ]
[ "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
There were no deaths .
[ "There", "were", "no", "deaths", "." ]
[ "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0 ]
PRETOX_REL
Clinical Signs : Labored respiration and decreased activity were observed in all groups , including the controls , and awkward gait or weakened limbs were observed in a single male treated with 300 mg / kg / day , and in several males and females given 600 mg / kg / day .
[ "Clinical", "Signs", ":", "Labored", "respiration", "and", "decreased", "activity", "were", "observed", "in", "all", "groups", ",", "including", "the", "controls", ",", "and", "awkward", "gait", "or", "weakened", "limbs", "were", "observed", "in", "a", "single", "male", "treated", "with", "300", "mg", "/", "kg", "/", "day", ",", "and", "in", "several", "males", "and", "females", "given", "600", "mg", "/", "kg", "/", "day", "." ]
[ "O", "O", "O", "B-FINDING", "I-FINDING", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "B-SEX", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]
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NO_PRETOX_REL
Four control samples were analyzed , and no COMPOUND_XXX was detected .
[ "Four", "control", "samples", "were", "analyzed", ",", "and", "no", "COMPOUND_XXX", "was", "detected", "." ]
[ "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
COMPOUND_XXX was administered at a dosage of 50 mg / kg / day ( at a dosage volume of 10 mL / kg ) , once daily , for 3 days prior to necropsy to specific subgroups for immunohistochemical investigations .
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[ "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", "O", "O", "O", "O", "O", "O", "O", "O" ]
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PRETOX_REL
After the first 3 - 4 applications the animals of this group were very sensitive to noise .
[ "After", "the", "first", "3", "-", "4", "applications", "the", "animals", "of", "this", "group", "were", "very", "sensitive", "to", "noise", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O" ]
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NO_PRETOX_REL
Toxicokinetic evaluations were performed on plasma samples obtained on days 112 and during weeks 4 and 39 .
[ "Toxicokinetic", "evaluations", "were", "performed", "on", "plasma", "samples", "obtained", "on", "days", "112", "and", "during", "weeks", "4", "and", "39", "." ]
[ "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
Light microscopic evaluation of toluidine blue stained semithin sections of heart and skeletal muscle did not show an alteration for all investigated animals treated intraperitoneally with 50 mg / kg / day COMPOUND_XXX for 28 days in comparison to the corresponding control animals .
[ "Light", "microscopic", "evaluation", "of", "toluidine", "blue", "stained", "semithin", "sections", "of", "heart", "and", "skeletal", "muscle", "did", "not", "show", "an", "alteration", "for", "all", "investigated", "animals", "treated", "intraperitoneally", "with", "50", "mg", "/", "kg", "/", "day", "COMPOUND_XXX", "for", "28", "days", "in", "comparison", "to", "the", "corresponding", "control", "animals", "." ]
[ "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-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
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PRETOX_REL
3 ) Decreased body weight in males and decreased food intake in females were observed in the 50 mg / kg group in the early stages of the administration period .
[ "3", ")", "Decreased", "body", "weight", "in", "males", "and", "decreased", "food", "intake", "in", "females", "were", "observed", "in", "the", "50", "mg", "/", "kg", "group", "in", "the", "early", "stages", "of", "the", "administration", "period", "." ]
[ "O", "O", "B-MANIFESTATION_FINDING", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-SEX", "O", "B-MANIFESTATION_FINDING", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-SEX", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
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PRETOX_REL
Terminal investigations revealed that administration of COMPOUND_XXX was associated with thymic atrophy and acute pneumonia in one animal ( Animal 16M ) .
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[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "O", "O", "O" ]
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PRETOX_REL
Terminal body weight was statistically significantly decreased at 30 mg / kg in both genders , and at 10 and 3 mg / kg in females only .
[ "Terminal", "body", "weight", "was", "statistically", "significantly", "decreased", "at", "30", "mg", "/", "kg", "in", "both", "genders", ",", "and", "at", "10", "and", "3", "mg", "/", "kg", "in", "females", "only", "." ]
[ "B-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "B-SEX", "I-SEX", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "B-SEX", "O", "O" ]
[ 2, 6, 6, 0, 0, 0, 1, 0, 3, 4, 4, 4, 0, 5, 7, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 5, 0, 0 ]
NO_PRETOX_REL
Exposure was similar after dosing for 13 or 39 weeks .
[ "Exposure", "was", "similar", "after", "dosing", "for", "13", "or", "39", "weeks", "." ]
[ "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
COMPOUND_XXX is the R,R - diastereomer of the diastereomeric mixture COMPOUND_XXX , a major active metabolite of the glucokinase activator , COMPOUND_XXX .
[ "COMPOUND_XXX", "is", "the", "R,R", "-", "diastereomer", "of", "the", "diastereomeric", "mixture", "COMPOUND_XXX", ",", "a", "major", "active", "metabolite", "of", "the", "glucokinase", "activator", ",", "COMPOUND_XXX", "." ]
[ "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
There were no adverse effects on urinalysis results .
[ "There", "were", "no", "adverse", "effects", "on", "urinalysis", "results", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL
Mortality was observed in all groups .
[ "Mortality", "was", "observed", "in", "all", "groups", "." ]
[ "B-FINDING", "O", "O", "O", "B-GROUP", "I-GROUP", "O" ]
[ 8, 0, 0, 0, 12, 13, 0 ]
NO_PRETOX_REL
At the mid and low doses , exposure to COMPOUND_XXX after multiple dose was similar to a single dose in both sexes .
[ "At", "the", "mid", "and", "low", "doses", ",", "exposure", "to", "COMPOUND_XXX", "after", "multiple", "dose", "was", "similar", "to", "a", "single", "dose", "in", "both", "sexes", "." ]
[ "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 15, 16, 16, 16, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL
There was an increase in absolute liver weight in females .
[ "There", "was", "an", "increase", "in", "absolute", "liver", "weight", "in", "females", "." ]
[ "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "B-SEX", "O" ]
[ 0, 0, 0, 1, 0, 0, 10, 2, 0, 5, 0 ]
NO_PRETOX_REL
The electrocardiograms ( including QT - intervals ) showed no changes up to and including group lll ( for individual and mean values of QT - intervals see appendix of the report ) .
[ "The", "electrocardiograms", "(", "including", "QT", "-", "intervals", ")", "showed", "no", "changes", "up", "to", "and", "including", "group", "lll", "(", "for", "individual", "and", "mean", "values", "of", "QT", "-", "intervals", "see", "appendix", "of", "the", "report", ")", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
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NO_PRETOX_REL
Toxicokinetics revealed that absorption was rapid and exposure to COMPOUND_XXX was up to 3-fold higher in female rats compared to male rats .
[ "Toxicokinetics", "revealed", "that", "absorption", "was", "rapid", "and", "exposure", "to", "COMPOUND_XXX", "was", "up", "to", "3-fold", "higher", "in", "female", "rats", "compared", "to", "male", "rats", "." ]
[ "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
Cmax and AUC values were slightly overproportional to dose .
[ "Cmax", "and", "AUC", "values", "were", "slightly", "overproportional", "to", "dose", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
Groups I and 4 each included two males and females , which were allowed a 4 - week post-treatment period after termination of dosing .
[ "Groups", "I", "and", "4", "each", "included", "two", "males", "and", "females", ",", "which", "were", "allowed", "a", "4", "-", "week", "post-treatment", "period", "after", "termination", "of", "dosing", "." ]
[ "B-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "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
All clinical signs noted during the treatment period generally resolved by day 8 of recovery .
[ "All", "clinical", "signs", "noted", "during", "the", "treatment", "period", "generally", "resolved", "by", "day", "8", "of", "recovery", "." ]
[ "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 objective of this study was to assess the potential toxicological effects of the test item COMPOUND_XXX , a h or , when administered to rats as three doses per week ( Monday , Wednesday , Friday dosing schedule ) for 26 weeks .
[ "The", "objective", "of", "this", "study", "was", "to", "assess", "the", "potential", "toxicological", "effects", "of", "the", "test", "item", "COMPOUND_XXX", ",", "a", "h", "or", ",", "when", "administered", "to", "rats", "as", "three", "doses", "per", "week", "(", "Monday", ",", "Wednesday", ",", "Friday", "dosing", "schedule", ")", "for", "26", "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", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
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PRETOX_REL
Hemosiderin , predominantly in the hepatocytes , and Kupffer cells of the periportal areas were observed in 1 high dose female ( grade 3 ) .
[ "Hemosiderin", ",", "predominantly", "in", "the", "hepatocytes", ",", "and", "Kupffer", "cells", "of", "the", "periportal", "areas", "were", "observed", "in", "1", "high", "dose", "female", "(", "grade", "3", ")", "." ]
[ "B-FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "B-SEX", "O", "O", "O", "O", "O" ]
[ 8, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 15, 16, 5, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
Complete necropsies were performed on all animals and organ weights and macroscopic observations were recorded .
[ "Complete", "necropsies", "were", "performed", "on", "all", "animals", "and", "organ", "weights", "and", "macroscopic", "observations", "were", "recorded", "." ]
[ "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
At 60 and 600 mg / kg / day , mean jejunal mucosa concentrations of COMPOUND_XXX were slightly to moderately higher at 20:00 , 23:00 and 08:00 than at the other time points , whereas PAG concentrations were generally in a similar range within each group at all time points with the exception of an increased value for the high - dose animals at 05:00 a.m. COMPOUND_XXX plasma concentrations were higher at night and in the early morning ( 23:00 , 02:00 and 05:00 ) than at the other time points in both dose groups , which corresponds to the main activity phase of the animals .
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PRETOX_REL
The severity of these findings did not increase but some animals were found dead which led the treatment period to be shorten to 8 weeks rather than 13 weeks for this dose level .
[ "The", "severity", "of", "these", "findings", "did", "not", "increase", "but", "some", "animals", "were", "found", "dead", "which", "led", "the", "treatment", "period", "to", "be", "shorten", "to", "8", "weeks", "rather", "than", "13", "weeks", "for", "this", "dose", "level", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "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
A dose limiting toxicity was not identified .
[ "A", "dose", "limiting", "toxicity", "was", "not", "identified", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
The patches were applied to the skin and covered with a FixomuiiR adhesive tape and stayed in place for approximately 23 hours .
[ "The", "patches", "were", "applied", "to", "the", "skin", "and", "covered", "with", "a", "FixomuiiR", "adhesive", "tape", "and", "stayed", "in", "place", "for", "approximately", "23", "hours", "." ]
[ "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
Animals were dosed once daily on study days 1 , 3 , 5 , 8 , 10 , 12 , 15 , 17 , etc. for at least 4 weeks .
[ "Animals", "were", "dosed", "once", "daily", "on", "study", "days", "1", ",", "3", ",", "5", ",", "8", ",", "10", ",", "12", ",", "15", ",", "17", ",", "etc.", "for", "at", "least", "4", "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" ]
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NO_PRETOX_REL
SUMMARY A study was conducted in Wistar ( HsdBrlHan : WIST ) rats to characterize the toxicity and toxicokinetic profile of COMPOUND_XXX when administered by oral intubation to rats for five days .
[ "SUMMARY", "A", "study", "was", "conducted", "in", "Wistar", "(", "HsdBrlHan", ":", "WIST", ")", "rats", "to", "characterize", "the", "toxicity", "and", "toxicokinetic", "profile", "of", "COMPOUND_XXX", "when", "administered", "by", "oral", "intubation", "to", "rats", "for", "five", "days", "." ]
[ "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
There were no significant clinical signs attributable to administration of COMPOUND_XXX at doses of 0.05 , 0.3 or 0.9 mg / kg for four cycles .
[ "There", "were", "no", "significant", "clinical", "signs", "attributable", "to", "administration", "of", "COMPOUND_XXX", "at", "doses", "of", "0.05", ",", "0.3", "or", "0.9", "mg", "/", "kg", "for", "four", "cycles", "." ]
[ "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", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 4, 4, 0, 0, 0, 0 ]
PRETOX_REL
By the end of dosing , the decreases in mean absolute weight gain were approximately 23 , 38 and 52 % and 35 , 50 and 42 % less than controls in males and females , respectively at doses of 30 , 100 and 300 mg / kg / day .
[ "By", "the", "end", "of", "dosing", ",", "the", "decreases", "in", "mean", "absolute", "weight", "gain", "were", "approximately", "23", ",", "38", "and", "52", "%", "and", "35", ",", "50", "and", "42", "%", "less", "than", "controls", "in", "males", "and", "females", ",", "respectively", "at", "doses", "of", "30", ",", "100", "and", "300", "mg", "/", "kg", "/", "day", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-SEX", "I-SEX", "I-SEX", "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" ]
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PRETOX_REL
- Increased degeneration / necrosis of corpus lutea was observed in the ovaries in females from 15 mg / kg .
[ "-", "Increased", "degeneration", "/", "necrosis", "of", "corpus", "lutea", "was", "observed", "in", "the", "ovaries", "in", "females", "from", "15", "mg", "/", "kg", "." ]
[ "O", "B-MANIFESTATION_FINDING", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "B-SPECIMEN", "O", "B-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]
[ 0, 1, 8, 9, 9, 9, 9, 9, 0, 0, 0, 0, 10, 0, 5, 0, 3, 4, 4, 4, 0 ]
PRETOX_REL
Serum chloride was decreased whilst calcium was increased .
[ "Serum", "chloride", "was", "decreased", "whilst", "calcium", "was", "increased", "." ]
[ "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "O", "B-MANIFESTATION_FINDING", "O" ]
[ 2, 6, 0, 1, 0, 2, 0, 1, 0 ]
NO_PRETOX_REL
At the start of dosing , the rats were approximately 8 weeks of age and body weights ranged from 220.2 to 267.4 g for males and 158.3 to 184.9 g for females .
[ "At", "the", "start", "of", "dosing", ",", "the", "rats", "were", "approximately", "8", "weeks", "of", "age", "and", "body", "weights", "ranged", "from", "220.2", "to", "267.4", "g", "for", "males", "and", "158.3", "to", "184.9", "g", "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" ]
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NO_PRETOX_REL
This finding is considered to be attributed to the known pharmacological activity of COMPOUND_XXX and no microscopic changes were evident in the thyroids of the animals .
[ "This", "finding", "is", "considered", "to", "be", "attributed", "to", "the", "known", "pharmacological", "activity", "of", "COMPOUND_XXX", "and", "no", "microscopic", "changes", "were", "evident", "in", "the", "thyroids", "of", "the", "animals", "." ]
[ "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
Body weight and food consumption were recorded weekly .
[ "Body", "weight", "and", "food", "consumption", "were", "recorded", "weekly", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL
Adrenal cortical atrophy in males at 0.9 mg / kg correlated with reduced adrenal weights and was reversible .
[ "Adrenal", "cortical", "atrophy", "in", "males", "at", "0.9", "mg", "/", "kg", "correlated", "with", "reduced", "adrenal", "weights", "and", "was", "reversible", "." ]
[ "B-SPECIMEN", "B-FINDING", "I-FINDING", "O", "B-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "O", "O", "O" ]
[ 10, 8, 9, 0, 5, 0, 3, 4, 4, 4, 0, 0, 1, 10, 2, 0, 0, 0, 0 ]
NO_PRETOX_REL
For most of the groups , exposure to COMPOUND_XXX was higher than dose - proportional on both study days , suggesting a saturable elimination pathway for COMPOUND_XXX .
[ "For", "most", "of", "the", "groups", ",", "exposure", "to", "COMPOUND_XXX", "was", "higher", "than", "dose", "-", "proportional", "on", "both", "study", "days", ",", "suggesting", "a", "saturable", "elimination", "pathway", "for", "COMPOUND_XXX", "." ]
[ "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
The following investigations were performed ; mortality , clinical signs , body weight , food consumption , necropsy , histopathology of macroscopic lesions , and electron microscopy ( heart and skeletal muscle ) .
[ "The", "following", "investigations", "were", "performed", ";", "mortality", ",", "clinical", "signs", ",", "body", "weight", ",", "food", "consumption", ",", "necropsy", ",", "histopathology", "of", "macroscopic", "lesions", ",", "and", "electron", "microscopy", "(", "heart", "and", "skeletal", "muscle", ")", "." ]
[ "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
Microscopic observations were performed on protocol - specified tissues .
[ "Microscopic", "observations", "were", "performed", "on", "protocol", "-", "specified", "tissues", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL
Most findings were fully reversible , except for atrophy of bone marrow and thymus and reduction in red blood cells and platelets , which improved significantly over the recovery period .
[ "Most", "findings", "were", "fully", "reversible", ",", "except", "for", "atrophy", "of", "bone", "marrow", "and", "thymus", "and", "reduction", "in", "red", "blood", "cells", "and", "platelets", ",", "which", "improved", "significantly", "over", "the", "recovery", "period", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "B-SPECIMEN", "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-STUDY_TESTCD", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 8, 0, 10, 11, 0, 10, 0, 1, 0, 2, 6, 6, 0, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL
Complete necropsies including macroscopic assessments were performed on all animals .
[ "Complete", "necropsies", "including", "macroscopic", "assessments", "were", "performed", "on", "all", "animals", "." ]
[ "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
Necropsy of pups on Day 4 did not evidence any compound - related changes .
[ "Necropsy", "of", "pups", "on", "Day", "4", "did", "not", "evidence", "any", "compound", "-", "related", "changes", "." ]
[ "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 the end of the treatment period , rats given 400 mg / kg / day had increased absolute neutrophil numbers ; increased monocyte numbers were present in males .
[ "At", "the", "end", "of", "the", "treatment", "period", ",", "rats", "given", "400", "mg", "/", "kg", "/", "day", "had", "increased", "absolute", "neutrophil", "numbers", ";", "increased", "monocyte", "numbers", "were", "present", "in", "males", "." ]
[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-MANIFESTATION_FINDING", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "B-SEX", "O" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 1, 0, 2, 6, 0, 1, 2, 6, 0, 0, 0, 5, 0 ]