Search

Background Glucocorticoids rarely cause anaphylaxis. Common methods for the determination of allergens include in vivo skin prick test (SPT) and intradermal skin test (IDST) and the in vitro basophil activation test (BAT). However, to our knowledge, the best strategy for diagnosing glucocorticoid-induced anaphylaxis has not been elucidated. Case presentation A 10-year-old boy was admitted to our hospital because of 2 weeks of fever and arthralgia. He had not been treated with glucocorticoids before, including methylprednisolone (mPSL). He was suspected to have bacterial myositis and was treated with ceftriaxone. However, his symptoms persisted for > 2 weeks. Autoinflammatory arthritis was suspected, and he was treated with mPSL sodium succinate (MPS) pulse therapy (30 mg/kg). After 15 min of mPSL injection, he had wheezing and generalized wheal formation with decreased oxygen saturation. As anaphylaxis was suspected, mPSL was discontinued, and olopatadine and oxygen were administered. The symptoms improved considerably without the use of epinephrine and disappeared in 30 min. One month after discharge, SPT, IDST, and BAT were performed without discontinuing his prescribed oral prednisolone. SPTs for MPS, hydrocortisone sodium succinate (HCS), prednisolone sodium succinate (PSS), dexamethasone sodium phosphate (DSP), and betamethasone sodium phosphate (BSP) were negative. IDSTs for MPS, HCS, and PSS were positive, whereas those for DSP and BSP were negative. By contrast, BATs for MPS, HCS, and PSS were negative. Although glucocorticoid-induced hypersensitivity caused by nonmedicinal ingredients such as lactose, carboxymethylcellulose, polyethylene glycol, and hexylene glycol has been reported; the glucocorticoids tested in this patient did not contain any of these nonmedicinal ingredients. As the glucocorticoids that were positive on IDST share a succinate ester, this might have caused MPS-induced anaphylaxis. Conclusions We report the case of MPS-induced anaphylaxis diagnosed by IDST but not BAT. In case reports of glucocorticoid-induced anaphylaxis in the literature, most patients were diagnosed with SPT or IDST. These results suggest that BAT should be considered when IDST and SPT are negative. Further studies are necessary to clarify the best strategy for diagnosing glucocorticoid-induced anaphylaxis.

Glucocorticoids such as prednisolone are commonly used in dogs but there is sparse quantitative pharmacokinetic and pharmacodynamic information of this drug in this species. The objective of this study was to quantitatively characterize the concentration-effect relationship for prednisolone in dogs on neutrophil and lymphocyte trafficking and cortisol suppression. Nine beagles, 2–12 years old and part of a group for teaching/research were used in a 4-way crossover experiment including two treatments, active or placebo, administered either per os (PO) or intravenously (IV). Plasma was analyzed for prednisolone and cortisol using ultra-high performance liquid chromatography – tandem mass spectrometry. Leucocyte counts were performed in whole blood. Data was then analyzed by non-linear mixed effect modeling to estimate pharmacokinetic and pharmacodynamic parameters. After administration of prednisolone sodium succinate IV, the typical value (between subject variation) for total body prednisolone clearance was 1,370 ml/h·kg (13.4%). The volumes of the central and peripheral compartment were 2,300 ml/kg (10.7%) and 600 ml/kg (16.0%), respectively. The terminal plasma half-life was 1.7 h. The prednisolone plasma concentration producing 50% of the maximum response was 10 ng/mL (90.3%), 22.5 ng/ml (52.3%) and 0.04 ng/mL (197.3%) for neutrophil, lymphocyte and cortisol response, respectively. The administered dose (1 mg/kg) increased neutrophil and decreased lymphocyte numbers but not over the entire dosage interval of 24 h, due to the short half-life. However, glucocorticoids have a wide range of responses. An anti-inflammatory response due to altered gene transcription might have a longer duration. Future studies on the anti-inflammatory potency together with data presented are needed to optimize future dosage recommendations in dogs.

The aim of this study is to evaluate the effects of corticosteroid application on each grade of burn, and to clarify the underlying mechanisms of the effects, especially in its acute inflammatory phase. To generate three-graded burn models (epidermal burn, or EB; dermal burn, or DB; and subcutaneous burn, or SB), hot water was applied on the back skin of Hos:HR-1 mice. Strongest-class (or high-potent) corticosteroid ointment (DD group) or petrolatum (control group) was applied on the back immediately after the hot water application on mice. Prednisolone sodium succinate (PDN group), 1 mg/kg was orally applied immediately after the hot water application on mice. The mice were sacrificed 1–3 days after hot water application, and the lesional skin samples were provided for histological assessment to enumerate the number of infiltrating inflammatory cells. The mRNA expression levels of inflammatory cytokines (IL-1b, TNFa, IL-6 and IFNg) in the lesional skin were also investigated. As a result, corticosteroid application suppressed the number of infiltrating inflammatory cells in the DD group of EB and SB at the early phase, and in DB at all time-points. However, the number of infiltrating inflammatory cells increased in EB on day 3. Expression of cytokines was generally suppressed in the PDN group of SB. In the cases of EB and DB, some cytokines had decreased but many of the others showed increased expression. In conclusion, the anti-inflammatory effects of corticosteroids are not simple inhibitory effects on inflammatory cell infiltration and cytokine production, but exert more complicated effects in vivo.

Glucocorticoids (GCs) induce growth arrest and apoptosis of B lineage cells, especially pre-B and immature B cells, but little is known about this mechanism. Since B cell-specific activator protein (BSAP) encoded by the Pax5 gene is an essential transcription factor for B-cell proliferation, we have investigated the effect of prednisolone sodium succinate (Pss) on BSAP expression in several human leukemic B lineage cell lines. Pss caused growth arrest of Nalm6 (pre-B) cells, but this is not the case for 207 (pro-B) and Raji (mature B) cells. In Nalm6 cells, the growth rate and the amount of BSAP bound to its recognition sequence decreased in proportion to the Pss dose. Pss also reduced the expression level of BSAP as well as of Pax5 mRNA. These data suggest that the suppression of Pax5/BSAP may be involved in the GCs-induced growth arrest of pre-B cells.

The possibility of direct delivery of steroids through the skin to the trachea and the effect of iontophoresis on delivery efficacy were evaluated after the application of an ionic steroidal prodrug, prednisolone sodium succinate (PS-Na), to the throat skin. Fluorescein sodium salt (FL-Na) and PS-Na were applied as model compounds at a concentration of 1% in pH 7.4 phosphate-buffered saline to the throat skin of hairless rats, and constant current-cathodal iontophoresis (0.4 mA/cm2) was performed for 8 or 10 h. In vitro permeation experiment involving cathodal iontophoresis through excised hairless rat abdominal skin revealed 30- and 10-times higher levels of skin permeation of PS and its active drug, prednisolone (P), than those induced without iontophoresis. In vivo iontophoresis treatment of the rat’s throat skin produced 2.6-, 1.6- and 12-times higher FL, PS and P concentrations, respectively, in the trachea than those observed without iontophoresis. The present results suggest the usefulness of topical application of the ionic steroidal prodrugs onto throat skin followed by iontophoresis treatment for directly delivering the steroid to the trachea.

Stabilities of steroids admixed with or without Alevaire ® or Bisolvon ®, which were treated with ultrasonic nebulization (UN), compressor nebulization (CN), or incubation at 45°C, were investigated with regard to its changes in appearance, pH, and residual potency.In this study, the following steroids were used: hydrocortisone sodium succinate (HC), prednisolone sodium succinate (PS), methylprednisolone sodium succinate (MPS), dexamethasone disodium phosphate (DM), betamethasone disodium phosphate (BM) and flunisolide (FS).The results are summarized as follows;1) No changes in pH were observed in all solutions of steroids admixed with or without Alevaire or Bisolvon, with treated with UN or CN and incubated at 45°C.But HC, PS, MPS and DM became turbid soon after admixing with Bisolvon ®.2) The residual potency of all steroids treated with CN for 30 minutes were maintained above 90%.3) The residual potency of HC, PS and BM treated with UN for 30 minutes tended to decrease below 90%.Also, the residual potencies of HC and PS in admixture with Alevaire ® or Bisolvon ®, BM in admixture with Alevaire ®, and MPS in admixture with Bisolvon ® treated with UN for 30 minutes tended to decrease.These results indicate that the use of UN is inadequate to steroids anemopathy of HC, PS and BM, and CN is recommendable for the treatment.

A 46-year-old man presented with frontal headache, a visual field defect and general fatigue. Magnetic resonance imaging (MRI) of the brain showed symmetrical enlargement of the pituitary gland and stalk due to the presence of a mass lesion extending toward the optic chiasm. Gadolinium injection further revealed homogeneous strong enhancement with involvement of the adjacent dura (dural tail). Basal plasma levels of ACTH, free thyroxine and gonadotropins were decreased, and 24-h urinary 17-OHCS excretion was reduced. An elevated anti-thyroglobulin antibody titer indicated the presence of autoimmune thyroiditis. Under the suspicion of autoimmune hypophysitis, 60 mg/day prednisolone sodium succinate was intravenously administered for two weeks followed by a decreasing dose of oral prednisolone. Clinical symptoms and pituitary dysfunction recovered during steroid treatment and MRI showed marked shrinkage of the pituitary mass. Early initiation of an intravenous dose of glucocorticoid followed by oral steroid administration therefore seems to be an efficient treatment for autoimmune hypophysitis even in patients with visual dysfunction.

Purpose To evaluate the six-month results of patients treated with intravitreal prednisolone sodium succinate injections for persistent diabetic macular edema. Design Retrospective, noncontrolled, clinical case series. Methods Nineteen eyes had intravitreal injections with prednisolone sodium succinate. Need for retreatment was based on fluorescein angiographic or optical coherence tomography evidence of persisting macular edema. Results Mean visual acuity at six weeks, three months, and six months after injection was significantly better than the mean preoperative visual acuity ( P = .015, P = .004, and P = .031, respectively). In none of the studied eyes intraocular pressure exceeded 22 mm Hg. No other adverse events, such as endophthalmitis or retinal detachment, occurred. Conclusions In this small pilot study, mean visual acuity improvement was statistically significant up to six months postoperatively. Current results suggest that intravitreal injection of the solution of prednisolone sodium succinate may be a safe and good alternative in eyes with macular edema.

The present study was designed to evaluate the effects of glucocorticoid (GC) treatment on bone turnover and bone mineral density in the growing rat. Because of the recent evidence that nitric oxide (NO) can counteract prednisolone-induced bone loss in mature rats, we examined the effect on bone of the NO donor L: -arginine in young male rats, in which bone mass is increased by the same biological mechanism as in children and adolescents. Thirty-six 10-week-old Sprague-Dawley male rats were assigned to six groups of six animals each, and treated for 4 weeks with either vehicle (once a week subcutaneous injection of 100 microl of sesame oil); prednisolone sodium succinate, 5 mg/kg, 5 days per week by intramuscular injection (i.m.); L-arginine, 10 mg/kg intraperitoneally (i.p.) once a day; N(G)-nitro-L-arginine methylester (L-NAME), 50 mg/kg subcutaneously once a day; prednisolone sodium succinate 5 mg/kg, 5 days per week i.m. +L-arginine 10 mg/kg i.p. once a day; or prednisolone sodium succinate, 5 mg/kg, 5 days per week i.m. +L-NAME 50 mg/kg subcutaneously once a day. Serum calcium, alkaline phosphatase (ALP), osteocalcin, and the C-terminal telopeptides of type I collagen (RatLaps) were measured at baseline conditions and after 2 and 4 weeks. Prior to treatment, and after 2 and 4 weeks, the whole body, vertebral, pelvic, and femoral bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) scanning. Prednisolone and prednisolone+L-NAME treated rats had significantly lower ALP and osteocalcin levels than controls at 2 and 4 weeks, and significantly higher levels of Rat-Laps than controls at 4 weeks. Prednisolone, L-NAME, and prednisolone+L-NAME produced a significant inhibition of bone accumulation and bone growth at all sites measured. Supplementation with L-arginine appeared to prevent the inhibition of bone growth and increase in bone resorption induced by prednisolone. These data would suggest, for the first time, that supplementation with an NO donor could be considered as a treatment for steroid-induced osteoporosis in the developing skeleton.

Purpose: To confirm whether long-term administration of prednisolone sodium succinate (prednisolone) alone is able to induce cataract in rat eyes. Materials and Methods: A 1% solution of prednisolone was administered topically as eye drops to Brown Norway rat eyes, and a systemic pulse administration of 10 mg/kg/day was given via the tail vein. Both administration methods were applied in different combinations. Eighty-three 6-week-old male rats were divided into 8 groups: group 1 = control; group 2 = topical instillation every day; group 3 = single pulse; group 4 = single pulse + eye drops; group 5 = 3 times pulse; group 6 = 3 times pulse + eye drops; group 7 = 3 times pulse per 2 months; group 8 = 3 times pulse per 2 months + eye drops. Observations for changes of lens transparency were made by slitlamp microscopy and documented by an anterior eye segment analysis system (Nidek EAS-1000®) from the onset of drug administration to a maximum period of 16 months. Results: Lens opacity in the shallow anterior and posterior lens layers developed from the tenth month following commencement of prednisolone administration. The incidence of anterior and/or posterior cortical cataract at the sixteenth month was 15% in group 2, 12.5% in group 5, 25% in group 6, 17.9% in group 7 and 35.3% in group 8. The lenses of groups 1, 3 and 4 maintained their transparency throughout the observation period. Light scattering intensity in groups 8 and 7 was the highest, followed by groups 6 and 5, then groups 2, 4, 3 and 1. Conclusion: Cortical cataract was successfully induced in Brown Norway rat eyes by sustained administration of prednisolone succinate alone applied as systemic pulse.

Several investigators have now established that chronic lymphocytic leukemia (CLL) is not a uniform disease entity, since approximately half of the cases of CLL have undergone immunoglobulin V region (IgV) hypermutation, whereas the other half display unmutated Ig genes. The median survival time of mutated CLL (M-CLL) cases has been shown to be approximately twice as long as that for unmutated CLL (UM-CLL), but no clear explanation for this difference is currently available. In this work, we have investigated a cohort of previously untreated CLL patients, to see whether the ex vivo sensitivities of leukemic cells of 16 UM-CLL patients differ from those of 8 M-CLL patients, using nine different drugs and two types of irradiation. Our results demonstrated very similar ex vivo sensitivities and tumor cell heterogeneity of sensitivity of UM-CLL and M-CLL cells when tested against chlorambucil, 2-chloro-2′-deoxyadenosine, cyclosporin A, cis -platinum(II)diammine-dichloride, doxorubicin hydrochloride, 2-fluoroadenine-9-β- d -arabinofuranoside, prednisolone sodium succinate, verapamil, vincristine, γ-irradiation, and UV-irradiation. This indicates that de novo chemo/radiosensitivity cannot explain the survival difference observed between UM-CLL and M-CLL.

Based on its efficacy for the treatment of human asthma, the corticosteroid prednisone is commonly used in horses for treatment of recurrent airway obstruction. However, recent studies have failed to show any benefit of prednisone tablets for the treatment of this condition. The purpose of this study was to determine why oral prednisone has poor efficacy for the treatment of heaves in horses. In a crossover study, 5 horses were given the following treatments: prednisone tablets, prednisone liquid, prednisolone tablets, prednisolone liquid and i.v. prednisolone sodium succinate (positive control). Blood samples were taken before drug administration and at selected time points during a 24 h period. Serum concentrations of prednisone and prednisolone were determined in order to evaluate gastrointestinal absorption and hepatic metabolism. Serum concentrations of the endogenous glucocorticoid hydrocortisone were also determined as an indicator of the biological activity of the drugs. Both prednisolone tablets and liquid were absorbed rapidly, with prednisolone detectable in serum within 15 min of administration and with peak concentrations occurring within 45 min. Small amounts of prednisone were detected in the serum samples after administration of both prednisone tablets and liquid. Prednisolone was not detected in serum samples after administration of prednisone liquid and was detected in serum samples from only one horse after administration of prednisone tablets. Endogenous hydrocortisone production was suppressed when horses received prednisolone. The results of these studies indicate that prednisone has poor efficacy for the treatment of heaves because it is poorly absorbed and the active metabolite prednisolone is rarely produced. In contrast, prednisolone tablets have excellent bioavailability and should be useful as a therapeutic agent in horses.

Background Arachidonic acid and its derivatives play an important role in inflammation including arthritis. Objectives To investigate the effects of heat shock (HS) treatment and geldanamycin (GM) on the release of arachidonic acid (AA) from human peripheral blood human mononuclear cells (PBMCs) (monocytes and lymphocytes). Methods Mononuclear cells prepared from blood of healthy subjects were preincubated with 3H-AA. The release of 3H-AA incorporated into the membrane was studied after pretreatment of cells by HS (43°C, 1 h), GM and prednisolone sodium succinate (PRED). The activation of AA producing enzymes took place by the addition of phorbol 12-myristate 13-acetate (PMA) or by the combination of PMA and calcium ionophore A 23187. Results The release of AA by mononuclear cells was dose dependently inhibited by GM similarly to PRED. The treatment of cells by HS also inhibited the release of AA. An additivity was found in the inhibitions induced by GM, PRED and HS. Conclusion HS treatment can decrease the release of AA from human mononuclear cells. GM also results in a dose dependent inhibition of AA release. In the mechanism of additivity In the mechanism of additivity found when HS and GM were applied concurrently, the increased blocking of mitogen-activated kinase cascade could be involved. In the additivity induced by HS + PRED and GM + PRED combinations different pathways, the MAPK (HS, GM) and some transcription factors (PRED) simultaneously could play a role. The inhibitory effect of GM on the AA release from mononuclear cells can be a new element in its antiinflammatory actions.

We have investigated the effects of prednisolone sodium succinate (Pss) and cyclosporin A (CSA), applied alone or concurrently, on the release of arachidonic acid (AA) (cytosolic phospholipase A2 (cPLA2) activity) and on the calcineurin (CN) activity of human peripheral blood mononuclear cells (PBMC). The cytotoxic damage to the cells treated by the drugs was estimated by the release of lactate dehydrogenase (LDH). We found that Pss (10−5 M) could inhibit the CN activity and higher concentrations (10−4 M) could decrease the cytotoxic damage caused by CSA (10−4 M) during their combined application. CSA had no specific effect on the release of AA from the cells. In the combined clinical use of glucocorticosteroids (GCS) and CSA, their additive inhibitory effect on CN activity and the protective membrane influence of GCS against the cytotoxicity of CSA may be beneficial.

A 29-year-old woman was diagnosed with systemic lupus erythematosus in 1986 because she had butterfly erythema, lupus nephritis, pancytopenia, high anti-DNA antibodies, and the presence of anti-nuclear antibodies (ANA). Her family history and previous medical history were unremarkable. She had no history of drug allergies. In February, 1997, she developed fever and butterfly erythema after a cold. Because of associated high ANA titres, high antibodies to double stranded (ds) DNA, and raised complement she was admitted to hospital. At the time of admission, she was taking oral prednisolone, 10 mg per day. On admission, she was alert, with a temperature of 37·5oC and butterfly erythema. There were multiple painless ulcers on her soft palate, and multiple ulcers on the tips of her toes. She had no abnormal neurological findings. Her erythrocyte sedimentation rate (ESR) was 48 mm/h. Her red-cell count, haemoglobin concentration, and packed cell volume were 4·08 10/L, 106 g/L, and 0·33, respectively. White blood cell count (WBC) was 1·7 10/L, and platelet count 143 10/L. She had no abnormal findings on biochemical examination of blood. Urinary protein was mildly increased to 152 mg/24 h. An assay for C-reactive protein (CRP) was negative (

A retrospective study of 105 dogs with neurological injury was conducted to evaluate the type and prevalence of complications encountered when treatment consisted of a high-dose corticosteroid protocol. All dogs were treated with high-dose prednisolone sodium succinate (HDPSS) (30 mg/kg body weight, administered intravenously [i.v.] q 6 hrs for 36 hrs). Thirty-five (33.3%) cases developed complications including diarrhea (n = 11), melena (n = 11), vomiting (n = 6), hematochezia (n = 3), hematemesis (n = 1), anorexia (n = 1), or a combination (n = 2). Most complications resolved without additional treatments after termination of the HDPSS therapy. None of the complications were considered serious, and none prolonged hospitalization.

The information contained in the electrical conductivity curves of pharmaceuticals measured as a function of temperature can be represented by a small set of parameters. This is achieved by approximating the electrical conductivity curve as a number of consecutive steps, using a suitable empirical model. The three parameters describing each step are: transition temperature, slope factor and step height. The validity of the calculated transition temperatures was established by applying the model to electrical conductivity curves measured on aqueous solutions of KCl, NaCl and on a KCl-NaCl mixture. It appears that the transition temperatures calculated for these inorganic salts are in good agreement with the respective eutectic temperatures reported in the literature. Subsequently, the method was applied to the corticosteroids prednisolone sodium succinate and prednisolone disodium phosphate. The mathematical model yields a satisfactory fit for both experimental conductivity curves. The actual consequences of freeze-drying an aqueous solution of prednisolone sodium succinate below and above the respective transition temperatures calculated are discussed in relation to the experimental conductivity data.

Prednisolone concentrations in serum after both subconjunctival and intravenous injections of prednisolone sodium succinate at a 1 mg/kg equivalent dose of prednisolone in rabbits were analyzed by regularly phased high-performance liquid chromatography. The systemic availability after subconjunctival injection was determined to be almost 1.0 by comparing areas under the serum concentration-time curves for both administration routes. The initial hydrolytic rate of prednisolone succinate ester was dependent on the amount of total protein in ocular tissue homogenates and fluids as well as that in serum. The rate followed Michaelis-Menten kinetics, with an almost consistent Michaelis constant. Although the maximum hydrolytic rate per unit amount of tissue protein was the highest in conjunctival tissue, followed by corneal tissue and serum, the esterase activity corrected by total protein in the whole rabbit body should be the highest in serum, followed by conjunctival tissue. These results indicate that prednisolone sodium succinate administered subconjunctivally is hydrolyzed rapidly by esterase and absorbed almost completely into the systemic circulation.

This is a report of a 62-year-old man with a history of asthmatic attack following therapy for bronchial asthma with intravenous injection of hydrocortisone sodium succinate (Saxizon®, Solu-Cortef®).He had had episodes of dyspnea since 1979 and was treated with oral bronchodilators and intermittent cortimosteroids (prednisolone), and at the exacerbation of asthmatic symptoms he was treated with intravenous drip infusion containing aminophylline and Saxizon®. On June 15, 1983, he complained of dyspnea. As a result, he was given 200mg of Saxizon® intravenously. After then, his asthmatic attack worsened. To confirm the suspected relationship between the drugs and asthmatic attack, intravenous provocative challenge tests were performed, and 100mg of Saxizon® and Solu-Cortef® revealed positive results, but intravenous challenge tests with 100mg of hydrocortisone disodium phosphate (Hydrocortone®) and 20mg of prednisolone sodium succinate (Predonine®, Shionogi) and oral challenge with 100mg of hydrocortisone (Hydrocortone®, Japan Merck-Banyu) were negative. Skin and P-K tests with hydrocortisone sodium succinate were positive. Although this type of adverse reaction to steroidal products is rare, it is very important in allergy practice.

A technique of inducing hypothermia using surface cooling and rewarming with a pump oxygenator has been applied clinically in infants with satisfactory results. Respiratory problems postoperatively, however, are reported to be among the complications contributing most to mortality and morbidity. Prednisolone sodium succinate (Solumedrol) has helped to obviate pulmonary damage in hemorrhagic and endotoxic shock and therefore may be effective in preventing pulmonary damage following hypothermia. This hypothesis was investigated in 12 mongrel puppies, 6 that had hypothermic cardiopulmonary bypass and circulatory arrest but were not given Solumedrol, and 6 that were treated preoperatively with Solumedrol. In lung biopsies taken immediately after bypass the pathological changes in both the group treated with steroids and the control group were similar. At six hours, however, lung biopsies from the control group showed further signs of progressive damage, while in the steroid-treated group there was a striking improvement with some lung biopsies showing a normal appearance. Thus, Solumedrol did not prevent initial lung damage, but the progressive and probably permanent changes were reduced.

The nuclear uptake and retention of [3H]dihydrotestosterone ([3H]DHT) or one of its metabolites was studied in the cerebellum and brain stem of the rhesus monkey. Three days before the injection of the tritiated hormone, we removed both ovaries and the right adrenal gland of 3 female rhesus monkeys under ketamine and halothane or fluothane anesthesia with aseptic surgical procedures. Two days later, we removed the left adrenal gland under similar conditions. Shortly after the second operation, each animal received 100 mg prednisolone sodium succinate. On the day of autopsy, we injected into a femoral vein of each animal 1 microgram of 5 alpha-dihydro[1,2,4,5,6,7-3H]-testosterone (107 Ci/mmol). One of these animals also received an i.v. injection of 100 micrograms/kg body weight of unlabeled DHT to serve as a control. One hour after injection, we rapidly exsanguinated each animal through a femoral venous catheter and perfused the vascular system with approximately 3 1 of Ringer's solution through a femoral arterial catheter. The cerebella and brain stems were removed and processed for autoradiography. Unlike in the rat, nuclear uptake and retention of [3H]DHT was found in both motor and sensory systems of these monkeys and in other areas less well defined. These data indicate that there are major species differences in the nuclear uptake and retention of androgen by the cerebellum and brain stem of rats and primates.

Changes in the level of neutrophil alkaline phosphatase (NAP) in a population of peripheral blood neutrophils were determined in healthy subjects dosed with either aetiocholanolone (Aetio, 4 mg/m2 im) or prednisolone sodium succinate (Pred, 30 mg/m2 iv). Before dosing the mean NAP score, as measured by a modified Gomori azo-dye method, was 109 and 118 in the Aetio and Pred groups, respectively. Fifteen hours after injection the NAP score in the Aetio group had risen to 187 concomitant with the appearance of large numbers of juvenile (band) and mature neutrophils. Twenty-four hours after dosing, the NAP score increased to 213 with still further concentrations of juvenile cells, while the numbers of mature neutrophils returned to approximately baseline values. Five hours after injection, in subjects given Pred, the NAP score had fallen to 108 concomitant with a marked increase in the numbers of mature neutrophils. These data in normals dosed with either Aetio or Pred appear to substantiate a 'first-in, first-out' cellular progression with initial release of the oldest of the mature bone marrow reserve neutrophils containing less (relative to juvenile forms) NAP activity. These data also indicate that NAP activity is inversely related to cellular age and may support previous findings in the rat that enzyme levels are higher in bone marrow relative to peripheral blood.

The effects of prednisolone sodium succinate on the responses of porcine lymphocytes to phytohemagglutinin (PHA) and pokeweed mitogen (PWM) were investigated. Sensitivity of peripheral blood lymphocytes (PBL) to the synthetic glucocorticoid, prednisolone, was related to age of the lymphocyte donor. The greatest sensitivity was found in PBL from animals less than one week old; PBL from animals between 2 to 4 months retained some glucocorticoid sensitive cells; whereas, PBL from animals older than 6 months were exceptionally resistant to steroid. Similar age-associated sensitivities were found for lymphocytes from lymph node, spleen and thymus. Significant differential sensitivities among the various lymphoid organs were found with the thymic lymphocyte possessing the greatest sensitivity to steroid and the PBL lymph node and splenic lymphocytes possessing the highest resistance to the suppressive effects of steroid. The age related differences in sensitivity to steroid did not appear to be caused by differences in the number of steroid receptors because lymphocytes from susceptible and resistant animals had similar numbers of receptors. The results suggest that the age related sensitivity may be associated with a higher percentage of sensitive thymic-derived lymphocyte in the PBL, lymph node and spleen of the younger animals. Results of this study also suggest that the adult pig (6 months) should be classified as a steroid resistant species.

Human neutrophils demonstrated a selective release of granule-associated β-glucuronidase and lysozyme but not of cytoplasmic lactate dehydrogenase during cell contact with N -formyl-methionyl-leucyl-phenylalanine (FMLP). Enzyme discharge was dependent upon treatment of neutrophils with cytochalasin B prior to exposure to FMLP. Prostaglandins (PG) D 2 , E 2 and I 2 inhibited enzyme release from cytochalasin B-treated neutrophils incubated with FMLP in phosphate buffered saline, pH 7.4, at 37°. Flurbiprofen, ibuprofen, indomethacin, ketoprofen and benoxaprofen reduced the extrusion of β-glucuronidase and lysozyme from FMLP-stimulated neutrophils; acetylsalicylic acid was inactive. Methylprednisolone sodium succinate, hydrocortisone sodium succinate, prednisolone sodium succinate and triamcinolone acetonide hemisuccinate also demonstrated the capacity to inhibit the selective release of granule-associated enzymes from human neutrophils. Aldosterone hemisuccinate and deoxycorticosterone hemisuccinate were inactive. These studies indicate that certain pharmacological and therapeutic agents may function to alleviate various inflammatory conditions by curtailing the extrusion of degradative enzymes from neutrophils.

Summary The advantages of rectal steroid therapy in ulcerative colitis are the rapidity of clinical response and the lack of troublesome complications encountered in systemic steroid therapy. The disadvantages of such therapy include expense, inconvenience, pathologic progression in some cases in spite of therapy, and the general lack of recognition that part of some of these compounds is absorbed in some patients. Those patients responding best to this mode of therapy have involvement only of the left colon demonstrable by x-ray and mucosal changes of mild to moderate activity seen proctoscopically. However, over half of the patients with involvement of the entire colon involved achieve a favorable response; therefore, such patients need not be excluded from this type of treatment. Chronic mucosal changes and long duration of disease seem to have no effect upon the prospects for a good response. The incidence of favorable response seemed similar in all preparations used; however, the concurrent appearance of fluid retention and acne is associated with hydrocortisone hemisuccinate and prednisolone sodium succinate. The results of the present method of administering local steroid enemas compare favorably with those of others. Long term use of steroid enemas reduces the incidence of relapse partially, but has no appreciable advantage over short term therapy as demonstrated by long term follow up. Complete remissions of ulcerative colitis are accomplished and sustained less frequently with the use of adrenal steroid enemas than with systemic steroid therapy.

[3H]Dexamethasone binding was detected in cytosol prepared from rat skin only in the presence of dithiothreitol (DTT). Simultaneous supplement of sodium molybdate (Mo) induced synergistic enhancement of the binding. In the presence of DTT and Mo the dissociation constant was approximately 1 nM, the number of maximum binding sites was approximately 100-200 fmol/mg protein, and only steroids that possessed glucocorticoid activity competed with [3H]dexamethasone binding. [3H]Dexamethasone-receptor complexes in dermal cytosol were able to bind to DNA-cellulose after brief heating, and receptors were eluted from DEAE-cellulose with 0.2 M KCl. These observations showed that [3H]dexamethasone binding sites observed in dermal cytosols have similar binding characteristics to glucocorticoid receptors in other glucocorticoid target tissues. Binding capacity in dermal cytosols was depleted after in vivo administration of all 4 glucocorticoids used in the present study. Both the extent and the duration of depletion were dose-dependent in all instances. Non-fluorinated glucocorticoids required higher doses to induce a profound depletion than did fluorinated ones and the duration of depletion induced by the former was shorter than by the latter. Since fluorinated glucocorticoids usually have higher anti-inflammatory potency than non-fluorinated ones, we concluded that the pattern of depletion and replenishment of the dermal cytosol binding capacity was correlated with glucocorticoid biopotency.

The interaction of two commonly used immunosuppressive agents, azathioprine (AZA) and prednisolone sodium succinate (PSS), with three mitogens, Concanavalin A (Con A), phytohemagglutinin (PHA), and pokeweed mitogen (PWM) was studied. Using the endpoint of 50% inhibition of 3H-thymidine incorporation (ID50) as an indicator of cellular replication, the affect of suboptimal and optimal concentrations of mitogen on the immunosuppressive action of AZA or PSS on human lymphocyte replication in vitro was determined by isobolic analysis. The AZA ID50 for optimal concentrations of Con A (60 mcm/cc) was 242 +/- 21 ngm/cc (mean +/- SEM, n = 8), and at a suboptimal concentration of Con A (20 mcg/cc) it was 233 +/- 42, i.e., the AZA ID50 was independent of the concentration of Con A. This same independent interaction was found for PHA and PWM. However, at the optimal concentration of Con A (60 mcg/cc) the PSS ID50 of 523 +/- 55 ngm/cc was significantly higher (p less than 0.001) than the PSS ID at the suboptimal concentration of Con A (20 mcg/cc) which was 234 +/- 24 ngm/cc. A similar antagonistic interaction was found between PSS and either PHA or PWM. These findings emphasize the importance of accurately defining the testing parameters when assessing a drug's effect on lymphocyte proliferation. The data, along with other studies, support the hypothesis that drugs which directly interfere with DNA synthesis will not be affected by the strength of the signal for cellular replication, whereas those that modulate cellular replication are affected by the strength for lymphocyte replication.

In vitro iontophoretic administration of drugs through a microporous polyolefin membrane with hydrophilic urethane polymerfilled pores was done for the ionized drugs dexamethasone sodium phosphate, hydrocortisone sodium phosphate, and prednisolone sodium succinate, and for a nonionizable drug cortisone acetate. Currents between 0.2 and 0.8 mA were demonstrated to be effective in increasing the transmembrane transport rate compared with passive diffusion for all the ionizable drugs studied. However, these currents failed to show any significant effect on the transmembrane transport rate of the nonionizable drug, cortisone acetate. There was a good linear relationship between the applied current (I, mA) and the transmembrane transport rate (J, micrograms/mL) in the receptor cell for all the ionized drugs (J = 1.97I + 0.70 for dexamethasone sodium phosphate; J = 2.05I + 1.49 for hydrocortisone sodium succinate; J = 2.25I + 1.93 for prednisolone sodium succinate). This in vitro iontophoretic study demonstrated that electric fields interact more efficiently with charged than with uncharged molecules.

The pharmacokinetics of prednisolone after 5- and 50-mg/kg doses given as the sodium succinate salt was examined in normal and adrenalectomized rats. Prednisolone, prednisone, and corticosterone concentrations in plasma were determined by HPCL and free prednisolone measured by equilibrium dialysis. Prednisolone sodium succinate was rapidly and completely hydrolyzed to prednisolone as indicated by the absence of the ester from plasma within 5 min after intravenous injection. Prednisolone was rapidly metabolized to prednisone, while corticosterone concentrations in normal rats declined rapidly and were undetectable by 1 hr. Adrenalectomy had no effect on the disposition and protein binding of prednisolone. Dose, however, had a marked effect on prednisolone pharmacokinetics, with mean plasma clearance decreasing from 6.18 to 3.07 L/h per kg and mean steady-state volume of distribution decreasing from 2.14 to 1.05 L/kg from the lower to higher steroid dose. Half-life (0.50 hr) and mean residence time (0.35 hr) were unaffected by dose. Prednisolone plasma protein binding was nonlinear due to saturation of transcortin binding. Changes in pharmacokinetic parameters were not related to the nonlinear plasma binding, but were more likely caused by saturation of elimination pathways and tissue binding sites.

Incubation of rat brain synaptosomes with xanthine and xanthine oxidase (X/XO) resulted in an inhibition of gamma-aminobutyric acid (GABA) uptake. The inhibitory effects of X/XO were temperature- and time-dependent, and were characterized by an increased Km for GABA and a decreased Vmax. Inhibition of GABA uptake by X/XO was associated with both the formation of malonyldialdehyde (MDA) and conjugated dienes, indicating that lipid peroxidation was involved. Studies with catalase, superoxide dismutase (SOD), mannitol, and chelated iron suggested that hydroxyl radical (OH X) was probably responsible for the initiation of lipid peroxidation. Both the peroxidation of synaptosomal membranes and the inhibition of GABA uptake by X/XO were enhanced by the addition of ADP and FeCl2. The X/XO-induced inhibition of GABA uptake by synaptosomes could be prevented by preincubation of synaptosomes with certain glucocorticoids prior to X/XO exposure. Methylprednisolone sodium succinate (MPSS), dexamethasone sodium phosphate (DMSP), and prednisolone sodium succinate (PSS) all prevented the inhibition of GABA uptake by X/XO. MPSS was most effective at concentrations around 100 microM, DMSP was slightly more potent, and PSS was optimal at around 300 microM. On the other hand, hydrocortisone sodium succinate (HCSS) was ineffective at preventing X/XO-induced inhibition of GABA uptake at concentrations up to 3 mM. The steroids are presumed to work through a mechanism that blocked the formation of lipid peroxides, as MPSS inhibited the formation of conjugated dienes in synaptosomes exposed to X/XO at a concentration that also protected GABA uptake.

• Short-term, high-dose steroids (prednisolone sodium succinate) were given to female Lewis rats in the chronic stage of experimental autoimmune myasthenia gravis (EAMG). Abnormally low amplitude miniature endplate potentials (MEPPs) persisted, and were even slightly lower than those seen in saline-treated animals with chronic EAMG. The MEPPs were also studied in normal female Lewis rats treated with short-term, high-dose steroids, and no significant change was noted when compared with normal controls. Previous investigators have reported normalization of the abnormally low amplitude MEPPs within 24 hours of high-dose steroid treatment. Our different results might be explained by our higher dose of receptor, addition of pertussis to the inoculum, and study of a different muscle. A survey of endplate ultrastructure revealed some definite postsynaptic membrane abnormalities in both steroid-treated and saline-treated rats with EAMG, but clear distinction among the groups studied was not possible by direct visualization.

患者は31才,女.気管支喘息発作に対しhydrocortisone sodium succinateを静注したところ呼吸停止し,半昏睡に陥つた.意識回復後, prednisolone sodium succinateの静注で再び同様に半昏睡に陥った.皮内反応および静注による誘発試験の結果より副腎皮質ステロイド(CS)薬そのものに対する過敏反応と考えた. CS薬は-時的な投与では副作用はまれと考えられているが,気管支喘息患老での過敏反応の報告が散見され,投与の際は注意が必要である.