Nonclinical Safety of the Sodium-Glucose Cotransporter 2 Inhibitor Empagliflozin

2014 ◽  
Vol 33 (6) ◽  
pp. 436-449 ◽  
Author(s):  
Matthew S. Bogdanffy ◽  
Robert F. Stachlewitz ◽  
Susan van Tongeren ◽  
Brian Knight ◽  
Dale E. Sharp ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Tubular Epithelial Cell ◽  
Serum Glucose ◽  
Global Market ◽  
Female Rats ◽  
Male Rats ◽  
Clinical Dose ◽  
Sodium Glucose Cotransporter ◽  
Nervous System Function ◽  
Renal Tubular

Empagliflozin, a selective inhibitor of the renal tubular sodium-glucose cotransporter 2, was developed for treatment of type 2 diabetes mellitus. Nonclinical safety of empagliflozin was studied in a battery of tests to support global market authorization. Safety pharmacology studies indicated no effect of empagliflozin on measures of respiratory or central nervous system function in rats or cardiovascular safety in telemeterized dogs. In CD-1 mouse, Wistar Han rat, or beagle dogs up to 13, 26, or 52 weeks of treatment, respectively, empagliflozin exhibited a toxicity profile consistent with secondary supratherapeutic pharmacology related to glucose loss and included decreased body weight and body fat, increased food consumption, diarrhea, dehydration, decreased serum glucose and increases in other serum parameters reflective of increased protein catabolism, gluconeogenesis, and electrolyte imbalances, and urinary changes such as polyuria and glucosuria. Microscopic changes were consistently observed in kidney and included tubular nephropathy and interstitial nephritis (dog), renal mineralization (rat) and tubular epithelial cell karyomegaly, single cell necrosis, cystic hyperplasia, and hypertrophy (mouse). Empagliflozin was not genotoxic. Empagliflozin was not carcinogenic in female mice or female rats. Renal adenoma and carcinoma were induced in male mice only at exposures 45 times the maximum clinical dose. These tumors were associated with a spectrum of nonneoplastic changes suggestive of a nongenotoxic, cytotoxic, and cellular proliferation-driven mechanism. In male rats, testicular interstitial cell tumors and hemangiomas of the mesenteric lymph node were observed; both tumors are common in rats and are unlikely to be relevant to humans. These studies demonstrate the nonclinical safety of empagliflozin.

scholarly journals Sex Differences and Similarities in Hippocampal Cellular Proliferation and the Number of Immature Neurons during Adolescence in Rats

2019 ◽  
Vol 41 (1-2) ◽  
pp. 132-138 ◽  
Author(s):  
Alina Siddiqui ◽  
Russell D. Romeo
Keyword(s):  
Sex Differences ◽  
Dentate Gyrus ◽  
Cellular Proliferation ◽  
Female Rats ◽  
Male Rats ◽  
Ki 67 ◽  
Cross Sectional ◽  
Male And Female Rats ◽  
Immature Neurons ◽  
Males And Females

Adolescence is associated with significant reductions in hippocampal cellular proliferation and neurogenesis, the physiological and behavioral implications of which are unclear. Though sex differences exist in these proliferative processes in adulthood, relatively little is known about the role sex plays in these adolescent-related changes. To address this gap, we examined cross-sectional area of the dentate gyrus and cellular proliferation, as measured by Ki-67 immunohistochemistry, in pre- (30 days), mid- (45 days), and post-adolescent (70 days) male and female rats. We also investigated the number of immature neurons using doublecortin (DCX) immunohistochemistry in pre- and post-adolescent males and females. Despite increases in the size of the dentate gyrus during adolescence, we found significant adolescent-related decreases in hippocampal proliferation in both males and females, with a more dramatic decrease in males, indicating both age- and sex-dependent changes in the dentate gyrus. We also found an adolescent-related decline in the number of immature neurons in the dentate gyrus of male rats and a female-biased sex difference in the number of immature neurons in adults. Given these significant changes in the dentate gyrus, these data suggest that this period in development might be particularly sensitive to internal and external factors known to modulate neurogenesis, with potential sex-specific neurobehavioral ramifications.

INDUCTION OF GOITRE BY PTU OR KClO4 IN MALE AND FEMALE RATS. EFFECT OF GONADECTOMY

1973 ◽  
Vol 74 (1) ◽  
pp. 88-104 ◽  
Author(s):  
T. Jolín ◽  
M. J. Tarin ◽  
M. D. Garcia
Keyword(s):  
Iodine Content ◽  
High Plasma ◽  
Disc Electrophoresis ◽  
Female Rats ◽  
Male Rats ◽  
Adult Rats ◽  
Male And Female ◽  
Glucose Levels ◽  
Male And Female Rats ◽  
Tsh Levels

ABSTRACT Male and female rats of varying ages were placad on a low iodine diet (LID) plus KClO4 or 6-propyl-2-thiouracil (PTU) or on the same diet supplemented with I (control rats). Goitrogenesis was also induced with LID plus PTU in gonadectomized animals of both sexes. The weight of the control and goitrogen treated animals, and the weight and iodine content of their thyroids were determined, as well as the plasma PBI, TSH, insulin and glucose levels. The pituitary GH-like protein content was assessed by disc electrophoresis on polyacrylamide gels. If goitrogenesis was induced in young rats of both sexes starting with rats of the same age, body weight (B.W.) and pituitary growth hormone (GH) content, it was found that both the males and females developed goitres of the same size. On the contrary, when goitrogenesis was induced in adult animals, it was found that male rats, that had larger B.W. and pituitary GH content than age-paired females, developed larger goitres. However, both male and female rats were in a hypothyroid condition of comparable degree as judged by the thyroidal iodine content and the plasma PBI and TSH levels. When all the data on the PTU or KClO4-treated male and female rats of varying age and B.W. were considered together, it was observed that the weights of the thyroids increased proportionally to B.W. However, a difference in the slope of the regression of the thyroid weight over B.W. was found between male and female rats, due to the fact that adult male rats develop larger goitres than female animals. In addition, in the male rats treated with PTU, gonadectomy decreased the B.W., pituitary content of GH-like protein and, concomitantly, the size of the goitre decreased; an opposite effect was induced by ovariectomy on the female animals. However, when goitrogenesis was induced in weight-paired adult rats of both sexes, the male animals still developed larger goitres than the females. Among all the parameters studied here, the only ones which appeared to bear a consistent relationship with the size of the goitres in rats of different sexes, treated with a given goitrogen, were the rate of body growth and the amount of a pituitary GH-like protein found before the onset of the goitrogen treatment. Moreover, though the pituitary content of the GH-like protein decreased as a consequence of goitrogen treatment, it was still somewhat higher in male that in female animals. The present results suggest that GH may somehow be involved in the mechanism by which male and female rats on goitrogens develop goitres of different sizes, despite equally high plasma TSH levels.

OXYDATION DES ANABOLIKUMS 1-METHYL-ANDROST-1-EN-17β-OL-3-ON MIT WASSERSTOFFTRANSFER AUF ÖSTRON

1971 ◽  
Vol 67 (3) ◽  
pp. 517-530 ◽  
Author(s):  
Martin Wenzel
Keyword(s):  
Rat Liver ◽  
Anabolic Steroid ◽  
Female Rats ◽  
Male Rats ◽  
Female Rat ◽  
Liver Slices ◽  
Androgen Effects ◽  
Biochemical Difference

ABSTRACT With the aid of metenolon-17α-T a tritium-transfer to oestrone in rat liver slices was demonstrated. This tritium-transfer from metenolon17α-T to oestrone yielding tritium-labelled oestradiol had a higher efficiency in male than in female rat liver. Correspondingly in the presence of metenolon the relation of oestrone to oestradiol is changed more in male than in female rat liver. Looking for biochemical differences between the anabolic steroid metenolon and testosterone the oxydation at C17 was measured in different organs of the rat using 17α-T-labelled steroids. The highest oxydation rate was found for both steroids in the liver. In the sexual organs of male rats the oxydation rate of testosterone was 50–10 times higher than that of the anabolic steroid. This difference was less in sexual organs of female rats. This result of a greater biochemical difference between both steroids in males than in females leads to the question, whether the dissociation between the anabolic and the androgen effects is higher in males than in females.

The effect of dexamethasone on mucosal immunity of uterine tissue during pregnancy in rat

2019 ◽  
Vol 20 (1) ◽  
pp. 75-84
Keyword(s):  
Early Pregnancy ◽  
Histopathological Examination ◽  
Early Period ◽  
Interleukin 10 ◽  
Treated Group ◽  
Female Rats ◽  
Male Rats ◽  
Mrna Levels ◽  
Uterine Tissue ◽  
Leukocytic Infiltration

Disturbances in early pregnancy immunity affect embryo development, endometrial receptivity, placental development, fetal growth and lead to subfertility, dexamethasone is a synthetic glucocorticoid used for treatment of various complications. Immune cells and cytokines were examined during the early pregnancy in twenty-four female rats and six male rats for mating. Rats were grouped into two group control and dexamethasone treated by a dose of 50µgm/kgm body weight daily starting from one week before mating and persisted for one week after pregnancy. Blood samples were collected from each rat at 5hrs and at 1,3,7 day of pregnancy. Extracted RNA was subjected to real time PCR to determine mRNA levels for immune related genes interleukin1a(IL1A) and interleukin 10(IL10). Histopathological examination was done to uterus in order to detect leukocyte infiltration in uterine tissue. Results showed that significant increase in white blood cell count mainly eosinophil at 5hrs and lymphocyte at three and seven day of pregnancy of dexamethasone treated group. Moreover, TNF, C-reactive protein and progesterone were increased mainly at seven day of pregnancy of dexamethasone treated group. Similarly, interleukin 1alpha and interleukin 10 significantly increased at 5hrs and one day of pregnancy of dexamethasone treated group. In contrast, serum levels of total antioxidant capacity and estrogen were decreased significantly at 5hrs and seven day in dexamethasone treated group. Histopathological examination of uterus revealed leukocytic infiltration especially neutrophil and few eosinophils at five hours and one day of gestation then eosinophil become absent at 3day and seven day of dexamethasone group. Epithelial height and uterine gland diameter significantly increased at 5hrs, three day and seven days of gestation of dexamethasone treated group. The present investigation demonstrated that using of dexamethasone by dose of 50µgm/kgm during early pregnancy had a conflicting impact on some immune cytokines and parameters and may reflect a harmful response of immune system toward early period of pregnancy

Quercetin alleviates kidney fibrosis by reducing renal tubular epithelial cell senescence through the SIRT1/PINK1/mitophagy axis

Life Sciences ◽  
2020 ◽  
Vol 257 ◽  
pp. 118116 ◽  
Author(s):  
Tao Liu ◽  
Qunfang Yang ◽  
Xuan Zhang ◽  
Rongxing Qin ◽  
Wenjun Shan ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Tubular Epithelial Cell ◽  
Cell Senescence ◽  
Renal Tubular Epithelial Cell ◽  
Kidney Fibrosis ◽  
Renal Tubular

Female rats display higher methamphetamine-primed reinstatement and c-Fos immunoreactivity than male rats

2021 ◽  
pp. 173089
Author(s):  
Steven T. Pittenger ◽  
Shinnyi Chou ◽  
Nathen J. Murawski ◽  
Scott T. Barrett ◽  
Olivia Loh ◽  
...  
Keyword(s):  
Female Rats ◽  
Male Rats

scholarly journals Kidney Injury Caused by Preeclamptic Pregnancy Recovers Postpartum in a Transgenic Rat Model

2021 ◽  
Vol 22 (7) ◽  
pp. 3762
Author(s):  
Sarah M. Kedziora ◽  
Kristin Kräker ◽  
Lajos Markó ◽  
Julia Binder ◽  
Meryam Sugulle ◽  
...  
Keyword(s):  
Rat Model ◽  
Renal Damage ◽  
Kidney Injury ◽  
Tissue Growth ◽  
Female Rats ◽  
Male Rats ◽  
Renal Diseases ◽  
Transgenic Rat ◽  
Increased Risk ◽  
Before And After

Preeclampsia (PE) is characterized by the onset of hypertension (≥140/90 mmHg) and presence of proteinuria (>300 mg/L/24 h urine) or other maternal organ dysfunctions. During human PE, renal injuries have been observed. Some studies suggest that women with PE diagnosis have an increased risk to develop renal diseases later in life. However, in human studies PE as a single cause of this development cannot be investigated. Here, we aimed to investigate the effect of PE on postpartum renal damage in an established transgenic PE rat model. Female rats harboring the human-angiotensinogen gene develop a preeclamptic phenotype after mating with male rats harboring the human-renin gene, but are normotensive before and after pregnancy. During pregnancy PE rats developed mild tubular and glomerular changes assessed by histologic analysis, increased gene expression of renal damage markers such as kidney injury marker 1 and connective-tissue growth factor, and albuminuria compared to female wild-type rats (WT). However, four weeks postpartum, most PE-related renal pathologies were absent, including albuminuria and elevated biomarker expression. Only mild enlargement of the glomerular tuft could be detected. Overall, the glomerular and tubular function were affected during pregnancy in the transgenic PE rat. However, almost all these pathologies observed during PE recovered postpartum.

scholarly journals Analysis of sex differences in dietary copper-fructose interaction-induced alterations of gut microbial activity in relation to hepatic steatosis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ming Song ◽  
Fang Yuan ◽  
Xiaohong Li ◽  
Xipeng Ma ◽  
Xinmin Yin ◽  
...  
Keyword(s):  
Sex Differences ◽  
Microbial Activity ◽  
Hepatic Steatosis ◽  
Female Rats ◽  
Male Rats ◽  
Calorie Intake ◽  
Dietary Copper ◽  
Male And Female ◽  
Male And Female Rats ◽  
Rrna Sequencing

Abstract Background Inadequate copper intake and increased fructose consumption represent two important nutritional problems in the USA. Dietary copper-fructose interactions alter gut microbial activity and contribute to the development of nonalcoholic fatty liver disease (NAFLD). The aim of this study is to determine whether dietary copper-fructose interactions alter gut microbial activity in a sex-differential manner and whether sex differences in gut microbial activity are associated with sex differences in hepatic steatosis. Methods Male and female weanling Sprague-Dawley (SD) rats were fed ad libitum with an AIN-93G purified rodent diet with defined copper content for 8 weeks. The copper content is 6 mg/kg and 1.5 mg/kg in adequate copper diet (CuA) and marginal copper diet (CuM), respectively. Animals had free access to either deionized water or deionized water containing 10% fructose (F) (w/v) as the only drink during the experiment. Body weight, calorie intake, plasma alanine aminotransferase, aspartate aminotransferase, and liver histology as well as liver triglyceride were evaluated. Fecal microbial contents were analyzed by 16S ribosomal RNA (16S rRNA) sequencing. Fecal and cecal short-chain fatty acids (SCFAs) were determined by gas chromatography-mass spectrometry (GC-MS). Results Male and female rats exhibit similar trends of changes in the body weight gain and calorie intake in response to dietary copper and fructose, with a generally higher level in male rats. Several female rats in the CuAF group developed mild steatosis, while no obvious steatosis was observed in male rats fed with CuAF or CuMF diets. Fecal 16S rRNA sequencing analysis revealed distinct alterations of the gut microbiome in male and female rats. Linear discriminant analysis (LDA) effect size (LEfSe) identified sex-specific abundant taxa in different groups. Further, total SCFAs, as well as, butyrate were decreased in a more pronounced manner in female CuMF rats than in male rats. Of note, the decreased SCFAs are concomitant with the reduced SCFA producers, but not correlated to hepatic steatosis. Conclusions Our data demonstrated sex differences in the alterations of gut microbial abundance, activities, and hepatic steatosis in response to dietary copper-fructose interaction in rats. The correlation between sex differences in metabolic phenotypes and alterations of gut microbial activities remains elusive.

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