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Corticosteroids are widely used for the treatment of allergic reactions but paradoxically themselves may induce acute, delayed, local or systemic allergic reactions and even anaphylaxis with Kounis syndrome. They can suppress the release of arachidonic acid from mast cell membranes, via phospholipase A2 and eicosanoid biosynthesis inhibition. Corticosteroids can promote cell apoptosis and mediate in annexin or lipocortin synthesis, substances that modulate inflammatory cell activation, adhesion molecule expression, transmigratory and phagocytic functions. Antigen-antibody reaction, hapten formation, and medication contaminants are some of the incriminated causes. Patients with atopic diathesis are particularly vulnerable. Complete and thorough previous history of drug reactions or allergies is necessary before administration of any particular medication including corticosteroids.

Acute lung injury (ALI) is a fatal syndrome in critically ill patients. It is characterized by lung edema and inflammation. Numerous pro-inflammatory mediators are released into alveoli. Among them, interleukin-1beta (IL-1β) causes an increase in solute permeability across the alveolar-capillary barrier leading to edema. It activates key effector cells (alveolar epithelial and endothelial cells) releasing inflammatory chemokines and cytokines. The purpose of the study was to demonstrate that nebulized liposomes inhibit ALI in vivo. In vivo ALI model was simulated through intra-tracheal instillation of IL-1β solution (100 μg/mL in PBS, pH 7.2, 200 μL) in male Sprague-Dawley rats. Various formulations were tested in ALI induced rats. These formulations include plain liposomes (PL), methylprednisolone sodium succinate solution (MPS solution), cRGD-peptide grafted liposomes (LcRGD) and methylprednisolone sodium succinate encapsulated and cRGD-peptide grafted liposomes (MPS-LcRGD). Formulations were nebulized in vivo in rats using micro-pump nebulizer. Liposome formulations exhibited higher levels of drug concentration in lungs. The physicochemical parameters demonstrated that the liposome formulations were stable. On the basis of aerodynamic droplet-size, nebulized formulations were estimated to deposit in different regions of respiratory tract, especially alveolar region, Among the formulations, MPS-LcRGD caused significant reduction of edema, neutrophil infiltration and inflammation biochemical marker levels. From the results, it can be inferred that nebulization of targeted liposomes had facilitated spatial and temporal modulation of drug delivery resulting in alleviation of ALI.

We performed a phase I/IIa clinical trial and confirmed the safety and feasibility of granulocyte colony-stimulating factor (G-CSF) as neuroprotective therapy in patients with acute spinal cord injury (SCI). In this study, we retrospectively analyzed the clinical outcome in SCI patients treated with G-CSF and compared these results to a historical cohort of SCI patients treated with high-dose methylprednisolone sodium succinate (MPSS). In the G-CSF group (n = 28), patients were treated from August 2009 to July 2012 within 48 h of the injury, and G-CSF (10 μg/kg/day) was administered intravenously for five consecutive days. In the MPSS group (n = 34), patients underwent high-dose MPSS therapy from August 2003 to July 2005 following the NASCIS II protocol. We evaluated the ASIA motor score and the AIS grade elevation between the time of treatment and 3-month follow-up and adverse events. The ΔASIA motor score was significantly higher in the G-CSF group than in the MPSS group (p

Fosaprepitant dimeglumine for injection is the water-soluble phosphorylated prodrug of the neurokinin-1 receptor antagonist aprepitant. Both agents are approved (in combination with a 5-HT3 antagonist and a corticosteroid) for prevention of chemotherapy-induced nausea and vomiting. Because fosaprepitant is likely to be combined and stored in the same intravenous (IV) bag with 5-HT3 antagonists and corticosteroids, the in vitro compatibility of fosaprepitant with these agents and other IV diluents was assessed.Fosaprepitant (1 mg/mL in 0.9 % sodium chloride injection solution) was combined in binary or tertiary fashion with therapeutic-dose preparations of a 5-HT3 antagonist (ondansetron, granisetron, palonosetron, or tropisetron) and/or a corticosteroid (dexamethasone sodium phosphate or methylprednisolone sodium succinate). For diluent compatibility assessment, fosaprepitant was also prepared 1 mg/mL in 0.9 % sodium chloride injection solution, water for injection, or 5 % dextrose injection solution. After 24-h storage under ambient conditions, samples were assayed for degradation.Fosaprepitant demonstrated compatibility when combined in the same IV infusion bag with common 5-HT3 antagonists and corticosteroids for storage and IV coadministration, with the exception of palonosetron (incompatible under all experimental conditions) and tropisetron (incompatible unless combined with a corticosteroid). No incompatibility was observed between fosaprepitant and any of the 3 diluents tested.Use of fosaprepitant in combination with other antiemetics may provide a flexible option for administration of antiemetics to patients receiving moderately or highly emetogenic chemotherapy.

The aim of this study is to explore the changes of matrix metalloproteinase-9 (MMP9) in the mouse brainstem during the development of facial paralysis induced by herpes simplex virus type 1 (HSV-1) and the inhibitory effect of methylprednisolone sodium succinate (MPSS) on MMP9 expression. HSV-1 was inoculated into the surface of posterior auricle of mouse to establish a paralyzed animal model. The paralyzed mice were divided randomly into three groups. In one group without any treatment, mice were killed at different time points of 6 h, 1, 2, 3, and 7 days post-induction of facial paralysis; in the other two groups, mice were injected daily with MPSS and a combination of MPSS and glucocorticoid receptor blocker (RU486) for 2 days, respectively. The expression of MMP9 in the facial nucleus of brainstem was detected by Western blot, quantitative real-time polymerase chain reaction, and immunofluorescence technique. A total of 52.07 % of mice developed unilateral facial paralysis after inoculated with HSV-1. Both mRNA and protein expression of MMP9 were present at low levels in normal facial nucleus of brainstem and were increased significantly after facial paralysis with its peak time at 2 days post-induction of facial paralysis. Expression of MMP9 of paralyzed mice was inhibited by MPSS, and the inhibition could be blocked by RU486. Our findings suggest that MMP9 in mouse brainstem is involved in the evolution of facial palsy induced by HSV-1 and may play an important role in the pathogenesis of this disease. MPSS might effectively relieve HSV-1-mediated damages by inhibitory effect on expression of MMP9 in HSV-1-induced facial paralysis.

The purpose of this study was to report a patient with acute zonal occult outer retinopathy (AZOOR) unilaterally, who received steroid pulse therapy. A 42-year-old woman presented with photopsias and severe vision loss in her left eye. Visual acuity was 0.04, and Humphrey visual field testing showed overall depression with a mean deviation (MD) value of -25.78 dB in the left eye. Fundus and angiographic examinations found no specific abnormal findings, leading to a diagnosis of AZOOR. Optical coherence tomography showed attenuation of the photoreceptor inner segment/outer segment junction (IS/OS) line. Focal macular electroretinography (fmERG) demonstrated that there were non-detectable responses at 5°, 10° and 15° (in diameter). Following steroid pulse therapy, her visual acuity was 1.0, her MD value improved to -16.08 dB, and there were both partial recovery of the IS/OS line and apparent improvements of fmERG responses (at 10° and 15°). The present findings suggest that steroid pulse therapy might potentially be an effective treatment in some AZOOR patients.

Despite a number of studies on steroid therapy as a prophylactic measure in fat embolism syndrome (FES), there is no universal agreement about its role in this critical situation. The present article attempts to search the available literature, and provides a more lucid picture to the readers on this issue. Seven articles (total 483 patients) were reviewed and analyzed. Total of 223 patients received steroid (methyl prednisolone sodium succinate), while the remaining 260 patients formed the control population. Among these subjects, 9 patients in steroid-receiving group and 60 patients in the control group developed FES (P

To characterize an experimental model of osteoporosis in rabbits induced either by ovariectomy (OVX), glucocorticoids, or by a combination of both. Thirty-five rabbits were randomly allocated into five groups: bilateral OVX, daily methylprednisolone hemisuccinate (MPH) injections at a 1.5 mg/kg/day dose for 4 consecutive weeks (MPH group), or variable dose of MPH between 0.5 and 2 mg/kg/day in combination with OVX (OVX + MPH at low, medium, and high dose). Twenty-two animals were killed 6 weeks after OVX, and 13 were killed 16 weeks later. Dual-energy X-ray absorptiometry was obtained at baseline and 6 and 16 weeks after OVX. High-resolution magnetic resonance imaging (MRI) was carried out at 0 and 6 weeks after OVX. Glucose, total cholesterol, triglyceride, and oestradiol blood levels before and 16 weeks after OVX were determined. Bone mineral density (BMD) decreased significantly at lumbar spine in MPH and OVX + MPH medium-dose groups, and at global knee and subchondral bone of the knee in MPH, OVX + MPH low- and medium-dosage groups (P < 0.05). BMD variations in OVX rabbits were not significant in any of the three anatomical locations analyzed. BMD variation 16 weeks after OVX was significant at lumbar spine and global knee in the OVX + MPH medium-dose group and only at global knee in the OVX + MPH low-dose group (P < 0.05). MRI did not show bone or cartilage changes. Osteoporosis can be induced experimentally in rabbits through isolated MPH or by a combination of OVX and medium dose corticosteroid for 4 weeks. OVX alone was not sufficient to induce osteoporosis.

This study examines methylprednisolone (MPL) effects on the dynamics of hepatic low-density lipoprotein receptor (LDLR) mRNA and plasma lipids associated with increased risks for atherosclerosis.Normal male Wistar rats were given 50 mg/kg MPL intramuscularly (IM) and sacrificed at various times. Measurements included plasma MPL and CST, hepatic glucocorticoid receptor (GR) mRNA, cytosolic GR density and hepatic LDLR mRNA, and plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDLC), high density lipoprotein cholesterol (HDLC), and triglycerides (TG).MPL showed bi-exponential disposition with two first-order absorption components. Hepatic GR and LDLR mRNA exhibited circadian patterns which were disrupted by MPL. Down-regulation in GR mRNA (40-50%) was followed by a delayed rebound phase. LDLR mRNA exhibited transient down-regulation (60-70%). Cytosolic GR density was significantly suppressed but returned to baseline by 72 h. Plasma TC and LDLC showed increases (55 and 142%) at 12 h. A mechanistic receptor/gene pharmacokinetic/pharmacodynamic model was developed to describe CS effects on hepatic LDLR mRNA and plasma cholesterols.Our PK/PD model was able to satisfactorily capture the MPL effects on hepatic LDLR, its relationship to various plasma cholesterols, and builds the foundation to explore this area in the future.

A patient with severe Behcet's disease (BD) was referred to our clinic because of severe pharyngolaryngeal involvement. This complication developed under treatment of prednisone and etanercept (Enbrel) 25 mg twice a week. A surgical approach was considered, but following three daily doses of Solu-Medrol (500 mg each) and 300 mg infliximab on the fourth day, the patient improved significantly. This is the first case reporting treatment with infliximab in laryngeal involvement of BD. Although some cases may still require surgical intervention, the therapeutic option of anti-TNF agents, specifically anti-TNF antibodies such as infliximab, may decrease the need for the surgical option.

Background: This study was performed to examine the efficacy and toxicity of the combination of adriamycin (ADR), methylprednisolone (solumedrol), cytarabine (Ara-C), and cisplatin (CDDP) in patients with recurrent and refractory malignant lymphomas. Patients and methods: Sixty-five patients with Hodgkin's disease (HD) (n=14) or non-Hodgkin's lymphomas (NHL) (n=51) were enrolled in the study. The ASHAP therapy consisted of ADR (40 mg/m2 by continuous infusion (CI) over 96 h), methylprednisolone (500 mg i.v., days 1–5), Ara-C (2 g/m2 as a 2-h infusion on day 5), and CDDP (100 mg/m2 by CI over 96 h). Results: Twenty-five patients (38%) achieved complete remission (CR) and 20 (31%) were taken into partial remission (PR) for an overall response rate of 69%. Thirty-two patients with CR or PR following ASHAP underwent high-dose therapy (HDT) with subsequent hematopoietic stem cell transplantation. After a median follow-up of 52 months, 13 patients are in continuous CR (CCR), the 3-year event-free survival (EFS) was 30% for responders and 21% for all patients. The median overall survival (OS) was 12 months (range 0–70 months), and the OS rate after 3 years was 32%. Unfavorable prognostic factors for EFS and OS by univariate analysis were an elevated value of the serum lactate dehydrogenase and refractory lymphoma. The most frequently observed side effects following ASHAP were leukocytopenia and thrombocytopenia of World Health Organization (WHO) grades III/IV in approximately 80% of all courses. Non-hematological toxicities such as gastrointestinal side effects, infections, mucositis, renal and neurotoxicity occurred more rarely and reached WHO grades III/IV only occasionally. No treatment-related mortality with ASHAP was observed. Conclusions: ASHAP is an effective and moderately toxic salvage therapy for patients with recurrent or refractory HD and NHL. The results in patients responding to ASHAP and afterwards undergoing HDT with stem cell support are comparable with other established protocols and indicate an improvement in survival if HDT is carried out as intensification.

The shrinking lung syndrome (SLS) is a rare manifestation in patients with established systemic lupus erythematosus (SLE). Only two cases have been reported in which this syndrome was the presenting manifestation of SLE. We describe a 21-year-old female Kuwaiti who presented with SLS. In addition to clinical and serological features of lupus, she had dyspnea, respiratory muscle dysfunction, characteristic chest radiographic findings of small lung volumes, elevated right hemidiaphragm, and basilar atelectasis. There was no pulmonary parenchymal or pulmonary vascular involvement. Nerve conduction study showed right phrenic nerve palsy. She responded well to treatment with corticosteroids.

The aim of this double-blind randomized study was to assess the effect of subconjunctival methylprednisolone hemisuccinate (MH) on the recovery of the blood aqueous barrier (BAB) following uncomplicated cataract surgery performed by the same surgeon in normal eyes. Fifty eyes of fifty patients (28 female, 22 male, mean age 72.3 +/- 11.2 years) were randomized into two groups: group 1 received a subconjunctival injection of MH (40 mg in 0.5 cc) at the end of the surgery and group 2 did not. All patients were free of other ocular or systemic diseases known to alter the BAB and were not taking any anti-inflammatory medications. Postoperative treatments were similar in both groups. The patients were submitted to laser flare photometry 30 minutes to one hour after mydriasis with a drop of tropicamide preoperatively and on the first, second and seventh day and then one month and six months following surgery. No difference in aqueous flare was seen between the two groups on any of postoperative visits. These data suggest that subconjunctival MH has no beneficial effect in postoperative BAB permeability following uncomplicated cataract surgery in normal eyes.

A series of 55 patients with ruptured cerebral aneurysms were treated with moderate removal of subarachnoid clot followed by intracranial irrigation with pH 8.0 Hartmann solution containing 1 mg/ml of methylpredonisolone sodium succinate after the aneurysmal clipping during early (before day 3) operation. Six (11%) of the 55 patients suffered vasospasm syndrome postoperatively. The clinical results are significantly better than a series of 68 patients operated on and treated before day 3 by intracranial irrigation with Hartmann solution (pH 8.0) only. The possible preventive effect of direct intracranial administration of steroid hormone is discussed.

Twenty-one patients (15 women, 6 men) with definite multiple sclerosis (MS) were treated with 1000 mg intravenous methylprednisolone-succinate (MP) daily for 10 days. Before MP treatment there was a negative correlation (r = 0.59, P = 0.0084) between serum vitamin B12 and progression rate, defined as the ratio of the score on Kurtzke's Expanded Disability Status Scale and disease duration. A significant decrease was demonstrated in the cerebrospinal fluid (CSF) and serum levels of folate and in the CSF level of vitamin B12 after MP treatment. The decrease in serum B12 was not statistically significant. After MP treatment all median levels of vitamin B12 and folate were below the reference medians. We hypothesize that low or reduced vitamin B12/folate levels found in MS patients may be related to previous corticosteroid treatments. Otherwise a more causal relationship between low vitamin B12/folate and MS cannot be excluded. Further studies may be required to clarify the vitamin B12 and folate metabolism in patients with MS.

Methylprednisolone pharmacokinetics and its directly suppressive effects on plasma cortisol, blood histamine (basophils), and circulating helper T cells were evaluated in six obese (at least 35% above ideal body weight) men and six nonobese male volunteers. Methylprednisolone doses of 0.6 mg/kg total body weight were administered as the 21-succinate sodium salt. Absolute clearance (in liters per hour) of methylprednisolone was 40% less in the obese subjects. Total volume of distribution (Vss) of methylprednisolone was unchanged (about 120 L), but when normalized for total body weight, Vss per kilogram was less in obesity. The patterns of cortisol, blood histamine, and helper T cell responses after methylprednisolone administration were similar in both groups, but more profound effects were observed in the obese subjects. Pharmacodynamic models were applied for these immediate effects of methylprednisolone based on the premise that receptor interactions of steroids are followed by rapid suppression of the circadian rhythm of cortisol and recirculation of basophils and helper T cells, which persist until inhibitory concentrations (IC50) of methylprednisolone disappear. Similar IC50 values for the three effects were obtained in both groups, indicating no intrinsic pharmacodynamic differences in sensitivity to these methylprednisolone effects in obesity. However, methylprednisolone should be administered on the basis of ideal body weight, and the dosing interval should be potentially lengthened because of decreased methylprednisolone clearance in obesity.

Background As supra-physiological intake of corticosteroids is a well known risk factor for the development of adrenal insufficiency, we investigated the function of the hypothalamic-pituitary-adrenal (HPA) axis during a 14-day course of systemic corticosteroids in patients with acute exacerbation of chronic obstructive pulmonary disease using clinical and laboratory measures. Methods A systematic clinical and laboratory assessment including measurement of basal cortisol levels and the response to low dose (1 μg) ACTH stimulation was performed in nine patients before, on the first and the last day of treatment, as well as 2, 7 and 21 days after corticosteroid withdrawal. Results At baseline, all nine patients had normal responses to 1 μg ACTH. On the first day of steroid treatment, 78% had a blunted peak cortisol response. This percentage increased to 89% after 14 days of steroid treatment. 78%, 33% and 33% of the patients had a blunted cortisol response to ACTH 2, 7, and 21 days after corticosteroid withdrawal, respectively. ROC curve analysis revealed that only basal cortisol concentrations (AUC 0.89), but not ACTH concentrations (AUC 0.49) or clinical signs (AUC 0.47) were predictive of an impaired function of the HPA axis. Basal cortisol levels of > 400 and < 150 nmol/l were 96% and 100% sensitive for a normal or pathological response to the ACTH stimulation test, respectively. Conclusion Immediate and prolonged suppression of the HPA axis is a common finding in otherwise asymptomatic patients undergoing systemic steroid treatment for acute exacerbation of chronic obstructive pulmonary disease and can reliably be assessed with the low-dose ACTH test.

We report two children, age 7 months and 5 years, who underwent surgery for congenital heart disease and developed persistent pleural effusions with elevated eosinophil counts. Given the elevation of eosinophil counts in both blood and pleural fluid of these patients, it was considered that an allergic response might have caused the persistent effusion. In both cases, the effusion resolved within 48 hours after treatment with corticosteroids was begun. It is possible that postoperative eosinophilic pleural effusion may represent a subgroup of effusions that are more likely to respond to treatment with corticosteroids.

To study the effects of glucocorticoids and chemotherapeutic agents on the pathophysiology of the tumor-induced brain edema, the site of Evans blue-albumin extravasation, the distribution of extravasated serum albumin, and the extent of local astrocytic reaction were examined in a rat model of implanted brain tumor. Experimental brain tumors were produced by implanting small pellets of Walker 256 carcinosarcoma into the cerebral cortex of Wistar rats. In the steroid group, rats were administered with intraperitoneal methylprednisolone succinate (15 mg/kg) daily on and after the 6th day postimplantation, and sacrificed on the 14th day. In the chemotherapy group, rats were given an intravenous injection of cyclophosphamide (30 mg/kg) on the 14th day, and sacrificed on the 21st day. Rats in the untreated group were sacrificed on the 14th day without any therapy. Each animal was sacrificed by the transcardiac perfusion with paraformaldehyde 30 min after intravenous injection of Evans blue. Firstly, coronal blocks of the brain were examined for Evans blue staining macroscopically. Paraffin embedded sections were studied for the Evans blue fluorescence and for the immunohistochemical reaction to serum albumin and GFAP. The examination of Evans blue demonstrated that the origin of extravasation of serum albumin was the tumor and the adjacent brain with dense tumor cell infiltration in any group of rats. The extravasated serum albumin distributed widely and the astrocytic reaction was prominent in the brain of the untreated group. A positive correlation was observed between the intensity of albumin immunoreaction and the degree of astrocytic proliferation. Chemotherapy effectively decreased the size of tumor and reduced the extravasation of serum albumin. The astrocytic reaction was however, not reduced. In the steroid group, the size of tumor was not significantly affected but the albumin extravasation as well as astrocytic reaction was markedly reduced. It was concluded that glucocorticoid is an effective drug against tumor-induced brain edema, which not only reduces the extravasation of serum components but also prevents histologic alterations of the brain.

Methylprednisolone in the form of its hemisuccinate ester was injected intravenously in doses of 10 mg/ kg and 63.1 mg. Plasma levels of methylprednisolone and of the ester were measured and their kinetics were calculated. Results indicate dose dependency in the kinetics of both. About 10% of the dose was excreted unchanged as hemisuccinate in the urine, indicating incomplete conversion of the prodrug. When methylprednisolone (80 mg) was also taken by mouth, the relative bioavailability of the tablets was 99%. Saliva levels of methylprednisolone were low but paralleled plasma levels in the postdistribution phase. No methylprednisolone hemisuccinate was found in saliva. Clinical Pharmacology and Therapeutics (1985) 37, 502–507; doi:10.1038/clpt.1985.79

A recent report from our laboratory showed that pancreatic inflammation induced by hypovolemic shock can be explained to some extent by spoliation in pancreatic perfusion as revealed by electromagnetic flow determinations on the gastroduodenal artery (GDA). On the other hand, when given early in the course of hypovolemic shock, methylprednisolone sodium succinate (MPSS) alleviated pancreatic inflammation as evidenced by gross and histological findings. Five dogs (18-23 kg) were submitted to a 3-hour hypovolemic shock (mean arterial blood pressure, MABP = 50 mm Hg) and received during bleeding 35 mg/kg of MPSS over a 30 min period. Recordings of cardiac output (CO), MABP, regional blood flows in the GDA and superior mesenteric (SMA) arteries were taken every 15 min. The effect of MPSS was appreciated by comparing GDA flow variations in this group with those previously published of a control group comprised of 12 dogs submitted to 3 hours of hypovolemic shock without steroids; operative protocol was in all points similar in both groups. At no time were any significant changes noted when MPSS was added as far as CO and GDA flows were concerned. In other words, the beneficial action of steroids on hypovolemic pancreases cannot be explained by alteration in regional blood flow.

The kinetics, specificity and morphology of cytolethal responses have been studied in human glucocorticoid-sensitive and -insensitive lymphoid cell lines (HLCL) and fibroblasts following treatment with high (10(-3)M) and low (10(-6)M) doses of steroid. The high dose cytolethal response appears non-specific occurring in all cell lines with every steroid tested. By contrast, the low dose (pharmacological) cytolethal response requires an active glucocorticoid and a sensitive HLCL. However, both high and low concentrations of steroid induce virtually identical morphological changes in dying cells and similar changes can be induced in cells killed by deliberate feed exhaustion. Although the morphological features in each case resemble apoptosis, the "programmed" physiological form of cell death, the intracellular events leading to cytolysis seem likely to differ. The earliest morphological changes presaging cell death comprise rounding up of cells and condensation of nuclear chromatin. Nuclear changes progress rapidly thereafter and appear to result from detachment of chromatin from the nuclear matrix. The low dose cytolethal response requires the continuous presence of glucocorticoid for periods in excess of 24h, prior to which cell growth appears unaffected. The constancy of this latent interval suggests glucocorticoids may influence some replication control mechanism unrelated initially to macromolecular biosynthesis. Images Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10

Noting that corticosteroid doses required for protection in shock models exceeded those required to saturate glucocorticoid receptors in mammalian cells, we postulated a nonspecific physicochemical effect of steroids upon the cell membrane, and therefore tested three noncorticoid steroids for their effects on granulocyte function. All three (conjugated equine estrogen, a synthetic progestogen, and a synthetic androgen) behaved in manner analogous to corticoids at similar concentrations, inhibiting granulocyte aggregation, chemotaxis, and chemiluminescence, as well as binding to the granulocytes of the synthetic oligopepitide agonist f-Met-Leu-Phe. Estrogen was further shown to reduce granulocyte membrane fluidity, assessed by electron paramagnetic resonance. We propose that the unique effects of extremely high-dose corticosteroids are not mediated via the glucocorticoid receptor, but result rather from physicochemical effects of the drugs upon the membranes of effector cells.

We have found a relationship between sensitivity to glucocorticoid induced cell death (at 10 microM glucocorticoid) and ploidy in the human lymphoid cell line CCRF/CEM-C7. Most sensitive clones are diploid, whilst resistant clones and the resistant parent line CCRF/CEM are tetraploid. Diploid sensitive clones have a tendency to become aneuploid within a few months of isolation, with alterations in their kinetic responses to glucocorticoids. This is followed by a doubling in DNA content which results in reversion to the tetraploid glucocorticoid resistant state of the parent line CCRF/CEM. A few sensitive clones have been found to be tetraploid but with different kinetic responses to glucocorticoids as compared to diploid clones. The principal difference being an extended lag period (48-72 h) prior to lethal response. The relationship between ploidy and glucocorticoid sensitivity does not appear to extend to other human lymphoid cell lines. Images Figure 1

The effects of ketoconazole and methylprednisolone on endogenous cortisol were studied in eight normal subjects. Intravenous methylprednisolone sodium succinate was given alone in doses of 15 or 30 mg. The methylprednisolone dose was reduced by 57% when ketoconazole was administered chronically for 1 week to seek equivalent methylprednisolone AUCs by compensating for the expected reduction in methylprednisolone clearance. Ketoconazole decreased clearance by 46% and increased mean residence time by 37%. The ratio of the cortisol AUC during each drug treatment compared with baseline conditions was used to assess the net extent and duration of cortisol suppression. This cortisol AUC ratio was reduced from 0.45 (methylprednisolone) to 0.39 (methylprednisolone plus ketoconazole), suggesting that ketoconazole modestly enhanced (P less than 0.01) cortisol suppression. Based on the reduction in methylprednisolone clearance and cortisol AUC by ketoconazole, a 50% lower dose of methylprednisolone during concomitant therapy with ketoconazole is recommended.