Chronic Prednisolone Research Articles

Prednisolone Does Not Regulate Factor VIII Expression in Mice Receiving AAV5-hFVIII-SQ: Valoctocogene Roxaparvovec

AAV5-hFVIII-SQ (valoctocogene roxaparvovec) is an adeno-associated virus (AAV)-mediated gene therapy vector containing a B-domain-deleted human factor VIII (hFVIII-SQ) transgene. In a phase 1/2 clinical study of AAV5-hFVIII-SQ for severe hemophilia A (FVIII < 1 IU/dL), participants received prednisolone to mitigate potential immune-mediated reactions to the gene therapy and demonstrated concomitant elevations in plasma FVIII levels, following a single administration of AAV5-hFVIII-SQ. To assess whether prednisolone is capable of directly modulating transgene expression or levels of circulating hepatic enzymes, C57BL/6 mice were given intravenous vehicle, 2 × 1013 vector genomes (vg)/kg AAV5-hFVIII-SQ, or 6 × 1013 vg/kg AAV5-hFVIII-SQ, followed by either daily oral prednisolone or water. Mice were euthanized 4 or 13 weeks after vector administration. Hepatic hFVIII-SQ DNA, RNA, and protein (immunostaining), plasma hFVIII-SQ protein and FVIII activity, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were measured. Liver hFVIII-SQ DNA, RNA, and plasma hFVIII-SQ protein and activity increased in a dose-dependent manner, with or without prednisolone. In summary, chronic prednisolone treatment in mice treated with AAV5-hFVIII-SQ did not modulate levels of liver hFVIII-SQ DNA, RNA, or the percentage and distribution of hFVIII-SQ-positive hepatocytes, nor did it regulate levels of plasma hFVIII-SQ protein or activity, or affect levels of plasma AST or ALT.

The effect of glucocorticoids on Thrombospondin-1, Osteocalcin and the Thrombospondin-1:Osteocalcin ratio in humans.

Thrombospondin-1 (TSP1), a matricellular protein, and Osteocalcin (OCN), a noncollagenous protein secreted by osteoblasts, are known to be up- and down-regulated, respectively, by glucocorticoids. The aim of this study was to determine whether a ratio between TSP1:OCN was altered by changes in glucocorticoid activity in humans. Prospective observational study. Tertiary university hospital in Queensland, Australia. Patients with Cushing's syndrome (CS, n=19), asthma or giant cell arteritis on chronic prednisolone treatment (PRED, n=13), adrenal insufficiency (AI, n=16) and healthy volunteers (HV, n=20). Plasma TSP1 and serum total OCN were measured by immunoassay at 0800h, 1200h and 1600h in patients with CS, patients with AI taking replacement glucocorticoids, HV before and after 4mg dexamethasone and PRED patients predose at 800 and 4hours post-dose at 1200hours. Plasma TSP1 in CS was higher (P<.0001), and serum OCN was lower (P<.0001) than HV. The TSP1:OCN ratio in HV increased significantly after 4mg dexamethasone (P<.0001) and in AI after taking their hydrocortisone replacement therapy (P<.001). PRED patients had a higher TSP1:OCN ratio compared with HV at both 800 and 1200hours (both P<.001), but no significant change occurred from pre- to post-dose. A TSP1:OCN ratio of >73 at 800hours differentiated CS from HV with a sensitivity of 95% and a specificity of 100%. The TSP1:OCN ratio is elevated in patients on prednisolone and in patients with CS compared with healthy volunteers. It may be a useful biomarker of total body glucocorticoid activity in humans.

Extended course of prednisolone in infants with severe bronchopulmonary dysplasia

BackgroundThere are few published data on the efficacy and safety of prednisolone in preterm infants with bronchopulmonary dysplasia (BPD). AimsTo describe the use of chronic prednisolone therapy in a population of infants with severe BPD, examine potential benefits on respiratory status, and document potential effects on growth. Study designSingle-center retrospective cohort study. SubjectsPreterm infants who had received ≥30 days of prednisolone for the treatment of severe BPD. Outcome measuresWeekly changes in Pulmonary Severity Score (PSS), as well as weekly changes in weight, length, and head circumference during prednisolone therapy. ResultsForty-three infants (mean birth weight 729 g; mean gestational age 26 weeks) were identified. The average age at start of prednisolone treatment was 42.5 ± 5.9 weeks; while the median duration and median cumulative dose of prednisolone therapy were 67 (IQR 57–107) days and 61.3 (IQR 39.9–93.3) mg/kg, respectively. PSS decreased after 1 week of prednisolone therapy (mean difference, 0.19; 95% Cl, 0.01 to 0.37; p = 0.03). No further reduction in PSS was noted despite continued treatment. Length z-scores decreased after 4 weeks of continued treatment (mean difference 0.6; 95% CI 0.01 to 1.1; P = 0.04), while weight and head circumference did not change. ConclusionsIn one of the first reports on prednisolone therapy for severe BPD, we describe that long-term prednisolone is associated with modest short-term improvement in PSS, but impairs linear growth. Our results suggest a risk-benefit profile of prednisolone that does not favor long-term use in infants with severe BPD.

Twenty-four hour urinary cortisol excretion and the metabolic syndrome in prednisolone-treated renal transplant recipients

Chronic prednisolone treatment in renal transplant recipients (RTR) causes metabolic abnormalities, which cluster in the metabolic syndrome (MS). It also suppresses the hypothalamic–pituitaryadrenal (HPA)-axis. We investigated whether HPA-axis suppression, as measured by 24h urinary cortisol excretion, is associated with presence of the MS and its individual components, in outpatient RTR with a functioning graft for >1year. Urinary cortisol was measured in 24h urine, using LC–MS/MS (LOQ 0.30nmol/L). We included 563 RTR (age 51±12years; 54% male) at median 6.0 [IQR, 2.6–11.5] years post-transplantation. MS was present in 439/563 RTR (78%). Median 24h urinary cortisol excretion was 2.0 [IQR, 0.9–5.1]nmol/24h. Twenty-four hour urinary cortisol excretion was independently associated with MS presence (OR=0.80 [95% CI, 0.66–0.98], P=0.02). It was also independently associated with bodyweight (st.β=−0.11, P=0.007), waist circumference (st.β=−0.10, P=0.01), BMI (st.β=−0.14, P=0.001), fasting triglycerides (st.β=−0.15, P=0.001), diabetes (st.β=−0.12, P=0.005), and number of antihypertensives used (st.β=−0.13, P=0.003). Suppressed HPA-axis activity, as reflected by decreased 24h urinary cortisol excretion, is associated with higher prevalence of MS and its individual components (i.e. central obesity, dyslipidemia, diabetes, hypertension) in prednisolone-treated RTR. Assessment of 24h urinary cortisol excretion by LC–MS/MS may be a tool to monitor metabolic side-effects of prednisolone in RTR.

Low dose prednisolone and insulin sensitivity differentially affect arterial stiffness and endothelial function: An open interventional and cross-sectional study

Background and aimsGlucocorticoids could impair vascular function directly, or indirectly by reducing insulin sensitivity. The aim of this study was to determine the direct and indirect effects of acute and chronic low dose prednisolone on arterial stiffness and endothelial function. MethodsTwelve subjects with inflammatory arthritis, who had not taken oral glucocorticoids for ≥6 months, and 12 subjects with inflammatory arthritis, taking chronic (>6 months) low dose (6.3 ± 2.2 mg/day) prednisolone, were studied. Patients not on glucocorticoids underwent measurement of arterial stiffness (pulse wave velocity (PWV)) and endothelial function (reactive hyperaemia index (RHI)) before and after 7–10 days of prednisolone (6 mg/day), to assess the acute effects of prednisolone. Baseline data from patients not on glucocorticoids were compared with patients on long-term prednisolone to assess the chronic effects of prednisolone. Hepatic insulin sensitivity was estimated from percentage suppression of endogenous glucose production and peripheral insulin sensitivity as glucose infusion rate (M/I) during a hyperinsulinaemic-euglycaemic clamp. ResultsThere were no significant changes in PWV with acute (9.2 ± 0.8 vs. 8.9 ± 0.8 m/sec, p = 0.33) or chronic (8.9 ± 0.8 vs. 9.0 ± 0.7 m/sec, p = 0.69) prednisolone. In multiple regression analysis, PWV was negatively associated with M/I during hyperinsulinemic-euglycemic clamp (p = 0.02), but not with suppression of endogenous glucose production (p = 0.15) or glucocorticoid use (p = 0.70). Chronic (2.4 ± 0.2 vs. 1.9 ± 0.1, p = 0.02), but not acute (1.8 ± 0.2 vs. 1.9 ± 0.1, p = 0.24), prednisolone resulted in a higher RHI. ConclusionsArterial stiffness is not affected by low dose prednisolone per se, but is negatively associated with peripheral insulin sensitivity. Patients with rheumatoid arthritis taking long-term prednisolone had better endothelial function.

Effects of prednisolone on energy and fat metabolism in patients with rheumatoid arthritis: tissue-specific insulin resistance with commonly used prednisolone doses.

Glucocorticoids can cause postprandial hyperglycaemia, but the effects on postprandial energy and fat metabolism are uncertain. We investigated the effects of acute and chronic low-dose prednisolone on fasting and postprandial energy expenditure and substrate metabolism. An open interventional and cross-sectional study was undertaken. Eighteen patients who had not taken oral glucocorticoids for ≥6 months were studied before and after 7 days prednisolone (6 mg/day) to assess the acute effects of prednisolone. Baseline data from patients, not on glucocorticoids, were compared with 18 patients on long-term prednisolone (6·5 ± 1·8 mg/day for >6 months) to assess the chronic effects. Energy expenditure and substrate oxidation were measured using indirect calorimetry before and after a mixed meal. Adipocyte insulin resistance index and insulin-mediated suppression of NEFA were calculated from fasting and postprandial insulin and NEFA concentrations. There were no significant differences in resting energy expenditure or diet-induced thermogenesis with prednisolone. Acute (-2·1 ± 6·2 vs -16·3 ± 4·8 mg/min, P = 0·01) and chronic (-1·4 ± 2·8 vs -16·3 ± 4·8 mg/min, P = 0·01) prednisolone attenuated postprandial suppression of fat oxidation. Chronic (31·6 ± 3·8 vs 17·0 ± 3·3, P = 0·007), but not acute, prednisolone increased adipocyte insulin resistance index. However, insulin-mediated suppression of NEFA was not significantly different after acute or chronic prednisolone. Prednisolone does not alter energy expenditure. However, even at low doses, prednisolone exerts adverse effects on fat metabolism, which could exacerbate insulin resistance and increase cardiovascular risk. Attenuated postprandial suppression of fat oxidation, but not lipolysis, suggests that prednisolone causes greater insulin resistance in skeletal muscle than in adipocytes.

The Efficacy and Tolerability of Mycophenolate Mofetil in Treating Neuromyelitis Optica and Neuromyelitis Optica Spectrum Disorder in Western China.

The aim of this study was to assess the efficacy and tolerability of mycophenolate mofetil (MMF) in neuromyelitis optica (NMO) or NMO spectrum disorder (NMOSD) in western China. We enrolled 90 patients with NMO or NMOSD who had received MMF between January 1, 2010, and June 15, 2015. Of 90 patients, 62 (4 men and 58 women; aged 44.6 [11.5] years) were included in the study. After being treated for a median of 1.5 years (range, 0.5-4.1 years), the median annualized relapse rate for these 62 patients decreased from 1.2 (range, 0.2-7.0) pre-MMF to 0 (range, 0-1.7) post-MMF (P = 0.000), and the median Expanded Disability Status Scale score decreased from 4 (range, 0.5-8.0) pre-MMF to 2 (range, 0.5-7.5) post-MMF (P = 0.000). Thirty-six of the 62 patients were relapse free during MMF treatment. In the Cox regression, none of the following were identified as risk factors: disease duration, pre-MMF annualized relapse rate and Expanded Disability Status Scale, sex, concurrent use of prednisolone during MMF treatment, previous use of other immunosuppressive therapies (other than chronic prednisolone), and abnormal autoantibodies (other than NMO-IgG). However, serum NMO-IgG positivity (hazard ratio [HR], 11.408; 95% confidence interval [CI], 1.330-97.833; P = 0.026) and older age at onset (HR, 0.957; 95% CI, 0.917-0.999; P = 0.043) were significant risk factors. Kaplan-Meier survival analysis indicated a lower risk of relapse during MMF treatment relative to the pre-MMF period (HR, 0.439; 95% CI, 0.272-0.707; P = 0.001). None of the 62 patients discontinued MMF because of adverse effects. Mycophenolate mofetil is an effective and tolerable agent for reducing relapse and improving or stabilizing disabilities resulting from NMO or NMOSD.

Chronic Prednisolone Treatment Aggravates Hyperglycemia in Mice Fed a High-Fat Diet but Does Not Worsen Dietary Fat-Induced Insulin Resistance

Synthetic glucocorticoids such as prednisolone have potent antiinflammatory actions. Unfortunately, these drugs induce severe adverse effects in patients, many of which resemble features of the metabolic syndrome, such as insulin resistance. In this study, we investigated whether adverse effects of prednisolone on glucose homeostasis are aggravated in mice with compromised insulin sensitivity due to a high-fat diet by applying various methods to analyze changes in insulin sensitivity in mice. C57BL/6J mice were fed a high-fat diet for 6 wk and treated with either prednisolone (10 mg/kg · d) or vehicle for the last 7 d. Insulin sensitivity and blood glucose kinetics were analyzed with state-of-the-art stable isotope procedures in different experimental conditions. Prednisolone treatment aggravated fasting hyperglycemia and hyperinsulinemia caused by high-fat feeding, resulting in a higher homeostatic assessment model of insulin resistance. In addition, prednisolone-treated high-fat diet-fed mice appeared less insulin sensitive by detailed analysis of basal glucose kinetics. Remarkably, using hyperinsulinemic-euglycemic or hyperglycemic clamp techniques, neither hepatic nor peripheral insulin resistance was worsened in the group that was treated with prednisolone. Yet analysis of hepatic glucose metabolism revealed that prednisolone did alter glycogen balance by reducing glycogen synthase flux under hyperinsulinemic as well as hyperglycemic conditions. In addition to elevated insulin levels, prednisolone-treated mice showed a major rise in plasma leptin and fibroblast growth factor 21 levels. Our data indicate that prednisolone-induced adverse effects on glucose metabolism in high-fat diet-fed mice do not reflect impaired insulin sensitivity but may be caused by other changes in the hormonal regulatory network controlling glucose metabolism such as fibroblast growth factor 21 and leptin.

Screening for diabetes in patients with inflammatory rheumatological disease administered long-term prednisolone: a cross-sectional study

The aim of the study was to assess the effect of long-term prednisolone on fasting and post-glucose load glucose concentration in patients with inflammatory rheumatological disease. We hypothesized that prednisolone would predominantly increase post-glucose load glucose concentration and that fasting glucose would have poor sensitivity as a screening test for diabetes in patients receiving chronic prednisolone therapy. In a cross-sectional study of subjects with inflammatory rheumatological disease but without known diabetes, 60 subjects [age = 70 (±10) years, 62% female] who were receiving chronic (>6 months) prednisolone [6.5 (±2.1) mg/day] (Group 1) and 58 controls [age = 70 (±11) years, 62% female] who had not received oral glucocorticoids for at least 6 months (Group 2) underwent an oral glucose tolerance test. Fasting glucose was significantly lower [5.0 (±0.1) vs. 5.3 (±0.1) mmol/l, P = 0.02) and post-glucose load glucose concentration significantly higher [8.0 (±0.4) vs. 6.8 (±0.3) mmol/l, P = 0.02] in Group 1 than in Group 2. In a multiple regression analysis, glucocorticoid use (P = 0.004) and log CRP (P = 0.02) were independently associated with fasting glucose, while waist circumference (P = 0.01), but not glucocorticoid use, was independently associated with post-glucose load glucose concentration. A fasting glucose ≥5.6 mmol/l had 33 and 83% sensitivity for diabetes in Groups 1 and 2, respectively. There is discordance between a reduced fasting and increased post-glucose load glucose concentration in rheumatological patients on long-term prednisolone. Therefore fasting glucose has poor sensitivity to screen for diabetes in prednisolone-treated patients. Treatment of prednisolone-induced hyperglycaemia should be directed at the postprandial period. Trial registration. Australian New Zealand Clinical Trials Registry, http://www.anzctr.org.au/, ACTRN12607000540415.

Chronic Prednisolone Treatment Reduces Hepatic Insulin Sensitivity while Perturbing the Fed-to-Fasting Transition in Mice

Chronic glucocorticoid use for treatment of inflammatory diseases is accompanied by severe side effects in humans (e.g. hyperglycemia and insulin resistance). The present studies were conducted to characterize consequences of chronic treatment with the synthetic glucocorticoid prednisolone on insulin sensitivity and blood glucose kinetics in mice. Prednisolone treatment increased fasting blood glucose and plasma insulin concentrations, but this apparently reduced insulin sensitivity could not be confirmed in hyperinsulinemic euglycemic clamp studies. Therefore, a novel method to study whole body glucose kinetics was used. This method revealed that prednisolone-treated mice show an increased hepatic glucose production (HGP). The increased HGP was accompanied by elevated plasma insulin concentrations, indicating reduced insulin sensitivity of hepatic glucose metabolism in prednisolone-treated mice. Compared with vehicle, prednisolone-treated mice had lower blood glucose concentrations, higher plasma free fatty acids, and higher plasma fibroblast growth factor-21 concentrations in the fed condition, i.e. mimicking a fasting situation. Next, the effects of 24-h fasting on energy metabolism were studied. Compared with controls, fasted prednisolone-treated mice had higher blood glucose concentrations and lower plasma beta-hydroxybutyrate concentrations. In conclusion, these results indicate that chronic prednisolone treatment reduces insulin sensitivity of HGP, induces a fasting-like phenotype in fed mice, and perturbs the fed-to-fasting transition.

The effect of prednisolone on serum sodium concentration

Background Glucocorticoids are widely used in clinical practice. In addition to their anti-inflammatory effects, they influence the salt and water homeostasis. Although parts of the latter action have been studied individually, there are no reports in stable outpatients on the net effect of glucocorticoids on serum sodium concentration. Methods A group of 23 patients on chronic prednisolone therapy was compared with a control population with respect to serum sodium concentration. Intra-individual changes in serum sodium concentration after the initiation of prednisolone therapy were studied separately in 14 patients. Results A significantly higher serum sodium level of 1.67 mmol/L ( P = 0.03) was observed in the prednisolone-treated patients, whereas initiation of prednisolone was accompanied by an increase of 2.61 mmol/L ( P = 0.004). The doses and duration of prednisolone therapy had no relation to the increase in serum sodium concentration. Conclusion Prednisolone therapy in stable outpatients results in a small, yet significant, increase in serum sodium concentration.

Remission of clinical signs in early Duchenne muscular dystrophy on intermittent low-dosage prednisolone therapy

We report a 5-year follow-up of two 4-year-old boys with classical Duchenne dystrophy, with an out-of-frame deletion in the Duchenne gene and absence of dystrophin in their muscle, who had a quite remarkable response to an intermittent, low-dosage, regime of prednisolone (0.75mg/kg/day for 10 days each month, or alternating 10 days on and 10 days off). In the first case there was complete remission of all clinical signs of dystrophy, sustained almost fully up to the present time; in the second, the initial response was almost as marked, sustained for almost 5 years, before showing a fairly rapid decline over the ensuing year that resulted in loss of independent ambulation at the age of 10. Both boys remained around the 50th centile for height and weight, and showed no evidence of demineralization of bone on consecutive dual X-ray absorptiometry scanning of the spine, nor any signs of chronic prednisolone toxicity. These carefully documented individual cases suggest there may be an optimal window for treatment in the early stages of the disease, and further larger scale controlled studies should be targeted more selectively at this stage of the disease. This report also confirms that our regime of low dosage, intermittent prednisolone, with cycles of 10 days of treatment, either per month or alternating with 10 days off treatment, is well tolerated and can therefore be recommended for long-term use in children with Duchenne muscular dystrophy.

Effect of chronic renal failure and prednisolone on the growth hormone-insulin-like growth factor axis.

Abnormalities of the growth hormone (GH)/ insulin-like growth factor (IGF) axis have been reported in children with chronic renal failure (CRF) and post-transplant, and are thought to contribute to poor growth. This study examined the effect of CRF and steroid therapy (given post-transplant and to children with normal renal function) on the GH-IGF axis in children with normal and abnormal growth. Thirty-one children with CRF, ten on dialysis, 26 with renal transplants and ten taking steroid therapy but with normal renal function, were studied. IGF-I, measured by radioimmunoassay, was normal but IGF bioactivity was low in groups with a decreased glomerular filtration rate (P<0.05). Transplanted children growing at a subnormal growth rate had lower IGF bioactivity than those growing at a normal rate (P=0.03), but there was no such difference in bioactivity in children with CRF. There was no correlation between IGF bioactivity and prednisolone treatment. There was no correlation between IGF binding proteins 1, 2 or 3 and growth.

Effects of acute and chronic prednisolone treatment on serum zinc levels in rats with adjuvant arthritis

Several studies in animals and humans have independently demonstrated that zinc metabolism is significantly affected either by inflammation or by glucocorticoid administration. The relative importance of these two factors was assessed in this study by the investigation of the effects on serum zinc concentrations of acute and chronic prednisolone treatments in adjuvant arthritis rats and in healthy controls animals. Acute steroid administration (3 mg/kg, i.p.) caused a rapid drop in serum zinc followed by a quick recovery, regardless to the fact that these concentrations were normal (healthy animals) or already reduced by the inflammatory process. However, the modification occurred faster in inflamed animals. Chronic steroid administration (0.58 to 0.78 mg/kg/day during 1 to 4 weeks) had a more complex effect. A previous experiment in healthy rats demonstrated that such a treatment only induced a slight decrease in serum zinc. In adjuvant arthritis animals, the early steroid treatment of the induced process promoted a further decrease in serum zinc level while a delayed treatment did not result in additional changes.

Caffeine enhances the speed of the recovery of the hypothalamo-pituitary-adrenocortical axis after chronic prednisolone administration in the rat.

Chronic administration of corticosteroids results in a suppression of the hypothalamo-pituitary-adrenocortical (HPA) axis. The time course of the recovery of the HPA axis depends on the dose and duration of corticosteroid administration. We investigated the recovery of the HPA axis after 14 days of prednisolone administration to rats at a dose of 2.0 mg/rat/day via the drinking water (188 mumol/l). The in vitro corticosterone production by dispersed adrenal cells in response to increasing concentrations of ACTH had recovered 3 days after stopping prednisolone administration. In parallel the initially suppressed plasma corticosterone concentrations had recovered after 3 days, while the pituitary ACTH content had recovered after 5 days. We investigated the possibility to enhance the speed of the recovery of the HPA axis by the simultaneous administration of two drugs with known CRF-stimulating activity via the drinking water. Caffeine in a dose of 100 mg/kg body weight enhanced the recovery of the prednisolone-suppressed HPA axis significantly. One day after the end of prednisolone administration a significant increase in the adrenal weight, in the corticosterone production by dispersed adrenal cells, as well as in the plasma corticosterone concentrations, and in the pituitary ACTH content was observed in the caffeine-treated rats. Chlorimipramine (20 mg/kg body weight), on the other hand, did not influence the prednisolone-mediated suppression of the HPA axis.(ABSTRACT TRUNCATED AT 250 WORDS)

Stress responsiveness of hypothalamic corticotrophin-releasing factor and pituitary pro-opiomelanocortin mRNAs following high-dose glucocorticoid treatment and withdrawal in the rat

In-situ hybridization with synthetic oligonucleotide probes was used to determine the mRNA content of corticotrophin-releasing factor (CRF) and proenkephalin A mRNA in the paraventricular nucleus, and of pro-opiomelanocortin (POMC) mRNA in the anterior pituitary gland of male rats immediately after, and during recovery from, chronic high-dose prednisolone treatment. Levels of transcripts for mRNA for both CRF and POMC were markedly reduced after the treatment, but there was a rapid return to control values for CRF mRNA within 18 h of steroid withdrawal. In untreated animals, the stressful stimulus of i.p. hypertonic saline increased CRF and proenkephalin A mRNA within 4 h with no significant difference in response seen whether the tissues were removed at 13.00 or 20.00 h. The increase in POMC mRNA did not reach statistical significance in these animals. Although prednisolone resulted in a marked reduction of basal CRF mRNA, the stress-induced increment of CRF mRNA remained comparable with that found in untreated animals. On the day following cessation of prednisolone treatment at 09.00 h, basal and stress levels of CRF mRNA were significantly higher in rats killed at 20.00 h than at 13.00 h. Proenkephalin A mRNA transcripts were below quantifiable levels of detection in control or non-stressed prednisolone-treated animals at all the time-points studied. Stress, however, resulted in the accumulation of proenkephalin A mRNA in control animals. This response was inhibited by prednisolone treatment and only returned 18 h after withdrawal. Prednisolone treatment reduced POMC mRNA below the levels detected in untreated animals, with no detectable response to stress.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of chronic prednisolone treatment on postjunctional membrane responses to agonist.

Using frogs treated 1 month with prednisolone, we studied responses of the muscle postjunctional membrane to acetylcholine and carbamylcholine. In control muscles following a bath application of 3 microM neostigmine or 30 microM pyridostigmine, there was an increased depolarization response to iontophoretically applied acetylcholine or carbamylcholine. Results with prednisolone-treated frog muscle were essentially identical. In some fibers of prednisolone-treated muscle there was a decrementing response to repetitive iontophoretic application of carbamylcholine. Prolonged administration of prednisolone may accelerate desensitization of acetylcholine receptors during repetitive application of agonist.

Effects of chronic prednisolone treatment on bone resorption and bone composition in intact and ovariectomized rats and in ovariectomized rats receiving beta-estradiol.

To examine the interactions between estrogen deficiency and glucocorticoid excess on bone metabolism the osteopenic effects of a standard dose of prednisolone (2 mg/kg BW.day) were studied in sham-ovariectomized (Sham-OVX), ovariectomized (OVX), and OVX rats given replacement beta-estradiol (OVX + E2). For 12 weeks six groups of female albino rats aged 4 months which had their skeletons labeled with 45Ca were fed matched amounts of low-calcium (0.1% Ca) hydroxyproline-free diet. The six treatment groups were: group 1, Sham-OVX; group 2, Sham-OVX + prednisolone; group 3, OVX; group 4, OVX + prednisolone; group 5, OVX + E2; group 6, OVX + E2 + prednisolone. Bone resorption was estimated by studying the urinary excretion of hydroxyproline and 45Ca. Parathyroid function was assessed indirectly from urinary cAMP excretion. Treatments did not influence parathyroid activity or serum levels of calcium or 1,25-dihydroxyvitamin D. However, ovariectomy increased bone resorption and induced osteopenia whereas prednisolone decreased bone resorption and formation and caused osteopenia. Ovariectomy increased the rate of bone resorption in prednisolone-treated rats; prednisolone lowered the rates of bone resorption and formation in OVX rats. The osteopenic effects of prednisolone and ovariectomy were additive and independent. E2 protected bone from the osteopenic effects of ovariectomy but did not affect bone loss induced by prednisolone. These results suggest prophylactic estrogen should help to avoid bone loss from estrogen deficiency in patients requiring chronic high dose glucocorticoid treatment.

Effects of dietary sodium chloride loading on parathyroid function, 1,25-dihydroxyvitamin D, calcium balance, and bone metabolism in female rats during chronic prednisolone administration.

The effects of dietary sodium chloride supplements (8 g/100 g diet) on parathyroid function, serum 1,25-dihydroxyvitamin D [1,25-(OH)2D], calcium balance, bone metabolism, and bone composition were studied in rats treated with prednisolone (2 mg/kg w X day) for 12 weeks. Animals on a low calcium diet (0.1% Ca) received the following treatments: group 1, control; group 2, NaCl; group 3, prednisolone; group 4, NaCl plus prednisolone. Parathyroid function was assessed indirectly from urinary cAMP excretion: bone resorption was estimated by studying urinary hydroxyproline excretion and mobilization of 45Ca from bone. Dietary salt loading increased the urinary excretion of calcium, 45Ca, cAMP, and hydroxyproline and raised serum 1,25-(OH)2D and net calcium absorption, but lowered calcium retention, femoral calcium, and total body calcium. Prednisolone slowed body growth and lowered net calcium absorption, calcium retention, femoral calcium, and total body calcium. Urinary calcium excretion was higher in rats receiving salt and prednisolone in combination than in animals taking salt without prednisolone, but other responses to salt and prednisolone were independent. Thus, salt and prednisolone each elicit osteopenia, and salt causes bone loss in rats receiving prednisolone. The osteopenic effect of salt is attributed to primary augmentation of urinary calcium excretion and secondary increases in PTH-medicated bone resorption. Although salt-treated rats have higher blood levels of 1,25-(OH)2D, bone loss occurs because alimentary calcium absorption is not elevated sufficiently to offset urinary calcium losses. Prednisolone lowers bone formation and net calcium absorption without lowering serum 1,25-(OH)2D values. The parathyroid-vitamin D axis remains intact in prednisolone-treated rats, as they show increases in PTH and 1,25-(OH)2D after salt treatment.