Lenhard D.C.,Bayer AG |
Pietsch H.,Bayer AG |
Sieber M.A.,Intendis GmbH |
Ernst R.,Bayer AG |
And 3 more authors.
Investigative Radiology | Year: 2012
OBJECTIVE: Nonionic iodinated contrast agents (CAs) can be divided into monomeric, low-osmolar, and dimeric, iso-osmolar classes. In clinical practice, renal tolerance of CAs is a concern, especially in patients with impaired renal function. With regard to renal safety, we wanted to evaluate the role of osmolality and viscosity in renal tolerance. MATERIAL AND METHODS: We generated a formulation (iodixanol/mannitol) consisting of the dimeric iodixanol with an osmolality of the monomeric iopromide. Male Han-Wistar rats were intravenously injected with low-osmolar iopromide 300, iso-osmolar iodixanol 320, and iodixanol/mannitol. Saline and diatrizoate were used as controls. A total number of 227 rats were used in the following experiments. We compared the impact of osmolality on renal iodine retention using computed tomography 2 and 24 hours postinjection (p.i.). The animals were killed 2, 24, and 72 hours after injection, and the kidneys were excised for further investigations. Changes in renal cell proliferation were analyzed by 5-bromo-2′-deoxyuridine incorporation 48 hours p.i. as a degree of tissue regeneration after induced injury. To specify potential renal injury, we quantified the expression of acute kidney injury (AKI) markers (kidney injury marker-1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL], and plasminogen activator inhibitor-1 [PAI-1]) by quantitative real-time polymerase chain reaction. Furthermore, the kidneys were analyzed histologically, including immunofluorescence analysis. RESULTS: After intravenous application of the CAs into Han-Wistar rats, renal iodine concentration was increased (3-fold) for iodixanol 2 hours p.i. and iodine retention was detected to be prolonged 24 hours p.i. compared with iopromide injection (iodixanol, 520 ± 50 Hounsfield Units [HU] vs iopromide, 42 ± 5 HU). The higher iodine concentration 2 hours p.i. upon iodixanol injection was reduced almost to the level of iopromide when injecting iodixanol/mannitol (iopromide: 289 ± 68 HU vs iodixanol/mannitol: 343 ± 68 HU). In addition, iodixanol application induced increased renal cell proliferation (2.7-fold vs saline), indicating renal injury, which was significantly lower in iopromide-treated animals (1.6-fold vs saline). More detailed analysis of markers for AKI revealed that iodixanol significantly induced the expression of PAI-1 (7.7-fold at 2 hours) as well as KIM-1 (2.1-fold) and NGAL (3.2-fold) at 2 and 24 hours when compared with saline treatment. In contrast, the expression of markers for AKI was low after iopromide (1.4-fold NGAL, 1.7-fold PAI-1, KIM-1 not significant) and iodixanol/mannitol (1.6-fold NGAL, 2.6-fold PAI-1, KIM-1 not significant) injection. CONCLUSION: The present results clearly show that prolonged iodine retention and the enhanced expression of kidney injury markers are caused mainly by the explicitly higher urine viscosity induced by iodixanol. We conclude that the osmolality of low-osmolar CAs such as iopromide induces a positive diuretic effect that is responsible for rapid iodine clearance and prevents increased expression of acute injury markers in the kidney. ©2012 by Lippincott Williams & Wilkins.
Havlickova B.,Intendis GmbH |
Havlickova B.,Charles University
Alimentary Pharmacology and Therapeutics | Year: 2010
Topical corticosteroids and local anaesthetics have been used for many years to relieve symptoms of anorectal diseases, such as pain, pruritus and bleeding. Few clinical trials have been published to allow comparisons of different combinations or different formulations, mainly because many of these products came to market before stringent peer review of clinical trials data was a prerequisite for registration. This article highlights why topical medications are necessary for the treatment of anorectal diseases, especially of inflammatory symptoms of haemorrhoids, anal eczema and others, particularly with respect to improving the quality of life of patients living with the pain and discomfort associated with such symptoms. It also demonstrates the efficacy and safety of combinations of topical corticosteroids and local anaesthetics in cream and suppository through reference to published clinical trials data, previously unpublished clinical trials data and real life clinical experience with these products. © 2010 Blackwell Publishing Ltd.
Jost G.,Bayer AG |
Lenhard D.C.,Bayer AG |
Sieber M.A.,Intendis GmbH |
Lengsfeld P.,Bayer AG |
And 2 more authors.
Investigative Radiology | Year: 2011
Objective: X-ray contrast agents (CA) possess specific physicochemical properties and are excreted renally by glomerular filtration. Thereby, they may affect the diffusion of water molecules within the kidney. The aim of our preclinical study was to investigate potential changes in the apparent diffusion coefficient (ADC) of the kidney after administration of monomeric, low-osmolar, and dimeric, iso-osmolar CA by using diffusion-weighted magnetic resonance imaging (DWI). MATERIAL AND METHODS:: First, the relationship between CA viscosity and the ADC of water was assessed by phantom measurements. Subsequently, Han Wistar rats (8 per group) received an intravenous injection of iso-osmolar CA (iodixanol) or low-osmolar CA (iopromide) at a dosage of 4 gI/kg body weight. The control group received saline (0.9% NaCl) at the same volume. The renal ADC was dynamically monitored up to 40 minutes postinjection (p.i.) by DWI using a 1.5-T clinical MR unit. After DWI, the animals were killed and the kidneys were removed for iodine measurements by X-ray fluorescence analysis. RESULTS:: The in vitro measurements yielded an inverse relationship between increasing viscosity and decreasing water diffusion. In vivo, a slight increase in ADC was observed immediately after administration of the low-osmolar iopromide (ΔADC = 80 ± 78 μm/s) and saline (ΔADC = 89 ± 53 μm/s), which normalized to the baseline level at 40 minutes p.i. In contrast, a strong decrease in ADC was observed after administration of the iso-osmolar iodixanol. This was most prominent 12 minutes p.i. (ΔADC =-555 ± 194 μm/s) and persisted throughout the investigation. Concomitantly, the kidney iodine concentration 50 minutes p.i. was significantly higher after iodixanol (58.6 ± 5.3 mgI/g kidney) compared with iopromide injection (18.4 ± 4.5 mgI/g kidney). CONCLUSION:: A significant difference in the renal ADC was observed between the low-osmolar CA/saline and the iso-osmolar CA. The in vitro measurements suggest that the substantial decrease in ADC observed after administration of the iso-osmolar CA is based on the high viscosity of the agent during renal passage. This, in turn, may explain the delayed iodine retention after administration of iso-osmolar CA and demonstrates the importance of the physicochemical properties of CA during their renal elimination. © 2011 by Lippincott Williams & Wilkins.
Del Rosso J.Q.,Valley Hospital Medical Center |
Bruce S.,Suzanne Bruce and Associates |
Jarratt M.,DermResearch Inc. |
Menter A.,Baylor Research Institute |
Staedtler G.,Intendis GmbH
Journal of Drugs in Dermatology | Year: 2010
Rosacea is a leading reason why people seek the care of a dermatologist, accounting for nearly 7 million office visits annually. Pharmacologic treatments include both topical and oral medications, which are increasingly being used in combination, especially at the outset of therapy. This exploratory study assesses the safety, effectiveness and speed of onset of two common topical agents for the treatment of rosacea - azelaic acid gel (AzA) 15% and metronidazole gel 1% - used in conjunction with anti-inflammatory dose doxycycline (40 mg once daily). Men and women (n=207) with mild-to-moderate papulopustular rosacea were enrolled and randomized to receive either AzA gel 15% twice daily plus doxycycline 40 mg once daily (AzA group) or metronidazole gel 1% once daily plus doxycycline 40 mg once daily (Metro group) for 12 weeks. Both regimens were safe, efficacious and well tolerated. Efficacy parameters revealed a possible trend toward greater and earlier benefit with the AzA-based regimen than with the metronidazole-based regimen. These findings warrant further investigation in a sufficiently powered study. Copyright © 2010 Journal of Drugs in Dermatology.
Mastrofrancesco A.,San Gallicano Dermatologic Institute IRCCS |
Ottaviani M.,San Gallicano Dermatologic Institute IRCCS |
Aspite N.,San Gallicano Dermatologic Institute IRCCS |
Cardinali G.,San Gallicano Dermatologic Institute IRCCS |
And 5 more authors.
Experimental Dermatology | Year: 2010
Azelaic acid (AzA), a nine-carbon dicarboxylic acid, is an agent for the topical treatment of acne. It has also been shown to be effective in rosacea; however, the mechanism of action has not been clarified. Because inflammation is a common feature of both conditions, we investigated the effects of azelaic acid on the inflammatory response of normal human keratinocytes to ultraviolet B light, which is a photosensitizer agent in rosacea. AzA, at 20 m. m, a concentration achievable following topical application of a 15% gel, suppresses ultraviolet B light-induced interleukins-1β, -6 and tumor necrosis factor-α mRNA expression and protein secretion. Mechanistically, azelaic acid significantly reduced the ultraviolet B light-induced nuclear translocation of nuclear factor kB p65 subunit and the phosphorylation of the p38 mitogen and stress-activated protein kinase. Moreover, as peroxisome proliferators-activated receptor γ, (PPARγ) which has a crucial role in the control of inflammation, is activated by fatty acids and products of lipid peroxidation, we further investigated the effect of azelaic acid on the expression of this nuclear receptor. AzA induced peroxisome proliferators-activated receptor-γ mRNA and its transcriptional activity. The PPARγ antagonist GW9662 abrogated the inhibitory effects of AzA on the UVB-induced pro-inflammatory cytokines release and on the cell proliferation. Our study provides new insights into the molecular mechanisms of the activity of azelaic acid and lands additional evidences for its therapeutic effects on inflammatory skin diseases, such as rosacea. © 2010 John Wiley & Sons A/S.