Effects Of Anti-inflammatory Agents Research Articles

Assessment of the Effect of Infliximab on Immunomodulation Properties of Mesenchymal Stem Cells In Vitro.

Purpose: Mesenchymal stem cells (MSCs) have immunomodulatory traits making them a promising choice in the treatment of inflammatory diseases such as graft-versus-host disease (GVHD). Tumor necrosis factor-alpha (TNFα) is a major player of inflammatory disease which is blocked by infliximab to reduce the inflammation. The present study aims to assess the infliximab effects on the anti-inflammatory properties of MSCs. Methods: In this study, bone marrow mesenchymal stem cells (BMMSCs) were co-cultured with peripheral blood mononuclear cells (PBMCs) of GVHD patients in the presence of 10, 20 and 30 µg/mL of infliximab for 48 and 72 hours. The mRNA expression of indoleamine-2,3- dioxygenase (IDO) and inducible nitric oxide synthase (iNOS), as well as the secreted amount of prostaglandin E2 (PGE2) in the culture supernatant, were examined. Results: The results of this study show that the expression of IDO and iNOS genes, as well as the secretion amount of PGE2 in co-cultured groups raised dramatically, compared to the culture of BMMSCs or PBMCs alone. In co-culture groups containing infliximab, the expression of IDO and iNOS and also the amount of released PGE2 was significantly decreased compared to the control group without infliximab. However, no difference was found in the expression of assayed factors between 48 and 72 hours of treatments. Conclusion: As an anti-TNFα agent, infliximab can decrease the inflammation in the microenvironment of MSCs, which might mitigate the immunomodulatory effects of MSCs. These effects of anti-inflammatory agents on the immunomodulatory capacity of MSCs should be considered in MSC therapy.

1015-P: Insulin-Excipient–Induced Inflammation and Pharmacokinetic Variability

Objective: To evaluate the impact of phenol-based insulin-excipient induced inflammation on insulin pharmacokinetic (PK) variability in diabetic mice and to evaluate effects of anti-inflammatory agents (dexamethasone and cromolyn) in minimizing excipient induced inflammation. Methods: Using a modified murine air pouch model, saline or insulin excipients were continuously infused for durations of 1 and 3 days. Subsequently, a single subcutaneous insulin injection of 0.3U (1:100; Humalog) was placed into the air pouch. Blood samples were taken periodically. Bioanalysis was done by ELISA for PK evaluation. A separate analysis determined effects of anti-inflammatory agents co-infused with insulin on maintaining glycemia during infusion pump therapy while extending its lifespan. Tissue was analyzed by standard histopathology (H and E). Results: Primary PK values Cmax, Tmax, AUC (0-120) for saline and excipient infused groups are depicted in Figure 1A and 1B. The excipient group demonstrated lower Tmax, AUC (0-120) and Cmax as compared to saline group. Figure 1C depicts a significantly greater degree of inflammation in all excipient treated groups. Usage of co-infusion with anti-inflammatory agents extends insulin infusion set lifespan. Conclusion: Insulin excipients induce site specific inflammation that alters insulin PK and diminishes the in vivo insulin bioavailability. Confirmation in a porcine model is underway. Disclosure M.K. Hidau: None. C. Kesserwan: None. Y. Qiao: None. D. Kreutzer: Other Relationship; Self; Abbott Laboratories, cell and molecualar tissue enginnering (cmte). U. Klueh: Research Support; Self; Abbott. Other Relationship; Self; Cell and Molecular Tissue Engineering, LLC. Funding The Leona M. and Harry B. Helmsley Charitable Trust

The effect of anti-inflammatory agents (glucosamine sulphate and aloe vera) on mouse mesenchymal stem cells

Use of stem cells for treating degenerative diseases like osteoarthritis has been gaining popularity. Glucosamine Sulphate is a nutritional supplement used for relieving inflammation during Osteoarthritis. Aloe vera juice is a widely consumed drink used in traditional practices to help reduce inflammation. In this experiment, the effect of Glucosamine Sulphate and Aloe vera on 2D and 3D proliferation of MSC cells was studied. Initial study to determine a suitable matrix for growing MSC cells was performed by growing the cells on 5mg/ml and 10mg/ml collagen and fibronectin coated wells for seven days. Cells adhered the least on fibronectin 10ug/ml and cells proliferated the highest on fibronectin at 10ug/ml, thus establishing fibronectin 10ug/ml as the matrix for the study. The effect of Glucosamine Sulphate on 2D proliferation of MSC cells growing on 10ug/ml fibronectin matrix was studied by exposing the cells to 0mg/ml, 0.1mg/ml, 0.5mg/ml and 1 mg/ml of Glucosamine Sulphate for seven days. The cells adhered the least on 0.5mg/ml and proliferated the highest on 0.5mg/ml as well (p<0.05). The effect of Aloe vera on MSC cells grown on fibronectin at 10ug/ml was studied by using concentrations of 0%, 2%, 5% and 10% Aloe vera juice for seven days. It was found that cell proliferation radically decreased in all conditions after Day 4 and the least proliferation was observed at 10%. 3D proliferation of MSC cells in a fibrin construct was studied with 0.1 mg/ml of Glucosamine Sulphate and 2% and 5% Aloe vera juice. It was observed that 5% Aloe vera juice allowed highest proliferation of cells, followed by 0.1 mg/ml Glucosamine Sulphate and 2% Aloe vera. This indicated that further analysis with 2% and 5% Aloe vera along with 0.1mg/ml as threshold could help identify an optimum dose range for uptake of Glucosamine Sulphate with Aloe vera juice to enhance relief from inflammation during osteoarthritis

Systematic review and meta-analysis of randomized clinical trials investigating antidepressant treatment effects of anti-inflammatory agents

Systematic review and meta-analysis of randomized clinical trials investigating antidepressant treatment effects of anti-inflammatory agents

The Effect of Anti-inflammatory Agents on the Permeability of Trabecular Meshwork Cell Monolayers

The Effect of Anti-inflammatory Agents on the Permeability of Trabecular Meshwork Cell Monolayers

Effects of Anti Inflammatory Agents Following Cataract Surgery

Objectives: To assess and compare the analgesic and anti inflammatory efficacy of nepafenac and prednisolone eye drops used individually and in combination in post-operative period of cataract surgery by estimating anterior chamber cell count(ACCC) and pain in visual analogue scale(VAS). Materials and Methods: A total of 156 subjects after cataract surgery were allocated through lottery to 3 groups (n=52 each). Group A: with topical nepafenac: 1 drop thrice daily for 3 weeks, Group B with topical prednisolone: 1 drop four times daily for 3 weeks. Group C with combination of nepafenac and prednisolone as per the schedule for group A and B respectively. Drugs were continued for 22 consecutive days and there were four follow-up visits on day 4, day 8, day 15 and day 22. Anterior chamber cell count (ACCC) and pain were determined by slit lamp bio microscope and visual analogue scale respectively. Results: End results of group A for ACCC and pain were 5.41 ± 0.44 and 1.27 ± 0.41 respectively. In case of group B, ACCC and pain were 1.09 ± 0.32 and 0. Group C showed the best results where for ACCC and pain were 0.40 ± 0.22 and 0 respectively. Conclusion: Combination of Prednisolone and nepafenac eye drops was the most efficacious in reducing inflammation and pain after cataract surgery.

Is Vascular Stiffness a Target for Therapy?

Early cardiovascular disease starts in the endothelium leading to functional changes in the vasculature. These changes can be depicted by assessment of arterial stiffness or elasticity. There are several techniques to assess arterial stiffness. Increased arterial stiffness or decreased arterial elasticity has been associated with cardiovascular risk factors. There is now evidence that small artery elasticity is a strong predictor for arterial hypertension. Moreover arterial elasticity provides extra prognostic information beyond arterial blood pressure measurement. Arterial stiffness attenuation may reflect the true reduction of arterial wall damage. ACE-inhibitors, angiotensin II receptor blockers, aldosterone antagonists and calcium antagonists have favorable effects in improving arterial elasticity, while beta-blockers have an inverse effect. Diuretics have not been evaluated. Lipid lowering therapy, some antidiabetic therapy have shown to reduce arterial stiffness. Inflammatory and infectious diseases have been associated with vascular inflammation and consequently increase in arterial stiffness. The effect of anti-inflammatory agents and antiretroviral therapy on arterial stiffness is under investigation. Measurement of arterial stiffness will not only be helpful in the detection of early vascular disease but also as a tool in the selection and follow-up monitoring of therapeutic strategies aimed at preventing or delaying progression of vascular disease.

Steroidal anti inflammatory drug betamethasone significantly alters level of striatal dopamine in a rat model of Parkinson’s disease

AbstractMany scientific efforts have been well done to investigate the effects of anti inflammatory agents on the degenerative brain diseases such as Parkinson’s (PD) or Alzheimer’s disease and their affiliated sings. Previously we showed the effectiveness of steroids on rigidity of PD and in the study for further mechanistic investigation of that observation the microdialysis technique was employed to determine the striatal dopamine changes in parkinsonian rats after administration of betamethasone (0.12, 0.24 mg/kg) respectively. Our findings showed us the significant increase in the striatal dopaminergic neurotransmission (P<0.05) after administration of betamethasone comparing to the controls. These observations suggest a new mechanism for betamethasone on striatum dopaminergic neurotransmission leading us to gather further evidence about effectiveness of betamethasone in PD.

Effect of anti-inflammatory agents on the integration of autogenous bone graft and bovine bone devitalized matrix in rats

To study the repair of bone defect filled with autograft or bovine bone devitalized matrix in rats under anti-inflammatory action. Two hundred and forty Wistar rats were distributed to two groups of 120 animals each. A 2mm-diameter defect was created in the femoral diaphysis. Animals of Group I had the bone defect filled with autograft and those of Group II, with bovine bone devitalized matrix. Animals of each group were redistributed to four subgroups according to the intramuscular administration of anti-inflammatory drug or saline solution: A - diclofenac sodium; B - dexamethasone; C - meloxicam; D - saline solution. Evaluation periods were 7, 14 and 30 days. Histological evaluation consisted of quantifying the inflammatory process, the bone neoformation, the collagen formation and the presence of macrophages. Animals of Group I did not show significant difference considering inflammatory reaction. Significant and progressive increase of bone neoformation was observed in both groups. The animals that received meloxicam and autograft showed less collagen formation at 14 and 30 days. The number of macrophages was higher in Group II than in Group I. The animals treated with dexamethasone and saline solution did not show statistically significant difference. Diclofenac sodium and meloxicam delayed bone graft repair and dexamethasone did not interfere in it.

Should treatments for asthma be aimed at the airway smooth muscle?

The airway smooth muscle (ASM) cell is an important part of the airway wall of asthma patients because of its increased contractile properties, which appear to be enhanced in this condition and which contribute to airflow obstruction and bronchial hyper-responsiveness. ASM cells are also abnormal in asthma with increased expression of certain chemokines, with increased proliferation rate, numbers and size. β-adrenergic agonists and corticosteroids are the two most important treatments for asthma; other drugs used are leukotriene receptor antagonists and theophylline. Combination therapy of β-adrenergic agonists and corticosteroids has become the treatment of choice for moderate-to-severe asthma. β-adrenergic agonists cause relaxation of ASM cells, leading to a decrease in airflow obstruction of asthma and acute relief of symptoms. Corticosteroids also have direct effects on ASM cells. It is postulated that the effect of anti-inflammatory agents on ASM cells is the most important determinant of the therapeutic effects of these agents. Targeting the ASM cell in asthma could be the focus of therapies for asthma. Specific delivery of active agents to ASM cells may also be part of this strategy.

An effective buprenorphine analgesic protocol increases post-operative adhesions in rats after laparotomy

The use of analgesics in post-operative adhesion (POA) research is problematic due to POA-inhibiting effects of anti-inflammatory agents and bowel motility-inhibiting effects of opioids, which may increase adhesion formation. This study was conducted to assess a buprenorphine (BUP) protocol for analgesic efficacy and its effects on POA formation in a rat cecal abrasion model. The protocol was approved by the University of Florida's Institutional Animal Care and Use Committee (IACUC). Forty-one female Sprague-Dawley rats were randomized into two groups (n = 20 or 21 group). Body weight, food and water intake were recorded daily from 2 days before until 7 days after surgery. Treatment rats received 0.05 mg kg–1 BUP SQ at anesthesia induction and 0.3 mg kg–1 BUP orally in flavored gelatin 6 hours after surgery. Control rats received saline placebo injection and plain gelatin. All rats underwent laparotomy and controlled cecal abrasion. At 3, 6 and 24 hours post-operatively rats were individually observed in 10-minutes periods for pain related behavior incidence: ‘twitch’ (contraction of muscles along dorsum and/or head), ‘back arch’ (cat-like position with front legs extended and pushing backward), ‘writhe’ (flank contraction), and ‘stagger/fall’ (momentary loss of balance while grooming or ambulating), using the method of Roughan and Flecknell (Pain 2001,90, 65–74). On post-op day seven rats were euthanized by CO2 inhalation and POA evaluated (0 to 4 scale; ³Grade 2 = clinically significant.) BUP treated rats had lower mean pain scores than control rats at 3 hours (1.6 ± 1.7 versus 20.3 ± 13.5 (mean ± SD); p < 0.001) and 6 hours (2.1 ± 2.7 versus 23.7 ± 12.9; p < 0.001) but not 24 hours (1.5 ± 1.3 versus 4.9 ± 6.6; p = 0.35) post-operatively. Predominant pain behavior was ‘writhe’ (flank contraction) in contrast to ‘twitch,’‘back arch,’ and ‘stagger/fall’ reported as most common pain indicators in other rat strains. BUP rats had greater mean adhesion incidence (2.4 ± 1.7 versus 1.4 ± 1.8; p < 0.03) and severity (90%³Gr.2 versus 65% of controls; p < 0.05). The BUP protocol appeared to provide effective analgesia for at least 24 hours post-operatively. Strain of rat may affect pain related behavior. BUP should be used with caution after abdominal surgical procedures having high risk of POA formation.

Effect of anti-inflammatory agents on transforming growth factor beta over-expressing mouse brains: a model revised

BackgroundThe over-expression of transforming growth factor β-1(TGF-β1) has been reported to cause hydrocephalus, glia activation, and vascular amyloidβ (Aβ) deposition in mouse brains. Since these phenomena partially mimic the cerebral amyloid angiopathy (CAA) concomitant to Alzheimer's disease, the findings in TGF-β1 over-expressing mice prompted the hypothesis that CAA could be caused or enhanced by the abnormal production of TGF-β1. This idea was in accordance with the view that chronic inflammation contributes to Alzheimer's disease, and drew attention to the therapeutic potential of anti-inflammatory drugs for the treatment of Aβ-elicited CAA. We thus studied the effect of anti-inflammatory drug administration in TGF-β1-induced pathology.MethodsTwo-month-old TGF-β1 mice and littermate controls were orally administered pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, or ibuprofen, a non steroidal anti-inflammatory agent, for two months. Glia activation was assessed by immunohistochemistry and western blot analysis; Aβ precursor protein (APP) by western blot analysis; Aβ deposition by immunohistochemistry, thioflavin-S staining and ELISA; and hydrocephalus by measurements of ventricle size on autoradiographies of brain sections. Results are expressed as means ± SD. Data comparisons were carried with the Student's T test when two groups were compared, or ANOVA analysis when more than three groups were analyzed.ResultsAnimals displayed glia activation, hydrocephalus and a robust thioflavin-S-positive vascular deposition. Unexpectedly, these deposits contained no Aβ or serum amyloid P component, a common constituent of amyloid deposits. The thioflavin-S-positive material thus remains to be identified. Pioglitazone decreased glia activation and basal levels of Aβ42- with no change in APP contents – while it increased hydrocephalus, and had no effect on the thioflavin-S deposits. Ibuprofen mimicked the reduction of glia activation caused by pioglitazone and the lack of effect on the thioflavin-S-labeled deposits.Conclusionsi) TGF-β1 over-expressing mice may not be an appropriate model of Aβ-elicited CAA; and ii) pioglitazone has paradoxical effects on TGF-β1-induced pathology suggesting that anti-inflammatory therapy may reduce the damage resulting from active glia, but not from vascular alterations or hydrocephalus. Identification of the thioflavin-S-positive material will facilitate the full appraisal of the clinical implication of the effects of anti-inflammatory drugs, and provide a more thorough understanding of TGF-β1 actions in brain.

Systematic review for non-surgical interventions for the management of late radiation proctitis.

Chronic radiation proctitis produces a range of clinical symptoms for which there is currently no recommended standard management. The aim of this review was to identify the various non-surgical treatment options for the management of late chronic radiation proctitis and evaluate the evidence for their efficacy. Synonyms for radiation therapy and for the spectrum of lower gastrointestinal radiation toxicity were combined in an extensive search strategy and applied to a range of databases. The included studies were those that involved interventions for the non-surgical management of late radiation proctitis. Sixty-three studies were identified that met the inclusion criteria, including six randomised controlled trials that described the effects of anti-inflammatory agents in combination, rectal steroids alone, rectal sucralfate, short chain fatty acid enemas and different types of thermal therapy. However, these studies could not be compared. If the management of late radiation proctitis is to become evidence based, then, in view of its episodic and variable nature, placebo controlled studies need to be conducted to clarify which therapeutic options should be recommended. From the current data, although certain interventions look promising and may be effective, one small or modest sized study, even if well-conducted, is insufficient to implement changes in practice. In order to increase recruitment to trials, a national register of cases with established late radiation toxicity would facilitate multi-centre trials with specific entry criteria, formal baseline and therapeutic assessments providing standardised outcome data.British Journal of Cancer (2002) 87, 134–143. doi:10.1038/sj.bjc.6600360 www.bjcancer.com© 2002 Cancer Research UK

Involvement of brain cytokines in the neurobehavioral disturbances induced by HIV-1 glycoprotein120

Intracerebroventricular (i.c.v.) administration of HIV-1 glycoprotein 120 (gp120), the envelope protein used by the virus to gain access into immune cells, induces neurobehavioral alterations in rats. To examine the role of proinflammatory cytokines in mediating these effects, we measured the effects of gp120 on brain proinflammatory cytokine expression and the effects of anti-inflammatory agents, including interleukin-1 receptor antagonist (IL-1ra), pentoxifylline (a TNFα synthesis blocker) and IL-10, on gp120-induced sickness behavior. I.c.v. administration of gp120 induced the expression of IL-1β, but not TNFα, mRNA in the hypothalamus, 3 h after the injection. Pretreatment of rats with IL-1ra, but not with pentoxifylline, significantly attenuated gp120-induced anorexia and loss in body weight, whereas both agents had no effect on gp120-induced reduction in locomotor activity in the open field. Pretreatment with either IL-1ra and pentoxifylline simultaneously, or with IL-10, produced effects that were similar to the effects of IL-1ra alone. Together, these findings indicate that IL-1, but not TNFα, mediates some of the behavioral effects of acute gp120 administration, suggesting that brain IL-1 may be involved in some of the neurobehavioral abnormalities evident in AIDS patients.

The effect of prednisolone and non-steroidal anti-inflammatory agents on the normal and noise-damaged guinea pig inner ear

The effect of anti-inflammatory agents, such as the synthetic glucocorticoid prednisolone, diclofenac sodium, and histamine H1-receptor antagonist, was studied in unexposed and noise-exposed (broad-band noise, bandwidth 1–12 kHz, 106 dB SPL, 30 min) guinea pigs. The results were compared with the results obtained from no treatment and with isotonic saline (placebo) therapy. The cochlear blood flow (CoBF) and the partial oxygen pressure in the perilymph (PL-pO 2) were continuously and simultaneously recorded over a period of 210 min. In addition, cochlear microphonics (CMs), compound action potentials of the auditory nerve (CAPs), and auditory brain stem responses (ABRs) were registered. Noise-induced hearing loss paralleled a decrease of PL-pO 2. Both were found to occur before evidence of reduced CoBF. PL-pO 2 and CoBF progressively declined post-exposure, while CMs, CAPs, and ABRs did not further deteriorate nor showed signs of recovery up to 180 min after cessation of noise. Treatment started 60 min post-exposure, or after 90 min without manipulation and was then further studied for 120 min. In the unexposed animals, diclofenac sodium and prednisolone induced a significant decline of PL-pO 2, while CoBF, CMs, CAPs, and ABRs revealed no change. Isotonic saline did not influence the measured parameters. After infusion of the histamine H1-receptor antagonist, a significant decrease of CoBF together with blood pressure and CMs was observed, while PL-pO 2, CAPs, and ABRs showed no change. In the noise-exposed animals, diclofenac sodium induced partial restoration of CM and CAP amplitudes and full restoration of ABRs. Following a high dose of prednisolone (25 mg), partial restoration of CMs and full restoration of CAPs and ABRs were registered. This effect was significantly less pronounced following a low dose of prednisolone (2.5 mg). Restoration of CMs, CAPs, and ABRs was immediate (i.e. 50 min after infusion) and remained stable for another 60 min until the end of the recording period. The histamine H1-receptor antagonist and isotonic saline did not influence CMs, CAPs, and ABRs. None of the applied drugs resulted in relief of progressive noise-induced cochlear hypoxia and post-traumatic ischemia. These findings indicate direct cellular effects of prednisolone and diclofenac sodium in the cochlea taking into account no blood flow and oxygenation. The possible mechanisms involved are discussed.

S43-7 - Effects of antiinflammatory agents on matrix metalloproteinase-3(MMP-3) and tissue inhibitor of metalloproteinase-1 (TIMP-1) production by human chondrocyte

S43-7 - Effects of antiinflammatory agents on matrix metalloproteinase-3(MMP-3) and tissue inhibitor of metalloproteinase-1 (TIMP-1) production by human chondrocyte

Acute Therapy of Bacterial Meningitis

Antimicrobial therapy for bacterial meningitis has markedly reduced mortality rates from this disorder. The efficacy of an antibiotic in meningitis depends on many factors, including its penetration into cerebrospinal fluid (CSF), the bactericidal efficacy of the antibiotic within purulent CSF, and the need for bactericidal activity in CSF because bacterial meningitis represents an infection in an area of impaired host defense. Penicillin G and ampicillin are equally efficacious for meningitis caused by Streptococcus pneumoniae or Neisseria meningitidis. This recommendation may change, however, with the emergence of strains of pneumococci or meningococci that are relatively or highly resistant to penicillin; a third-generation cephalosporin (cefotaxime or ceftriaxone) should be used for meningitis due to relatively resistant strains and vancomycin for pneumococcal meningitis caused by strains that are highly resistant to penicillin. With the high percentage of strains of Haemopbilus influenzae type b that produce β-lactamase, empiric therapy when this organism is suspected should consist of a third-generation cephalosporin; these agents are also used for meningitis caused by enteric gram-negative bacilli, and one agent, ceftazidime, is effective against Pseudomonas aeruginosa meningitis. Despite the availability of effective bactericidal antibiotics, morbidity and mortality from bacterial meningitis remains unacceptably high. Recent studies using animal models of infection have demonstrated the beneficial effect of antiinflammatory agents in attenuating the CSF inflammatory response that may lessen many of the pathophysiological consequences of meningitis. Studies of adjunctive dexamethasone therapy suggest that these agents may reduce morbidity (specifically sensorineural hearing loss) and mortality (due to S. pneumoniae) in patients with bacterial meningitis. Controversy remains, however, concerning the use of dexamethasone in all patients with bacterial meningitis and further studies are necessary. In critically ill patients with bacterial meningitis, control of increased intracranial pressure and seizures may be useful and necessary in improving outcome.

Elevation of synovial plasminogen activator activity after injection of interleukin-1α into rabbit knee joint

We investigated production of plasminogen activator (PA) and cartilage degradation induced by injection of recombinant human interleukin-1 (rhIL-1 alpha) in rabbit knees. Rabbits were injected intra-articularly (i.a.) with 100 ng rhIL-1 alpha and necropsied at 0, 3, 6, 18 and 54 h and synovial lavage and articular cartilage were collected. PA activity in the joint lavage was measured using Z-Lys-thiobenzyl ester as a substrate. Cartilage degradation was assessed by quantitating sulfated glycosaminoglycan (S-GAG) to hydroxyproline (Hyp) and appearance of keratan sulfate (KS) in synovial lavage by and ELISA. The PA activity in the lavage of IL-1 injected knees at 3, 6, and 18 h was elevated 8 to 10 fold compared to vehicle controls. At 54 h the activity declined to approximately one third of that seen at the earlier time points. KS in the joint lavage was highest at 18 h, suggesting proteoglycan degradation. The maximal loss of cartilage proteoglycan (S-GAG/Hyp) occurred by 54 h. These observations demonstrate that i.a. injection of IL-1 stimulated the production of PA activity within the rabbit joint. Since elevation of PA activity is followed by cartilage degradation, we investigated effect of anti-inflammatory agents on PA activity and cartilage degradation in this model. We found that triamcinolone, indomethacin and dexamethasone were able to suppress PA activity but not the cartilage degradation. These observations suggest that in this model of cartilage degradation suppression of PA is not sufficient to inhibit cartilage degradation.

Detection of interleukin 8 and tumor necrosis factor in normal humans after intravenous endotoxin: the effect of antiinflammatory agents.

Interleukin 8 (IL-8), a potent activator of neutrophils, may be important in the early host response to serious Gram-negative infections. IL-8 was measured with other acute phase cytokines (tumor necrosis factor alpha [TNF-alpha], IL-6 and IL-1 beta) in 25 normal humans randomized to receive either intravenous endotoxin alone or endotoxin after oral administration of ibuprofen or pentoxifylline, agents that alter some of the inflammatory responses induced by endotoxin in vitro. TNF immunoreactivity was maximum at 1.5 h, and total TNF (area under the curve) was 4.2- and 4.5-fold greater in subjects given endotoxin/ibuprofen compared to subjects given endotoxin alone (p = 0.026) or endotoxin/pentoxifylline (p = 0.004), respectively. IL-6 levels were maximum at 2-3 h and did not differ among the three groups. No IL-1 beta was detected in any subject. IL-8 levels peaked at 2 h in subjects given either endotoxin alone or endotoxin/pentoxifylline, falling towards baseline by 5 h. Subjects given endotoxin/ibuprofen had a more sustained rise in IL-8 with peak levels 2.8- and 2.5-fold higher at 3 h compared to endotoxin alone (p = 0.048) or endotoxin/pentoxifylline (p = 0.023), respectively. Differences in total IL-8 release among groups approached statistical significance (ANOVA, p = 0.07). This trend reflected the increased release of IL-8 by the subjects receiving ibuprofen compared to pentoxifylline (1.9-fold higher; p = 0.024). This suggests that cyclooxygenase products may provide important negative feedback loops for cytokine production in vivo. Increases in circulating IL-8 are part of the acute inflammatory response of humans to endotoxin. Altered cytokine responses caused by antiinflammatory therapy may have important implications for both host defense and injury during septicemia.

Experimental Neoplastic Spinal Cord Compression; Effect of Anti-Inflammatory Agents and Glutamate Receptor Antagonists on Vascular Permeability

It has been demonstrated in paraplegic rats harboring an epidural neoplasm that an antiedema effect can be achieved by in vivo treatment with either steroidal or nonsteroidal anti-inflammatory agents or by glutamate receptor antagonists. The effect of these treatments on vascular permeability of the normal and compressed spinal cord was quantitated by the Evans blue dye technique. Tumor-free and tumor-bearing rats were assigned randomly for treatment as follows: 0.5 ml of saline or three doses at 12-hour intervals of either dexamethasone (5 mg/kg), methylprednisolone (30 mg/kg), indomethacin (5 mg/kg every 24 hours), or a single dose of either ketamine (110 mg/kg) or MK-801 (3 mg/kg). Treatment was given at the onset of paraplegia, and the animals were killed after 30 hours. In tumor-bearing rats in the early symptomatic stage, extravasation of Evans blue dye was 4.8 times greater than that of the normal cord (P less than 0.001) and at the onset of paraplegia it was 9.9 times greater (P less than 0.0006). Glucocorticoids and indomethacin reduced dye extravasation in paraplegic animals (P less than 0.01 and P less than 0.003, respectively), but the decreased permeability induced by ketamine and MK-801 did not reach the level of significance. In tumor-free control animals permeability was not changed by administration of either glucocorticoids or indomethacin but was significantly reduced by ketamine or MK-801 (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)