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  • 1
    Language: English
    In: European radiology, 2009-01-24, Vol.19 (6), p.1417-1424
    Description: Several publications suggest a potential association between the administration of Gadolinium-based contrast agents (GBCAs) and the onset of a rare but serious disease, Nephrogenic Systemic Fibrosis (NSF). The aim of this study was to determine the elimination time-course of Gadolinium (Gd) from skin tissue after application of GBCAs in rats. Seven different marketed GBCAs were injected on five consecutive days at a dose of 2.5 mmol/kg bodyweight into the tail vein of Han-Wistar rats and the Gd concentrations were determined by Inductively Coupled Plasma Mass Spectrometry (ICP-MS) in skin biopsies taken at various time-points up to a year after the last injection. Most of the administered Gd was eliminated from the skin within a time-period of about 2 months. However, the repeated administration of linear GBCAs resulted in long-term retention of a small portion of the administered Gd in the skin tissue of rats, with substantially higher values observed in animals treated with non-ionic linear agents than in those that received ionic linear GBCAs. Following treatment with macrocyclic GBCAs, Gd values in the skin were in the same range as observed in the controls from day 24 post-injection onwards. In summary, we observed a correlation between the complex stability of GBCAs and the amount of residual Gd in the skin up to a year after application of GBCAs.
    Subject(s): Administration, Topical ; Animals ; Contrast Media ; Contrast Media - administration & dosage ; Contrast Media - pharmacokinetics ; Dermatologic agents ; Dermatology ; Diagnostic Radiology ; Formulae, receipts, prescriptions ; Gadolinium ; Gadolinium - administration & dosage ; Gadolinium - pharmacokinetics ; Imaging ; Internal Medicine ; Interventional Radiology ; Mass spectrometry ; Medicine ; Medicine & Public Health ; Metabolic Clearance Rate ; Neuroradiology ; Radiology ; Rats ; Rats, Wistar ; Skin - metabolism ; Skin Absorption - physiology ; Surface active agents ; Ultrasound
    ISSN: 0938-7994
    E-ISSN: 1432-1084
    Source: Alma/SFX Local Collection
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  • 2
    Language: English
    In: Nature medicine, 2012-01-22, Vol.18 (2), p.252-259
    Description: Noise-induced hearing loss (NIHL) is a global health hazard with considerable pathophysiological and social consequences that has no effective treatment. In the heart, lung and other organs, cyclic guanosine monophosphate (cGMP) facilitates protective processes in response to traumatic events. We therefore analyzed NIHL in mice with a genetic deletion of the gene encoding cGMP-dependent protein kinase type I (Prkg1) and found a greater vulnerability to and markedly less recovery from NIHL in these mice as compared to mice without the deletion. Prkg1 was expressed in the sensory cells and neurons of the inner ear of wild-type mice, and its expression partly overlapped with the expression profile of cGMP-hydrolyzing phosphodiesterase 5 (Pde5). Treatment of rats and wild-type mice with the Pde5 inhibitor vardenafil almost completely prevented NIHL and caused a Prkg1-dependent upregulation of poly (ADP-ribose) in hair cells and the spiral ganglion, suggesting an endogenous protective cGMP-Prkg1 signaling pathway that culminates in the activation of poly (ADP-ribose) polymerase. These data suggest vardenafil or related drugs as possible candidates for the treatment of NIHL.
    Subject(s): Animals ; Care and treatment ; Cellular signal transduction ; Cyclic GMP-Dependent Protein Kinase Type I ; Cyclic GMP-Dependent Protein Kinases - physiology ; Cyclic guanylic acid ; Cyclic Nucleotide Phosphodiesterases, Type 5 - drug effects ; Cyclic Nucleotide Phosphodiesterases, Type 5 - physiology ; Deafness, Noise induced ; Ears & hearing ; Enzyme Activation ; Female ; Genetic aspects ; Hair cells (Mechanoreceptors) ; Hair Cells, Auditory - metabolism ; Hair Cells, Auditory - physiology ; Hair Cells, Auditory, Inner - metabolism ; Hair Cells, Auditory, Inner - physiology ; Hair Cells, Auditory, Outer - metabolism ; Hair Cells, Auditory, Outer - physiology ; Hearing impairment ; Hearing Loss, Noise-Induced - genetics ; Hearing Loss, Noise-Induced - physiopathology ; Hearing Loss, Noise-Induced - prevention & control ; Imidazoles - pharmacology ; Mice ; Mice, Mutant Strains ; Noise ; Noise - adverse effects ; Phosphodiesterase 5 Inhibitors - pharmacology ; Physiological aspects ; Piperazines - pharmacology ; Poly Adenosine Diphosphate Ribose - biosynthesis ; Poly(ADP-ribose) Polymerases - metabolism ; Rats ; Rats, Wistar ; Research ; Signal Transduction - genetics ; Signal Transduction - physiology ; Sulfones - pharmacology ; Triazines - pharmacology ; Up-Regulation - drug effects ; Vardenafil Dihydrochloride
    ISSN: 1078-8956
    E-ISSN: 1546-170X
    Source: Academic Search Ultimate
    Source: Get It Now
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  • 3
    Language: English
    In: Nuclear medicine and biology, 2014, Vol.41 (7), p.562-569
    Description: Abstract Introduction Atherosclerotic plaque rupture is the primary cause for myocardial infarction and stroke. During plaque progression macrophages and mast cells secrete matrix-degrading proteolytic enzymes, such as matrix metalloproteinases (MMPs). We studied levels of MMPs and tissue inhibitor of metalloproteinases-3 (TIMP-3) in relation to the characteristics of carotid plaques. We evaluated in vitro two radiolabeled probes targeting active MMPs towards non-invasive imaging of rupture-prone plaques. Methods Human carotid plaques obtained from endarterectomy were classified into stable and vulnerable by visual and histological analysis. MMP-1, MMP-2, MMP-8, MMP-9, MMP-10, MMP-12, MMP-14, TIMP-3, and CD68 levels were investigated by quantitative polymerase chain reaction. Immunohistochemistry was used to localize MMP-2 and MMP-9 with respect to CD68-expressing macrophages. Western blotting was applied to detect their active forms. A fluorine-18-labeled MMP-2/MMP-9 inhibitor and a tritiated selective MMP-9 inhibitor were evaluated by in vitro autoradiography as potential lead structures for non-invasive imaging. Results Gene expression levels of all MMPs and CD68 were elevated in plaques. MMP-1, MMP-9, MMP-12 and MMP-14 were significantly higher in vulnerable than stable plaques. TIMP-3 expression was highest in stable and low in vulnerable plaques. Immunohistochemistry revealed intensive staining of MMP-9 in vulnerable plaques. Western blotting confirmed presence of the active form in plaque lysates. In vitro autoradiography showed binding of both inhibitors to stable and vulnerable plaques. Conclusions MMPs differed in their expression patterns among plaque phenotypes, providing possible imaging targets. The two tested MMP-2/MMP-9 and MMP-9 inhibitors may be useful to detect atherosclerotic plaques, but not the vulnerable lesions selectively.
    Subject(s): Aged ; Aged, 80 and over ; Animals ; Antigens, CD - genetics ; Antigens, CD - metabolism ; Antigens, Differentiation, Myelomonocytic - genetics ; Antigens, Differentiation, Myelomonocytic - metabolism ; Arteries - metabolism ; Atherosclerosis ; Autoradiography ; Benzoic Acid - chemistry ; Carotid artery plaque ; Female ; Gene expression ; Gene Expression Regulation, Enzymologic ; Humans ; Immunohistochemistry ; Inflammation ; Isotope Labeling ; Macrophages - metabolism ; Male ; Matrix Metalloproteinase Inhibitors - chemistry ; Matrix metalloproteinases ; Matrix Metalloproteinases - genetics ; Matrix Metalloproteinases - metabolism ; Mice ; Middle Aged ; Molecular Imaging - methods ; Plaque, Atherosclerotic - diagnosis ; Plaque, Atherosclerotic - genetics ; Plaque, Atherosclerotic - metabolism ; Proteases ; Protein Transport ; Radiology ; Tissue inhibitor of metalloproteinase-3 ; Tissue Inhibitor of Metalloproteinase-3 - genetics ; Tissue Inhibitor of Metalloproteinase-3 - metabolism ; Tritium
    ISSN: 0969-8051
    E-ISSN: 1872-9614
    Source: Backfile Package - All of Back Files EBS [ALLOFBCKF]
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  • 4
    Language: English
    In: Journal of medicinal chemistry, 2013-06-27, Vol.56 (12), p.4912-4920
    Description: The activity of matrix metalloproteinases (MMPs) is elevated locally under many pathological conditions. Gelatinases MMP2 and MMP9 are of particular interest because of their implication in angiogenesis, cancer cell proliferation and metastasis, and atherosclerotic plaque rupture. The aim of this study was to identify and develop a selective gelatinase inhibitor for imaging active MMP2/MMP9 in vivo. We synthesized a series of N-sulfonylamino acid derivatives with low to high nanomolar inhibitory potencies. (R)-2-(4-(4-Fluorobenzamido)phenylsulfonamido)-3-(1H-indol-3-yl)propanoic acid (7) exhibited the best in vitro binding properties: MMP2 IC50 = 1.8 nM, MMP9 IC50 = 7.2 nM. Radiolabeling of 7 with no carrier added 18F-radioisotope was accomplished starting from iodonium salts as precursors. The radiochemical yield strongly depended on the iodonium counteranion (ClO4 – 〉 Br– 〉 TFA– 〉 tosylate). 18F-7 was obtained in up to 20% radiochemical yield (decay corrected), high radiochemical purity, and 〉90 GBq/μmol specific radioactivity. The radiolabeled compound showed excellent stability in vitro and in mice in vivo.
    Subject(s): Animals ; Chemistry Techniques, Synthetic ; Drug Design ; Fluorine Radioisotopes ; Humans ; Matrix Metalloproteinase 2 - metabolism ; Matrix Metalloproteinase 9 - metabolism ; Matrix Metalloproteinase Inhibitors - chemical synthesis ; Matrix Metalloproteinase Inhibitors - chemistry ; Matrix Metalloproteinase Inhibitors - pharmacology ; Mice ; Mice, Inbred C57BL ; Multimodal Imaging - methods ; Positron-Emission Tomography ; Tomography, X-Ray Computed
    ISSN: 0022-2623
    E-ISSN: 1520-4804
    Source: Hellenic Academic Libraries Link
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  • 5
    Language: English
    In: Investigative radiology, 2008-12, Vol.43 (12), p.817-828
    Description: Assessment of the complex stability and Gd3+ dissociation rate of all marketed gadolinium-based MRI contrast agents (GBCA) in human serum at pH 7.4 and 37 degrees C. The kinetic profiles of Gd3+ dissociation of GBCAs were determined by incubation for 15 days in human serum from healthy volunteers at a concentration of 1 mmol/L, pH 7.4, and 37 degrees C. The initial rates of Gd3+ release and the amounts of Gd3+ released after 15 days were established by HPLC-ICP-MS analysis. In an attempt to simulate the situation in patients with end-stage renal disease who often have elevated serum phosphate levels, the influence of 10 mmol/L phosphate on Gd3+ dissociation was also investigated.The GBCAs were grouped and ranked in the following order according to their stabilities in native human serum at pH 7.4 and 37 degrees C [% Gd release after 15 days and initial rate (%/d) (95% confidence interval) in brackets]. NONIONIC LINEAR GBCAS: Optimark [21 (19-22) %, 0.44 (0.40-0.51) %/d) and Omniscan [20 (17-20) %, 0.16 (0.15-0.17) %/d]. IONIC LINEAR GBCAS: Magnevist [1.9 (1.2-2.0) %, 0.16 (0.12-0.36) %/d], Multihance [1.9 (1.3-2.1) %, 0.18 (0.13-0.38) %/d], Vasovist [1.8 (1.4-1.9) %, 0.12 (0.11-0.18) %/d], and Primovist [1.1 (0.76-1.2) %, 0.07 (0.05-0.08) %/d]. MACROCYCLIC GBCAS: Gadovist, Prohance, and Dotarem (all 〈 limit of quantification of 0.1%, 〈0.007%/d).In the presence of additional 10 mmol/L phosphate in serum, the initial Gd release rates of the nonionic linear GBCAs, Omniscan, and Optimark increased about 100-fold, and, after 15 days, the amount of Gd3+ released from these agents was more than 75% higher than in native serum. The initial rates found for the ionic linear GBCAs increased about 12- to 30-fold, but, despite this, increase in the initial rate, the amount of Gd3+ released after 15 days was comparable to that in native serum. The elevated phosphate level did not lead to any measurable release of Gd3+ from the 3 macrocyclic GBCAs. The release of Gd from all linear Gd3+ complexes in human serum was several orders of magnitude greater than predicted by the conditional stability constants. After 15 days, release of Gd3+ from the nonionic linear GBCAs was about 10 times higher than from the ionic linear GBCAs. Elevated serum phosphate levels accelerated the release of Gd3+ from nonionic linear GBCAs and, to a lesser degree, from the ionic linear GBCAs. All 3 macrocyclic GBCAs remained stable in human serum at both normal and elevated phosphate levels.
    Subject(s): Blood Chemical Analysis ; Body Temperature ; Chemistry ; Contrast Media - chemistry ; Drug Stability ; Gadolinium - chemistry ; Humans ; Magnetic Resonance Imaging - methods ; Serum - chemistry
    E-ISSN: 1536-0210
    Source: Hellenic Academic Libraries Link
    Source: Alma/SFX Local Collection
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  • 6
    Language: English
    In: BJU international, 2006-12, Vol.98 (6), p.1259-1263
    Description: OBJECTIVE To evaluate the potential of sildenafil, vardenafil and tadalafil, all phosphodiesterase‐5 (PDE‐5) inhibitors used for treating erectile dysfunction, for treating benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). MATERIALS AND METHODS The mRNA expression of the PDE‐5 was determined in rat LUT tissues. The PDE‐5 inhibitors were also tested in organ‐bath experiments and in a partial bladder outlet obstruction (BOO) rat model in vivo. RESULTS The highest PDE‐5 mRNA expression was in the bladder, followed by the urethra and prostate. PDE‐5 inhibitors dose‐dependently reduced the contraction of the isolated bladder, urethral and prostate strips. The rank order of potency was vardenafil 〉 sildenafil 〉 tadalafil. In human prostate stromal cells vardenafil inhibited cell proliferation and was more effective than tadalafil and sildenafil. In the BOO model, there was a reduction in the non‐voiding contractions after bolus intravenous administration of 3 mg/kg sildenafil and vardenafil. CONCLUSION These results show that PDE‐5 is expressed in LUT tissues. PDE‐5 inhibitors induced significant relaxation of these tissues, inhibited the proliferation of human prostate stromal cells and reduced the irritative symptoms of BPH/LUTS in vivo. Therefore, PDE‐5 inhibitors could be used as an effective treatment for BPH/LUTS.
    Subject(s): 3',5'-Cyclic-GMP Phosphodiesterases - antagonists & inhibitors ; 3',5'-Cyclic-GMP Phosphodiesterases - metabolism ; Analysis ; Animals ; Biological and medical sciences ; bladder outlet obstruction ; BPH ; Carbolines - therapeutic use ; Cyclic Nucleotide Phosphodiesterases, Type 5 ; Genital system. Reproduction ; Hypertrophy ; Imidazoles - therapeutic use ; LUTS ; Male ; Medical sciences ; Nephrology. Urinary tract diseases ; PDE‐5 inhibitors ; Pharmacology. Drug treatments ; Phosphodiesterase Inhibitors - therapeutic use ; Piperazines - therapeutic use ; Prostate ; Prostatic Hyperplasia - complications ; Prostatic Hyperplasia - drug therapy ; Prostatism - drug therapy ; Prostatism - etiology ; Purines ; Rats ; Rats, Sprague-Dawley ; RNA, Messenger - metabolism ; Sildenafil Citrate ; Sulfones - therapeutic use ; Tadalafil ; Treatment Outcome ; Triazines - therapeutic use ; Tumors of the urinary system ; Urinary tract. Prostate gland ; Usage ; Vardenafil Dihydrochloride
    ISSN: 1464-4096
    E-ISSN: 1464-410X
    Source: Hellenic Academic Libraries Link
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
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  • 7
    Language: English
    In: Investigative radiology, 2008-12, Vol.43 (12), p.817-828
    Description: OBJECTIVES:Assessment of the complex stability and Gd dissociation rate of all marketed gadolinium-based MRI contrast agents (GBCA) in human serum at pH 7.4 and 37°C. METHODS AND RESULTS:The kinetic profiles of Gd dissociation of GBCAs were determined by incubation for 15 days in human serum from healthy volunteers at a concentration of 1 mmol/L, pH 7.4, and 37°C. The initial rates of Gd release and the amounts of Gd released after 15 days were established by HPLC-ICP-MS analysis. In an attempt to simulate the situation in patients with end-stage renal disease who often have elevated serum phosphate levels, the influence of 10 mmol/L phosphate on Gd dissociation was also investigated.The GBCAs were grouped and ranked in the following order according to their stabilities in native human serum at pH 7.4 and 37°C [% Gd release after 15 days and initial rate (%/d) (95% confidence interval) in brackets]. NONIONIC LINEAR GBCAS:Optimark [21 (19–22) %, 0.44 (0.40–0.51) %/d) and Omniscan [20 (17–20) %, 0.16 (0.15–0.17) %/d]. IONIC LINEAR GBCAS:Magnevist [1.9 (1.2–2.0) %, 0.16 (0.12–0.36) %/d], Multihance [1.9 (1.3–2.1) %, 0.18 (0.13–0.38) %/d], Vasovist [1.8 (1.4–1.9) %, 0.12 (0.11–0.18) %/d], and Primovist [1.1 (0.76–1.2) %, 0.07 (0.05–0.08) %/d]. MACROCYCLIC GBCAS:Gadovist, Prohance, and Dotarem (all 〈 limit of quantification of 0.1%, 〈0.007%/d).In the presence of additional 10 mmol/L phosphate in serum, the initial Gd release rates of the nonionic linear GBCAs, Omniscan, and Optimark increased about 100-fold, and, after 15 days, the amount of Gd released from these agents was more than 75% higher than in native serum. The initial rates found for the ionic linear GBCAs increased about 12- to 30-fold, but, despite this, increase in the initial rate, the amount of Gd released after 15 days was comparable to that in native serum. The elevated phosphate level did not lead to any measurable release of Gd from the 3 macrocyclic GBCAs. CONCLUSIONS:The release of Gd from all linear Gd complexes in human serum was several orders of magnitude greater than predicted by the conditional stability constants. After 15 days, release of Gd from the nonionic linear GBCAs was about 10 times higher than from the ionic linear GBCAs. Elevated serum phosphate levels accelerated the release of Gd from nonionic linear GBCAs and, to a lesser degree, from the ionic linear GBCAs. All 3 macrocyclic GBCAs remained stable in human serum at both normal and elevated phosphate levels.
    ISSN: 0020-9996
    E-ISSN: 1536-0210
    Source: Hellenic Academic Libraries Link
    Source: Alma/SFX Local Collection
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  • 8
    Language: English
    In: European journal of cardio-thoracic surgery, 2007-08, Vol.32 (2), p.340-345
    Description: Objective: Aprotinin is a widely used serine protease inhibitor during cardiopulmonary bypass to reduce blood loss and preserve platelet function. However, the bovine-derived aprotinin can induce hypersensitivity reaction with fatal complications. Furthermore, vascular effects of aprotinin are not completely elucidated. The current study is designed to investigate the effects of recently developed recombinant aprotinin on blood loss and coronary vascular function in a clinically relevant canine model of cardiopulmonary bypass without aortic cross-clamping and cardioplegia. Methods: Twenty-four dogs underwent cardiopulmonary bypass without aortic cross-clamping and cardioplegia. Dogs were divided into three groups in a blinded fashion: control animals (n = 8) received placebo, aprotinin treatment groups received bovine (n = 8) or recombinant aprotinin (n = 8) according to the Hammersmith method. The doses of bovine and recombinant aprotinin were the same. Coagulation parameters and blood loss were measured regularly at different time points. Endothelium-dependent and -independent vasorelaxation were investigated in isolated left anterior descendent coronary arterial rings by using acetylcholine and bradykinin or sodium nitroprusside and adenosine, respectively. Results: Postoperative blood loss was significantly reduced in the aprotinin-treated groups in comparison to control and there was no significant difference between the two aprotinin-treated groups. Endothelium-dependent relaxation of coronary arteries to acetylcholine and bradykinin was unaffected in the aprotinin treatment groups. Both types of aprotinin significantly increased vasorelaxation to adenosine when compared with controls, but did not affect that to sodium nitroprusside. Conclusions: The effectiveness of recombinant aprotinin on blood loss was equivalent to bovine-derived aprotinin. Neither types of aprotinin impaired endothelium-dependent relaxation in a canine model of cardiopulmonary bypass.
    Subject(s): 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - pharmacology ; Acetylcholine - pharmacology ; Analysis ; Animals ; Aprotinin ; Aprotinin - administration & dosage ; Biological and medical sciences ; Blood Coagulation - drug effects ; Blood Coagulation - physiology ; Blood loss ; Bradykinin - pharmacology ; Cardiology. Vascular system ; Cardiopulmonary bypass ; Cardiopulmonary Bypass - methods ; Cattle ; Coronary artery bypass ; Coronary endothelial function ; Coronary heart disease ; Coronary Vessels - drug effects ; Coronary Vessels - physiopathology ; Dogs ; Drug Administration Schedule ; Endothelium, Vascular - drug effects ; Endothelium, Vascular - physiopathology ; Heart ; Medical sciences ; Models, Animal ; Myocardial Contraction - drug effects ; Myocardial Contraction - physiology ; Nitroprusside - pharmacology ; Postoperative Hemorrhage - prevention & control ; Recombinant Proteins - administration & dosage ; Serine Proteinase Inhibitors - administration & dosage ; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases ; Surgery of the heart ; Vasoconstrictor Agents - pharmacology ; Vasodilator Agents - pharmacology ; Vasorelaxation
    ISSN: 1010-7940
    E-ISSN: 1873-734X
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: Alma/SFX Local Collection
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  • 9
    Language: English
    In: Investigative radiology, 2010-05, Vol.45 (5), p.255-261
    Description: OBJECTIVE:The iodinated contrast agents (CAs) that are currently used in radiographic procedures possess special physicochemical properties and a high safety profile; however, according to a large retrospective study (Swedish registry), the viscosity of CAs may have an underestimated impact on renal failure. The aim of our study was to investigate the possible consequences of CA viscosity differences, such as CA retention in the kidney. MATERIAL AND METHODS:Five Göttingen minipigs were each intravenously injected in a crossover setting at intervals of at least 7 days with monomeric (Iopromide) and dimeric (Iodixanol) CAs at 2 doses (1 and 2 g iodine/kg bodyweight), and the retention of the CA in the kidneys was determined during the first 6 hours postinjection using a 64-slice computed tomography scanner. Additionally we performed in vitro dialysis of the monomeric and dimeric CAs across the various physiological osmolalities of the renal tubulus (300, 600, 800, and 1200 mOsm/kg H2O) to estimate CA viscosity in vivo. Following the dialyzes, iodine concentrations and CA viscosities were determined. RESULTS:A different exposure of the kidneys to iodine and a different elimination kinetics from the kidneys was observed after the administration of monomeric and dimeric CAs. The monomeric agent was observed to clear from the kidney immediately after administration. In contrast, after administration of the dimeric CA an increase in iodine concentration in the kidney was observed up to 180 minutes postinjection, before the CA was observed to begin clearing; however, no difference was observed between the plasma half-lives of the 2 investigated CAs. In vitro dialysis of the dimeric CA increased iodine concentrations and strongly increased viscosity at all of the tested osmolalities. In contrast, the monomeric agent only demonstrated increases in iodine concentration and viscosity at 800 and 1200 mOsm/kg, and these changes were smaller than those observed for the dimeric CA. In summary, dialysis strongly enhanced the viscosity differences between the 2 investigated CAs. CONCLUSION:The viscosity differences between the investigated monomeric and dimeric CAs are strongly enhanced by concentration processes, such as the process taking place in the tubular system. These viscosity differences may be the cause of the prolonged retention and the different elimination kinetics from the kidney observed after application of the dimeric CA relative to the monomeric CA.
    Subject(s): Animals ; Contrast Media - pharmacokinetics ; Dialysis ; Female ; Half-Life ; Iodine - blood ; Iodine - chemistry ; Iodine - pharmacokinetics ; Iohexol - analogs & derivatives ; Iohexol - pharmacokinetics ; Kidney - diagnostic imaging ; Kidney - physiology ; Male ; Osmolar Concentration ; Swine ; Swine, Miniature ; Tomography, X-Ray Computed ; Triiodobenzoic Acids - pharmacokinetics ; Viscosity
    ISSN: 0020-9996
    E-ISSN: 1536-0210
    Source: Hellenic Academic Libraries Link
    Source: Alma/SFX Local Collection
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  • 10
    Language: English
    In: Investigative radiology, 2009-04, Vol.44 (4), p.226-233
    Description: OBJECTIVE:Several publications have suggested a possible association between Gd-based contrast agents (GBCAs) and the development of nephrogenic systemic fibrosis, a rare but serious disease. To date, nephrogenic systemic fibrosis has been observed only in patients with severe renal insufficiency.The aim of this study was to determine the impact of a prolonged circulation time of GBCAs caused by reduced renal clearance on the long-term retention of Gd in the skin of rats after administration of different GBCAs. MATERIAL AND METHODS:Renally impaired Han Wistar Rats (5/6-nephrectomized rats) were injected with Omniscan, OptiMARK, Magnevist, or Gadovist. The contrast agents were administered once daily for 5 consecutive days into the tail vein at a dose of 2.5 mmol Gd/kg b.w. Skin biopsies were taken at various time points, and the gadolinium (Gd) concentration was determined by inductive coupled plasma mass spectrometry (ICP-MS) over an observation period of 168 days post injection (p.i.). RESULTS:Differences in the skin Gd concentrations were observed between the 4 investigated GBCAs. For the nonionic linear compounds, Omniscan and OptiMARK, high Gd concentrations were maintained in the skin over the observation period of up to 168 days p.i. For the ionic linear compound, Magnevist, comparatively lower Gd retention in the skin was observed over time. For the macrocyclic compound, Gadovist, the Gd values in the skin were even lower, and significantly lower than Gd values in the skin in Omniscan and OptiMARK treated animals. CONCLUSION:The results of this preclinical study support the use of 5/6-nephrectomized rats as a model for prolonged circulation time of GBCAs as seen in patients with severe renal impairment. Surgically induced severe renal impairment resulted in delayed clearance of the administered GBCAs in the study animals. The highest amount of Gd was observed in the skin after treatment with the nonionic linear GBCAs, whereas the lowest Gd values were observed after treatment with the macrocyclic agent. This suggests that the difference in the Gd values observed in rat skin tissue after treatment with the different GBCAs is caused of a different propensity of the different GBCAs to release Gd in vivo. However, the analytical method used does not distinguish between chelated and unchelated Gd.
    Subject(s): Animals ; Contrast Media - pharmacokinetics ; Gadolinium - pharmacokinetics ; Male ; Nephrogenic Fibrosing Dermopathy - chemically induced ; Rats ; Rats, Wistar ; Renal Insufficiency ; Skin - physiopathology
    ISSN: 0020-9996
    E-ISSN: 1536-0210
    Source: Hellenic Academic Libraries Link
    Source: Alma/SFX Local Collection
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