Influence of quinidine, fluvoxamine, and ketoconazole on the enantioselective pharmacokinetics of citalopram in rats

2008 ◽  
Vol 86 (11) ◽  
pp. 770-776 ◽  
Author(s):  
Adriana Rocha ◽  
Eduardo B. Coelho ◽  
Vera L. Lanchote
Keyword(s):  
Single Dose ◽  
Wistar Rats ◽  
Vehicle Control ◽  
Racemic Mixture ◽  
Blood Samples ◽  
Chiralcel Od ◽  
Male Wistar Rats ◽  
Enantioselective Pharmacokinetics ◽  
Enantioselective Metabolism ◽  
Cyp Inhibitors

Citalopram (CITA) is available as a racemic mixture or as (+)-(S)-CITA. In humans, CITA is metabolized to demethylcitalopram (DCITA) by CYP2C19, CYP2D6, and CYP3A and to didemethylcitalopram by CYP2D6. There are no data regarding the enzymes involved in CITA and DCITA metabolism in rats. The present study investigated the influence of CYP inhibitors on the enantioselective metabolism of CITA in rats. Male Wistar rats (n = 6) received a single dose of 20 mg·kg–1 CITA after pretreatment with 80 mg·kg–1 quinidine, 10 mg·kg–1 fluvoxamine, 50 mg·kg–1 ketoconazole, or vehicle (control). Blood samples were collected up to 20 h after CITA administration. The CITA and DCITA enantiomers were analyzed by LC-MS/MS using a Chiralcel OD-R column. The kinetic disposition of CITA was enantioselective in rats (AUCS/R ratio = 0.4). Coadministration with quinidine resulted in non-enantioselective inhibition of the metabolism of CITA. Coadministration with fluvoxamine or ketoconazole, however, inhibited only the metabolism of (+)-(S)-CITA, but not of (–)-(R)-CITA when the racemic drug was administered to rats.

Reduction of enantioselectivity in the kinetic disposition and metabolism of verapamil in rats exposed to toluene

2008 ◽  
Vol 86 (5) ◽  
pp. 232-239 ◽  
Author(s):  
F.H. Mateus ◽  
J.S. Lepera ◽  
M.P. Marques ◽  
V.B. Boralli ◽  
V.L. Lanchote
Keyword(s):  
Single Dose ◽  
Oxidative Metabolism ◽  
Wistar Rats ◽  
Plasma Concentrations ◽  
Wilcoxon Test ◽  
Control Group ◽  
Chiral Drugs ◽  
Blood Samples ◽  
Male Wistar Rats ◽  
Air Control

Toluene and verapamil are subject to extensive oxidative metabolism mediated by CYP enzymes, and their interaction can be stereoselective. In the present study we investigated the influence of toluene inhalation on the enantioselective kinetic disposition of verapamil and its metabolite, norverapamil, in rats. Male Wistar rats (n = 6 per group) received a single dose of racemic verapamil (10 mg/kg) orally at the fifth day of nose-only toluene or air (control group) inhalation for 6 h/day (25, 50, and 100 ppm). Serial blood samples were collected from the tail up to 6 h after verapamil administration. The plasma concentrations of verapamil and norverapamil enantiomers were analyzed by LC-MS/MS by using a Chiralpak AD column. Toluene inhalation did not influence the kinetic disposition of verapamil or norverapamil enantiomers (p > 0.05, Kruskal–Wallis test) in rats. The pharmacokinetics of verapamil was enantioselective in the control group, with a higher plasma proportion of the S-verapamil (AUC 250.8 versus 120.4 ng·h·mL–1; p ≤ 0.05, Wilcoxon test) and S-norverapamil (AUC 72.3 versus 52.3 ng·h·mL–1; p ≤ 0.05, Wilcoxon test). Nose-only exposure to toluene at 25, 50, or 100 ppm resulted in a lack of enantioselectivity for both verapamil and norverapamil. The study demonstrates the importance of the application of enantioselective methods in studies on the interaction between solvents and chiral drugs.

Abstract TP272: Selective Inhibition of Histone Deacetylase 3 Decreases Cerebral Edema and Blood-Brain Barrier Leakage

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Amjad Shehadah ◽  
Hui Lu ◽  
Victoria Clendaniel ◽  
Rudy Matheson ◽  
Marc Fisher ◽  
...  
Keyword(s):  
Cerebral Edema ◽  
Wistar Rats ◽  
Selective Inhibition ◽  
Vehicle Control ◽  
Tnf Alpha ◽  
Tight Junction Proteins ◽  
Ischemic Brain ◽  
Histone Deacetylase 3 ◽  
Male Wistar Rats ◽  
Junction Proteins

Introduction: Histone deacetylase 3 (HDAC3) has been implicated as neurotoxic in several neurodegenerative conditions. However, its role in ischemic stroke has not been thoroughly explored. In this study, we examined HDAC3 expression after stroke and tested whether selective inhibition of HDAC3 decreases cerebral edema and blood-brain barrier (BBB) leakage after ischemia. Methods: To examine HDAC3 expression over time, adult male Wistar rats (n=6/group) were subjected to middle cerebral artery occlusion (MCAO) and sacrificed at different time points after stroke. Another set of adult male Wistar rats was subjected to 2-h MCAO, and randomly selected animals were treated i.p. with either vehicle (1% Tween 80) or a selective HDAC3 inhibitor (RGFP966, 10 mg/kg) at 2 and 24 h after MCAO. Behavioral tests were performed, and infarct volumes and cerebral edema were measured. Evans blue dye (EBD) assay was employed to assess BBB leakage. Immunostaining for HDAC3, CD31, claudin-5, occludin, and ZO-1; and Western Blot for TNF-alpha and matrix metalloproteinase-9 (MMP9) were performed. Results: Total and neuronal HDAC3 significantly increased in the peri-infarct cortex as early as 3 hours after ischemia. HDAC3 levels continued to be significantly elevated at 3 days and returned to baseline at 7 days. Selective HDAC3 inhibition improved functional outcome (p=0.01) and reduced infarct volumes (p<0.001). Compared to vehicle control, RGFP966 treatment significantly decreased cerebral edema (p<0.001) as well as BBB leakage, as measured by EBD assay. Immunostaining showed that RGFP966 significantly increased the expression of tight junction proteins (claudin-5, occludin, and ZO-1) in the peri-infarct area compared to vehicle control group. Western Blot showed that RGFP966 treatment significantly decreased the expression of TNF-alpha and MMP9 in the ischemic brain. Conclusions: HDAC3 is upregulated in the ischemic brain as early as 3 hours after stroke. Early administration of a selective HDAC3 inhibitor improves neurological functional outcome and decreases infarct volume, cerebral edema, and BBB leakage. BBB protection by selective inhibition of HDAC3 is mediated in part by upregulation of tight junction proteins and attenuation of TNF-alpha and MMP9.

scholarly journals Effect of Hydroalcoholic Extract ofCydonia oblongaMiller (Quince) on Sexual Behaviour of Wistar Rats

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Muhammad Aslam ◽  
Ali Akbar Sial
Keyword(s):  
Body Weight ◽  
Single Dose ◽  
Sexual Behaviour ◽  
Wistar Rats ◽  
Sexually Active ◽  
Cydonia Oblonga ◽  
Hydroalcoholic Extract ◽  
Male Wistar Rats ◽  
Mating Performance ◽  
Remarkable Manner

Cydonia oblongaMiller (quince) is regarded as a potent libido invigorator in Tib-e-Nabvi and Unani System of Medicine. This study was carried out to evaluate the aphrodisiac activity of the hydroalcoholic extract of the fruits ofCydonia oblongaMiller (quince) in Wistar rats. The extract was administered orally by gavage in the dose of 500 mg/kg and 800 mg/kg body weight per day as a single dose for 28 days. The observed parameters were mounting frequency, assessment of mating performance, and orientation activities towards females, towards the environment, and towards self. The results showed that after administration of the extract mounting frequency and the mating performance of the rats increased highly significantlyP<0.01. The extract also influenced the behaviour of treated animals in comparison to nontreated rats in a remarkable manner, making them more attracted to females. These effects were observed in sexually active male Wistar rats.

Differences in the Composition of Inflammatory Cell Infiltrate in Lens-Induced Uveitis under Therapy with Allopurinol or Steroids

2001 ◽  
Vol 11 (3) ◽  
pp. 264-268 ◽  
Author(s):  
W. Sekundo ◽  
A.J. Augustin
Keyword(s):  
Single Dose ◽  
Wistar Rats ◽  
Inflammatory Cell ◽  
Control Group ◽  
Inflammatory Cell Infiltrate ◽  
Polymorphonuclear Leucocytes ◽  
Cell Infiltrate ◽  
Anterior Capsule ◽  
Male Wistar Rats ◽  
Qualitative Changes

Purpose The aim of this study was to compare the qualitative changes in the composition of inflammatory cell infiltrate in lens-induced uveitis (LIU) under treatment with allopurinol (Allo), methylprednisolone (Pred) or the two drugs combined (Allo/Pred). Methods Twenty male Wistar rats were sensitized with lens proteins for eight weeks. Intravenous (IV) therapy was started after anterior capsule disruption in one eye of each animal. Five rats were randomly assigned to each of the four groups: controls, Allo (50 mg/kg bw), Pred (7.5 mg/kg bw) and Allo/Pred (50 mg/7.5 mg per kg bw). Eyes were enucleated 24 hours later and fixed in paraformaldehyde/glutaraldehyde. Sections at three levels were stained with Giemsa and examined using a 0 to 4+ score for each type of inflammatory cell. Granulocytes were seen as neutrophils and eosinophils. Neutrophils were divided into polymorphs and “others”, and graded with lymphocytes. Results In all therapy groups there was a significant reduction of polymorphs (p<0.05) in comparison to the control group. There was also a significant reduction in lymphocytes (p<0.05) in the Pred and Allo/Pred groups as compared to the control group and the Allo group. Conclusions Single-dose IV allopurinol significantly reduced the overall number of polymorphonuclear leucocytes in LIU. Unlike methylprednisolone, allopurinol did not have any significant impact on lymphocytes.

scholarly journals Experimental hypogonadism: insulin resistance, biochemical changes and effect of testosterone substitution

2019 ◽  
Vol 30 (3) ◽  
Author(s):  
Ilias P. Doulamis ◽  
Aspasia Tzani ◽  
Panagiotis Konstantopoulos ◽  
Afroditi Daskalopoulou ◽  
Theodoros Spinos ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipid Profile ◽  
Metabolic Profile ◽  
Wistar Rats ◽  
Sham Operation ◽  
Blood Samples ◽  
Testosterone Substitution ◽  
Negative Effect ◽  
Male Wistar Rats

Abstract Background We sought to clarify the role of testosterone substitution in terms of insulin resistance and metabolic profile dysregulation in hypogonadism. Methods Twenty-nine male Wistar rats aged 11–12 weeks were divided in three groups: control (C, n = 10), sham operation; orchiectomy (ORX, n = 9); and orchiectomy + testosterone substitution (ORX+T, n = 10). Blood samples were obtained at day 1 (operation), after 10 days (intramuscular T injection 100 μg/100 g b.w.), 25 days (second T injection) and 40 days (sacrifice). Results Hormonal replacement significantly attenuated the negative effect of orchiectomy on insulin resistance as indicated by the successive changes in both insulin levels (1.44 ± 2.94 vs. 4.10 ± 2.47 vs. 1.78 ± 0.68 ng/mL, for D1, D10 and D40, respectively; p = 0.028 and p = 0.022, respectively) and HOMA-IR index (1.36 ± 2.75 vs. 3.68 ± 1.87 vs. 1.74 ± 0.69 ng/mL, for D1, D10 and D40, respectively; p = 0.024 and p = 0.026, respectively) in the ORX+T group. Irisin levels peaked at the 10th postoperative day and were decreased at the end of the experiment (0.27 ± 0.11 vs. 0.85 ± 0.54 vs. 0.02 ± 0.07 ng/mL for D1, D10 and D40, respectively; p = 0.028 in both cases), whereas resistin levels did not differ. Experimental hypogonadism results in an unfavorable lipid profile and insulin resistance, which is not observed when the ORX animals are substituted for T.

Effect of Khatamines and Their Enantiomers on Plasma Triiodothyronine and Thyroxine Levels in Normal Wistar Rats

1990 ◽  
Vol 18 (01n02) ◽  
pp. 71-76 ◽  
Author(s):  
M.W. Islam ◽  
M. Tariq ◽  
F.S. El-Feraly ◽  
I.A. Al-Meshal
Keyword(s):  
Wistar Rats ◽  
Peak Effect ◽  
Pharmacological Effects ◽  
Catha Edulis ◽  
Blood Samples ◽  
Male Wistar Rats ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Higher Doses ◽  
Plasma Triiodothyronine

The effect of cathinone and N-formylnorephedrine, two psychoactive amines of khat (Catha edulis Forsk.) and their enantiomers have been studied on plasma levels of triiodothyronine (T3) and thyroxine (T4) in male Wistar rats. The rats were injected with 5, 10 and 30 mg/kg. body weight of four khatamines and the blood samples were collected 2 h after administration. In the separate set of experiments the effect of these khatamines at 1, 2 and 4 h after their administration was also examined. All khatamines failed to produce a significant dose dependent increase in T3 and T4 levels in the dose of 5 mg/kg. However, all these compounds produced a significant dose dependent increase in T3 and T4 levels at higher doses but only T4 levels were increased following the dose of 10 mg/kg. Our studies on the effect of khatamines in T3 and T4 levels at various time showed a significant increase in T4 levels in all the four groups treated with various khatamines and the peak effect was observed in 2 h in case of (-)- and (+)-cathinone and 4 h in case of (-) and (+)N-formylnorephedrine. This study suggests that the symptoms observed in khat chewers including hyperthermia, anorexia, and metabolic changes may to some extent be attributed to the thyroid stimulating effect of khatamines. However, further studies are needed to establish the mechanism of release of thyroid hormones by these compounds and their involvement in the pharmacological effects.

Role of thioredoxin nitration in bleomycin-induced pulmonary fibrosis in rats

2016 ◽  
Vol 94 (1) ◽  
pp. 59-64 ◽  
Author(s):  
Lei Wang ◽  
Yimin Song ◽  
Xiankui Li ◽  
Haizhou Guo ◽  
Guojun Zhang
Keyword(s):  
Single Dose ◽  
Pulmonary Fibrosis ◽  
Wistar Rats ◽  
Intratracheal Instillation ◽  
Treated Group ◽  
Control Group ◽  
Tyrosine Nitration ◽  
Male Wistar Rats ◽  
Phosphate Buffered Saline

Oxidant stimulation has been suggested to play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Our study aimed to investigate the role and mechanisms of thioredoxin (Trx) nitration during the development of IPF. A rat model of IPF was established by intratracheal instillation of bleomycin (BLM). Male Wistar rats were randomly distributed among the control group and BLM-treated group, in which rats were intratracheally instilled with a single dose of BLM (5.0 mg/kg body mass in 1.0 mL phosphate-buffered saline). At 7 or 28 days after instillation the rats were euthanized. Histopathological and biochemical examinations were performed. The activity and protein level of thioredoxin were assessed. The thioredoxin nitration level was determined using immunoprecipitation and immunoblotting techniques. Our results demonstrated that protein tyrosine nitration increased in the BLM-treated group compared with the control group. Trx activity decreased in the BLM group compared with control group, whereas Trx expression and nitration level increased dramatically in the BLM group compared with the control group. Our results indicated that Trx nitration might be involved in the pathogenesis of IPF.

Pulsatile secretion of growth hormone and insulin in relation to feeding in rats

1987 ◽  
Vol 253 (5) ◽  
pp. R772-R778
Author(s):  
P. Even ◽  
J. Danguir ◽  
S. Nicolaidis ◽  
C. Rougeot ◽  
F. Dray
Keyword(s):  
Growth Hormone ◽  
Insulin Secretion ◽  
Food Intake ◽  
Wistar Rats ◽  
Plasma Concentrations ◽  
Endocrine Activity ◽  
Blood Samples ◽  
Gh Secretion ◽  
Male Wistar Rats ◽  
Intracardiac Catheters

In unrestrained male Wistar rats chronically implanted with intracardiac catheters, blood samples were taken every 20 min throughout the 24 h of the diurnal cycle. Plasma concentrations of growth hormone (GH), insulin, and glucose were measured. The pattern of food intake was continuously monitored. The existence of 3-h pulsatile cycles of GH secretion was confirmed. In addition, short bursts of insulin secretion were observed in the middle of every second GH peak-to-peak interval. Food intake appeared to be enhanced during short periods that corresponded with GH release into the blood and was reduced during the GH peak-to-peak periods in which the bursts of insulin secretion were observed. From these observations this study draws a schematic relationship between the rhythmicity of the secretion of GH and insulin and the probability of occurrence of feeding. We speculate that the rhythmic endocrine activity may be causally related to feeding.

Intravenous Infusion of Tridihomo-γ-Linolenoyl-Glycerol Reduces Leukotriene B4 Production in the Rat and Rabbit

1993 ◽  
Vol 84 (5) ◽  
pp. 511-516 ◽  
Author(s):  
Norio Nakamura ◽  
Tomohito Hamazaki ◽  
Hirofumi Taki ◽  
Katsuya Yamazaki ◽  
Masashi Kobayashi
Keyword(s):  
Fatty Acid ◽  
Linolenic Acid ◽  
Wistar Rats ◽  
Peritoneal Macrophages ◽  
Fatty Acid Analysis ◽  
Leukotriene B4 ◽  
Polymorphonuclear Leucocytes ◽  
Blood Samples ◽  
Peritoneal Cells ◽  
Male Wistar Rats

1. We have formulated an infusible emulsion of 10% tridihomo-γ-linolenoyl-glycerol (94% pure) and investigated the effects of its infusion on leukotriene B4 production. 2. We infused the emulsion into the ear veins of two rabbits in a dose of 0.8 g of tridihomo-γ-linolenoyl-glycerol/kg. Polymorphonuclear leucocytes were obtained from rabbits before the infusion, and 6, 24, 72 and 168 h after. The ionophore-stimulated leukotriene B4 production by polymorphonuclear leucocytes was reduced to about 50% of baseline as early as 6 h after the infusion and remained reduced until 24 h after the infusion. 3. To closely investigate the changes in leukotriene B4 production at 6 h after the infusion, we infused 1.0 g of tridihomo-γ-linolenoyl-glycerol/kg into the tail veins of eight male Wistar rats. Six hours later, peritoneal macrophages were obtained from four rats for the analysis of ionophore-stimulated leukotriene B4 production. Peritoneal cells and blood samples were also obtained from the remaining rats for fatty acid analysis. Another eight rats were used without prior infusion for baseline determination. 4. The production of leukotriene B4 by macrophages was significantly reduced to 42% of baseline, and the plasma free dihomo-γ-linolenic acid was markedly increased from 0.26 to 4.82 mol%, in 6 h. 5. We conclude that the infusion of a tridihomo-γ-linolenoyl-glycerol emulsion is able to decrease leukotriene B4 production and to increase the dihomo-γ-linolenic acid concentrations in the plasma and peritoneal cells of rats in 6 h.

Development of a Hypoparathyroid Male Rodent Model for Testing Delayed-Clearance PTH Molecules

Endocrinology ◽  
2021 ◽  
Vol 163 (2) ◽  
Author(s):  
Narjes Ramezanipour ◽  
Sayyed Hamid Zarkesh Esfahani ◽  
Richard Eastell ◽  
John Newell-Price ◽  
Graham Trevitt ◽  
...  
Keyword(s):  
Animal Model ◽  
Biological Activity ◽  
Single Dose ◽  
Wistar Rats ◽  
Biphasic Response ◽  
Serum Samples ◽  
Post Dose ◽  
Male Wistar Rats ◽  
Long Acting ◽  
Prolonged Response

Abstract Context Parathyroid hormone (PTH) replacement is a promising approach in the management of hypoparathyroidism but long-acting analogues need to be developed. To date, animal models for testing PTH required parathyroidectomy by surgery. We have developed a nonsurgical rodent hypoparathyroid model and tested a delayed-clearance PTH molecule (DC-PTH). Objective The aim of this study was to use cinacalcet to suppress calcium levels in normal rats and to reverse these effects with the administration of PTH or PTH analogues Methods Male Wistar rats were gavaged with either 30 mg/kg cinacalcet-HCl (cinacalcet) or vehicle only. Animals were then dosed with either single or repeated subcutaneous doses of PTH 1-34 or a DC-PTH at 20 nmol/kg. Control animals received vehicle only. Serum samples were analyzed for ionized calcium (iCa), phosphate, PTH, and DC-PTH. A pharmacokinetic-pharmacodynamic (PK-PD) model was built for cinacalcet, PTH 1-34, and DC-PTH using Phoenix64. Results Cinacalcet reduced iCa levels between 2 and 24 hours, returning to baseline by 72 hours post dose with nadir at 8 hours (analysis of variance P &lt; .001), associated with a fall in rat PTH. For phosphate there was a variable biphasic response. Single-dose PTH abrogated the cinacalcet-induced fall in iCa for up to 2 hours. DC-PTH prevented the fall in iCa from 4 hours post dose and gave a prolonged response, with iCa levels quicker to return to baseline than controls. DC-PTH has a half-life of 11.5 hours, approximately 44 times longer than human PTH 1-34. The PK-PD models defined the reproducible effect of cinacalcet on iCa and that DC-PTH had prolonged biological activity. Conclusion The administration of cinacalcet provides a robust and reproducible nonsurgical animal model of hypoparathyroidism. DC-PTH holds promise for the treatment of hypoparathyroidism in the future.

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