Systemic Administration Of Dexamethasone Research Articles

The dorsal hippocampus modifies the negative feedback effect of glucocorticoids on the adrenocortical and median eminence CRF-41 responses to photic stimulation

In the present study we have evaluated the role of the dorsal hippocampus on the negative feedback effect of glucocorticoids (GC) following photic stimulation. In hippocampectomized rats the recovery of serum corticosterone (CS) to basal levels following photic stimulation, was significantly attenuated in relation to sham hippocampectomized rats. The inhibitory effect of either systemic dexamethasone administration or CS implanted in the paraventricular nucleus (PVN), on the adrenocortical responses to photic stimulation, was completely prevented in hippocampectomized rats in comparison to sham operated animals. In rats with sham operation, the depletion of median eminence CRF-41 induced by photic stimulation, was prevented by pretreatment with CS PVN implants or systemic dexamethasone. These effects were reversed in rats with dorsal hippocampectomy. The results suggest that the dorsal hippocampus modulates the negative feedback of GC on the adrenocortical response following photic stimulation at the PVN level and this effect is mediated by median eminence CRF-41.

Mast cells and tissue reaction to intraperitoneally implanted polymer capsules

The inflammatory reaction to implanted biomaterials often compromises the clinical usefulness of implantable devices. Dexamethasone, an anti-inflammatory agent, acts on macrophages to decrease production of inflammatory mediators, and on mast cells to prevent degranulation. Systemic administration of dexamethasone (dms) in rats decreases the tissue reaction to intraperitoneally implanted vinyl chloride-acrylic copolymer capsules. Local release of even smaller amounts of dms from a polymeric substrate placed inside an acrylic copolymer capsule may control the tissue reaction while avoiding the undesirable side effects of systemic treatment. Such a system also allows investigation of the local effect of soluble molecules on tissue-material interactions without altering the surface properties of the implant or adding the effect of a releasing material. In the present study, we investigated the effect of dms released from ethylene vinyl acetate (EVAc) rods placed in acrylic copolymer capsules and implanted in the peritoneal cavity of rats. In vitro the release of dms from EVAc rods was quasilinear for 5 weeks. When implanted intraperitoneally into rats, polymer capsules containing EVAc/dms rods generated a tissue reaction that was significantly thinner and featured fewer fibroblast and collagen layers than that around capsules containing pure EVAc rods at all time points studied. The tissue reaction layer was also thinner than that previously described in rats treated systemically with dms. The trabeculae of implants with dms-loaded EVAc rods contained significantly more intact mast cells than implants with EVAc alone, suggesting that degranulation of mast cells is involved in the tissue reaction to intraperitoneal polymer implants.

Interstitial delivery of dexamethasone in the brain for the reduction of peritumoral edema

Controlled-release polymers have facilitated the interstitial delivery of drugs within the central nervous system. In the present study, dexamethasone was incorporated into ethylene-vinyl acetate polymers, which were then implanted adjacent to a 9L gliosarcoma in the brain of Fischer 344 rats. The effect of interstitial delivery of dexamethasone on peritumoral edema was assessed and compared to the effect of dexamethasone delivered systemically. Eighty-five rats underwent intracranial implantation of the 9L gliosarcoma. Five days later, the animals were randomly assigned to one of four treatment groups: Group 1 received intracranial implantation of controlled-release polymers containing dexamethasone; Group 2 received intraperitoneal implantation of controlled-release polymers containing dexamethasone; Group 3 received serial intraperitoneal injections of dexamethasone; and Group 4 received sham treatment. The animals were sacrificed 3 days after initiation of therapy and their brains were removed for measurement of the water content (edema) in the tumor-bearing and contralateral hemispheres. Brain and plasma samples were analyzed by reverse-phase high-performance liquid chromatography to determine the tissue and plasma concentrations of dexamethasone. Measurement of the release kinetics of dexamethasone from the ethylene-vinyl acetate polymers in an in vitro system showed that the drug was released in a controlled, tapering fashion. During the first 3 days of controlled release in vitro, 330 micrograms of a total content of 7.5 mg of dexamethasone was released into the medium. Analysis of tissue for drug levels demonstrated, however, that the interstitial delivery of this fractional amount of dexamethasone within the brain resulted in levels 19 times higher than those achieved by administering the full dose of 7.5 mg systemically over a 3-day period. Conversely, the systemic administration of dexamethasone resulted in plasma levels 16 times higher than those measured in the interstitial delivery of dexamethasone in the brain. Brain-water content determinations showed that the interstitial controlled release of the fractional amount of dexamethasone within the brain was as effective in controlling peritumoral edema as systemic administration of the full dose by serial intraperitoneal injections. The study demonstrates the following: 1) controlled-release polymeric carriers deliver biologically active dexamethasone in a sustained fashion; 2) very high concentrations of dexamethasone in brain tissue can be achieved using interstitial polymer-mediated drug delivery while minimizing plasma concentrations of this drug which are sometimes associated with serious systemic side effects; and 3) peritumoral brain edema can be effectively treated by the interstitial delivery of dexamethasone directly within the tumor bed.

Normal responsiveness of superficial hand veins to alpha- and beta-adrenergic stimuli in allergic asthma: Effects of terbutaline and prednisolone on beta-adrenergic responsiveness

Impaired function of the adrenergic-receptor system has been postulated to contribute to the pathogenesis of bronchial asthma. Using the dorsal hand-vein compliance technique, we compared the changes in diameter of superficial hand veins in response to phenylephrine, an alpha-adrenoceptor agonist, and to isoproterenol, a beta-adrenoceptor agonist, in 14 untreated patients with allergic asthma and in 16 nonatopic control subjects. There were no significant differences in the median effective dose of phenylephrine that produced 50% of maximal venoconstriction (ED50) or in the maximal response (Emax) between the two groups. Bronchial hyperreactivity (assessed by methacholine-challenge tests) in the patients with asthma was uncorrelated with the ED50 or Emax of isoproterenol. These results demonstrate no evidence for a generalized change in alpha- or beta-adrenergic responsiveness on smooth muscle cells in asthma. Hand-vein responsiveness to isoproterenol was unchanged after treatment for 7 days with oral terbutaline (5 mg three times per day). Thus, unlike leukocytes, smooth muscle appears not readily susceptible to beta-adrenoceptor desensitization in vivo. Local infusions of prednisolone or dexamethasone during 2 hours and systemic administration of dexamethasone (24 hours) caused a significant fall in the Emax for isoproterenol. The mechanism of attenuation of beta-adrenoceptor responsiveness by corticosteroids remains to be determined.

Oxytocinergic Neurons in Rat Hypothalamus

Recent results have demonstrated altered corticotropin-releasing factor (CRF)-41 content of the neurointermediate lobe (NIL) of the pituitary gland in response to various manipulations including osmotic stimulation. This study was undertaken to determine whether changes in CRF-41 content of the NIL are accompanied by changes in intensity of CRF-41-like immunoreactivity (CRF-41-LI) of neurosecretory neurones of the hypothalamus in response to osmotic stimulation. Wistar rats of both sexes given either tap water ad libitum, 2% NaCl solution, or access to tap water was limited to 20 min daily, for 7 days. Subsets of rats from each group were adrenalectomized (ADX) or treated with dexamethasone (DEX). Thirty-six hour before perfusion with fixative consisting of buffered formaldehyde and picric acid, animals received 75 micrograms colchicine i.c.v. Forty micrometer thick vibratome sections were stained for CRF-LI, arginine vasopressin (AVP-LI) and oxytocin (OXY-LI) using the avidin-biotin-peroxidase complex method. In response to both types of osmotic stimulation magnocellular neurones of the paraventricular (PVN) and supraoptic nuclei (SON) showed increased CRF-LI, AVP-LI and OXY-LI, while CRF-LI of parvocellular perikarya of the PVN decreased. The enhanced CRF-LI seemed to appear in a subset of magnocellular neurones with OXY-LI but not AVP-LI. Increased staining intensities were also observed in magnocellular neurones in ADX rats challenged osmotically. In contrast, systemic DEX administration, as well as implantation of DEX in the area on the SON, sharply attenuated CRF-LI but not AVP-LI or OXY-LI of magnocellular neurones in osmotically stimulated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasocortin: a novel glucocorticoid-induced anti-inflammatory protein.

The preliminary characterization of ;vasocortin' a novel glucocorticoid-induced anti-inflammatory protein, is described. Vasocortin is released into the rat peritoneal cavity following systemic dexamethasone administration, has an apparent mol. wt. of 100 kD and inhibits rat dextran oedema. Vasocortin is distinct from lipocortin and is likely to be associated with the anti-inflammatory effect of glucocorticoids.

Physiological changes in rat hypothalamic CRF: Circadian, stress and steroid suppression

Hypothalamic CRF-like immunoreactivity was measured in the a.m. and p.m., after systemic dexamethasone administration or after either stress in adult male rats. Measurement of plasma corticosterone levels revealed the expected circadian rhythmicity, suppression after dexamethasone administration and increase after ether stress. The hypothalamic content of CRF-like immunoreactivity was significantly decreased in the p.m. and after dexamethasone administration. However, no change in hypothalamic CRF-like immunoreactivity was observed after ether stress. The results are consistent with an increased release in the p.m. and decreased synthesis of hypothalamic CRF after systemic dexamethasone administration. The observation that there is no change in content of hypothalamic CRF-like immunoreactivity after ether stress could be due to the fact that the animals were stressed by handling. The results show that this immunoreactivity present in the hypothalamus is altered by changes in the hypothalamic-pituitaryadrenal axis and thus suggest that this peptide is a physiologically significant CRF in the rat.

266 INFLUENCE OF DEXAMETHASONE AND ACTH ON DRUG CLEARANCE IN CHILDREN

The rate of disappearance of antipyrine from the plasma is a useful indicator for the in vivo capacity for hepatic mixed function oxidation. The short term effects of systemic administration of dexamethasone, a potent glucocorticoid, and ACTH on antipyrine metabolism were studied in 10 children. Dexamethasone (2 mg/d × 4 days) was given to 6 subjects. The effects of ACTH (40 U/24 h i.v. × 5 days) were evaluated in 4 patients. The half-life of antipyrine (t½) was measured before and after drug therapy in each patient. The mean t½ was not affected by administration of dexamethasone (t½ 7.6 ± 1.14 h versus 7.8 ± 0.84 h). The apparent volume of distribution (aVd) remained unchanged as well (aVd 0.52 ± 0.076 L/kg versus 0.56 ± 0.063 L/kg). Administration of ACTH, causing a 5-25 fold increase in urinary 17-hydroxy-corticosteroid excretion, also did not affect the half-life of antipyrine (t½ 11.5 ± 2.8 h versus 11.2 ± 2 h). The aVd also remained unchanged (0.60 ± 0.05 L/kg versus 0.59 ± 0.03 L/kg). We conclude that the short term administration of dexamethasone and ACTH with ensuing stimulation of endogenous glucocorticoid production is unlikely to produce clinically significant changes in the rate of drug metabolism.

Effect of dexamethasone on pituitary-adrenal activation following intrahypothalamic implantation of "neurotransmitters".

Intrahypothalamic implantation of “neuro transmitter” substances (carbachol and norepinephrine) has previously been found to result in pituitary-adrenal activation. The present studies demonstrate that such activation is not abolished by the prior systemic administration of dexamethasone. These studies therefore support the hypothesis that the terminal hypothalamic neurosecretory neuron is steroid insensitive. (Endocrinology87: 179, 1970) THERE IS still disagreement as to whether steroid feedback regulation of adrenocortical secretion is accomplished by a direct action on the adenohypophysis (1–3), on the hypothalamus, on limbic system sites (4–6), or on all these structures. We have shown (7) that chemical implantation of minute amounts of “ neurotransmitter” substances (carbachol, an acetylcholine-like agent, and norepinephrine), when placed into the median eminence, but not in the adenohypophysis, is effective in producing an acute rise in plasma corticosteroid levels. The present studies describe the effect of prior systemic dexamethasone administration on the plasma corticosteroid (11-OHCS) responses to such intrahypothalamic implantation.