In vivo pharmacological evaluation of compound 48/80-induced airways edema by MRI

In vivo pharmacological evaluation of compound 48/80-induced airways edema by MRI

Br J Pharmacol. 2008 May 12

Karmouty-Quintana H, Blé FX, Cannet C, Zurbruegg S, Fozard JR, Page CP, Beckmann N.

[1] 1Global Imaging Group, Novartis Institutes for BioMedical Research, Basel, Switzerland [2] 2King's College, Division of Pharmaceutical Sciences, Sackler Institute of Pulmonary Pharmacology, London, UK [3] 3Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada.

Correspondence: Dr N Beckmann, Global Imaging Group, Novartis Institutes for BioMedical Research, Forum 1, Novartis Campus, WSJ-386.2.09, Basel CH-4056, Switzerland. E-mail: nicolau.beckmann@novartis.com

Background and purpose: Allergen-induced airways edema in actively sensitized rats has been studied earlier by magnetic resonance imaging (MRI). We used MRI to follow the consequences of non-immunological mast cell activation induced by compound 48/80 in the rat lungs in vivo.

Experimental approach: Male naïve rats were scanned by MRI prior to and at several time points following intratracheal administration of the mast cell secretagogue, compound 48/80. The effects of a range of drugs on the response induced by compound 48/80 were studied.

Key results: Strong fluid signals were detected by MRI in the lungs at 24 h after compound 48/80, correlating with increased protein concentration and inflammatory cell infiltration in bronchoalveolar lavage, and with perivascular oedema observed histologically. Pharmacological intervention demonstrated that the increase in MRI signal volume induced by compound 48/80 24 h after challenge was blocked by disodium cromoglycate and the glucocorticoid, budesonide.

Pretreatment with wortmannin, capsazepine, DNK333 (a dual neurokinin (NK) 1 and NK2 antagonist) or the anti-allergy drug CGS8515, but not indomethacin, resulted in partial inhibition.

Conclusions and implications: Compound 48/80 induced a complex inflammatory reaction which did not solely involve mast cell degranulation but also activation of sensory nerves and was qualitatively similar to allergen challenge. Changes observed by MRI correlated with decreases in protein concentration in BAL fluid. However, the magnitude of the changes detected was greater using MRI.

Our results demonstrate that MRI is a sensitive and efficient tool to assess the effects of drugs on lung inflammation.

British Journal of Pharmacology advance online publication, 12 May 2008; doi:10.1038/bjp.2008.174.

Keywords:
prostaglandin, leukotriene, cromoglycate, wortmannin, PI3-kinase, capsazepine, imaging, magnetic resonance imaging (MRI), lung, rat

Abbreviations:
AA, arachidonic acid; BAL, bronchoalveolar lavage; DSCG, disodium cromoglycate; EPO, eosinophil peroxidase; LO, lipoxygenase; 5-LO, 5-lipoxygenase; MRI, magnetic resonance imaging; NK, neurokinin; PG, prostaglandin; PI-3K, PI-3-kinase; TRPV, transient receptor potential vanilloid

Nature

Intravitreal pegaptanib sodium for refractory pseudophakic macular oedema.

Intravitreal pegaptanib sodium for refractory pseudophakic macular oedema.

Eye. 2008 Apr 18

Cervera E, Diaz-Llopis M, Udaondo P, Garcia-Delpech S.
1Department of Ophthalmology, Hospital General de Valencia, Valencia, Spain.

Purpose

Evaluate the efficacy of intravitreal pegaptanib sodium (Macugen((R))) in refractory pseudophakic cystoid macular oedema (CME).

Design and methods

Prospective, nonrandomized, interventional case series. Four eyes of four patients with refractory pseudophakic CME to pars plana vitrectomy and intravitreal bevacizumab and triamcinolone, were treated with pegaptanib sodium, with a mean follow up of 4 months. Pre- and postinfection examinations included assessment of best-corrected visual acuity (BCVA) using the Early Treatment Diabetic Retinopathy Study chart (ETDRS), fluorescein angiography (FA), and optical coherence tomography (OCT).

Results

Visual acuity increased in all patients after intravitreal pegaptanib sodium. OCT showed improvement of the retinal thickness in the macular area.

Conclusion

Intravitreal pegaptanib sodium (Macugen((R))) is a promising treatment for pseudophakic cystoid macular oedema resistant to other medical treatment strategies. However, further study is needed to assess the treatment's long term efficacy and the need for retreatment.Eye advance online publication, 18 April 2008; doi:10.1038/eye.2008.2.

PubMed

Ranibizumab for macular edema due to retinal vein occlusions: implication of VEGF as a critical stimulator

Ranibizumab for macular edema due to retinal vein occlusions: implication of VEGF as a critical stimulator

Mol Ther. 2008 Apr

Campochiaro PA, Hafiz G, Shah SM, Nguyen QD, Ying H, Do DV, Quinlan E, Zimmer-Galler I, Haller JA, Solomon SD, Sung JU, Hadi Y, Janjua KA, Jawed N, Choy DF, Arron JR.
Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA. pcampo@jhmi.edu

Macular edema is a major cause of vision loss in patients with central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO). It is not clear how much of the edema is due to hydrodynamic changes from the obstruction and how much is due to chemical mediators. Patients with macular edema due to CRVO (n = 20) or BRVO (n = 20) were randomized to receive three monthly injections of 0.3 or 0.5 mg of ranibizumab. At the primary endpoint, month 3, the median improvement in letters read at 4 m was 17 in the 0.3-mg group and 14 in the 0.5-mg group for CRVO, and 10 and 18, respectively for the BRVO group. Optical coherence tomography (OCT) showed that compared to injections of 0.3 mg, injections of 0.5 mg of ranibizumab tended to cause more rapid reductions of central retinal thickening that lasted longer between injections, but in 3 months, excess central retinal thickening which is a quantitative assessment of the macular edema, was reduced by approximately 90% in all four treatment groups. There was no correlation between the amount of improvement and duration of disease or patient age at baseline, but there was some correlation between the aqueous vascular endothelial growth factor (VEGF) level at baseline and amount of improvement. These data indicate that excess production of VEGF in the retinas of patients with CRVO or BRVO is a major contributor to macular edema and suggest that additional studies investigating the efficacy of intraocular injections of ranibizumab are needed.

Nature

Intravitreal steroids for macular edema: the past, the present, and the future

Intravitreal steroids for macular edema: the past, the present, and the future

Surv Ophthalmol. 2008 Mar-Apr

Cunningham MA, Edelman JL, Kaushal S.
Department of Ophthalmology, University of Florida College of Medicine, Gainesville, Florida.

Macular edema, a condition usually associated with an underlying disease process, is a common cause of severe visual loss. There have been a variety of approaches to the treatment of macular edema; within the past few years, however, intravitreal corticosteroid treatments have emerged as an increasingly used treatment option for patients with macular edema. Intravitreal delivery allows the steroid to bypass the blood-retinal barrier, leading to a more concentrated dose of steroid for a prolonged period of time. Corticosteroids have likely been successful in the treatment of various forms of macular edema, due to their known anti-angiogenic, anti-edematous, anti-inflammatory, anti-apoptotic, and anti-proliferative effects. Intravitreal triamcinolone acetonide has been repeatedly successful in reducing macular edema and improving visual acuity, although the duration of action is typically short-term. Due to the recurrent and chronic nature of macular edema, biodegradable implants may be the future of intravitreal steroids. Intravitreal corticosteroids are not without risks. Steroid-related side effects include cataract formation and elevated intraocular pressure. Injection-related side effects include retinal detachment, vitreous hemorrhage, bacterial endophthalmitis, and sterile endophthalmitis. This article reviews the evolving role of intravitreal corticosteroids in the treatment of macular edema secondary to uveitis, diabetes, and retinal vascular disorders.

Elsevier

Histopathological perspective on bone marrow edema, reactive bone change and haemorrhage.

Histopathological perspective on bone marrow oedema, reactive bone change and haemorrhage.

Eur J Radiol. 2008 Mar 11

Thiryayi WA, Thiryayi SA, Freemont AJ.
Department of Histopathology, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, United Kingdom.

This article presents a systematic review of the current biomedical literature surrounding the aetiopathogenesis and histopathological features of bone marrow oedema, reactive bone change and haemorrhage. Bone marrow oedema is generally demonstrated as a non-specific finding on magnetic resonance imaging in association with infections, tumours and avascular necrosis. When it occurs in isolation as a primary event not triggered by any obvious bony pathology in the clinical setting of debilitating joint pain, it constitutes the "bone marrow oedema syndrome". Although the latter diagnosis is based on magnetic resonance (MR) imaging, showing the lesion as areas of signal hyperintensity within the marrow, recent radiology-histology correlational studies have shown variably interstitial marrow oedema, necrosis, fibrosis and trabecular bone abnormalities. In light of these facts, the use of the term bone marrow oedema syndrome in a radiological context might be considered questionable, but histopathological techniques are not sensitive in detecting increased extracellular fluid. Reactive bone changes may be focal or diffuse and usually amount to increased bone formation. Bone marrow haemorrhage, due to trauma, results in bone bruising, a condition in which the size of the bruise and associated osteochondral injury determines the outcome, although the natural history of these lesions is still being researched.

PMID: 18337044 [PubMed - as supplied by publisher]

Bone Marrow Edema in the Cervical Spine of Symptomatic Rheumatoid Arthritis Patients

Bone Marrow Edema in the Cervical Spine of Symptomatic Rheumatoid Arthritis Patients

Semin Arthritis Rheum. 2008 Mar 11

Narváez JA, Narváez J, Albert MD, De Lama E, Serrallonga M, Nolla JM.
Department of Radiology, Hospital Universitario de Bellvitge-IDIBELL, Barcelona, Spain.

OBJECTIVE: To investigate the frequency and clinical significance of bone marrow edema (BME) in a series of patients with rheumatoid arthritis (RA) and symptomatic involvement of the cervical spine.

METHODS: We studied 19 consecutive RA patients with cervical spine magnetic resonance imaging (MRI) according to a specifically designed protocol that included short inversion time inversion recovery sequences. All cases had neck pain unresponsive to conventional treatment, neurological symptoms, or signs suggestive of cervical myelopathy, or cervical pain with evidence of atlantoaxial subluxation on radiographs.

RESULTS: The mean age of the 19 patients (15 women and 4 men) at time of the study was 59 +/- 12 years (range, 23-82) and the median disease duration was 14 +/- 7.4 years (range, 4-30). BME was observed in 74% (14/19) of the patients: at the atlantoaxial level alone in 16% of the patients; subaxially alone in 16%; and at both levels in 42% of the patients. At the atlantoaxial level, BME was usually observed involving the odontoid process, whereas subaxially BME was limited to the vertebral plates and the interapophyseal joints. Patients with BME had higher erythrocyte sedimentation rate (ESR) values at the time of MRI examination (P = 0.014) and more severe atlantoaxial joint MRI synovitis scores (P = 0.05) compared with the remaining patients; the frequency of odontoid erosions was also greater in this group, but the difference did not reach statistical significance. Altogether, these data suggest a more severe inflammatory response in these patients. In this group a significant correlation was found between BME scores at atlantoaxial level and (1) ESR values (r = 0.854; P = 0.001) and (2) atlantoaxial joint MRI synovitis scores (r = 0.691; P = 0.001).

CONCLUSION: BME is frequently observed in patients with established RA and symptomatic cervical spine involvement. Both atlantoaxial and subaxial levels are equally affected. Presence of BME seems related to the intensity of the inflammatory response and to the severity of the atlantoaxial joint synovitis.

PubMed

Burn Plasma Transfer Induces Burn Edema in Healthy Rats

Burn Plasma Transfer Induces Burn Edema in Healthy Rats
Shock. 2008 Feb 21
Kremer T, Abé D, Weihrauch M, Peters C, Gebhardt MM, Germann G, Heitmann C, Walther A.
*Department of Hand, Plastic and Reconstructive Surgery, Burn Center-BG Trauma Center Ludwigshafen, Plastic and Hand Surgery, University of Heidelberg, Ludwigshafen; †Departments of Anesthesiology and ‡Experimental Surgery, University of Heidelberg, Heidelberg, Germany.

Thermal injuries greater than 20% body surface area (BSA) result in systemic shock with generalized edema in addition to local tissue destruction. Burn shock is induced by a variety of mediators, mainly immunomodulative cytokines. This experimental study evaluates if burn shock can be induced in healthy rats by transfer of burn plasma (BP) with mediators. Thermal injury was induced by hot water (100 degrees C water, 12 s, 30% BSA) in male syngenic Wistar rats. Donor rats were killed 4 h posttrauma, and BP was harvested. Burn plasma was transferred to healthy animals by continuous intravenous infusion in three types of dilution (100%, 10%, and 1%). Positive controls were directly examined 4 h after thermal injury, and negative control rats had a continuous infusion done with sham burn (SB) plasma (37 degrees C water, 12 s, 30% BSA). Afterwards, intravital fluorescence microscopy was performed in postcapillary mesenteric venules at 0, 60, and 120 min. Edema formation was assessed by relative changes over time in fluorescence intensity of fluorescein isothiocyanate-albumin in the intravascular versus the extravascular space. The interactions of leucocytes and endothelium were evaluated by quantification of leukocyte sticking. Additionally, microhemodynamic (volumetric blood flow, erythrocyte velocity, venular wall shear rate, venular diameters) and macrohemodynamic parameters (blood pressure, heart frequency, temperature) were assessed online (arterial catheter). For statistics, an ANOVA was performed with Bonferroni adjustment procedure. Differences were considered significant when P less 0.05. There are no statistically significant differences in microhemodynamics or macrohemodynamics between study groups. Burn plasma infusion and thermal injury lead to significant increases in fluorescein isothiocyanate-albumin extravasation, whereas SB plasma shows no significant changes. Even BP diluted in 0.9% saline (10% and 1%) results in a similar transvascular flux of plasma proteins as direct thermal injury. Differences between positive controls and BP infusion are not significant, whereas all groups are statistically different from the SB group (P less than 0.05). Leukocyte sticking is significantly increased in all groups except the SB group, and the number of adherent leukocytes is dose dependent. The present study demonstrates that as early as 4 h after thermal injury, there are sufficient factors (e.g., cytokines) in BP to induce systemic burn shock in healthy rats even in diluted plasma (1%). However, the "key" cytokines are not identified at this point. The burned tissue is no longer required for burn shock induction, and the pathophysiologic process seems to be self-perpetuating as early as 4 h posttrauma. Leukocytes are activated by thermal injury and BP infusion. The role of leukocyte-endothelium interactions for edema formation remains uncertain and requires further investigation.

PubMed

The Role of Aquaporin-4 Polymorphisms in the Development of Brain Edema After Middle Cerebral Artery Occlusion.

The Role of Aquaporin-4 Polymorphisms in the Development of Brain Edema After Middle Cerebral Artery Occlusion.

Stroke. 2008 Feb 28

Ilka Kleffner MD*; May Bungeroth; Hagen Schiffbauer MD; Wolf-Ruediger Schäbitz MD; E. Bernd Ringelstein MD; and Gregor Kuhlenbäumer MD
From the Departments of Neurology (I.K., W.R.S., E.B.R., G.K.), and Clinical Radiology (H.S.), and the Leibniz-Institute of Atherosclerosis Research (M.B., E.B.R., G.K.), University of Münster, Münster, Germany.

* To whom correspondence should be addressed. E-mail: kleffnil@uni-muenster.de

BACKGROUND AND PURPOSE: Some patients develop severe brain edema after complete middle cerebral artery occlusion, whereas others do not. Aquaporin-4 (AQP4) is the main water channel in the brain and has been shown to be critical for the development of brain edema after ischemia. We asked whether genetic variation in the AQP4 gene is related to the severity of brain edema after middle cerebral artery occlusion.

METHODS: We genotyped 10 single nucleotide polymorphisms distributed across the AQP4 gene in 41 patients with middle cerebral artery occlusion with and without severe brain edema and assessed single marker association as well as the linkage dysequilibrium structure across AQP4.

RESULTS: One single nucleotide polymorphism (rs9951307) at the 3' end of AQP4 was associated with severe brain edema (dominant model, P=0.01; OR, 0.10; 95% CI, 0.02 to 0.49 for the protective G-allele). Linkage dysequilibrium across AQP4 was low; no clear haplotype blocks could be identified for the assessment of haplotype association.

CONCLUSIONS: This explorative study shows that genetic variation in AQP4 might contribute to brain edema formation after middle cerebral artery occlusion and warrants further investigation.

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