Chronic Methylprednisolone Research Articles

Modeling Pathway Dynamics of the Skeletal Muscle Response to Intravenous Methylprednisolone (MPL) Administration in Rats: Dosing and Tissue Effects

A model-based approach for the assessment of pathway dynamics is explored to characterize metabolic and signaling pathway activity changes characteristic of the dosing-dependent differences in response to methylprednisolone in muscle. To consistently compare dosing-induced changes we extend the principles of pharmacokinetics and pharmacodynamics and introduce a novel representation of pathway-level dynamic models of activity regulation. We hypothesize the emergence of dosing-dependent regulatory interactions is critical to understanding the mechanistic implications of MPL dosing in muscle. Our results indicate that key pathways, including amino acid and lipid metabolism, signal transduction, endocrine regulation, regulation of cellular functions including growth, death, motility, transport, protein degradation, and catabolism are dependent on dosing, exhibiting diverse dynamics depending on whether the drug is administered acutely of continuously. Therefore, the dynamics of drug presentation offer the possibility for the emergence of dosing-dependent models of regulation. Finally, we compared acute and chronic MPL response in muscle with liver. The comparison revealed systematic response differences between the two tissues, notably that muscle appears more prone to adapt to MPL.

P6378Characteristics of hypertensive iron ore miners with oral glucocorticoid induced diabetes mellitus and compromised lung function

Abstract Introduction Oral glucocorticoids are efficacious agents for treating respiratory diseases, with high risk to induce metabolic diseases including diabetes and hypertension Purpose To analyse the hypertensive patient population from the rural setting on ongoing glucocorticoid treatment and diagnosed as diabetic due to the extensive chronic methylprednisolone equivalent glucocorticoid dose of more than 4 mg/day for at least 3 months for treatment of respiratory ailments due to occupational hazard Methods We diagnosed the identified and analysed a subset of patients from the Redi iron ore miners (n=25,500), who were newly diagnosed diabetics (n=1100) and with associated systemic hypertension (systolic BP >140 mmHg, diastolic BP > than 90 mmHg). Patients diagnosed as Oral Glucocorticoid Induced Diabetes Mellitus (GIDM) and hypertensives (n=847; 572 males and 275 females) were characterised on metabolic parameters. t-test was utilised for statistical analysis Results We observed a high incidence of GIDM (4.31%) with a high rate of hypertension (77%, 847/1100). Mean SBP was 150 mmHg (SD ± 9.9, 95% CI 147–152), mean DBP was 90 mmHg (SD ± 8.9, 95% CI 88–92). BMI in GIDM with hypertension (GIDM-H) group was similar to GIDM group (26 kg/m2) (Table), with relatively older age in GIDM–H (53 vs 51 years). The glycemic parameters were relatively more deranged in GIDM-H group. There was significant correlation for a high propensity of relatively younger <50 years (n=506) and near normal weight people with BMI <26 kg/m2 (n=594) to develop GIDM (p=0.006) Metabolic Parameters GIDM Vs GIDM-H Mean ±SD, min, max, 95% CI GIDM (n=1100) GIDM with Hypertension (n=847) Age (yrs) 51 (SD ±14, 95% CI 48–54) 53 (SD ±13, 95% CI 50–56) HbA1c (%) 7.1 (SD ±0.62, 95% CI 7–7.3), 7.2 (SD ±0.60, 95% CI 7.1–7.3) BMI (kg/m2) 26 (SD ±3.6, 95% CI 25–27) 26 (SD ±3.4, 95% CI 25–27) Fasting Plasma Glucose (mg/dl) 146 (SD ±49, 95% CI 136–155) 149 (SD ±48, 95% CI 138–160) Post Prandial Glucose (mg/dl) 207 (SD ±74, 95% CI 192 - 221) 212 (SD ±74, 95% CI 195–228) Conclusions The high rates of hypertension in patients with GIDM is an alarmingly problem which has pronounced harmful comorbid implications, especially in younger, economically productive population in limited resource setting. The health care professionals need to be educated to limit use of glucocorticoids to inhalational therapy with minimal systemic effects. Specific pathophysiological approach to address the steroid induced insulin resistance, strategies to reduce cardiovascular risk and damage, makes treatment of hypertension and GIDM difficult, which calls for action to limit the mining activities and mitigate risk of chronic complications

CHARACTERISTICS OF HYPERTENSIVE PATIENTS FROM LIMITED RESOURCE SETTING ASSOCIATED WITH COMPROMISED LUNG FUNCTION AND ORAL GLUCOCORTICOID INDUCED DIABETES MELLITUS

Objective: Oral glucocorticoids are efficacious agents for treating respiratory diseases with a high risk to induce diabetes and facilitate the development of metabolic disease including hypertension. We analysed a subset of patients from the Redi iron ore miners from a rural setting (n = 25,500), who were newly diagnosed diabetics (n = 1100) and with associated systemic hypertension (SBP greater than 140 mmHg, DBP greater than 90 mmHg) (n = 847) on extensive chronic methylprednisolone equivalent glucocorticoid dose of more than 4 mg/day for at least 3 months for treatment of respiratory ailments due to occupational hazardDesign and method: The patients diagnosed as Oral Glucocorticoid Induced Diabetes Mellitus (GIDM) were evaluated for the presence of hypertension (n = 847; 572 males and 275 females) and characterised based on the various metabolic parameters. t-test was utilised for the statistical analysis Results: We observed high incidence of GIDM (4.31 %) with a high rate of hypertension (77 %, 847/1100). The mean SBP was 150 mmHg (SD ± 9.9, 95% CI 147–152) and the mean DBP was 90 mmHg (SD ± 8.9, 95% CI 88–92). The BMI in the GIDM with hypertension (GIDM-H) group was similar to the GIDM group (26 Kg/m2) (Table), with relatively older age in GIDM–H (53 Vs 51 years). The glycemic parameters were relatively more deranged in the GIDM-H group. There was a significant correlation for a high propensity of relatively younger <50 years (n = 506) and near normal weight people with BMI <26 kg/m2 (n = 594) to develop GIDM (p = 0.006). Conclusions: The high rates of hypertension in patients with GIDM is an alarmingly harmful problem which has pronounced comorbid implications, especially in the younger, economically productive population in the limited resource setting. The health care professionals need to be educated to limit the use of glucocorticoids to inhalational therapy with minimal systemic effects. Specific pathophysiological approach to address the steroid induced insulin resistance in this population, strategies to reduce cardiovascular risk and damage, makes treatment of hypertension and GIDM difficult, which calls for action to limit the mining activities and mitigate the risk of chronic complications due to diabetes and hypertension.

1625-P: Characteristics of the Oral Glucocorticoid-Induced Diabetes Mellitus (GIDM) in Miners with Compromised Lung Function in a Limited Resource Setting

Oral glucocorticoids are efficacious for treating respiratory diseases but with a high risk to induce diabetes. We analysed a subset of patients from the Redi iron ore miners from a rural setting (n=25,500), who were newly diagnosed diabetics on extensive chronic methylprednisolone equivalent glucocorticoid dose of ≥4 mg/day for at least 3 months for treatment of respiratory ailments due to occupational hazard (n=1100, males= 660, females=4400). t test and Fisher's exact test were used for the statistical analysis. The mean HbA1c was 7.1% (SD ± 0.62, 95% CI 7-7.3), mean age 51 years (SD ± 14, 95% CI 48 - 54), mean BMI 26 kg/m2 (SD ± 3.6, 95% CI 25 - 27), mean Fasting Plasma Glucose 146 mg/dl (SD ± 49, 95% CI 136-155) mg/dl, mean Post Prandial Glucose 207mg/dl (SD±74, 95% CI 192 - 221). HbA1c at diagnosis in the relatively low risk group (young - normal weight group with age &amp;lt; 40 years, BMI &amp;lt;25 kg/m2) (n=231) was less than the high risk group (older - overweight with age &amp;gt; 40 years, BMI &amp;gt;25 kg/m2) (n=616); mean HbA1c 6.7% (SD±0.33, 95% CI 6.5 - 6.8) vs. mean HbA1c 7.3% (SD±0.65, 95% CI 7.1 - 7.5) (p&amp;lt;0.0001). There was a significant correlation for a high propensity of relatively younger &amp;lt;50 years (n=506) and near normal weight people with BMI &amp;lt; 26 kg/m2 (n=594) to develop GIDM (p=0.006). We observed that high incidence of GIDM (4.31%) is an alarmingly harmful problem which has pronounced comorbid implications, especially in the younger, economically productive population in the limited resource setting. The health care professionals need to be educated to limit the use of glucocorticoids to inhalational therapy with minimal systemic effects. Specific pathophysiological approach to address the steroid induced insulin resistance in this population, makes the treatment of GIDM difficult, which calls for action to limit the mining activities and mitigate the risk of chronic complications due to diabetes. Disclosure V. Redkar: None. S. Redkar: None. M. Inamdar: None. A. Inamdar: None. S. Redkar: None. M. Jagtap: None. S. Rane: None. S.V. Kulkarni: None. J. Deshpande: None. U. Wadhwa: None.

Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing.

Pharmacological time-series data, from comparative dosing studies, are critical to characterizing drug effects. Reconciling the data from multiple studies is inevitably difficult; multiple in vivo high-throughput -omics studies are necessary to capture the global and temporal effects of the drug, but these experiments, though analogous, differ in (microarray or other) platforms, time-scales, and dosing regimens and thus cannot be directly combined or compared. This investigation addresses this reconciliation issue with a meta-analysis technique aimed at assessing the intrinsic activity at the pathway level. The purpose of this is to characterize the dosing effects of methylprednisolone (MPL), a widely used anti-inflammatory and immunosuppressive corticosteroid (CS), within the liver. A multivariate decomposition approach is applied to analyze acute and chronic MPL dosing in male adrenalectomized rats and characterize the dosing-dependent differences in the dynamic response of MPL-responsive signaling and metabolic pathways. We demonstrate how to deconstruct signaling and metabolic pathways into their constituent pathway activities, activities which are scored for intrinsic pathway activity. Dosing-induced changes in the dynamics of pathway activities are compared using a model-based assessment of pathway dynamics, extending the principles of pharmacokinetics/pharmacodynamics (PKPD) to describe pathway activities. The model-based approach enabled us to hypothesize on the likely emergence (or disappearance) of indirect dosing-dependent regulatory interactions, pointing to likely mechanistic implications of dosing of MPL transcriptional regulation. Both acute and chronic MPL administration induced a strong core of activity within pathway families including the following: lipid metabolism, amino acid metabolism, carbohydrate metabolism, metabolism of cofactors and vitamins, regulation of essential organelles, and xenobiotic metabolism pathway families. Pathway activities alter between acute and chronic dosing, indicating that MPL response is dosing dependent. Furthermore, because multiple pathway activities are dominant within a single pathway, we observe that pathways cannot be defined by a single response. Instead, pathways are defined by multiple, complex, and temporally related activities corresponding to different subgroups of genes within each pathway.

Microglia polarization by methylprednizolone acetate accelerates cuprizone induced demyelination.

Glucocorticoids (GC) are known as inflammatory drugs, which are used in neuroinflammatory diseases. Unlike the classic picture, recent studies have revealed that some GC drugs exacerbate inflammatory responses in their acute and prolonged administration. Multiple sclerosis (MS) is a demyelinating inflammatory disorder, in which reactive M1 microglia phenotype play a central role. Since methylprednisolone (MP), as a synthetic GC, are commonly used by MS patients, in this study, we evaluated the effect of long-term administration of MP on microglia polarization in cuprizone (CPZ)-induced MS model. The immunostaining results showed that chronic exposure to MP in the CPZ treated mice increased the number of Iba-1 positive microglia, which significantly expressed IP10 as M1 marker than arginase as M2 marker. MP treatment induced significant amplification in the transcript levels of iNOS and TNF-α (M1-related markers) in the corpus callosum of the MS mice, whereas no change detected in the expression of IL-10 (M2-related marker) between the groups. In addition, evaluation of myelin by luxol fast blue staining and transmission electron microscopy revealed that prolonged MP administration increased demyelination in comparison to the CPZ group. In conclusion, our results show that chronic MP therapy in the CPZ-induced demyelination model of MS polarized microglia to M1 pro-inflammatory phenotype.

Mechanistic Multi-Tissue Modeling of Glucocorticoid-Induced Leucine Zipper Regulation: Integrating Circadian Gene Expression with Receptor-Mediated Corticosteroid Pharmacodynamics.

The glucocorticoid-induced leucine zipper (GILZ) is an important mediator of anti-inflammatory corticosteroid action. The pharmacokinetic/pharmacodynamic/pharmacogenomic effects of acute and chronic methylprednisolone (MPL) dosing on the tissue-specific dynamics of GILZ expression were examined in rats. A mechanism-based model was developed to investigate and integrate the role of MPL and circadian rhythms on the transcriptional enhancement of GILZ in multiple tissues. Animals received a single 50-mg/kg intramuscular bolus or a 7-day 0.3-mg/kg/h subcutaneous infusion of MPL and were euthanized at several time points. An additional group of rats were euthanized at several times and served as 24-hour light/dark (circadian) controls. Plasma MPL and corticosterone concentrations were measured by high-performance liquid chromatography. The expression of GILZ and glucocorticoid receptor (GR) mRNA was quantified in tissues using quantitative real-time reverse-transcription polymerase chain reaction. The pharmacokinetics of MPL were described using a two-compartment model. Mild-to-robust circadian oscillations in GR and GILZ mRNA expression were characterized in muscle, lung, and adipose tissues and modeled using Fourier harmonic functions. Acute MPL dosing caused significant down-regulation (40%-80%) in GR mRNA and enhancement of GILZ mRNA expression (500%-1080%) in the tissues examined. While GILZ returned to its rhythmic baseline following acute dosing, a new steady-state was observed upon enhancement by chronic dosing. The model captured the complex dynamics in all tissues for both dosing regimens. The model quantitatively integrates physiologic mechanisms, such as circadian processes and GR tolerance phenomena, which control the tissue-specific regulation of GILZ by corticosteroids. These studies characterize GILZ as a pharmacodynamic marker of corticosteroid actions in several tissues.

Methylprednisolone-Induced Lymphocytosis in Patients with Immune-Mediated Inflammatory Disorders

BackgroundTransient acute reversible lymphopenia occurring within hours after glucocorticoid administration is a well-known phenomenon. The objective of this study was to establish the impact of chronic methylprednisolone (mPDN) administration on lymphocyte counts in patients with immune-mediated inflammatory disorders. MethodsThe charts of 44 women and 17 men (median age, 59 years) with several immune-mediated inflammatory disorders receiving oral mPDN for at least 4 months were reviewed. Morning lymphocyte counts measured during treatment (LP) were compared with pretreatment values (LA). In addition, the acute effect of mPDN on lymphocyte counts was evaluated in 43 of these patients by quantifying lymphocyte subpopulations before and 8 hours after mPDN administration. Values are expressed as median with 25%-75% interquartile range. ResultsThe initial daily oral mPDN dose was 28 mg (12-32 mg). An increase in morning lymphocyte counts was detected 13 days (8.5-16 days) after initiation of mPDN treatment (LP: 2130/μL vs LA: 1650/μL; P = .0121) and persisted over time. Morning lymphocytosis (LP ≥4000/μL) was observed in 15 patients, including 7 with hyperlymphocytosis (LP ≥5000/μL). The increase in morning lymphocyte counts during treatment was most marked for CD4 T cells. In the subset of patients who agreed to a second blood test after mPDN absorption, a 49% decrease in the lymphocyte count (P <.0001) was transiently observed at the 8-hour time point. ConclusionsA significant increase of the morning lymphocyte count is frequently observed in patients with immune-mediated inflammatory disorders chronically treated with oral mPDN. Heightened awareness that the timing of blood sampling in corticosteroid-treated patients affects lymphocyte counts, with possible hyperlymphocytosis before absorption, should help avoid unnecessary investigations and worry.

Comparison of the effects of chronic intra-articular administration of tenoxicam, diclofenac, and methylprednisolone in healthy rats.

Lyophilized drug manufacturing and intra-articular (IA) applications have increased to address gastrointestinal side effects resulting from chronic treatment with non-steroidal anti-inflammatory drugs (NSAIDs) for degenerative joint disease. Accordingly, we histologically examined joint and stomach tissues from rats to determine and compare the effects of long-term treatment with an IA corticosteroid (methylprednisolone acetate), lyophilized NSAID (tenoxicam), and non-lyophilized NSAID (diclofenac) following application to the knee joint. One hundred Wistar albino rats were divided into 4 groups of 25 rats: control, methylprednisolone, tenoxicam, and diclofenac. Ten IA injections were administered at 1-week intervals. Rats were sacrificed at 48 h and 1, 2, 4, and 8 weeks after the tenth injection. Histomorphologically, knee joint samples were examined for osteoarthritic changes and stomach tissue samples for gastric changes. Unlike methylprednisolone, diclofenac and tenoxicam caused increased fibrosis and fibroblast production; furthermore, chronic methylprednisolone use had no negative effects on the synovium or cartilage. Chronic tenoxicam and diclofenac use affects joints more negatively than chronic steroid treatment.

Clinical Reasoning: A middle-aged woman with progressive symmetric weakness and a CSF pleocytosis

A 54-year-old Ecuadorian American woman presented with 4 days of progressive bilateral extremity weakness, which began in the upper extremities but quickly spread to the lower extremities. The patient also reported reduced gait stability, bilateral distal paresthesias, and patchy decreased sensation with pain over her lower abdomen and pelvis. At presentation, she denied symptoms of dysautonomia or bulbar dysfunction. Past medical history included longstanding rheumatoid arthritis treated with chronic methylprednisolone, hypertension, left sciatic radiculopathy, scoliosis, uterine prolapse, and thyroid disease. On examination, the patient's vitals were stable. Mental status and cranial nerves were normal. Motor strength was decreased symmetrically in the upper and lower extremities (4/5) with areflexia and absent plantar reflexes. The patient had decreased pinprick sensation over the T6–T8 dermatomes and diminished vibratory sense distally. Joint position sense was preserved bilaterally. The patient demonstrated a paraparetic slow gait with assistance. ### Questions for consideration: 1. What is the differential diagnosis? How does the presence of both sensory deficits and motor involvement narrow the differential? 2. What is the next step in management for this patient? What additional testing would you order? An acute inflammatory neuropathy or cervical myelopathy were top on the differential diagnosis. Neuromuscular junction disorders and myopathies were considered less likely due to the patient's sensory involvement. Infectious etiologies, such as Lyme disease and HIV, were also considered and tested in the serum and CSF. To exclude a myelopathic process, x-rays of the cervical and lumbar spine were initially performed and showed no evidence of subluxation or fracture. An MRI spinal survey was significant for compound scoliosis of the lower thoracic and lumbar spine, multilevel disc bulges, and mild enhancement of the cauda equina. However, neither intramedullary lesions …

Mathematical Modeling of Corticosteroid Pharmacogenomics in Rat Muscle following Acute and Chronic Methylprednisolone Dosing

The pharmacogenomic effects of a corticosteroid (CS) were assessed in rat skeletal muscle using microarrays. Adrenalectomized (ADX) rats were treated with methylprednisolone (MPL) by either 50 mg/kg intravenous injection or 7-day 0.3 mg/kg/h infusion through subcutaneously implanted pumps. RNAs extracted from individual rat muscles were hybridized to Affymetrix Rat Genome Genechips. Data mining yielded 653 and 2316 CS-responsive probe sets following MPL bolus and infusion treatments. Of these, 196 genes were controlled by MPL under both dosing conditions. Cluster analysis revealed that 124 probe sets exhibited three typical expression dynamic profiles following acute dosing. Cluster A consisted of up-regulated probe sets which were grouped into five subclusters each exhibiting unique temporal patterns during the infusion. Cluster B comprised down-regulated probe sets which were divided into two subclusters with distinct dynamics during the infusion. Cluster C probe sets exhibited delayed down-regulation under both bolus and infusion conditions. Among those, 104 probe sets were further grouped into subclusters based on their profiles following chronic MPL dosing. Several mathematical models were proposed and adequately captured the temporal patterns for each subcluster. Multiple types of dosing regimens are needed to resolve common determinants of gene regulation as chronic exposure results in unexpected differences in gene expression compared to acute dosing. Pharmacokinetic/pharmacodynamic (PK/PD) modeling provides a quantitative tool for elucidating the complexities of CS pharmacogenomics in skeletal muscle.

Glucocorticoid inhibition of vascular abnormalities in a tibia fracture rat model of complex regional pain syndrome type I

Tibia fracture in rats evokes chronic hindpaw warmth, spontaneous extravasation, edema, allodynia, and periarticular bone loss, a syndrome resembling complex regional pain syndrome type I (CRPS I). Glucocorticoids such as methylprednisolone (MP) are probably effective analgesic and anti-edematous agents in patients suffering from CRPS and this study examined the effects of chronic MP treatment in the rat CRPS I model. Bilateral hindpaw thickness, temperature, and nociceptive thresholds were determined, and the hindlimb bone density was measured using dual-energy X-ray absorptiometry (DXA). Spontaneous cutaneous extravasation and substance P infusion evoked extravasation were determined using an Evans blue vascular permeability assay. After baseline testing, the distal tibia was fractured and the hindlimb casted for 4 weeks. At 2 weeks post-fracture MP infusion was started (1 mg/kg/day for 28 days). The rats were retested at 4, 6, and 8 weeks post-fracture. Hindpaw edema and warmth after fracture were reversed by MP infusion and these effects persisted after discontinuing treatment. Furthermore, there was an increase in spontaneous protein extravasation and an enhanced substance P evoked extravasation and edema response in the hindpaw at 4 weeks that was inhibited by MP infusion. Glucocorticoid treatment had no effect on the allodynia, hindpaw unweighting, or the periarticular bone loss observed after tibia fracture. We postulate that post-junctional facilitation of substance P signaling contributes to the hindpaw warmth, edema, and the enhanced spontaneous protein extravasation observed in this CRPS I model, and that the anti-edematous effects of glucocorticoid treatment are due to inhibition of post-junctional neuropeptide signaling.

Receptor/gene-mediated pharmacodynamic effects of methylprednisolone on phosphoenolpyruvate carboxykinase regulation in rat liver.

Phosphoenolpyruvate carboxykinase (PEPCK) is the rate-limiting enzyme for gluconeogenesis. To investigate underlying mechanisms of corticosteroid (CS) action in regulating glucose, temporal patterns of hepatic PEPCK gene expression, enzyme activity, and cAMP content were examined in adrenalectomized rats receiving acute and chronic methylprednisolone (MPL) treatments. After single MPL intravenous doses, PEPCK mRNA showed a fast increase, reaching a maximum at around 0.75 h, which was followed by an immediate decline to below baseline after 4 h, an apparent acute tolerance/rebound phenomenon. However, PEPCK enzyme showed continuous hyperactivity for over 72 h. This may be the result of generation of cAMP, an important inducer of PEPCK activity, which peaked at around 6 h. During 7-day subcutaneous infusion of MPL, PEPCK mRNA showed profiles consistent with single-dose results, whereas PEPCK activity increased to a comparable maximum followed by a slow decline. However, the extent of cAMP induction was markedly higher during infusion, which could be attributed to amplification of cAMP synthesis and/or a stabilizing effect of MPL on cAMP degradation. A pharmacokinetic/pharmacodynamic model was developed based on receptor/gene mechanisms of CS action. It successfully described the dual effects of MPL on regulating PEPCK message and the post-transcriptional control by cAMP. Our results exemplify the importance of the extent and duration of steroid exposure in mediating pharmacological effects. The model provides quantitation of multiple controlling factors regulating PEPCK and presents insights into its function in glucose metabolism.

Glucocorticoid inhibition of neuropathic limb edema and cutaneous neurogenic extravasation

Sciatic nerve section in rats evokes chronic limb edema, pain behavior, and hindpaw hyperalgesia, a syndrome resembling the complex regional pain syndrome type II (CRPS II or causalgia) in man. Glucocorticoids such as methylprednisolone (MP) have been used as analgesic and anti-edematous agents in patients suffering from CRPS, and interestingly these therapeutic effects appear to persist in some patients after stopping the medication. Similar to the CRPS clinical response to glucocorticoids, we now demonstrate that chronic hindpaw edema in the sciatic transection CRPS model is reversed by a continuous infusion of MP (3 mg/kg/day over 21 days), and this anti-edematous effect persists for at least 1 week after discontinuing MP. Furthermore, there is a chronic increase in spontaneous protein extravasation in the hindpaw skin of rats after sciatic transection, similar to the increased protein extravasation observed in the edematous hands of CRPS patients. A 2-week infusion of MP (3 mg/kg/day) reduced spontaneous protein extravasation in the hindpaw skin by 80%. We postulated that increased spontaneous neurogenic extravasation resulted in development of limb edema in both the animal model and the CRPS patient, and that the anti-edematous effects of MP are due to an inhibition of spontaneous extravasation. Additional experiments examined the inhibitory effects of MP infusion on electrically-evoked neurogenic extravasation in the hindpaw skin of normal rats. MP inhibition was dose- and time-dependent, with an ED 50 of 1.2 mg/kg/day for a 14-day continuous infusion of MP, and a maximum inhibitory effect requiring 17 days of MP infusion (3 mg/kg/day). MP (3 mg/kg/day for 14 days) also blocked both capsaicin- and SP-evoked neurogenic extravasation, indicating a post-junctional inhibitory effect. Our interpretation is that increased spontaneous neurogenic extravasation in this CRPS model contributed to the development and maintenance of hindpaw edema, and that chronic MP administration dose- and time-dependently blocked neurogenic extravasation at a post-junctional level, thus reversing spontaneous extravasation and limb edema in this model.

Glucocorticoid Inhibition of Neuropathic Hyperalgesia and Spinal Fos Expression

Glucocorticoids are used to treat patients suffering from neuropathic pain and complex regional pain syndromes (CRPS). Previously we found that once-daily injections of the glucocorticoid methylprednisolone had no antihyperalgesic effect in the rat sciatic nerve transection model for CRPS, but on the basis of CRPS clinical data, we hypothesized that a continuous infusion of methylprednisolone might prove effective. We further postulated that the antihyperalgesic effects of glucocorticoids were mediated by the inhibition of spinal neuron hyperactivity and by the depletion of substance P or its NK1 receptor. This study tested the effects of continuously infused methylprednisolone in sciatic nerve-transected rats. Continuous infusion of methylprednisolone (3 mg · kg−1 · d−1 for 21 days), started after the development of neuropathic hyperalgesia, reversed both heat and mechanical hyperalgesia over 2 wk, and this effect persisted for at least 1 wk after discontinuing methylprednisolone. In addition, continuous methylprednisolone infusion partially reversed nerve injury-evoked Fos expression in the dorsal horns, suggesting that glucocorticoids can inhibit the spinal neuron hyperactivity induced by chronic sciatic nerve transection. Finally, no changes were observed in spinal substance P or NK1 immunoreactivity after chronic methylprednisolone infusion, suggesting that the depletion of this neuropeptide or its receptor does not contribute to the antihyperalgesic actions of glucocorticoids. Implications Chronic continuous infusion of the glucocorticoid, methylprednisolone, relieved pain in a rodent model of nerve injury, and this effect persisted after discontinuing the drug. Methylprednisolone may be a curative treatment for some types of neuropathic pain when administered in divided daily doses over several weeks.

Glucocorticoid inhibition of neuropathic hyperalgesia and spinal Fos expression.

Glucocorticoids are used to treat patients suffering from neuropathic pain and complex regional pain syndromes (CRPS). Previously we found that once-daily injections of the glucocorticoid methylprednisolone had no antihyperalgesic effect in the rat sciatic nerve transection model for CRPS, but on the basis of CRPS clinical data, we hypothesized that a continuous infusion of methylprednisolone might prove effective. We further postulated that the antihyperalgesic effects of glucocorticoids were mediated by the inhibition of spinal neuron hyperactivity and by the depletion of substance P or its NK(1) receptor. This study tested the effects of continuously infused methylprednisolone in sciatic nerve-transected rats. Continuous infusion of methylprednisolone (3 mg. kg(-1). d(-1) for 21 days), started after the development of neuropathic hyperalgesia, reversed both heat and mechanical hyperalgesia over 2 wk, and this effect persisted for at least 1 wk after discontinuing methylprednisolone. In addition, continuous methylprednisolone infusion partially reversed nerve injury-evoked Fos expression in the dorsal horns, suggesting that glucocorticoids can inhibit the spinal neuron hyperactivity induced by chronic sciatic nerve transection. Finally, no changes were observed in spinal substance P or NK(1) immunoreactivity after chronic methylprednisolone infusion, suggesting that the depletion of this neuropeptide or its receptor does not contribute to the antihyperalgesic actions of glucocorticoids.

The diagnostic role of gadolinium enhanced MRI in distinguishing between acute medullary bone infarct and osteomyelitis

The objective of the study was to evaluate the diagnostic utility of contrast enhanced magnetic resonance imaging (MRI) for distinguishing between acute medullary bone infarct and osteomyelitis. There were 11 patients (age 6–34 years) presented to our institution between December 1994 and February 1998 with a clinical differential diagnosis of acute bone infarct versus osteomyelitis and inconclusive radiographs were imaged using MRI. All but one received i.v. gadolinium. Nine of the patients had homozygous Sickle Cell disease (SCD) and two had Systemic Lupus Erythematosus (SLE), the latter requiring chronic methylprednisolone. Osteomyelitis was confirmed either by biopsy alone or by the combination of Gallium 67 scan in conjunction with positive blood cultures and clinical resolution following antibiotics. Infarcts without osteomyelitis were confirmed either by biopsy or resolution of symptoms without antibiotic therapy. All patients had at least six months clinical follow-up. The results found that seven of nine patients with SCD had acute infarct only. One patient with SCD had osteomyelitis only. Three patients (two SLE and one SCD) had both acute-on-chronic infarcts and superimposed osteomyelitis, one with an adjacent soft tissue abscess. Accurate distinction between infarct and osteomyelitis was impossible for one patient with SLE who did not receive contrast. All other cases were correctly diagnosed prospectively based on distinct patterns of MRI contrast enhancement. In all adult patients, acute infarcts demonstrated thin, linear rim enhancement on MRI while osteomyelitis revealed more geographic and irregular marrow enhancement. Two of four cases of osteomyelitis also demonstrated subtle cortical defects with abnormal signal traversing marrow and soft tissue. The single pediatric patient demonstrated elongated, serpiginous central medullary enhancement with periostitis. We concluded that the pattern of MR contrast enhancement may allow accurate distinction between acute infarct and osteomyelitis, or recognition of osteomyelitis superimposed on bone infarction.

Methylprednisolone prevents the development of autotomy and neuropathic edema in rats, but has no effect on nociceptive thresholds

Corticosteroids are probably an effective treatment for some types of neuropathic pain and complex regional pain syndromes. This study examined the effects of systemic methylprednisolone (MP) on acute nociception and on pain behavior and hyperalgesia in normal and neuropathic rats. There was no dose-response to intraperitoneal MP (up to 12 mg/kg) for nociceptive thresholds to heat (Peltier) or mechanical (analgesy-meter and von Frey fibers) stimuli in normal rats. Chronic high dose MP (3 mg/kg per day for 21 days) also had no effect on acute nociceptive thresholds in normal rats. After sciatic nerve section in rats a saphenous nerve mediated hyperalgesia to heat and mechanical stimuli gradually developed over 21 days. High dose MP (3 mg/kg per day for 21 days) had no effect on this adjacent neuropathic hyperalgesia. When systemic MP was started immediately after bilateral sciatic and saphenous nerve transection there was a dose-dependent reduction in autotomy behavior. Substance P has been proposed as a mediator of neuropathic pain and edema. Single dose MP (12 mg/kg) slightly reduced the substance P mediated extravasation induced with electrical stimulation of the saphenous nerve. Chronic MP (3.4 mg/kg per day for 28 days) severely reduced the neurogenic extravasation induced with saphenous nerve stimulation. Sciatic sectioned rats developed hindpaw edema between 7 and 14 days after surgery, and this neuropathic edema did not develop in rats chronically treated with MP (3.4 mg/kg per day). These results demonstrate that corticosteroids did not affect nociceptive thresholds in normal or neuropathic hyperalgesic rats. Chronic steroid treatment did prevent the development of autotomy and neuropathic edema, and completely blocked neurogenic extravasation, findings consistent with the hypothesis that primary afferent substance P release mediates autotomy pain behavior and neuropathic edema. This may be a relevant model for examining the effects of corticosteroids on neuropathic pain and complex regional pain syndromes.

RADIOLOGIC AND BIOCHEMICAL CORRELATES OF STEROID-INDUCED BONE CHANGES IN FEMALE RENAL TRANSPLANT RECIPIENTS (RTR)

648 A number of biochemical bone markers that have been identified to characterize bone remodeling in normal individuals. However, these markers have not been studied to systematically assess steroid-induced osteoporosis (OS) in RTR. This study evaluated biochemical bone markers in female RTR receiving chronic steroid therapy for at least 6 months and bone mineral density as assessed by DEXA scan. A total of 15 female {10 pre-menopausal (PRE) and 5 post-menopausal (POST)} RTR with stable renal function {PRE: CrCl- 52 ± 21 ml/min and POST: CrCl- 55 ± 21 ml/min} were evaluated during the post-transplant period ranging from 0.5 to 24 years. Patients (age range: 30-68 years) received either chronic methylprednisolone or prednisone therapy. Patients had no active infections, cardiovascular, GI or hepatic disease prior to study inclusion. A first morning urine was collected for determination of pyridinoline (PYR) and deoxypyridinoline (D-PYR). These samples were analyzed by EIA assays and results normalized to urinary creatinine excretion. Serum was collected at 8AM of study day for determination of bone-specific alkaline phosphatase (ALK PHOS) and intact osteocalcin (OSTEO) which were analyzed by EIA assays. In 5/14 RTR (3 PRE; 2 POST), normal DEXA scans were noted with the D-PYR and PYR found to be within normal limits. The ALK PHOS was in the normal limits for 4/5 patients with OSTEO elevated in 2/5 RTR. DEXA scans revealed osteopenia (OP) in 8/15 RTR with OS in 2/15 patients. The PYR were within normal range (13 to 36.2 nM/mM creatinine) for 8/9 patients with abnormal DEXA scans. D-PYR was within normal limits (range:3.0 to 7.0 nM/mM creatinine) in 7/9 patients with either OP or OS. Two RTR had slightly elevated D-PYR concentration (9.94 and 15.7 nM/mM creatinine). The ALK PHOS was within the normal range (13.7 to 27.6 U/L) in 5 patients with abnormal DEXA scans. The OSTEO was elevated in 8/10 patients (15.3-50.0 ng/ml) with OP or OS. This data suggests that the urinary bone markers may not provide accurate information regarding bone resorption in RTR. ALK PHOS fails to provide specific insight regarding bone remodeling. In contrast, OSTEO concentrations appear to correlate with radiologic bone changes. This marker may provide a reliable serial parameter to monitor development of steroid-induced bone OS.

Methylprednisolone pharmacokinetics, cortisol response, and adverse effects in black and white renal transplant recipients.

It is generally assumed that chronic glucocorticoid therapy is similar pharmacologically when administered to either black or white renal transplant recipients, resulting in adrenal suppression, low circulating plasma cortisol concentrations, and a similar degree of drug exposure and toxicity. To examine this theory and to investigate the relationship of glucocorticoid metabolism to steroid-induced adverse effects among specific ethnic groups of renal transplant recipients, 9 black and 9 white male patients chronically receiving methylprednisolone were enrolled. All patients had stable renal function and were matched for age, weight, and time since transplant. Standard pharmacokinetic parameters for methylprednisolone were determined and cortisol responses were characterized by total cortisol area under the concentration curve (AUC), return cortisol AUC, and cortisol suppression half-life. All patients received their daily oral dose of methylprednisolone (mean daily dose = 11 mg for blacks and 11 mg for whites) as an intravenous infusion with serial plasma samples obtained over 24 h. The patients were assessed for the presence of specific cushingoid manifestations (buffalo hump, moon facies) and steroid-associated diabetes. Methylprednisolone and cortisol were analyzed via HPLC. In the black patients, the mean clearance of methylprednisolone (206 +/- 70 ml/hr/kg) was significantly slower with a smaller volume of distribution (0.95 +/- 0.32 L/kg) when compared with the white group (327 +/- 129 ml/hr/kg, P = 0.03; volume of distribution = 1.33 +/- 0.27 L/kg, P = 0.015). Despite chronic methylprednisolone therapy, a definite 24-hr cortisol response pattern was noted in 15 of the 18 patients with a mean total cortisol AUC of 732 +/- 443 ng.hr/ml in blacks and 539 +/- 361 ng.hr/ml in whites (P = 0.17, black vs. white). The mean cortisol suppression half-life was 4.31 +/- 1.54 hr in black recipients and 4.11 +/- 1.49 hr in whites (P = 0.48). The mean return cortisol AUC for the black patients was 327 +/- 279 ng.hr/ml and 370 +/- 207 ng.hr/ml for white patients (P = 0.28). The serum cortisol nadir for black patients was 12.3 +/- 7.2 ng/ml, which was significantly higher than the cortisol nadir in white patients (6.4 +/- 4.4 ng/ml; P = 0.03). A majority (94%) of patients (9 black, 8 white) had moon facies and 27% of patients (3 black, 1 white) had a buffalo hump. While 5 of 9 black patients had steroid-associated diabetes, no white patients manifested this adverse effect. The black patients with diabetes had higher cortisol AUCs with lower methylprednisolone clearances than the white group.(ABSTRACT TRUNCATED AT 400 WORDS)