Administration Of Hydrocortisone Acetate Research Articles

Design and Evaluation of Buccal Adhesive Hydrocortisone Acetate (HCA) Tablets

Many studies have shown that topical buccal therapy with steroid anti-inflammatory drugs is useful in controlling ulcerative and inflammatory mucosal diseases. This local treatment is based on the concept that a high activity of steroids can be produced at the site of administration and, at the same time, the degree of systemic side effects can be minimized or avoided. In this study we developed a new formulation consisting of a mucoadhesive tablet formulation for buccal administration of hydrocortisone acetate (HCA). Three types of tablet were developed containing three mucoadhesive components: hydroxypropylmethyl cellulose (Methocel K4M), carboxyvinyl polymer (Carbopol 974P), and polycarbophyl (Noveon AA1); the first polymer is a cellulose derivative, the others are both polyacrylic acid derivatives. For each of those, three tablet batches were produced changing the quantity of the mucoadhesive component (10, 20, and 30%), resulting in 9 different formulations. The compatibility of HCA with all excipients using Differential Scanning Calorimetry (DSC) was assessed. Tablets were manufactured by wet granulation followed by compression. Technological controls on granulates (Hausner index, Carr index, granulometry and Karl-Fischer percentage humidity) and tablets (thickness, diameter, friability, hardness, uniformity of content, weigh uniformity and dissolution kinetic) were carried out. Mucoadhesion properties, ex vivo permeability through porcine buccal mucosa, in vivo behavior and compliance were evaluated. Technological controls have demonstrated that the increase in the (percentage) of mucoadhesive causes an increase in granulometry followed by a reduction in the granulate flowability, however all the tablets have given satisfactory technological results and conformed to the 3rd Ed. European Pharmacopoeia specifications. Mucoadhesion, ex vivo permeability and in vivo behavior results notably differed among tablets, depending on the quality and quantity of the mucoadhesive component. An overall comparison of results showed the tablets containing Carbopol 20% resulted to be the best formulation among those developed.

Increased susceptibility of salmonids to the monogenean Gyrodactylus salaris following administration of hydrocortisone acetate.

Gyrodactylus salaris infects numerous salmonid species, ranging from the fully susceptible (Norwegian strains of Salmo salar), through species which, though initially susceptible, eventually eliminate their infections (Salvelinus alpinus and S. fontinalis) to entirely resistant (Salmo trutta) species. Here we describe experiments in which Salvelinus alpinus, S. fontinalis and Salmo trutta, implanted with hydrocortisone acetate to simulate stress-induced immunosuppression, were challenged with G. salaris. With previously uninfected Salvelinus fontinalis, G. salaris infections on fish treated with hydrocortisone acetate grew larger, and for longer, than on sham-treated controls. A similar result was obtained with S. trutta. Patterns of infection on Arctic charr, Salvelinus alpinus, were more complex, because individual fish varied from susceptible to highly resistant. Fish were therefore initially infected with G. salaris, and the most highly resistant group of individuals identified and disinfected. After 6 months recovery from this primary infection, hydrocortisone acetate was administered to half the fish, and all were challenged with G. salaris. Parasite populations on the hydrocortisone-treated individuals were consistently larger than those on the sham-treated controls, exceeding 30 parasites per fish after 5 weeks, in comparison with less than 10 parasites per fish on controls. These results indicate that hydrocortisone administration can lead to enhanced gyrodactylid populations on a range of salmonids. This suggests that the response to G. salaris is mediated by the immune system, and that the spectrum of responses observed in different species are, at least in part, due to the same mechanism. At a practical level, stress-induced immunosuppression during handling and transport of cultured salmonids may prove an important factor in the dissemination of G. salaris between watersheds.

Development and hormonal control of thioredoxin and the thioredoxin-reductase system in the rat liver during the perinatal period

The development and hormonal regulation of thioredoxin and of the thioredoxin-reductase system were investigated during the perinatal period in rat liver. An immunological procedure was developed in order to quantify thioredoxin in fetal and neonatal hepatocytes. Both immunoreactive thioredoxin and thioredoxin-reductase activity appeared on day 16.5 of pregnancy. The level of immunoreactive thioredoxin increased during the late fetal period, and its level was the same 24 h after birth. Moreover, its development was not subjected to hormonal regulation by corticosteroids and glucagon. In contrast, thioredoxin-reductase activity increased 3 times during the late fetal period and presented a marked increase 24 h after birth. In the absence of glucocorticoids there was no increase in the level of thioredoxin reductase, while administration of hydrocortisone acetate and glucagon to fetuses prematurely evoked its activity. This study suggests that if thioredoxin acts physiologically, this activity is related to the state of reduction of the molecule rather than to the total concentration in the liver.

Glucocorticoid-induced polycystic kidney disease—A threshold trait

Administration of hydrocortisone acetate (250 mg/kg) to newborn mice caused polycystic kidney disease (PKD) of varying proportions in each of 18 different inbred strains; none of the injected controls were affected. All kidneys were histologically examined and scored for degree of cyst formation using a semi-continuous (0 to 4+) grading scheme. Results suggested that this condition is a multifactorial threshold trait. For each strain, estimates of the mean and standard deviation of normally distributed liability were determined by maximum likelihood methods. Concomitant analyses showed: 1) a significant environmental effect related to drug source; 2) a variation in thresholds ranging from 0.94 (N = 46) for the B10.M strain to -0.71 (N = 297) for the C57B1/6J strain; and 3) three groups of strains with different susceptibility to PKD. These results are consistent with a multifactorial basis for susceptibility to PKD. Quantitative analysis of thresholds and liability distributions reveals that genetic, environmental and random elements all contribute to the expression and extent of the cystic trait.

Influence of Hydrocortisone Acetate Administered to the Lactating Rat on Lipid Composition of the Milk and Serum Lipid Levels in Dams and Pups

The influence of i.m. administration of hydrocortisone acetate to the mother (doses of 0.4, 0.8 or 2 mg/100 g body weight/day) during the first 15 days of lactation on milk composition in fatty acids mother and pups serum levels of lipids and their effect on pups' growth is studied. Serum levels of cholesterol and triglycerides in mothers increase at any of the experimental doses. Daily injections of 2 mg/100 g bw to the mother cause an increase in the percentage of C16 as well as in the level of fatty acids derived from linoleic and linolenic acids while reducing the percentage of C18:1. The treatment brings about a higher level in total lipids in the milk which is proportional to the dose. Doses of 0.4 and 0.8 mg increase the percentage of C8 and C10, while the dose of 2 mg enhances the % of C16. A fall in the uptake of linoleic acid by the mammary gland is observed when using any of the experimental doses. No change is observed either in the weight of pups or in serum cholesterol levels while triglyceride level is increased by the effect of treatment. The higher dose increases the level of linolenic acid and some of its derivates.

Bilateral adrenalectomy worsens gastric mucosal lesions induced by indomethacin in the rat

Abstract The mechanism by which bilateral adrenalectomy worsens indomethacin-induced gastric lesions was investigated in rats. In sham-operated rats subcutaneously administered indomethacin produced gastric lesions at doses of 10 mg/kg body wt or greater, in association with lowering of blood glucose levels. In a parallel study, indomethacin induced gastric hypermotility at the same dose levels but had no effect on acid output or mucosal blood flow even at 25 mg/kg body wt. Adrenalectomy (2 wk) itself significantly reduced the blood glucose levels (~50%) and markedly potentiated the ulcerogenic and motility responses caused by indomethacin; the ED 50 values dropped to ~10 times lower than those in sham-operated rats. Both acid output and mucosal blood flow were significantly reduced by adrenalectomy, but these values were increased after indomethacin treatment (3 mg/kg body wt). The ulcerogenic and motility responses caused by indomethacin were significantly reduced by acute infusion of glucose (25% wt/wt, 1.2 ml/h) intravenously in both sham-operated and adrenalectomized rats, and by subcutaneous administration of hydrocortisone acetate (10 mg/kg body wt for 2 wk) in the latter group. When the motility and the ulcer score were determined in the same animals, a highly significant relationship was found between these two factors in both sham-operated and adrenalectomized rats. These results suggest that (a) the increased gastric motility may be a key element in the pathogenesis of indomethacin-induced lesions and in the mechanism for aggravation of the lesions by adrenalectomy, and (b) abrasion of adrenal glands by inducing hypoglycemia may sensitize the system to indomethacin and increase gastric motility.

Cytological and quantitative cytochemical changes in the hepatocyte population of newborn rats following hydrocortisone administration

Changes have been assessed in cytological and quantitative cytochemical parameters of the hepatocyte population of newborn rats under glucocorticoid stimulation. Administration of hydrocortisone-acetate at the dose of 25 micrograms/g b.w./d during the 2nd week of postnatal life, caused: 1. an increase of the liver weight and of average dry mass, protein content, and volume of the hepatocytes; 2. a decrease of the number of hepatocytes per mg of liver tissue; 3. a reduction of the mitotic activity in liver parenchyma; 4. a gain in number of hepatocytes per liver lower than under normal conditions; 5. an increase of frequency of binuclear cells; 6. an increase of DNA-Feulgen per hepatocyte nucleus; 7. an increase per cell, greater than the mean protein increase per cell, in activity of arylhydrocarbonmonooxygenase and 7-ethoxycoumarin 0-deethylase, 2 enzymes dependent on cytochrome P-450. Induction of arylhydrocarbonmonooxygenase activity was prevalent in centrolobule. All the examined parameters, except that of DNA-Feulgen per nucleus and that of mitotic activity, changed strictly correlated with the duration of hormonal treatment. The values of a number of hepatocyte parameters (particularly: mean cell dry mass and volume, frequency of binuclear cells, enzymic activity) detected in the 12 d old rats after a 5 d long hormonal pretreatment, were in the range of those of animals 1 to 2 weeks older.

Influence of hydrocortison acetate on the evolution of the nutritive utilization of calcium and phosphorus and their contents on the longissimus dorsi muscle during gestation in the rat.

The evolution of the nutritive utilization and plasma and muscular content of calcium and phosphorus in rats is studied, as well as the influence that hydrocortisone acetate has (4 mg/100 g weight and day), on them. In pregnant rats injected with saline solution, the retention of calcium is higher on the days 15-18 as a consequence of the increase on the net absorption of the cation. The balance of phosphorus reaches its maximum hight on days 18-21 of gestation, due to the decrease of the urinary excretion during these days. The administration of hydrocortisone acetate to pregnant rats originate a decrease of the net absorption and an increase of the urinary excretion of calcium and phosphorus, which leads to significantly lower balances than those of animals injected with saline solution. The hormone maintains the animals in a negative balance of phosphorus until day 18 of gestation. Besides, it impedes the high retention of calcium which is found with the control pregnant rats on days 15-18. In general, the content in calcium and phosphorus by gram of dry matter of Longissimus dorsi muscle is not modified during gestation. From day 9 of the treatment with hydrocortisone acetate a significant decrease of calcium and phosphorus of the muscle is observed, that in calcium is the more marked the more the treatment is prolonged. This effect seems to be due to the catabolic action of the hormone.

The effect of hydrocortisone acetate treatment on non-specific esterases of the pancreas during development in the marsupial Didelphis albiventris

Abstract 1. 1. When studied by polyacrylamide gel electrophoresis method, non-specific esterase activity in the pancreas of Didelphis albiventris was observed to be increased in animals longer than 90 mm crown-rump length. 2. 2. The administration of hydrocortisone acetate to suckling opposum young resulted in zymograms in which the esterase bands presented the same pattern as that observed in opossums longer than 90 mm CR length.

Pulmonary tissue and cigarette smoke: 2. Parenchymal response

Cigarette smoke and hydrocortisone acetate (HCA) induce marked abnormalities in lungs of C57BL 6 J male mice. In many pulmonary regions of smoke-exposed, HCA-treated animals, alveoli were highly congested with surfactant and flocculent material. In addition, prominent alveolar collapse and septal hypertrophy were common. These conditions resembled pulmonary alveolar proteinosis described in humans. Administration of HCA to sham-treated animals also produced lung abnormalities, however, considerably milder in severity, while stress (resulting from sham treatment) or HCA injections of mice alone failed to induce any pulmonary tissue disorder. Data reported indicate that the genesis of abnormal conditions which resemble pulmonary alveolar proteinosis is potentiated by cumulative effects of different treatments (i.e., smoke, HCA, and stress), most significant being the interaction between cigarette smoke and the steroid.

Neonatal hormone treatment and maturation of the pineal noradrenergic system: hydrocortisone and thyroxine.

The circadian release of norepinephrine from nerve terminals in the pineal gland drives acetyl-CoA:serotonin N-acetyltransferase (NAT; EC 2.3.1.5) activity in the adult pineal from a daytime low to a nighttime high. In the newborn, enzyme activity is intermediate between the adult's daily extremes and has only a small circadian fluctuation. With age, these fluctuations increase in amplitude until the adult pattern is attained at about days 10-12. Treatment of neonates with thyroxine for the first 3 days of life accelerated, whereas administration of hydrocortisone acetate at birth retarded the developmental decline in daytime serotonin-N-acetyltransferase activity. Maximal differences in daytime enzyme activity of controls and thyroxine-treated animals were seen at day 4 and between controls and steroid-treated pups at day 8. Desipramine treatment increase NAT activity in 8-day-old animals; hydrocortisone-treated animals were least affected. Freshly cultured pineals from steroid-treated animals were more responsive to low, and less responsive to high, concentrations of norepinephrine than glands from thyroxine-treated or control animals. They were also less responsive to isoproterenol both in acute and 48-h organ culture. Pineals from hydrocortisone-treated animals in culture accumulated less exogeneous norepinephrine than glands from controls but released a greater fraction of their content on transfer to fresh medium. Normal and steroid-treated animals released the same fraction of their norepinephrine contents into the medium when reuptake was blocked by desipramine (DMI).

Androgenic action of glucocorticoids on the granular ducts of mouse submandibular glands.

The administration of cortisol acetate and dexamethasone to castrated-adrenalectomized mice increased the submandibular gland weight, the granular duct cell size of the gland and the number of androgen-dependent granules detected with the staining for tryptophan in the duct cell. These changes were not as pronounced as when testosterone propionate was given. Similar effects on the duct cells and an increase in androgen-dependent esteroprotease activity of the submandibular glands were observed in castrated mice, but not in mice with testicular feminization which are genetically deficient in androgen receptors. These results suggest that glucocorticoids exert a certain degree of androgenic action on the granular duct cell through androgen receptors when androgens are absent or deficient.

Premature induction of hepatic tryptophan oxygenase

Subcutaneous administration of hydrocortisone acetate to the newborn rat produces a premature induction of hepatic tryptophan oxygenase consisting of a transient rise in activity 6-8 h after treatment, followed by a second sustained rise beginning 40 h later, which plateaus at 10 days of age. Cycloheximide treatment at the midpoint of this second elevation inhibits protein synthesis, but not tryptophan oxygenase activity. In older animals, cycloheximide treatment does both. Tryptophan administration at this midpoint rapidly elevates tryptophan oxygenase activity. This elevation can be partially blocked by treatment with actinomycin D within 1 h of tryptophan administration, but not thereafter. Actinomycin treatment is ineffective in blocking the tryptophan-induced rise in older animals. Administration of hydrocortisone acetate to 5- and 10-day-old pups leads to a more rapid and sustained rise in tryptophan oxygenase activity without appearance of a transient induction phase. Neither tryptophan alone, δ-aminolevulinic acid alone, nor tryptophan plus δ-aminolevulinic acid prematurely induces tryptophan oxygenase in newborn or 5-day-old rats.

Ovarian responses to perphenazine-induced prolactin secretion in the rats: Effect of ovulation, stress, and steroids.

A single injection of 2.5 mg perphenazine (PH)/kg body wt to rats on the day of estrus (day 0) did not result in increased serum progesterone 24 hr later. Continued daily injections, however, resulted in a 2.5-fold increase in serum progesterone between days 1 and 3 and a 1.6-fold increase between days 3 and 5 to a final concentration of 58 plus or minus 4 ng/ml on day 5 in serially anesthetized and bled rats. Neither daily administration of 5.0 nor 10.0 mg PH/kg body wt to rats subjected to the stressful conditions of this regimen resulted in further increases in serum progesterone, but the 5.0 mg dose of PH in unstressed rats bled only on day 5 resulted in a highly significant increase in serum progesterone to 110 plus or minus 7 ng/ml. In unstressed rats the increase in serum progesterone over control values after five daily injections of 2.5 mg PH/kg body wt could be attributed to decreased 20alpha-reduction of progesterone, but when the dose of PH was increased to 5.0 mg/kg, a highly significant increase in both progesterone and total progestins occurred indicating that prolactin can increase steroidogenesis as well as reduce 20alpha-hydroxysteroid dehydrogenase activity. After inhibition of ovulation, the 5.0 mg daily dose of PH resulted in serum progesterone of only 25 plus or minus 8 ng/ml on day 5 in unstressed rats. Thus, serum progesterone in ovulating rats treated with PH originated primarily in the corpora lutea. Perphenazine, 5.0 mg/kg, administered only on estrus and the first day of diestrus was sufficient to induce pseudopregnancy of 14.5 plus or minus 1.6 days. No evidence for gonadotropin stimulation of the ovaries of any rats was observed. The effect of stress on the progesterone response was not mimicked by administration of cortisol acetate and is assumed to be medicated by suppression of prolactin secretion.

Effect of hydrocortisone and acute hypoxia on gluconeogenesis in the rat liver

Acute hypoxic hypoxia leads to increased glucose formation by rat liver slices from pyruvate,α-glycerophosphate,α-ketoglutarate, and fructose. During exposure to hypoxia after prolonged administration of hydrocortisone acetate, increasing gluconeogenesis from the above-mentioned substances and also from alanine, lactate, and glycerol, the rate of glucose synthesis in liver slices was higher than in the control but lower than after the action of hydrocortisone alone.

Influence of the adrenal glands on the sialic acid content of submaxillary and retrolingual glands in the rat.

Adrenalectomy decreased sialic acid content in the submaxillary and retrolingual glands of normal male rats. The administration of cortisol acetate to adrenalectomized rats increased submaxillary and retrolingual sialic acid content; administration of desoxycorticosterone acetate decreased the submaxillary gland content but not the retrolingual gland content.

Effect of experimental manipulation of circulatory cortisol levels in lambs on their growth rate and carcass quality

Relationships between the activity of the adrenal cortex and the productivity of lambs were investigated by administering cortisol acetate or melengestrol acetate. Initial experiments indicated that cortisol acetate administered every second day effectively maintained elevated levels of serum cortisol and that the administration of melengestrol acetate brought about some suppression in the levels of serum cortisol. However, when administered to growing lambs over an 8-week period, melengestrol acetate at a rate of 0.6 mg every second day had no measurable effect on serum cortisol. Cortisol acetate at a dosage of 50 mg every second day increased serum cortisol concentrations for the first 4 weeks only, after which they declined to the levels in the control lambs. In the group treated with cortisol acetate, serum and adrenal levels of cortisol at slaughter were significantly lower than the control group, but there were no differences in meat tenderness. Elevated levels of cortisol at slaughter were obtained by acute administration of cortisol acetate at the rate of 150 mg/day for 3 days. Meat from these animals was appreciably more tender than that from the controls. It is concluded that the negative relationships reported to exist between endogenous cortisol levels and growth rate or meat tenderness of cattle, either do not exist in lambs or they are not the simple cause and effect type.

CONTRIBUTION TO THE EXISTENCE OF REGULATORY MECHANISMS AT THE ADRENAL LEVEL

ABSTRACT Rat adrenal glands atrophied by the administration of cortisol acetate in vivo were used as a model for the study of early metabolic processes occurring in vitro. Atrophied adrenals incubated in the presence of 14C-leucine incorporated subnormal quantities of this amino acid per mg of protein for the first 120 min. When the incubation lasted for a total period of 180 or 240 min a supranormal rise in the 14C-leucine incorporation was observed. Similar changes occurred with some delay with regard to corticosterone production as expressed per 100 mg of tissue. No differences in 14C-leucine incorporation were observed between the control and atrophied adrenals in vivo. Homogenates from atrophied glands incorporated 14C-leucine to a greater extent than the control homogenates. The in vitro incorporation of 14C-orotic acid into the RNA was also higher in atrophied adrenals. The in vitro use of actinomycin D, cycloheximide and amphenone indicated that corticosterone production depended on the incorporation of 14C-leucine. The addition of cortisol to the incubation media markedly decreased the enhancement of 14C-lysine incorporation into the protein of atrophied adrenals. These, as well as additional results suggest rebound phenomena: once atrophic adrenals are transferred to cortisol-free media, reparative processes begin after a delay period. Such phenomena seem to be mediated by regulatory mechanisms at the adrenal level.

The adrenal gland and lactogenesis.

Pregnant rats injected subcutaneously with aqueous suspensions of hydrocortisone acetate in doses of 2–6 mg/day for various periods of time around midpregnancy did not show evidence of induced lactation as measured by appearance of a casein-like protein, greater amounts of RNA or high rate of incorporation of 32P into polysomal RNA in the mammary gland. If injections were begun on day 14 and continued through day 19 of pregnancy, traces of lactation were detected which were similar in amount to that found in saline-injected controls at the same stage of pregnancy. Prior adrenalectomy diminished markedly the levels of protein and RNA which could be attained on ovariectomy of pregnant subjects. Administration of hydrocortisone acetate or corticosterone, but not ACTH peptide, promoted the formation of approximately normal levels of the casein-like protein in adrenalectomized-ovariectomized animals. The data support the concept that glucocorticoids are essential for the initiation of lactation but do not supp...

Effects of androstenedione on early pregnancy in the hamster.

Interference with pregnancy has androstenedione before implantation. The failure of pregnancy was attributed to the regression of the corpora lutea of pregnancy. The effects of androstenedione on pregnancy were dose dependent and could be prevented by concomitant administration of cortisol acetate. Adrenalectomy on day 1 of pregnancy did not alter the effects ofandrostenedione on pregnancy, and only the effects of the lower doses of androstenedione could be prevented by cortisol in adrenalectomized animals. Progesterone was able to protect intact hamsters against all the effects of androstenedione except the decrease in ovarian weight. It is suggested that sufficient androstenedione is metabolized in vivo to estrogen to produce the observed effects. {Endocrinology 80: 1152, 1967)