Pharmacokinetics and Efficacy of a Long-lasting, Highly Concentrated Buprenorphine Solution in Rats

2021 ◽  
Author(s):  
Elizabeth R Houston ◽  
Sarah M Tan ◽  
Samantha M Thomas ◽  
Ulana L Stasula ◽  
Mollie K Burton ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Opioid Analgesic ◽  
Plasma Concentrations ◽  
Pain Tolerance ◽  
Female Rats ◽  
Male Rats ◽  
Suitable Alternative ◽  
Male And Female ◽  
Male And Female Rats ◽  
Drug Concentrations

Buprenorphine (Bup) is an opioid analgesic that is commonly used in laboratory rodents to provide postoperative analgesia. However, dosing every 4 to 6 h is necessary to maintain an analgesic plasma concentration of the drug. A long lasting,highly concentrated veterinary formulation of Bup (LHC-Bup) has been used to provide prolonged analgesia in cats and nonhuman primates. In the current study, we evaluated the duration of efficacy of LHC-Bup to determine if this formulation would provide a similarly prolonged analgesia in rats. Drug concentrations were measured after subcutaneous injectionof 0.5 mg/kg LHC-Bup in both male and female rats. Plasma levels were measured at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36, 48, and72 h. Male and female rats had peak plasma levels of LHC-Bup at 90 ng/and 34 ng/mL, respectively, at 15 min after administration, with a steady decrease by 24 h to 0.7 ng/mL in males and 1.3 ng/mL in females. Mechanical pain tolerance wasevaluated after LHC-Bup administration using a Randall-Selitto analgesiometer to assess paw withdrawal. Male rats had a significantly longer paw withdrawal time for up to 12 h after administration, and females had longer paw withdrawal timesfor up to 24 h. An experimental laparotomy model was then used to assess the clinical efficacy of LHC-Bup at 0.5 mg/kg. LHC-Bup treatment was associated with a greater total distance traveled, reduced time to retrieve a food treat, and reduced grooming from 3 to 12 h after surgery as compared with saline controls. Groups receiving LHC-Bup showed coprophagy whereas other rats did not. These results suggest that administering LHC-Bup at 0.5 mg/kg provides therapeutic plasma concentrations for 12 to 24 h after administration and analgesic efficacy for at least 12 h after dosing. As such, LHC-Bup is a suitable alternative to Bup-HCl.

Sex- and age-dependent differences in the hormone and drinking responses to water deprivation

2020 ◽  
Vol 318 (3) ◽  
pp. R567-R578 ◽  
Author(s):  
Susana Quirós Cognuck ◽  
Wagner L. Reis ◽  
Marcia S. Silva ◽  
Gislaine Almeida-Pereira ◽  
Lucas K. Debarba ◽  
...  
Keyword(s):  
Water Deprivation ◽  
Plasma Concentrations ◽  
Female Rats ◽  
Male Rats ◽  
Ang Ii ◽  
Adult Males ◽  
Adaptive Responses ◽  
Male And Female ◽  
Male And Female Rats ◽  
Female Wistar Rats

Maintenance of the volume and osmolality of body fluids is important, and the adaptive responses recruited to protect against osmotic stress are crucial for survival. The objective of this work was to compare the responses that occur in aging male and female rats during water deprivation. For this purpose, groups of male and female Wistar rats aged 3 mo (adults) or 18 mo (old) were submitted to water deprivation (WD) for 48 h. The water and sodium (0.15 M NaCl) intake, plasma concentrations of oxytocin (OT), arginine vasopressin (AVP), corticosterone (CORT), atrial natriuretic peptide (ANP), and angiotensin II (ANG II) were determined in hydrated and water-deprived animals. In response to WD, old male and female rats drank less water and saline than adults, and both adult and old females drank more water and saline than respective males. Dehydrated old animals displayed lower ANG II plasma concentration and CORT response compared with the respective normohydrated rats. Dehydrated adult males had higher plasma ANP and AVP as well as lower CORT concentrations than dehydrated adult females. Moreover, plasma OT and CORT levels of old female rats were higher than those in the dehydrated old male rats. Relative expression of ANG II type 1 receptor mRNA was decreased in the subfornical organ of adult and old male rats as well as adult female rats in response to WD. In conclusion, the study elucidated the effect of sex and age on responses induced by WD, altering the degree of dehydration induced by 48 h of WD.

THE PITUITARY RESPONSE TO EXOGENOUS LUTEINIZING HORMONE RELEASING FACTOR IN STEROID-TREATED GONADECTOMIZED RATS

1976 ◽  
Vol 69 (2) ◽  
pp. 255-262 ◽  
Author(s):  
M. S. AIYER ◽  
M. C. SOOD ◽  
K. BROWN-GRANT
Keyword(s):  
Plasma Concentrations ◽  
Female Rats ◽  
Male Rats ◽  
Postnatal Life ◽  
Marked Rise ◽  
Male And Female ◽  
Male And Female Rats ◽  
Gonadotrophin Secretion ◽  
Males And Females ◽  
Concentration Curves

SUMMARY Rats gonadectomized 1–2 months previously were anaesthetized with sodium pentobarbitone and 50 ng/100 g body weight of a synthetic decapeptide gonadotrophin releasing factor (LH-RF) injected intravenously. Plasma concentrations of LH and FSH were determined by radioimmunoassay in samples taken before and at intervals up to 60 min after the injection of LH-RF. The pituitary response was evaluated by determining the maximal increment in plasma gonadotrophin concentrations and by estimating the area under the plasma gonadotrophin concentration curves. In both males and females the pituitary response was increased in animals given 20 μg oestradiol benzoate 3 days earlier. Progesterone (2·5 mg) had no effect on the response measured 4 h later in oil-treated rats, male or female. In oestrogen-primed rats progesterone administration produced a significantly increased response in females that was not seen if sodium pentobarbitone was given at the time of progesterone injection. In oestrogen-primed males progesterone produced some increase in sensitivity but less than was seen in females. Both in males and in females that had received androgen on day 4 of postnatal life sodium, pentobarbitone had no effect on the responses of oestrogen plus progesterone-treated rats to LH-RF. When two injections of LH-RF were given 60 min apart, the second response was greater than the first in animals, both male and female, that had been primed with oestrogen. The second response was no greater than the first in oil-treated females. The results suggest that oestrogen can increase pituitary sensitivity to LH-RF in both male and female rats and that LH-RF itself can increase pituitary sensitivity to a second injection of LH-RF in both male and female rats if they have received oestrogen. It is suggested that the differences between the pituitary responses of females and males after oestrogen plus progesterone treatment and the major differences in gonadotrophin secretion reported previously (Brown-Grant, 1974) may be accounted for on the basis of there being a relatively slight increase in endogenous LH-RF secretion with a consequent marked rise in pituitary responsiveness in female but not in male rats.

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.

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.

scholarly journals Sex Differences in Escalated Methamphetamine Self-Administration and Altered Gene Expression Associated With Incubation of Methamphetamine Seeking

2019 ◽  
Vol 22 (11) ◽  
pp. 710-723 ◽  
Author(s):  
Atul P Daiwile ◽  
Subramaniam Jayanthi ◽  
Bruce Ladenheim ◽  
Michael T McCoy ◽  
Christie Brannock ◽  
...  
Keyword(s):  
Sex Differences ◽  
Nucleus Accumbens ◽  
Fixed Ratio ◽  
Female Rats ◽  
Male Rats ◽  
Mrna Levels ◽  
Self Administration ◽  
Male And Female ◽  
Orexin Receptors ◽  
Male And Female Rats

Abstract Background Methamphetamine (METH) use disorder is prevalent worldwide. There are reports of sex differences in quantities of drug used and relapses to drug use among individuals with METH use disorder. However, the molecular neurobiology of these potential sex differences remains unknown. Methods We trained rats to self-administer METH (0. 1 mg/kg/infusion, i.v.) on an fixed-ratio-1 schedule for 20 days using two 3-hour daily METH sessions separated by 30-minute breaks. At the end of self-administration training, rats underwent tests of cue-induced METH seeking on withdrawal days 3 and 30. Twenty-four hours later, nucleus accumbens was dissected and then used to measure neuropeptide mRNA levels. Results Behavioral results show that male rats increased the number of METH infusions earlier during self-administration training and took more METH than females. Both male and female rats could be further divided into 2 phenotypes labeled high and low takers based on the degree of escalation that they exhibited during the course of the METH self-administration experiment. Both males and females exhibited incubation of METH seeking after 30 days of forced withdrawal. Females had higher basal mRNA levels of dynorphin and hypocretin/orexin receptors than males, whereas males expressed higher vasopressin mRNA levels than females under saline and METH conditions. Unexpectedly, only males showed increased expression of nucleus accumbens dynorphin after METH self-administration. Moreover, there were significant correlations between nucleus accumbens Hcrtr1, Hcrtr2, Crhr2, and Avpr1b mRNA levels and cue-induced METH seeking only in female rats. Conclusion Our results identify some behavioral and molecular differences between male and female rats that had self-administered METH. Sexual dimorphism in responses to METH exposure should be considered when developing potential therapeutic agents against METH use disorder.

Effects of trenbolone acetate and testosterone on growth and on plasma concentrations of corticosterone and ACTH in rats

1990 ◽  
Vol 126 (3) ◽  
pp. 461-466 ◽  
Author(s):  
M. N. Sillence ◽  
R. G. Rodway
Keyword(s):  
Weight Gain ◽  
Growth Response ◽  
Plasma Concentrations ◽  
Female Rats ◽  
Male Rats ◽  
Adrenal Weight ◽  
Trenbolone Acetate ◽  
Male And Female Rats ◽  
Age Related ◽  
Old Rats

ABSTRACT The effects of trenbolone acetate (TBA) on growth and on plasma concentrations of corticosterone were examined in male and female rats. At 5 weeks of age, rats were injected with TBA (0·8 mg/kg) dissolved in peanut oil, or with oil alone, daily for 10 days. In female rats, TBA caused an increase in weight gain (20–38%), a reduction in adrenal weight (19%) and a reduction in plasma concentrations of corticosterone (55%). In contrast, TBA-treated male rats showed no significant increase in weight gain, no significant change in adrenal weight and no reduction in plasma concentrations of corticosterone. The mechanism by which adrenal activity was suppressed in TBA-treated female rats was examined and the response compared with that to testosterone. Female rats (8 weeks old) were injected daily either with oil vehicle, TBA (0·8 mg/kg) or testosterone propionate (0·8 mg/kg). Testosterone increased weight gain (24%), but the growth response to TBA treatment was significantly greater (97%). A reduction in plasma concentrations of corticosterone (45%) was again observed in response to TBA. However, testosterone increased plasma concentrations of corticosterone (52%) above those of control values. Neither androgen affected plasma concentrations of ACTH. Finally, the effects of TBA were examined in 6-week-old female rats, to characterize further the apparent age-related increase in responsiveness. The growth response of 6-week-old rats (60–74%) was intermediate between that seen in 5- and 8-week-old animals. It is concluded that part of the anabolic activity of TBA may be related to a reduction in circulating concentrations of corticosterone. The effect of TBA on corticosterone concentrations differs from that of the natural androgen, testosterone, and does not appear to be mediated by a reduction in plasma concentrations of ACTH. Journal of Endocrinology (1990) 126, 461–466

scholarly journals The Preventive Effects of Diminazene Aceturate in Renal Ischemia/Reperfusion Injury in Male and Female Rats

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Maryam Malek ◽  
Mehdi Nematbakhsh
Keyword(s):  
Angiotensin Ii ◽  
Angiotensin Converting Enzyme ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Female Rats ◽  
Male Rats ◽  
Converting Enzyme ◽  
Diminazene Aceturate ◽  
Male And Female ◽  
Male And Female Rats

Background. Angiotensin-converting enzyme 2/angiotensin (1-7)/Mas receptor (ACE2/Ang-1-7/MasR) appears to counteract most of the deleterious actions of angiotensin-converting enzyme/angiotensin II/angiotensin II receptor 1 (ACE/Ang II/AT1R) in renal ischemia/reperfusion (I/R) injury but ACE2 activity and its levels are sexually dimorphic in the kidney. This study was designed to evaluate the effects of activation endogenous ACE2 using the diminazene aceturate (DIZE) in renal I/R injury in male and female rats.Methods. 36 Wistar rats were divided into two groups of male and female and each group distinct to three subgroups (n=6). I/R group was subjected to 45 min of bilateral ischemia and 24 h of reperfusion, while treatment group received DIZE (15 mg/kg/day) for three days before the induction of I/R. The other group was assigned as the sham-operated group.Results. DIZE treatment in male rats caused a significant decrease in blood urea nitrogen (BUN), creatinine, liver functional indices, serum malondialdehyde (MDA), and increase kidney nitrite levels (P<0.05), and in female rats a significant increase in creatinine and decrease serum nitrite levels compared to the I/R group (P<0.05).Conclusions. DIZE may protect the male kidney from renal I/RI through antioxidant activity and elevation of circulating nitrite level.

Gender-based differences in the effect of dietary cholesterol in rats

2012 ◽  
Vol 7 (6) ◽  
pp. 980-986 ◽  
Author(s):  
Milan Marounek ◽  
Zdeněk Volek ◽  
Eva Skřivanová ◽  
Marian Czauderna
Keyword(s):  
Dietary Cholesterol ◽  
Female Rats ◽  
Male Rats ◽  
Cholesterol Concentration ◽  
Hepatic Cholesterol ◽  
Bile Acid Concentration ◽  
Male And Female ◽  
Relative Expression ◽  
Male And Female Rats ◽  
Cholesterol Supplementation

AbstractMale and female rats were fed diets supplemented with cholesterol and palm fat at 10 and 50 g/kg, respectively; serum, hepatic tissue and faeces were analysed. Cholesterol supplementation significantly increased serum and hepatic cholesterol both in male and female rats. Male and female rats fed the cholesterol-containing diet differed significantly in serum cholesterol concentration (2.48 µmol/mL vs 2.92 µmol/mL), concentration of serum triacylglycerols, but not in hepatic cholesterol concentration. The serum and hepatic cholesterol concentrations correlated non-significantly in male rats (r=0.491; P=0.063) and significantly in female rats (r=0.818; P<0.001). Cholesterol supplementation non-significantly decreased relative expression of the hepatic LDL receptor gene and significantly increased relative expression of the hepatic cholesterol 7α-hydroxylase gene in rats of both genders. The faeces of control rats contained similar amounts of cholesterol and bile acids. Cholesterol supplementation increased cholesterol concentration 10 times in the faeces of male rats and 12 times in faeces of female rats. The corresponding increases of bile acid concentration were much lower (83% in male rats and 108% in female rats). It can be concluded that the effects of cholesterol supplementation were more pronounced in female than in male rats.

scholarly journals 17-β-Estradiol Induces Heat Shock Proteins in Brain Arteries and Potentiates Ischemic Heat Shock Protein Induction in Glia and Neurons

2002 ◽  
Vol 22 (2) ◽  
pp. 183-195 ◽  
Author(s):  
Aigang Lu ◽  
Rui-qiong Ran ◽  
Joseph Clark ◽  
Melinda Reilly ◽  
Alex Nee ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Female Rats ◽  
Male Rats ◽  
Western Blots ◽  
Male And Female ◽  
Male And Female Rats

Estradiol reduces brain injury from many diseases, including stroke and trauma. To investigate the molecular mechanisms of this protection, the effects of 17-β-estradiol on heat shock protein (HSP) expression were studied in normal male and female rats and in male gerbils after global ischemia. 17-β-Estradiol was given intraperitoneally (46 or 460 ng/kg, or 4.6 μg/kg) and Western blots performed for HSPs. 17-β-Estradiol increased hemeoxygenase-1, HSP25/27, and HSP70 in the brain of male and female rats. Six hours after the administration of 17-β-estradiol, hemeoxygenase-1 increased 3.9-fold (460 ng/kg) and 5.4-fold (4.6 μg/kg), HSP25/27 increased 2.1-fold (4.6 μg/kg), and Hsp70 increased 2.3-fold (460 ng/kg). Immunocytochemistry showed that hemeoxygenase-1, HSP25/27,and HSP70 induction was localized to cerebral arteries in male rats, possibly in vascular smooth muscle cells. 17-β-Estradiol was injected intraperitoneally 20 minutes before transient occlusion of both carotids in adult gerbils. Six hours after global cerebral ischemia, 17-β-estradiol (460 ng/kg) increased levels of hemeoxygenase-1 protein 2.4-fold compared with ischemia alone, and HSP25/27 levels increased 1.8-fold compared with ischemia alone. Hemeoxygenase-1 was induced in striatal oligodendrocytes and hippocampal neurons, and HSP25/27 levels increased in striatal astrocytes and hippocampal neurons. Finally, Western blot analysis confirmed that estrogen induced heat shock factor-1, providing a possible mechanism by which estrogen induces HSPs in brain and other tissues. The induction of HSPs may be an important mechanism for estrogen protection against cerebral ischemia and other types of injury.

scholarly journals Glutathione Conjugates of Ochratoxin a as Biomarkers of Exposure / Glutationski Konjugati Okratoksina A Kao Biomarkeri Izloženosti

2012 ◽  
Vol 63 (4) ◽  
pp. 417-427 ◽  
Author(s):  
Mariana Tozlovanu ◽  
Delphine Canadas ◽  
Annie Pfohl-Leszkowicz ◽  
Christine Frenette ◽  
Robert J. Paugh ◽  
...  
Keyword(s):  
Ochratoxin A ◽  
Rat Kidney ◽  
Female Rats ◽  
Amide Bond ◽  
Male Rats ◽  
Dark Agouti ◽  
Female Rat ◽  
Male And Female ◽  
Male And Female Rats ◽  
Liver And Kidney

AbstractIn the present study the photoreactivity of the fungal carcinogen ochratoxin A (OTA) has been utilised to generate authentic samples of reduced glutathione (GSH) and N-acetylcysteine (NAC) conjugates of the parent toxin. These conjugates, along with the nontoxic OTα, which is generated through hydrolysis of the amide bond of OTA by carboxypeptidase A, were utilised as biomarkers to study the metabolism of OTA in the liver and kidney of male and female Dark Agouti rats. Male rats are more susceptible than female rats to OTA carcinogenesis with the kidney being the target organ. Our studies show that the distribution of OTA in male and female rat kidney is not significantly different. However, the extent of OTA metabolism was greater in male than female rats. Much higher levels of OTα were detected in the liver compared to the kidney, and formation of OTα is a detoxification pathway for OTA. These findings suggest that differences in metabolism between male and female rats could provide an explanation for the higher sensitivity of male rats to OTA toxicity

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