Pharmacokinetics and Pharmacodynamics of Dexamethasone after Intravenous Administration in Camels: Effect of Dose

The pharmacokinetics and pharmacodynamics of dexamethasone were evaluated in healthy camels after single intravenous bolus doses of 0.05, 0.1 and 0.2 mg/kg body weight. Dexamethasone showed dose-independent pharmacokinetics. The pharmacokinetic parameters of the two-compartment pharmacokinetic model for the lowest intravenous dose (mean+/-SD) were as follows: terminal elimination half-life 8.17 +/- 1.79 h; total body clearance 100.7 +/- 52.1 (ml/h)/kg; volume of distribution at steady state 0.95 +/- 0.23 L/kg; and volume of the central compartment 0.22 +/- 0.07 L/kg. The extent of plasma protein binding was linear over the concentration range 5-100 ng/ml and averaged 75% +/- 2%. Pharmacodynamic effects were evaluated by measuring endogenous plasma cortisol concentrations, numbers of circulating lymphocytes and neutrophils and plasma glucose concentrations and were analysed using indirect pharmacokinetic/pharmacodynamic models. The cumulative systemic effect increased with dose for markers of pharmacodynamic activity. The estimated IC50 of dexamethasone for cortisol and lymphocytes for the lowest dose were 3.74 +/- 2.44 and 5.58 +/- 8.37 ng/ml, respectively and the EC50 values for neutrophils and glucose were 45.8 +/- 36.9 and 1.17 +/- 0.71 ng/ml, respectively.     

聚乙二醇1000维生素E琥珀酸酯对小鼠胸腺细胞凋亡的影响

通过地塞米松体内给药建立小鼠胸腺细胞凋亡模型,普通光镜下观察凋亡细胞形态学改变并统计凋亡率,结合琼脂糖凝胶电泳检测,定性定量研究不同浓度聚乙二醇1000VE琥珀酸酯(TPGS)对胸腺细胞凋亡的影响。结果表明,TPGS能够抑制地塞米松诱导的小鼠胸腺细胞凋亡,降低凋亡率,该抑制作用呈现剂量依赖性,在低浓度(1倍需要量和5倍需要量)下最为显著,当浓度升高至10倍需要量和20倍需要量时,凋亡率与阳性对照组无显著差别。     

地塞米松对特发性血小板减少性紫癜外周血淋巴细胞凋亡及Fas/FasL的影响

目的 :观察地塞米松对特发性血小板减少性紫癜 (ITP)外周血淋巴细胞凋亡及 Fas、Fas L表达的影响及其临床意义。方法 :用流式细胞仪检测 30例 ITP患儿治疗前后外周血淋巴细胞凋亡率及 Fas、Fas L蛋白表达。结果 :治疗前淋巴细胞凋亡率及 Fas、Fas L蛋白表达与对照组相比差异无统计学意义 (P>0 .0 5)。治疗后血小板增加时淋巴细胞凋亡率增加 ,Fas、Fas L蛋白表达上调 ,与治疗前相比差异有显著性意义 (P<0 .0 1 )。结论 :地塞米松可显著促进 ITP患儿外周血淋巴细胞的凋亡 ,上调淋巴细胞 Fas、Fas L的表达 ,有助于清除激活的淋巴细胞。     

Effect of dexamethasone on the expression of atrogin‐1/MAFbx in chick skeletal muscle

Expression of atrogin‐1/MAFbx, a muscle‐specific E3 ubiquitin ligase, is high under catabolic conditions, that result in muscle atrophy. Messenger RNA (mRNA) expression of atrogin‐1/MAFbx is increased by the glucocorticoid dexamethasone in mammalian skeletal muscle. This study investigated the effects of dexamethasone on expression of atrogin‐1/MAFbx in skeletal muscle of neonatal chicks and in chick myotubes. Chicks were given a single intraperitoneal injection of dexamethasone at a concentration of 10 mg/kg body weight. Twenty‐four hours after dexamethasone administration, the Pectoralis muscle weight of chicks was decreased. mRNA expression of atrogin‐1/MAFbx in skeletal muscle of chicks was significantly increased by dexamethasone administration. Expression of other proteolytic‐related genes (20S proteasome C2 subunit, m‐calpain large subunit, and cathepsin B) in skeletal muscle of chicks was not increased by dexamethasone administration. Chick myotubes were incubated with dexamethasone (1, 10 or 100 µmol/L) for 6 h. Expression of atrogin‐1/MAFbx mRNA in chick myotubes was increased in the presence of all concentrations of dexamethasone. However, expression of other proteolytic‐related genes (20S proteasome C2 subunit, m‐calpain large subunit and cathepsin B) in chick myotubes was not affected by dexamethasone treatment. These results indicate that dexamethasone enhances atrogin‐1/MAFbx expression in chick skeletal muscle, resulting in increased muscle atrophy.     

Tissue distribution of dexamethasone in feline ocular structures following single topical application of dexamethasone as an ointment or suspension

Objective To compare the dexamethasone concentration in various structures of the feline eye following a single topical application of dexamethasone as an ophthalmic ointment or suspension. Animals studied Nineteen cats, euthanized due to reasons not related to this study, were selected and their ocular health status evaluated. Selected animals were treated with dexamethasone ointment or suspension. Procedure The concentration of dexamethasone was determined in the following structures of the eye: third eyelid, cornea, aqueous humor, iris, lens, vitreous body, and choroid/retina. The dexamethasone concentration in the eye was measured by radioimmunoassay. The applied amount of dexamethasone was 0.05 mg in 0.05 mL Isopto Dex^® ophthalmic suspension and 0.05 mL Isopto Dex^® ophthalmic ointment, respectively. Cats were treated once with ointment or suspension and were euthanized 3 h or 6 h after treatment. Results At 3 h after topical administration the highest concentrations of dexamethasone were measured in the anterior structures of the eye. The concentrations after application of ointment and suspension were comparable. However, 6 h after administration, the concentrations decreased after administration of suspension and increased further after administration of the ointment, leading to significantly higher concentrations of dexamethasone in the third eyelid, cornea and choroid/retina after treatment with ointment. Conclusion Therapeutically relevant concentrations of dexamethasone after a single topical administration were only achieved in the anterior structures of the eye. Six hours after application there was a substantially higher amount of dexamethasone in the anterior structures of cat eyes treated with ophthalmic ointment compared to ophthalmic suspension.     

Peripheral plasma levels of corticosteroids in normal beagles and greyhounds measured by a rapid competitive protein binding technique

A rapid competitive protein binding method for the measurement of peripheral plasma levels of corticosteroids in dogs was evaluated and applied. The rapid method was found to give a minor overestimation of the Cortisol levels as compared to the method including purification of the plasma extract on Sephadex LH-20 columns. In Beagles and Greyhounds mean peripheral plasma levels of corticosteroids of 25.4 and 18.0 ng/ml were found respectively. No diurnal variation of peripheral plasma levels of corticosteroids was obtained. After the intravenous administration of dexamethasone peripheral plasma levels of corticosteroids were found to decrease to about 20 % of the pretreatment levels. When ACTH was administered i.m. a nearly 10 fold increase of the corticosteroid levels was found 60 to 90 min. after the injections. The rapid method described and evaluated should be of value for diagnosis of adrenal syndrome in the dog.     

氯前列烯醇和地塞米松诱导家兔白天分娩的研究

为了提高母兔分娩管理效率与新生仔兔成活率,挑选健康妊娠29 d母兔28只,随机分为7组,分别注射氯前列烯醇钠注射液0．1、0．2、0．3 mL 和地塞米松磷酸钠注射液0．15、0．3、0．45 mL,对照组注射0．3 mL 生理盐水,各组用药至分娩间隔时间依次为50 h±1 h、48 h±1 h、36 h ±1 h、55h±1 h、68 h±1 h、52 h±1 h、57 h±1 h。再挑选健康妊娠29 d 母兔56只,分为7组。根据上述结果,分别用上述低、中、高剂量的氯前列烯醇钠注射液和地塞米松磷酸钠注射液,注射时间依次为11：00,13：00,1：00;6：00,17：00,9：00;对照组4：00。各组白天同期分娩率依次为62．5％、87．5％、75％、37．5％、50％、62．5％、25％。氯前列烯醇钠注射液与地塞米松磷酸钠注射液处理组效果均显著优于对照组（P ＜0．05）,而且白天同期分娩率与仔兔意外死亡率呈负相关。产后24h 内正常泌乳母兔数分别为87．5％、87．5％、100％、87．5％、85％、100％及87．5％。结果表明,29日龄孕兔注射0．2 mL 氯前列烯醇钠注射液的白天同期分娩率最为理想。     

Review of glucocorticoid therapy in horses. Part 1: Pharmacology

This article is the first in a three part review series examining glucocorticoid use in treatment of medical conditions and musculoskeletal disorders of the horse. This article provides a review of the structure and function of corticosteroids together with a summary of the available literature pertaining to the pharmacodynamics, pharmacokinetics and indications for use of, and adverse effects associated with, glucocorticoids currently available for use by equine veterinarians.     

The effects of dexamethasone and prednisolone on pituitary and ovarian function in the mare

Reasons for performing study: Persistent mating induced endometritis is among the most common causes of infertility in the mare. Recently, improved pregnancy rates have been reported when corticosteroids were administered to ‘problem mares’ specifically, to modulate the post mating inflammatory response; however, the effect of treatment on pituitary and ovarian function requires further study. Objectives: To evaluate the effects of prolonged treatment with glucocorticoids on pituitary and ovarian function. Methods: Eighteen cycling Quarter Horse mares in early oestrus were assigned randomly to one of 3 treatment groups: dexamethasone 0.05 mg/kg bwt i.v. twice a day, prednisolone 0.5 mg/kg per os twice a day, or placebo for 5 days. Mares were examined by ultrasound daily to evaluate reproductive function. Blood samples were collected daily to measure luteinising hormone (LH), progesterone and cortisol levels. Results: Dexamethasone treatment caused greater (P<0.05) suppression of endogenous cortisol concentration (9.4 ± 1.1 ng/ml) compared to prednisolone‐ (41.9 ± 4.0 ng/ml) or placebo‐treated mares (32.4 ± 3.8 ng/ml). After 24 h, mares treated with dexamethasone exhibited lower uterine oedema scores than prednisolone‐ or placebo‐treated mares. An ovulation rate of 40% was observed in dexamethasone‐treated mares (2/5) compared to 83% for prednisolone (5/6) and 100% for placebo‐treated (6/6) mares. An absence of a LH surge was noted in 3 of 5 dexamethasone‐treated mares and one of 6 prednisolone‐treated mares. Conclusions: Repeated administration of dexamethasone to mares in oestrus is associated with decreased uterine oedema, suppression of LH and a high rate of ovulation failure. It is recommended that dexamethasone treatment is limited to only 1 or 2 days and that a lower dose is considered in the management of persistent mating induced endometritis to avoid potential adverse affects on reproductive function.