Concurrent Administration Of Dexamethasone Research Articles

The Concurrent Administration of Dexamethasone and Aldosterone Effectively Mitigates the Pronounced Pro-ulcerogenic Effect of Dexamethasone on the Gastric Mucosa in Rats

We previously established that the effect of dexamethasone (Dex) on the gastric ulceration is time dependent. Administering Dex 1 hour before an ulcerogenic stimulus provides gastroprotection, but extending the interval to 24 hours transforms its effect into a pro-ulcerogenic one. The prolonged maintenance of blood glucose levels induced by Dex, accompanied by catabolic effects, may, in part, account for its pro-ulcerogenic nature (Filaretova et., Inflammopharmacology 2009). Given the evidence that Dex primarily binds to glucocorticoid receptors (GRs), we hypothesized that Dex-induced imbalance in the activation of GRs and mineralocorticoid receptors (MRs) could contribute to the pro-ulcerogenic effect of Dex. We partly confirmed this (Filaretova and Sudalina, FASEB J. 2019). To further validate this hypothesis, we conducted a study to determine whether correcting the imbalance in the activation of GRs and the MRs, induced by Dex, through co-administering Dex with the MR agonist aldosterone (Aldo), can mitigate the pro-ulcerogenic effect of Dex. The effects of separate and combined administration of Dex and Aldo at a dose of 1 mg/kg (i.p.) 1 hour and 24 hours before the onset of ulcerogenic stimulus on the gastric erosions was evaluated in rats. Gastric injury was induced by indomethacin (IM, 35 mg/kg, sc) in preliminary fasted rats. Four hours after IM administration, the rats were decapitated, the stomachs were removed to estimate the erosion area; the adrenal glands, thymus and spleen were remove to estimate their weight, and trunk blood was collected to test the corticosterone and glucose levels. We confirmed the gastroprotective effect of Dex administered 1 hour and the pronounced pro-ulcerogenic effect of Dex administered 24 hours before IM. Aldo itself, administered 1 hour before IM had no effect on the gastric erosions, however, when administered 24 hours before IM, it led to a pro-ulcerogenic effect of IM, but much less pronounced comparing with that of Dex. Co-administration Dex and Aldo 1 hour before IM resulted in the gastroprotection similar to that of Dex alone. Co-administration Dex and Aldo 24 hours before IM effectively mitigates the pronounced pro-ulcerogenic effect of dexamethasone on the gastric mucosa. Dex administration resulted in a sharp decrease in the blood corticosterone level both when administered 1 hour and 24 hours before IM, however, the corticosterone levels in 24 hours were significantly lower than in 1 hour. Aldo itself did not lead to a significant decrease the corticosterone levels neither after 1 hour nor after 24 hours. We confirmed our previous results that Dex administration both 1 hour and 24 hours before IM leads to an increase in blood glucose levels. Administration of Aldo alone did change glucose levels. The effect of the combined administration of Dex and Aldo on glucose levels did not differ from that of Dex alone. 24 hours after Dex administration alone or co-administration Dex with Aldo, pronounced catabolic effects appeared: a decrease in the relative weight of the adrenal glands, thymus and spleen. In conclusion, the concurrent administration of Dex and Aldo effectively mitigates the pronounced pro-ulcerogenic effect of Dex on the gastric mucosa in rats. The results further confirmed our hypothesis. State Program 47 SP “Scientific and Technological Development of the Russian Federation” (2019-2030), 0134-2019-0001. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Alleviating iatrogenic effects of paclitaxel via antiinflammatory treatment.

Paclitaxel (PTX) is touted as an essential medicine due to its extensive use as a chemotherapeutic agent for various cancers and an antiproliferative agent for endovascular applications. Emerging studies in cardio-oncology implicate various vascular complications of chemotherapeutic agents. We evaluated the inflammatory response induced by the systemic administration of PTX. The investigation included RNAseq analysis of primary human endothelial cells (ECs) treated with PTX to identify transcriptional changes in pro-inflammatory mediators. Additionally, we used dexamethasone (DEX), a well-known antiinflammatory compound, to assess its effectiveness in counteracting these PTX-induced changes. Further, we studied the effects of PTX on monocyte chemoattractant protein-1 (MCP-1) levels in the media of ECs. The study also extended to in vivo analysis, where a group of mice was injected with PTX and subsequently harvested at different times to assess the immediate and delayed effects of PTX on inflammatory mediators in blood and aortic ECs. Our RNAseq analysis revealed that PTX treatment led to significant transcriptional perturbations in pro-inflammatory mediators such as MCP-1 and CD137 within primary human ECs. These changes were effectively abrogated when DEX was administered. In vitro experiments showed a marked increase in MCP-1 levels in EC media following PTX treatment, which returned to baseline upon treatment with DEX. In vivo, we observed a threefold increase in MCP-1 levels in blood and aortic ECs 12 h post-PTX administration. Similar trends were noted for CD137 and other downstream mediators like tissue factor, vascular cell adhesion molecule 1, and E-selectin in aortic ECs. Our findings illustrate that PTX exposure induces an upregulation of atherothrombotic mediators, which can be alleviated with concurrent administration of DEX. Considering these observations, further long-term investigations should focus on understanding the systemic implications associated with PTX-based therapies and explore the clinical relevance of DEX in mitigating such risks.

Combined Anticancer Therapy for Prostate Cancer - Literature Review

Prostate cancers represent a significant health problem, and their etiology is complex and multifaceted. It is estimated that in 2018, 1.3 million new cases and 359,000 deaths due to prostate cancer were diagnosed. They constitute the second most common group of cancers and the fifth most common cause of cancer-related deaths in men worldwide. The present study encompasses a literature review aimed at conducting an analysis of the potential of combined anticancer therapy as a prospective method for enhancing treatment efficacy, minimizing side effects, and improving long-term survival outcomes for prostate cancer patients. Combinations of compounds such as sunitinib with docetaxel, carboplatin with paclitaxel, estramustine or flutamide with luteinizing hormone-releasing hormone agonists, as well as docetaxel in conjunction with dexamethasone and octreotide, have demonstrated synergistic effects and an augmentation of therapeutic effectiveness. It is noteworthy to emphasize the potential enhancement of docetaxel's anticancer activity with concurrent administration of dexamethasone and octreotide, as well as combined therapy involving docetaxel, prednisone, and curcumin.

Concurrent Dexamethasone Limits the Clinical Benefit of Immune Checkpoint Blockade in Glioblastoma.

Dexamethasone, a uniquely potent corticosteroid, is frequently administered to patients with brain tumors to decrease tumor-associated edema, but limited data exist describing how dexamethasone affects the immune system systemically and intratumorally in patients with glioblastoma (GBM), particularly in the context of immunotherapy. We evaluated the dose-dependent effects of dexamethasone when administered with programmed cell death 1 (PD-1) blockade and/or radiotherapy in immunocompetent C57BL/6 mice with syngeneic GL261 and CT-2A GBM tumors. Clinically, the effect of dexamethasone on survival was evaluated in 181 patients with isocitrate dehydrogenase (IDH) wild-type GBM treated with PD-(L)1 blockade, with adjustment for relevant prognostic factors. Despite the inherent responsiveness of GL261 to immune checkpoint blockade, concurrent dexamethasone administration with anti-PD-1 therapy reduced survival in a dose-dependent manner. Concurrent dexamethasone also abrogated survival following anti-PD-1 therapy with or without radiotherapy in immune-resistant CT-2A models. Dexamethasone decreased T-lymphocyte numbers by increasing apoptosis, in addition to decreasing lymphocyte functional capacity. Myeloid and natural killer cell populations were also generally reduced by dexamethasone. Thus, dexamethasone appears to negatively affect both adaptive and innate immune responses. As a clinical correlate, a retrospective analysis of 181 consecutive patients with IDH wild-type GBM treated with PD-(L)1 blockade revealed poorer survival among those on baseline dexamethasone. Upon multivariable adjustment with relevant prognostic factors, baseline dexamethasone administration was the strongest predictor of poor survival [reference, no dexamethasone; <2 mg HR, 2.16; 95% confidence interval (CI), 1.30-3.68; P = 0.003 and ≥2 mg HR, 1.97; 95% CI, 1.23-3.16; P = 0.005]. Our preclinical and clinical data indicate that concurrent dexamethasone therapy may be detrimental to immunotherapeutic approaches for patients with GBM.

IMMU-09. CONCURRENT DEXAMETHASONE LIMITS THE CLINICAL BENEFIT OF IMMUNE CHECKPOINT BLOCKADE IN GLIOBLASTOMA

Abstract BACKGROUND Dexamethasone, a uniquely potent corticosteroid, is frequently administered to brain tumor patients to decrease tumor-associated edema, but limited data exist describing how dexamethasone affects the immune system systemically and intratumorally in glioblastoma patients – particularly in the context of immunotherapy. METHODS We evaluated the dose-dependent effects of dexamethasone when administered with anti-PD-1 and/or radiotherapy in immunocompetent C57BL/6 mice with syngeneic GL261 or CT-2A glioblastoma tumors, including analyses of intracranial tumors, draining lymph nodes, and spleen. Clinically, the effect of dexamethasone on survival was additionally evaluated in 181 consecutive IDH-wildtype glioblastoma patients treated with anti-PD-(L)1, with adjustment for relevant prognostic factors. RESULTS Despite the inherent responsiveness of GL261 to immune checkpoint blockade, concurrent dexamethasone administration with anti-PD-1 therapy decreased survival in a dose-dependent fashion and decreased survival following anti-PD-1 plus radiotherapy in both GL261 and immunoresistant CT-2A models. Dexamethasone quantitatively decreased T lymphocytes by reducing the proliferation while increasing apoptosis. Dexamethasone also decreased lymphocyte functional capacity. Myeloid and NK cell populations were also generally reduced. Thus, dexamethasone negatively affects both the adaptive and innate immune responses. As a clinical correlate, a retrospective analysis of 181 consecutive IDH-wildtype glioblastoma patients treated with PD-(L)1 blockade revealed worse survival among those on baseline dexamethasone. Upon multivariable adjustment with relevant prognostic factors, baseline dexamethasone use – regardless of dose – was the strongest predictor of poor survival (reference no dexamethasone; &amp;lt; 2mg HR 2.28, 95%CI=1.41–3.68, p=0.001; ≥2mg HR 1.97, 95%CI=1.27–3.07, p=0.003). CONCLUSIONS Our preclinical and clinical data indicate that concurrent dexamethasone therapy may be detrimental to immunotherapeutic approaches for glioblastoma patients. Our preclinical analyses also suggest that dexamethasone’s detrimental effects are dose-dependent, suggesting that the lowest possible dose should be used for patients when dexamethasone use is unavoidable. Careful evaluation of dexamethasone use is warranted for neuro-oncology patients undergoing immunotherapy clinical trials.

Effectiveness of the Concurrent Intravenous Injection of Dexamethasone and Metoclopramide for Pain Management in Patients with Primary Headaches Presenting to Emergency Department.

Introduction:Headache is a common reason for visiting emergency departments, and pain control is a major therapeutic goal in patients with headaches. Objective:The present study was conducted to examine the effectiveness of the concurrent intravenous administration of dexamethasone and metoclopramide in pain control in patients presenting to emergency departments with complaints of primary headache. Methods:This quasi-experimental study examined patients with moderate to severe headache attacks presenting to emergency departments. An 8-mg dose of dexamethasone and a 10-mg dose of metoclopramide were intravenously administered to the patients. The degree of headache was measured and recorded using the Numeric Rating Scale (NRS) upon admission and one hour and two hours after the injection.Results:A total of 51 patients with a mean age of 38.3±10.5 years participated in the study. The patients’ mean pain score was 8.4±1.3 upon admission and reduced to 6.2±2.3 one hour after the administration of the medication and to 3.1±2.9 two hours after the administration, suggesting significant reductions on both occasions (P<0.05). The therapeutic success was 39.2% one hour after the administration of the medication and 84.3% two hours after the administration.Conclusion:Based on these findings, the concurrent administration of dexamethasone and metoclopramide appears to affect the control of headache intensity in patients with primary headaches presenting to emergency departments.

Concurrent administration effect of antibiotic and anti-inflammatory drugs on the immunotoxicity of bacterial endotoxins

Pseudomonas aeruginosa (P. aeruginosa) is a gram-negative bacterium that causes a variety of diseases in compromised hosts. Bacterial endotoxins such as lipopolysaccharide (LPS) are the major outer surface membrane components that are present in almost all gram-negative bacteria and act as extremely strong stimulators of innate immunity and inflammation of the airway. This study was undertaken to determine the effect of combined administration of Gentamicin (GENT) as an antibiotic and Dexamethasone (DEXA) as an anti-inflammatory drug on some immunological and histological parameters. After determination of LD50 of P. aeruginosa, mice groups were injected with DEXA, GENT and lipopolysaccharide alone or in combination. Lipopolysaccharide single injection caused a significant increase of total leukocyte count, lymphocytes, neutrophils and levels of IgM and IgG. DEXA induced an increase of neutrophilia and lymphopenia. Immunological examination demonstrated that combined treatment has a significant effect of decreasing lymphocytes and IgG levels than single treatment does. Histological examination demonstrated that the inflammation of thymus, spleen, lymph node and liver decreases in mice that received combined treatment than those that received individual treatment. Concurrent administration of DEXA and GENT has a great effect on protecting organs against damage in case of endotoxemia.

Prophylactic Use of Oral Dexamethasone to Alleviate Fatigue During Regorafenib Treatment for Patients With Metastatic Colorectal Cancer

BackgroundFatigue is the most common toxicity of all grade toxicities with regorafenib, was the second most common toxicity in the CORRECT (regorafenib monotherapy for previously treated metastatic colorectal cancer) study, and is a major reason for early dose modification. The results from a recent randomized study suggested that dexamethasone (DEX) can improve cancer-related fatigue. Patients and MethodsWe retrospectively analyzed the effect of prophylactic use of an oral DEX on fatigue during regorafenib treatment in patients with metastatic colorectal cancer (mCRC). A total of 105 patients who had received regorafenib at our institution from May 2013 to August 2014 were divided into 2 groups according to oral DEX use (2 mg/day; at the physician's discretion). ResultsOf the 105 patients, 31 received prophylactic DEX and 74 received regorafenib alone. The time to dose modification was significantly longer in the DEX group than in the no DEX group (15 days vs. 9 days; P = .009). The incidence of fatigue (grade ≥ 1) was significantly lower with DEX than without DEX (25.8% vs. 50.0%; P = .022). Fewer patients experienced a decreased appetite (grade ≥ 1; 3.2% vs. 35.1%; P < .001) and hand–foot skin reaction (HFSR; grade ≥ 3; 3.2% vs. 25.7%, P = .002) with DEX than without DEX. ConclusionDEX was effective in reducing fatigue during regorafenib treatment, resulting in prolonging the time to dose modification for regorafenib. The decreased incidence of appetite loss and HFSR also suggest that concurrent DEX administration with regorafenib warrants further investigation.

Dexamethasone regulates differential expression of carboxylesterase 1 and carboxylesterase 2 through activation of nuclear receptors

Carboxylesterases (CESs) play important roles in the metabolism of endogenous and foreign compounds in physiological and pharmacological responses. The aim of this study was to investigate the effect of dexamethasone at different doses on the expression of CES1 and CES2. Imidapril and irinotecan hydrochloride (CPT-11) were used as special substrates for CES1 and CES2, respectively. Rat hepatocytes were cultured and treated with different concentrations of dexamethasone. The hydrolytic activity of CES1 and CES2 was tested by incubation experiment and their expression was quantitated by real-time PCR. A pharmacokinetic study was conducted in SD rats to further evaluate the effect of dexamethasone on CESs activity in vivo. Western blotting was performed to investigate the regulatory mechanism related to pregnane X receptor (PXR) and glucocorticoid receptor (GR). The results showed that exposure of cultured rat hepatocytes to nanomolar dexamethasone inhibited the imidapril hydrolase activity, which was slightly elevated by micromolar dexamethasone. For CES2, CPT-11 hydrolase activity was induced only when dexamethasone reached micromolar levels. The real-time PCR demonstrated that CES1 mRNA was markedly decreased by nanomolar dexamethasone and increased by micromolar dexamethasone, whereas CES2 mRNA was significantly increased by micromolar dexamethasone. The results of a complementary animal study showed that the concurrent administration of dexamethasone significantly increased the plasma concentration of the metabolite of imidapril while the ratio of CPT-11 to its metabolite SN-38 was significantly decreased. PXR protein was gradually increased by serial concentrations of dexamethasone. However, only nanomolar dexamethasone elevated the level of GR protein. The different concentrations of dexamethasone required suggested that suppression of CES1 may be mediated by GR whereas the induction of CES2 may result from the role of PXR. It was concluded that dexamethasone at different concentrations can differentially regulate CES1 and CES2.

The immunostimulatory effect of lenalidomide on NK-cell function is profoundly inhibited by concurrent dexamethasone therapy

AbstractLenalidomide combined with dexamethasone is an effective treatment for refractory/relapsed multiple myeloma (MM). Lenalidomide stimulates natural killer (NK) cells and enhances antitumor responses. We assessed NK cell number and function in 25 patients with MM participating in a clinical trial of lenalidomide and dexamethasone. NK cell numbers increased from a mean of 2.20 ± 0.05 × 105/mL (baseline) to a mean of 3.90 ± 0.03 × 105/mL (cycle 6; P = .05); however, in vitro NK-cell–mediated cytotoxicity decreased from 48.9% ± 6.8% to 27.6% ± 5.1% (P = .0028) and could not be rescued by lenalidomide retreatment. Lenalidomide increased normal donor NK-cell cytotoxicity in vitro from 38.5% to 53.3%, but this was completely abrogated by dexamethasone. Dexamethasone suppression of NK cell–mediated cytotoxicity was partially reversed by a 3-day washout, but these cells remained refractory to lenalidomide-induced enhanced function. Lymphocyte subset depletion experiments revealed that lenalidomide's enhancement of NK cell–mediated cytotoxicity was mediated by CD4+ T-cell production of interleukin 2 and that dexamethasone acted by suppressing interleukin-2 production. Similarly, the reduced ability of NK cells from patients with MM to respond to lenalidomide was also due to impaired CD4 T-cell function. Our findings indicate that lenalidomide immunostimulatory effects on patient NK cells are severely blunted by concurrent dexamethasone administration.

Effects of Tanespimycin On Glucocorticoid Receptor Translocation.

Abstract 4921 INTRODUCTIONTanespimycin (BMS-722782) exhibits antitumor activity in diverse models of hematologic malignancies and solid tumors by suppressing the chaperoning activity of heat shock protein 90 (Hsp90) including its ability to preserve the proper three-dimensional structure and intracellular trafficking of its client proteins. However, not all potential client proteins are affected to the same degree by Hsp90 inhibitors. Tanespimycin is in phase 3 clinical development with bortezomib for the treatment of multiple myeloma (MM). Because glucocorticoids form the backbone of many anti-myeloma regimens, this preclinical study examined the effect of tanespimycin on the glucocorticoid receptor (GR), a chaperone protein of Hsp90. METHODSOur objective is to evaluate whether tanespimycin impedes the nuclear translocation of GR in the presence or absence of GR ligand stimulation and examine the anti-myeloma activity of tanespimycin combinations with glucocorticoids. COS-7 cells transiently transfected with YFP-GR (fluorescently tagged GR) were incubated in the presence or absence of GR ligands (eg, prednisolone), tanespimycin, combinations thereof, or DMSO control. The cellular location of GR (cytoplasm or nucleus) was evaluated using a confocal high content imager. The in vitro anti-MM activity of combinations of tanespimycin with dexamethasone was evaluated by MTT survival assays. RESULTSWith prednisolone (100 nM; 30 min) stimulation, GR rapidly translocates to the nucleus, consistent with previous observations. Tanespimycin did not induce GR nuclear translocation, but resulted in heterogeneous cytoplasmic aggregates of GR. Pretreatment of COS-7/YFP-GR cells with tanespimycin for 30 minutes inhibited prednisolone-induced (5 nM; 2 h and 4 h) GR nuclear translocation at higher tanespimycin concentrations (eg, 1.25 μM), but partial GR translocation was observed at lower (4.8 nM) concentrations. However, complete ligand-induced GR nuclear translocation was observed when COS-7/YFP-GR cells were pretreated with either prednisolone or dexamethasone (dose ranges 10 μM–0.019 nM; 30 min) prior to the addition of clinically relevant tanespimycin concentrations (200 nM; 1, 2, 6, and 24 h). In vitro cell viability assays with the human MM cell line MM.1S were consistent with these observations. Concurrent administration of dexamethasone (40–80 nM; 72 h) and tanespimycin (0.5–1 μM) to MM cells did not exhibit antagonistic interaction. Similarly, no antagonistic interaction was observed when dexamethasone pretreatment was followed by tanespimycin. Interestingly, for some of the experimental conditions of these combinations, at least additive effects on suppression of MM cell survival were observed. CONCLUSIONThese results suggest that appropriate sequencing of tanespimycin and GR ligands can avoid any theoretical antagonistic effect of Hsp90 inhibition on GR nuclear translocation, thus providing a framework for incorporation of dexamethasone or other glucocorticoids into tanespimycin-based regimens. DisclosuresMitsiades:Millennium, Novartis, BMS, Merck, Kosan, Pharmion: Honoraria; Amgen, AVEO, EMD Serono and Sunesis: Research Funding; Millennium, Novartis, BMS, Merck, Kosan, Pharmion: Consultancy; PharmaMar: Patents & Royalties. Anderson:Celgene, Novartis, Millennium, BMS: Consultancy; Celgene, Novartis, Millennium, BMS: Research Funding; Celgene, Novartis, Millennium, BMS: Honoraria. Richardson:Celgene: Speakers Bureau; Millennium Pharmaceuticals, Inc.: Research Funding, Speakers Bureau.

Endoscopic evaluation of the gastroduodenal mucosa to determine the safety of short-term concurrent administration of meloxicam and dexamethasone in healthy dogs.

To evaluate the safety, with respect to the development of gastric ulcers and erosions, of concurrent administration of meloxicam and dexamethasone for 3 days to healthy dogs. 20 conditioned purpose-bred research Beagles. Seven days prior to treatment, dogs were anesthetized for endoscopic evaluation of the upper portion of the gastrointestinal tract (ie, the gastric and duodenal mucosa). Five regions of the gastroduodenal area were scored by 2 investigators. Dogs were randomly assigned to 1 of 4 treatment groups as follows: saline-saline, dexamethasone-saline, saline-meloxicam, and dexamethasone-meloxicam groups. On days 1, 2, and 3, dogs received either dexamethasone or saline (0.9% NaCl) solution injections SC twice daily. On days 2, 3, and 4, dogs received either meloxicam or saline solution injections SC once daily. On day 2, dogs were anesthetized for a sham surgery (ie, electrostimulation). On day 5, the gastroduodenal area of each dog was reevaluated by use of endoscopic evaluation and histologic examination of biopsy specimens. The total endoscopic score of the dexamethasone-meloxicam group was significantly greater than the scores of the other groups. The dexamethasone-saline group had a mean cumulative score that was significantly greater than the saline-meloxicam or saline-saline groups. Endoscopic scores of the saline-meloxicam group were not significantly different from scores of the saline-saline group. No significant differences in histologic findings were found between groups. In healthy dogs, meloxicam appears to be safe with regard to adverse effects on the gastrointestinal tract. Concurrent administration of dexamethasone and meloxicam is more likely to cause gastric erosions than meloxicam administration alone.

Cysticercosis.

Cysticercosis, the consequence of ingesting viable eggs of the porcine tapeworm Taenia solium, currently remains one of the most common human parasitic conditions worldwide. Although preventable by the proper disposal of human wastes, cysticercosis of the central nervous system (neurocysticercosis) accounts for a substantial proportion of cases of epilepsy and hydrocephalus among children and adults in many developing countries. Cases also occur in nonendemic regions, reflecting patterns of immigration from highly endemic countries, especially Mexico and other areas of Latin America. Antiparasitic treatment during active infections, using albendazole or praziquantel, can eradicate the parasite, may lower the risk of late complications, and potentially reduces the morbidity of acute disease. Considerable controversy persists regarding the role of antiparasitic therapy in neurocysticercosis, however. Persons with active parenchymal or extraparenchymal disease, defined by the neuroradiographic appearance of lesions, can be treated with albendazole, 15 mg/kg/d divided into two daily doses for 8 days. Patients with parenchymal disease who do not respond to albendazole can receive a second course of albendazole or praziquantel, 50 mg/kg/d divided into three daily doses for 15 days. Concurrent administration of dexamethasone in standard doses is usually required during the first several days of antiparasitic therapy to minimize the inflammation and cerebral edema associated with death of the parasites. Patients with intraventricular cysts and hydrocephalus require shunting and surgical removal of cysticerci. By contrast, persons with inactive lesions and seizures as a consequence of remote infections typically require only symptomatic therapy with standard anticonvulsants.

Increased expression of vascular angiotensin II type 1A receptor gene in glucocorticoid-induced hypertension

We recently demonstrated that glucocorticoid increases the number of angiotensin II type 1 (AT1) receptors and their gene expression in cultured vascular smooth muscle cells. To clarify whether this mechanism participates in glucocorticoid-induced hypertension, we investigated the effect of dexamethasone on the modulation of vascular AT1 receptor messenger RNA (mRNA) expression in rats. The effects were studied of administering dexamethasone orally to rats at a dose of 0.1 mg/day on the modulation of the expression of vascular AT1 receptor mRNA and the blood pressure. The effects of enalapril maleate, an angiotensin converting enzyme inhibitor, were also evaluated. The dexamethasone-treated rats showed a rise in systolic blood pressure beginning on day 3. On day 5 the blood pressure rose significantly. Before dexamethasone administration the vascular AT1 receptor mRNA was difficult to detect by Northern blot analysis. However, the level of vascular AT1A receptor mRNA began to increase on day 2, when the blood pressure was not yet elevated, and increased further on day 5. The concurrent administration of dexamethasone and enalapril maleate attenuated the elevation of blood pressure. However, as in the dexamethasone-treated rats, the level of AT1A receptor mRNA began to increase on day 2 and increased further on day 5. In rats treated with enalapril maleate alone, the AT1 receptor mRNA was difficult to detect during the experiment. Glucocorticoid increased the amount of vascular AT1 receptor mRNA and contributed to the elevation of blood pressure.

Inhibition of Interleukin-2-Induced Tumor Necrosis Factor Release by Dexamethasone: Prevention of an Acquired Neutrophil Chemotaxis Defect and Differential Suppression of Interleukin-2-Associated Side Effects

High concentrations of tumor necrosis factor (TNF) alpha have been detected in the plasma of patients undergoing immunotherapy with interleukin 2 (IL-2), suggesting that this cytokine may play a role in the fever and shocklike state induced by the administration of high-dose IL-2. Dexamethasone has been shown to inhibit the synthesis of TNF by monocytes activated in vitro by endotoxin. To determine if dexamethasone can exert a similar suppressive effect on IL-2-induced TNF synthesis in vivo, the concentration of TNF alpha was measured in plasma samples serially obtained (a) from cancer patients participating in a phase I dose escalation clinical trial with high-dose IL-2 administered in conjunction with dexamethasone (IL-2/Dex) and (b) from patients participating in concurrent studies with IL-2 alone. In contrast to the high plasma levels of TNF alpha detected in patients receiving IL-2 alone, TNF levels in most of the IL-2/Dex patients remained below the threshold of detectability of our TNF radioimmunoassay. The concurrent administration of dexamethasone also prevented the IL-2-induced increase in serum levels of C-reactive protein, a hepatic acute phase reactant whose synthesis is regulated by proinflammatory cytokines such as TNF. The steroid-treated patients also failed to develop the neutrophil chemotactic defect characteristic of IL-2 recipients. The concomitant administration of dexamethasone increased the maximum tolerated dose of IL-2 approximately threefold and markedly reduced the hypotension and organ dysfunction ordinarily observed in these patients. These results demonstrate that dexamethasone inhibits the release of TNF into the circulation of patients undergoing immunotherapy with IL-2. They further suggest that the altered spectrum and reduced severity of IL-2 side effects observed in patients receiving dexamethasone may be attributable in part to the suppressive effect of steroids on IL-2-induced TNF synthesis.

Inhibition of interleukin-2-induced tumor necrosis factor release by dexamethasone: prevention of an acquired neutrophil chemotaxis defect and differential suppression of interleukin-2-associated side effects [see comments

High concentrations of tumor necrosis factor (TNF) alpha have been detected in the plasma of patients undergoing immunotherapy with interleukin 2 (IL-2), suggesting that this cytokine may play a role in the fever and shocklike state induced by the administration of high- dose IL-2. Dexamethasone has been shown to inhibit the synthesis of TNF by monocytes activated in vitro by endotoxin. To determine if dexamethasone can exert a similar suppressive effect on IL-2-induced TNF synthesis in vivo, the concentration of TNF alpha was measured in plasma samples serially obtained (a) from cancer patients participating in a phase I dose escalation clinical trial with high-dose IL-2 administered in conjunction with dexamethasone (IL-2/Dex) and (b) from patients participating in concurrent studies with IL-2 alone. In contrast to the high plasma levels of TNF alpha detected in patients receiving IL-2 alone, TNF levels in most of the IL-2/Dex patients remained below the threshold of detectability of our TNF radioimmunoassay. The concurrent administration of dexamethasone also prevented the IL-2-induced increase in serum levels of C-reactive protein, a hepatic acute phase reactant whose synthesis is regulated by proinflammatory cytokines such as TNF. The steroid-treated patients also failed to develop the neutrophil chemotactic defect characteristic of IL-2 recipients. The concomitant administration of dexamethasone increased the maximum tolerated dose of IL-2 approximately threefold and markedly reduced the hypotension and organ dysfunction ordinarily observed in these patients. These results demonstrate that dexamethasone inhibits the release of TNF into the circulation of patients undergoing immunotherapy with IL-2. They further suggest that the altered spectrum and reduced severity of IL-2 side effects observed in patients receiving dexamethasone may be attributable in part to the suppressive effect of steroids on IL-2-induced TNF synthesis.

Modulation of inflammation and cachectin activity in relation to treatment of experimental Hemophilus influenzae type b meningitis.

By use of an experimental lapin model, the effect of ceftriaxone therapy on inflammation during Hemophilus influenzae type b (Hib) meningitis was evaluated. Meningitis was induced by intracisternal inoculation of 2 x 10(4) to 2 x 10(5) colony-forming units of Hib. Administration of ceftriaxone 6 h after infection provoked rapid bacterial lysis associated with greatly increased concentrations of bacteria-free endotoxin (lipooligosaccharide) and tumor necrosis factor alpha (TNF) in the cerebrospinal fluid (CSF). CSF TNF activity peaked 2 h after initiation of antibiotic therapy (24.4 +/- 2 ng/ml), was significantly higher than that in untreated controls (1.4 +/- 1.1 ng/ml; P less than .05), and was associated with a substantially increased inflammatory response as reflected by higher CSF white blood cell count (24,500 +/- 8,151 vs. 1,920 +/- 644 in untreated controls; P less than .05), lower glucose, and higher protein and lactate concentrations. Simultaneous administration of dexamethasone with antibiotic therapy resulted in a significant reduction in CSF TNF activity that was associated with a substantial reduction in CSF white blood cell count. These data suggest that initiation of ceftriaxone therapy in experimental Hib meningitis exacerbates the meningeal inflammatory response, which can be modulated by concurrent dexamethasone administration.

Role of renin-angiotensin system in glucocorticoid hypertension in rats.

The role of the renin-angiotensin system in the regulation of the blood pressure of dexamethasone-treated rats (Dex) was evaluated using saralasin, an angiotensin II antagonist, and SQ 14225 (SQ) (d-3-mercapto-2-methylpropranoyl-1-proline), an angiotensin-converting enzyme inhibitor. During a 7-day period blood pressure rose 65 +/- 10 mmHg (P less than 0.001) in Dex with no significant changes in plasma renin activity. Concurrent administration of dexamethasone and SQ attenuated the elevation of blood pressure (P less than 0.05). In the conscious, freely moving state, intravenous injection of SQ (10, 30, 100 micrograms/kg) reduced blood pressure of DEX in a dose-dependent manner (P less than 0.05). Also, intravenous injection of saralasin (10 micrograms.kg-1 . min-1) reduced blood pressure significantly (P less than 0.01). Bilateral nephrectomy abolished the effects of saralasin and SQ on blood pressure in Dex. These results indicate that the elevation of blood pressure in DEX depends partially on the renin-angiotensin system.

Effects of androgenic and oestrogenic hormones on mating behaviour in rams castrated before and after puberty.

Adult sheep which has been castrated either before or after puberty were treated with a variety of steroids. The administration of testosterone propionate, oestrone, oestradiol-17 beta or diethylstilboestrol to animals castrated before puberty caused them to mount oestrous ewes. Oestradiol-17 alpha was less effective than these hormones in this regard, whilst oestriol, hexoestrol and 5 alpha-dihydrotestosterone were ineffective. The response to oestradiol-17 beta was not altered by the concurrent administration of dexamethasone to block the pituitary-adrenal axis which suggests that oestradiol-17 beta was not exerting its effect indirectly by causing the release of adrenal steroids. When 5 alpha-dihydrotestosterone was administered in conjunction with oestradiol-17 beta intromission and ejaculation were observed in addition to mounting behaviour. When rams were castrated as adults their mating behaviour slowly declined over the course of 2 years. After this time, mounting behaviour was rapidly restored by the administration of oestradiol-17 beta but not by 5 alpha-dihydrotestosterone. These results are consistent with the hypothesis that oestrogens are the ultimate agents responsible for promoting mating behaviour in male animals and hence aromatizable androgens, such as testosterone, are effective whereas non-aromatizable androgens, such as 5 alpha-dihydrotestosterone, are not.

In utero evidence for a functional fetoplacental unit in rhesus monkeys.

To test the hypothesis that a fetoplacental unit for estrogen biosynthesis is operative in the rhesus monkey, studies were performed in chronically catheterized animals during late gestation. Changes in fetal and maternal plasma concentrations of estrone, estradiol, dehydroepiandrosterone sulfate (DHEAS), and androstenedione were determined in response to infusions of dexamethasone into mothers, and of ACTH, DHEAS, or androstenedione into fetuses. A significant (P<0.0l) maternal: fetal concentration difference (∿20:1) was observed in control samples for estradiol, but not for estrone, DHEAS, or androstenedione (P>0.05). Dexamethasone administration decreased (P<0.05) maternal estrone, estradiol, and DHEAS, as well as fetal estrone and DHEAS. Subsequent administration of ACTH to fetuses increased (P<0.05) fetal estrone, DHEAS and androstenedione, and also maternal estrone and estradiol. Fetal estradiol and maternal DHEAS and androstenedione were not significantly changed (P>0.05). The concentrations of fetal estrone and DHEAS, and of maternal estrone and estradiol returned to pre-dexamethasone control values during infusion of ACTH into fetuses. Administration of DHEAS or androstenedione to fetuses without concurrent dexamethasone administration increased (P<0.05) fetal estrone and maternal estrone and estradiol. No significant changes (P>0.05) were observed in maternal or fetal cortisol or progesterone concentrations. Fetal estradiol levels were relatively low in all of the experiments, and they were not significantly altered by dexamethasone, ACTH, DHEAS, or androstenedione infusions (P>0.05). Collectively, these data indicate that the increases in fetal and maternal estrogens after administration of ACTH to fetuses are the result of ACTH stimulation of fetal adrenal DHEAS and androstenedione production. Androstenedione and DHEAS are transported via the fetal circulation to the placenta, where they are converted to estrogens. Thus, the rhesus monkey, like the human, has a functional fetoplacental unit.