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1.
Nature ; 441(7089): 62-4, 2006 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-16672964

RESUMO

The rotation rate of a planet is one of its fundamental properties. Saturn's rotation, however, is difficult to determine because there is no solid surface from which to time it, and the alternative 'clock'--the magnetic field--is nearly symmetrically aligned with the rotation axis. Radio emissions, thought to provide a proxy measure of the rotation of the magnetic field, have yielded estimates of the rotation period between 10 h 39 min 22 s and 10 h 45 min 45 s (refs 8-10). Because the period determined from radio measurements exhibits large time variations, even on timescales of months, it has been uncertain whether the radio-emission periodicity coincides with the inner rotation rate of the planet. Here we report magnetic field measurements that revealed a time-stationary magnetic signal with a period of 10 h 47 min 6 s +/- 40 s. The signal appears to be stable in period, amplitude and phase over 14 months of observations, pointing to a close connection with the conductive region inside the planet, although its interpretation as the 'true' inner rotation period is still uncertain.

2.
Invest Radiol ; 28(8): 753-61, 1993 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8376008

RESUMO

In the development of liver CM for MRI, three mainstream approaches have been undertaken: targeting of water-soluble MRI-CM to the hepatocytes, targeting of particles to the Kupffer cells of the liver, and application of macromolecular CM to tumorous tissue. As with the biliary iodinated CM, the physiological function of the liver has been used to target paramagnetic chelates (T1 agents) to the hepatocytes. Gd-EOB-DTPA and Gd-BOPTA are taken up mainly by hepatocytes and excreted into the bile by organic anion transporter (bilirubin transporter), whereas MnDPDP also uses the ability of hepatocytes to excrete metal ions, such as manganese. However, unlike the biliary iodinated CM, besides the specific accumulation in the hepatocytes, the low binding to plasma proteins and the high sensitivity of MRI, combined with the strong increase in relaxivity inside the hepatocellular environment, make the paramagnetic chelates very effective in the detection of liver lesions. Targeting of T2 agents (e.g. SPIO) to the Kupffer cells of the liver also has proved to be very effective in liver lesion detection. However, limited information is available regarding the pharmacokinetics of these particles in man and other problems, such as cardiovascular tolerance and manufacturing, must be overcome before widespread use of particulate CM can be implemented. The third approach is based on the differences in the vessel permeability, the vessel density, and functional lymphatics between normal and tumorous liver tissue when macromolecular CM are administered. This approach, however, is at an early research stage.


Assuntos
Meios de Contraste/farmacocinética , Fígado/anatomia & histologia , Imageamento por Ressonância Magnética/métodos , Animais , Bile/metabolismo , Transporte Biológico , Meios de Contraste/farmacologia , Humanos , Fígado/metabolismo , Substâncias Macromoleculares , Ligação Proteica/efeitos dos fármacos , Sensibilidade e Especificidade , Baço/anatomia & histologia , Baço/metabolismo
3.
Invest Radiol ; 26(11): 975-9, 1991 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-1743921

RESUMO

We investigated the pharmacokinetics of dimeglumine gadopentetate (Gd-DTPA), a contrast agent for magnetic resonance imaging (MRI), in 24 patients with chronic renal failure whose creatinine clearance ranged from 7.2 to 70.0 mL/minute (median 25.4 mL/minute). After single intravenous administration of 0.1 mmol/kg, the serum levels of Gd-DTPA were monitored up to five days and urine and feces were collected quantitatively up to two days. The pharmacokinetic parameters were calculated from the concentration-time profile in the serum and urine using an open two-compartment model. No changes in the volume of distribution (Vc and Varea) or in the half-life of distribution were found for patients with chronic renal failure as compared to patients with normal renal function. However, in correlation with the reduced glomerular filtration rate in patients with chronic renal failure, the half-life of elimination was prolonged and serum and renal clearance were decreased. The recovery of Gd-DTPA in urine was 92.1% +/- 12.1% of the dose administered, and extrarenal elimination was less than 0.4%, indicating that glomerular filtration remains the predominant route of elimination. Only for patients with highly impaired renal function (creatinine clearance less than 20 mL/minute) was the recovery in the urine less than complete.


Assuntos
Meios de Contraste/farmacocinética , Falência Renal Crônica/metabolismo , Compostos Organometálicos/farmacocinética , Ácido Pentético/farmacocinética , Feminino , Gadolínio DTPA , Taxa de Filtração Glomerular/fisiologia , Meia-Vida , Humanos , Rim/metabolismo , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade
4.
Invest Radiol ; 30(11): 644-9, 1995 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-8557505

RESUMO

RATIONALE AND OBJECTIVES: The efficacy of the neutral lanthanide contrast agent gadobutrol was compared to that of the iodinated contrast agent iopromide in rabbits. METHODS: The computed tomography (CT) attenuation of increasing concentrations of gadolinium (Gd) (gadobutrol) and iodine (I) (iopromide) was measured in Hounsfield units (HU) in aqueous solution at 80, 120, and 137 kV. The peak enhancement (net increase in CT attenuation compared with baseline) and the time-enhancement product in the aorta and in the renal parenchyma of the outer and inner cortex were measured in rabbits over a 5-minute period after the animals were given single intravenous injections of 0.7, 1.0, and 1.5 mmol Gd/kg of gadobutrol and 1.0 and 2.4 mmol I/kg of iopromide. RESULTS: In vitro, the CT attenuation of gadolinium was 40% higher than that of iodine at equivalent mass concentrations (120 kV). The mean peak enhancements in the aorta after the injections of 0.7, 1.0, and 1.5 mmol Gd/kg and 1.0 and 2.4 mmol I/kg were 216, 313, 591, 224, and 498 HU, respectively. In addition, a 30-second injection of the high dose of gadobutrol resulted in an attenuation profile that was suitable for a three-dimensional reconstruction of the aorta and the renal vasculature. CONCLUSIONS: Because of the higher CT attenuation of gadolinium compared with that of iodine, the neutral macrocyclic chelate gadobutrol is a more effective contrast agent than iopromide for CT at lower doses of the imaging atom.


Assuntos
Meios de Contraste , Gadolínio , Compostos Organometálicos , Tomografia Computadorizada por Raios X , Angiografia , Animais , Aortografia , Meios de Contraste/administração & dosagem , Modelos Animais de Doenças , Feminino , Gadolínio/administração & dosagem , Processamento de Imagem Assistida por Computador , Injeções Intravenosas , Iohexol/administração & dosagem , Iohexol/análogos & derivados , Córtex Renal/irrigação sanguínea , Córtex Renal/diagnóstico por imagem , Metais Terras Raras/administração & dosagem , Compostos Organometálicos/administração & dosagem , Coelhos , Intensificação de Imagem Radiográfica/métodos , Fatores de Tempo
5.
Invest Radiol ; 30(12): 745-53, 1995 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8748189

RESUMO

RATIONALE AND OBJECTIVES: The study was designed to compare the hemodynamic effects of 11 iodinated contrast media (CM), including ionic (diatrizoate, ioxaglate), nonionic monomeric (iohexol, iopromide, iopamidol, iopentol, ioversol, iomeprol, ZK 139129), and nonionic dimeric (iotrolan, iodixanol) compounds. METHODS: Following left ventricular bolus injection of 1.2 g I/kg body weight in anesthetized rats, cardiohemodynamic parameters were measured. RESULTS: Compared with the control group, except for blood pressure (BP), all CM showed a similar response regarding the direction of the cardiohemodynamic changes after CM injection. A biphasic change in BP was observed for diatrizoate and iodixanol, whereas all other CM showed a transient increase in BP being most pronounced for ioxaglate. No arrhythmias were detected. The increase in LVEDP was lowest for the isotonic dimeric CM iotrolan and iodixanol. CONCLUSIONS: Only mild transient side effects were observed. Low osmolar, especially isotonic, dimeric CM show a clear benefit regarding cardiovascular side effects.


Assuntos
Meios de Contraste/toxicidade , Hemodinâmica/efeitos dos fármacos , Radiografia , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Diatrizoato/toxicidade , Relação Dose-Resposta a Droga , Ácido Ioxáglico/toxicidade , Masculino , Ratos , Ratos Wistar
6.
Invest Radiol ; 37(5): 241-7, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-11979149

RESUMO

RATIONALE AND OBJECTIVES: To investigate the efficacy of the new liver-specific x-ray contrast agent, Dy-EOB-DTPA, in rabbits with VX2 liver tumors by spiral computed tomography (CT) in comparison to iopromide. MATERIALS AND METHODS: The time course of liver enhancement was determined in five groups of two normal anesthetized rabbits, which received intravenous injections of Dy-EOB-DTPA before anesthesia at a dose of 0.5 mmol/kg. Fifteen, 30, 45, 60, and 90 minutes after administration spiral CT images were obtained and the attenuation in the livers were determined. A second group of ten rabbits with implanted VX2 tumors received in a random crossover design either Dy-EOB-DTPA at a dose of 0.5 mmol/kg or, 1 day later, iopromide at a dose of 600 mg iodine/kg. CT images were obtained 60 minutes after Dy-EOB-DTPA administration and both in the arterial and portal-venous phases after iopromide injection. Three radiologists evaluated the images. The rabbits were killed, and their livers were investigated histologically for liver tumors. RESULTS: In normal animals, 0.5 mmol/kg Dy-EOB-DTPA resulted in a liver enhancement of 30 HU during the whole observation period of 90 minutes. In tumor-bearing animals, histology revealed 14 implanted tumors of 3-20 mm diameter. Sixty-five percent of the tumors were below 10 mm. Dy-EOB-DTPA was able to detect 13 tumors (93%), iopromide 11 (79%) both in the arterial and in the portal-venous phase. The difference was statistically not significant. In plain CT, seven tumors (50%) were found (P < 0.01 vs iopromide and Dy-EOB-DTPA). One scar and two sites of necrosis were detected by each of the methods. CONCLUSION: Dy-EOB-DTPA injection at a dose of 0.5 mmol/kg resulted in a long-lasting detectability of 93% of all implanted tumors versus 79% found with iopromide.


Assuntos
Meios de Contraste/administração & dosagem , Iohexol/análogos & derivados , Neoplasias Hepáticas Experimentais/diagnóstico por imagem , Fígado/diagnóstico por imagem , Ácido Pentético/análogos & derivados , Ácido Pentético/administração & dosagem , Animais , Meios de Contraste/farmacocinética , Injeções Intravenosas , Iohexol/administração & dosagem , Fígado/metabolismo , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Estrutura Molecular , Ácido Pentético/química , Ácido Pentético/farmacocinética , Coelhos , Fatores de Tempo , Tomografia Computadorizada por Raios X
7.
Invest Radiol ; 28(11): 1028-32, 1993 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-8276573

RESUMO

RATIONALE AND OBJECTIVES: Iopromide-carrying liposomes were prepared and were characterized pharmaceutically and biologically. METHODS: The liposomes were prepared by the ethanol evaporation method and were characterized by quasi-elastic light scattering (size) and equilibrium dialysis (encapsulation efficiency and stability). Acute and subchronic toxicity was tested in mice and/or rats and cardiovascular tolerance in rabbits. Pharmacokinetic parameters were determined in rats. Computed tomography (CT) imaging efficiency was obtained from rat and rabbit studies. RESULTS: The mean diameter was 0.5 +/- 0.1 micron and the encapsulation efficiency ranged between 30% and 40%. The liposomes were stable in human and rabbit plasma for approximately 24 hours. The LD50 in mouse and rat was approximately 3 g iodine/kg. In a subchronic toxicity study in rats with six doses of 1 g iodine/kg given every three days, no adverse effects were observed. The pharmacokinetics in rats were dose-dependent. Increasing the dose resulted in lower total clearance, and longer terminal half-life. Elimination of iodine was complete and the main route of excretion was via the kidneys. A clinically relevant computed tomography enhancement of the liver was reached after approximately 200 mg iodine/kg in rats and 150 mg iodine/kg in rabbits. CONCLUSIONS: The iopromide-carrying liposomes were well tolerated in animal studies and seemed to be suitable for the imaging of the liver.


Assuntos
Iohexol/análogos & derivados , Animais , Meios de Contraste/farmacocinética , Meios de Contraste/toxicidade , Relação Dose-Resposta a Droga , Feminino , Hemodinâmica/efeitos dos fármacos , Iohexol/farmacocinética , Iohexol/toxicidade , Lipossomos , Fígado/diagnóstico por imagem , Masculino , Camundongos , Coelhos , Ratos , Ratos Wistar , Tomografia Computadorizada por Raios X
8.
Invest Radiol ; 26(11): 969-74, 1991 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-1743920

RESUMO

Polylysine covalently linked to moieties of gadopentetate (Gd-DTPA), for use as a macromolecular blood pool marker for contrast material-enhanced magnetic resonance imaging (MRI), was characterized by means of physicochemical measurements and pharmacokinetics in rats and rabbits and compared with Gd-DTPA. Gd-DTPA-polylysine was composed of a series of polymers of different molecular sizes that on average were labeled with 60 to 70 Gd-DTPA moieties (average molecular weight, 48,700 daltons [D]). For the macromolecular compound Gd-DTPA-polylysine, relaxivity was three times higher than that of Gd-DTPA. The LD50 value of 17 mmol/kg reflects a fairly high acute intravenous tolerance of the macromolecular compound in mice. Even though the volume of distribution of Gd-DTPA-polylysine in rabbits approached the extracellular fluid space (indicating that the macromolecular compound was also leaking slowly into the interstitial space), the half-life of distribution of the macromolecular compound in the extracellular fluid space was significantly prolonged, thus making the compound suitable as a blood pool marker for MRI. In rats the elimination of Gd-DTPA-polylysine occurred predominantly via the renal route. High-pressure liquid chromatography-size-exclusion chromatography of the fractionated urine samples revealed that the renal clearance must be the integral sum of the separate clearances of each molecular weight species. No biodegradation of the polypeptide was observed, and biodistribution studies revealed only minimal retention of Gd in the body of the rat.


Assuntos
Meios de Contraste , Imageamento por Ressonância Magnética , Compostos Organometálicos , Ácido Pentético , Polilisina , Animais , Meios de Contraste/farmacocinética , Feminino , Gadolínio DTPA , Técnicas In Vitro , Dose Letal Mediana , Camundongos , Compostos Organometálicos/farmacocinética , Ácido Pentético/farmacocinética , Polilisina/farmacocinética , Coelhos , Ratos , Distribuição Tecidual
9.
Invest Radiol ; 29(7): 709-15, 1994 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-7960618

RESUMO

RATIONALE AND OBJECTIVES: Gadobutrol is a new gadolinium-based hydrophilic and neutral macrocyclic contrast medium for magnetic resonance imaging. In this article, the authors report on the first application of gadobutrol in humans, up to a dose of 0.5 mmol/kg. METHODS: Gadobutrol was investigated after single intravenous administration in two phase-1 studies testing low (0.5 mol/L) and high concentrations (1 mol/L) in healthy, male volunteers using a double-blind, randomized, placebo-controlled study with n = 55 for the low concentration (0.04, 0.1, 0.2, 0.3, and 0.4 mmol/kg body weight), followed by n = 36 for the high concentration (0.3, 0.4, and 0.5 mmol/kg body weight). Vital signs and laboratory parameters were measured for all dose groups investigated, whereas for the calculation of the pharmacokinetic parameters, the dose groups 0.04, 0.1, and 0.4 mmol/kg body weight were selected. RESULTS: Gadobutrol was well tolerated up to doses of 0.5 mmol/kg, and no relevant changes in vital signs and laboratory parameters occurred. The terminal disposition half-life of gadobutrol in plasma was approximately 1.5 hours. Total clearance approximated renal clearance and approximated the value of 120 mL/min, indicating glomerular filtration as the main pathway of elimination. The steady-state volume of distribution indicated predominantly extracellular distribution of gadobutrol. No metabolites were detected. The renal excretion rate was linear over the large dose range tested, indicating dose-proportionate, first-order kinetics of gadobutrol. CONCLUSION: Single intravenous administration of gadobutrol was well tolerated up to the dose level of 0.5 mmol/kg body weight. These factors suggest that gadobutrol will be a safe magnetic resonance imaging contrast agent.


Assuntos
Meios de Contraste/farmacocinética , Gadolínio/farmacocinética , Compostos Organometálicos/farmacocinética , Adulto , Meios de Contraste/administração & dosagem , Meios de Contraste/metabolismo , Meios de Contraste/farmacologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Tolerância a Medicamentos , Fezes/química , Gadolínio/administração & dosagem , Gadolínio/metabolismo , Gadolínio/farmacologia , Meia-Vida , Humanos , Injeções Intravenosas , Masculino , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/metabolismo , Compostos Organometálicos/farmacologia , Placebos , Segurança
10.
Invest Radiol ; 27(2): 153-6, 1992 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-1601607

RESUMO

Safety data for renal tolerance of gadolinium-DTPA(Gd-DTPA)/dimeglumine were evaluated in 21 patients (age: mean +/- standard deviation [SD], 58 +/- 12 years) with impaired renal function. The mean +/- SD serum creatinine level at baseline was 213 +/- 101 mumol/L (range, 89.2-551 mumol/L). Creatinine clearance at baseline averaged 34.5 +/- 19.2 mL/minute (range, 7.2-70 mL/minute). Gd-DTPA was injected at a dose of 0.1 mmol/kg body weight. Serum parameters (creatinine, sodium, and potassium) were determined before and 6, 24, 48, and 120 hours after administration of Gd-DTPA. Urinary parameters (N-acetyl-beta-D-glucosaminidase [beta-NAG], protein, and albumin) were determined before (spot urine sample) and after treatment for collection periods 0 to 3, 3 to 6, 6 to 12, 12 to 24, and 24 to 48 hours. A final spot urine sample was taken at 120 hours. There was no significant statistical change of serum creatinine level within the observation period, and there was no single patient matching the criteria of acute renal failure (increase of serum creatinine level of 88.4 mumol/L [1 mg/dL] or more within 48 hours after injection). Serum values of sodium and potassium levels remained unchanged. Beta-NAG was slightly increased 0 to 3 hours after injection, but returned to baseline values during the collection periods up to 120 hours. There was no increase of protein or albumin excretion. These preliminary results suggest Gd-DTPA has good renal tolerance in patients with pre-existing chronic renal failure.


Assuntos
Meios de Contraste/efeitos adversos , Gadolínio/efeitos adversos , Falência Renal Crônica/metabolismo , Rim/efeitos dos fármacos , Meglumina/efeitos adversos , Compostos Organometálicos/efeitos adversos , Ácido Pentético/efeitos adversos , Adulto , Idoso , Ensaios Clínicos como Assunto , Meios de Contraste/farmacocinética , Combinação de Medicamentos , Tolerância a Medicamentos , Feminino , Gadolínio/farmacocinética , Gadolínio DTPA , Humanos , Rim/metabolismo , Falência Renal Crônica/diagnóstico , Imageamento por Ressonância Magnética , Masculino , Meglumina/farmacocinética , Pessoa de Meia-Idade , Compostos Organometálicos/farmacocinética , Ácido Pentético/farmacocinética , Fatores de Tempo
11.
Invest Radiol ; 31(8): 502-11, 1996 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8854197

RESUMO

RATIONALE AND OBJECTIVES: A series of studies was conducted to determine whether metal complexes of the EOB-DTPA type are useful as contrast agents for computed tomography (CT). METHODS: Metal complexes using EOB-DTPA as ligand were synthesized with lanthanide metal ions (lanthanum [La], cerium [Ce], praseodyme [Pr], gadolinium [Gd], dysprosium [Dy], ytterbium [Yb], and lutetium [Lu]) and with nonlanthanides (lead [Pb] and bismuth [Bi]). Complex stability was assessed by measuring binding to bone meal. The physicochemical parameters partition coefficient, osmolality, viscosity, and protein binding were determined in vitro. Tolerability was tested both in vitro (thromboplastin time, effect on erythrocytes) and in vivo (acute, neural, and cardiovascular toxicities). Biliary excretion and tissue distribution, especially liver, kidney, and bone concentrations, were measured in rats after intravenous doses of 0.5 mmol/kg. Imaging performance using CT was investigated in vitro in a phantom model and, for Gd-EOB-DTPA, in vivo by injecting doses of 0.5 mmol/kg into healthy or tumor-bearing rats and rabbits. RESULTS: The kinetic stability of M-EOB-DTPA complexes differed widely. Nonlanthanide metals, especially Pb-EOB-DTPA, provided less stable complexes than lanthanides with an optimum of stability for the metals Gd, Dy, Yb, and Lu. Tolerability was good for all compounds, best results were obtained for Gd and Yb. Concentrations in rat liver after administration of Gd-EOB-DTPA, 0.5 mmol/kg intravenous, were approximately 1 mumol/g, resulting in CT enhancement of 16 Hounsfield units (HU). Tumor tissue was not enhanced. In rabbits, at the same dose level 30 HU was found. CONCLUSIONS: Metal complexes of the EOB-DTPA type, especially those of Gd and Yb seem to be useful as iodine-free liver-specific contrast agents for CT.


Assuntos
Meios de Contraste/química , Disprósio , Fígado/diagnóstico por imagem , Compostos Organometálicos , Ácido Pentético/análogos & derivados , Tomografia Computadorizada por Raios X , Itérbio , Animais , Produtos Biológicos , Bismuto/química , Osso e Ossos/química , Cério/química , Quelantes/química , Fenômenos Químicos , Físico-Química , Meios de Contraste/farmacocinética , Disprósio/química , Disprósio/farmacocinética , Eritrócitos/efeitos dos fármacos , Humanos , Lantânio/química , Chumbo/química , Fígado/metabolismo , Lutécio/química , Minerais/química , Compostos Organometálicos/química , Compostos Organometálicos/farmacocinética , Concentração Osmolar , Tempo de Tromboplastina Parcial , Ácido Pentético/química , Ácido Pentético/farmacocinética , Imagens de Fantasmas , Praseodímio/química , Ligação Proteica , Coelhos , Intensificação de Imagem Radiográfica/métodos , Ratos , Distribuição Tecidual , Viscosidade , Itérbio/química , Itérbio/farmacocinética
12.
Invest Radiol ; 28(10): 925-32, 1993 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8262747

RESUMO

OBJECTIVES: Manganese (III) mesoporphyrin (Mn-mesoporphyrin) was investigated for its pharmaceutical properties and magnetic resonance imaging characteristics as a potential hepatobiliary contrast agent. METHODS: Solubility, partition coefficient, plasma binding, proton relaxation enhancement, biodistribution, biliary excretion, liver extraction ratio, and liver enhancement were measured in various in-vitro and in-vivo systems. RESULTS: Mn-mesoporphyrin was soluble and stable at moderate alkaline pH in phosphate buffer. The octanol/water coefficient was 25.98, and the compound was highly protein bound. R1 for water and plasma were 1.94 and 2.35 L/mmol sec, respectively. R1 in liver was calculated to be 15.72 L/mmol sec. Biodistribution studies in rats and mice confirmed hepatotrophic properties and biliary excretion was 65% over 24 hours. First pass liver uptake was 15%. Magnetic resonance imaging studies showed persistent liver enhancement at 0.05 mmol/kg. CONCLUSION: Mn-mesoporphyrin is a lipophilic compound that shows potential as a hepatobiliary magnetic resonance contrast agent.


Assuntos
Imageamento por Ressonância Magnética , Mesoporfirinas , Animais , Bile/metabolismo , Sistema Biliar/anatomia & histologia , Neoplasias do Colo/metabolismo , Meios de Contraste , Feminino , Fígado/anatomia & histologia , Fígado/metabolismo , Mesoporfirinas/farmacocinética , Mesoporfirinas/farmacologia , Camundongos , Camundongos Nus , Transplante de Neoplasias , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Distribuição Tecidual
13.
J Clin Pharmacol ; 37(7): 587-96, 1997 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9243351

RESUMO

This study was performed to evaluate the effect of dose on the pharmacokinetics and efficacy of the gadolinium-based contrast medium gadoxetic acid, disodium, [gadolinium (4S)-4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6, 9-triazaundecandioic acid-disodium salt] (Gd-EOB-DTPA) as a liver-specific hepatobiliary contrast medium for computed tomography. Pharmacokinetics in serum and the pattern of elimination were investigated in 18 healthy volunteers up to 6 days after a 10-minute infusion of 0.2 mmol, 0.35 mmol, and 0.5 mmol of gadolinium per kilogram of body weight. Pharmacokinetic behavior was compared with the compute tomographic attenuation data in the liver parenchyma after the same doses in patients. Urinary and fecal excretion accounted for approximately equal portions of the administered dose. The degree of renal elimination increased with increasing doses, whereas renal clearance and half-life from urine data were not affected by dose. Dose-normalized area under the concentration-time curve was significantly increased with increasing doses indicating saturation in liver uptake for the highest dose. This finding was in agreement with the measured net increase in liver attenuation by computed tomography. Hepatic disposition revealed slight saturation phenomena for the highest dose (0.5 mmol gadolinium/kg). Nevertheless, this dose resulted in sufficient uptake by human liver, allowing for computed tomographic imaging.


Assuntos
Meios de Contraste/farmacocinética , Gadolínio DTPA , Gadolínio/farmacocinética , Fígado/metabolismo , Compostos Organometálicos/farmacocinética , Ácido Pentético/análogos & derivados , Adulto , Meios de Contraste/efeitos adversos , Método Duplo-Cego , Fezes/química , Gadolínio/efeitos adversos , Gadolínio/sangue , Gadolínio/urina , Humanos , Fígado/diagnóstico por imagem , Masculino , Compostos Organometálicos/efeitos adversos , Ácido Pentético/efeitos adversos , Ácido Pentético/farmacocinética , Tomografia Computadorizada por Raios X
14.
J Pharm Sci ; 82(8): 799-803, 1993 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8377117

RESUMO

The introduction of a lipophilic moiety into the gadolinium chelate Gd-DTPA (dimeglumine gadopentetate, Magnevist) yielded Gd-EOB-DTPA (short form), which has potential as a magnetic resonance contrast agent for liver mass screening. The pharmacokinetics of Gd-EOB-DTPA in rats is nonlinear because after correction for the 10-fold difference in dose, the area under the curve of plasma concentration versus time from time zero to infinity after single intravenous application of two different doses were not superimposable, and the amounts excreted renally and extrarenally differed significantly. However, for both dose groups tested, the values of renal clearance (9.96 and 11.1 mL/min.kg, respectively) were close to the value of glomerular filtration in the rat. Michaelis-Menten kinetics in the extrarenal elimination was therefore considered as the rate-limiting process of Gd-EOB-DTPA, the binding to plasma protein of which is small (10.3 +/- 1.4%). Thus, biliary elimination was significantly inhibited by the intravenous coadministration of sulfobromophthalein (a decrease from 39.5 +/- 3.17 to 30.7 +/- 5.30% of the dose was observed from 0 to 90 min postinoculation under coadministration of the inhibitor), whereas tauroglycocholate revealed no effect, indicating the involvement of the so-called organic anion plasma membrane transport system for the hepatic uptake. The transport of Gd-EOB-DTPA from the cytoplasm to the bile is mainly determined by the capacity of the transport protein glutathione-S-transferase as demonstrated by in vitro binding studies. A hepatobiliary transport maximum of 9.2 mumol/min.kg was evaluated by infusion studies. No metabolites were detected either in the bile or in the urine, and enterohepatic circulation can be excluded.


Assuntos
Meios de Contraste/farmacocinética , Gadolínio DTPA , Fígado/metabolismo , Compostos Organometálicos/farmacocinética , Ácido Pentético/análogos & derivados , Animais , Biotransformação , Cromatografia Líquida de Alta Pressão , Feminino , Glutationa Transferase/metabolismo , Infusões Intravenosas , Fígado/enzimologia , Imageamento por Ressonância Magnética , Masculino , Compostos Organometálicos/metabolismo , Ácido Pentético/metabolismo , Ácido Pentético/farmacocinética , Ratos
15.
Acad Radiol ; 2(11): 967-72, 1995 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9419668

RESUMO

RATIONALE AND OBJECTIVES: We studied the feasibility of using iodinated liposomes as computed tomography (CT) liver contrast agents in nonhuman primates. METHODS: Iopromide-containing liposomes were investigated as reticuloendothelial (RES) contrast agents for CT scanning of the liver in normal adult baboons. For intravenous (i.v.) injection, liposomes were resuspended in mannitol solution, filtered under sterile conditions, and injected i.v. at doses of 200 and 400 mg l/kg to each of five anesthetized adult baboons. RESULTS: Animals tolerated the injections without measurable electrocardiographic changes and recovered uneventfully from anesthesia. Sequential CT scans of the baboons' upper abdomen acquired up to 60 min postinjection showed persistent enhancement of the liver 10-60 min after injection. Maximum enhancement levels were 36 and 61 delta Hounsfield units (delta H) after the 200- and 400-mg/kg doses, respectively. The mean time to plateau enhancement was 20 min with the 200-mg/kg dose and 10 min with the 400-mg/kg dose. The greatest splenic enhancements were 181 and 301 delta H after the 200- and 400-mg/kg doses, respectively. CONCLUSION: Iopromide liposomes are effective as RES contrast agents in primates.


Assuntos
Meios de Contraste/administração & dosagem , Aumento da Imagem/métodos , Iohexol/análogos & derivados , Fígado/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Animais , Tolerância a Medicamentos , Estudos de Viabilidade , Feminino , Injeções Intravenosas , Iohexol/administração & dosagem , Lipossomos/administração & dosagem , Masculino , Papio , Fatores de Tempo
16.
Eur J Radiol ; 11(3): 227-9, 1990.
Artigo em Inglês | MEDLINE | ID: mdl-2265637

RESUMO

After intravenous administration of Gd-DTPA (0.1 mmol/kg) hemodialysis was performed five times within 6 days in a patient with endstage renal failure. During the fifth hemodialysis a blood sample of 5 ml was withdrawn and Gd-concentration was measured in plasma at 342.247 nm using the method of Inductively Coupled Plasma Atomic Emission Spectrometry. Gd-concentration measured in venous and arterial blood was 6 x 10(-6) mol/liter, corresponding to 1.5% of the dose administered. If these data can be confirmed in more patients with endstage renal failure, this is the proof of effective hemodialysis of Gd-DTPA in a clinical setting.


Assuntos
Falência Renal Crônica/metabolismo , Compostos Organometálicos/farmacocinética , Ácido Pentético/farmacocinética , Diálise Renal , Adulto , Neoplasias Cerebelares/diagnóstico , Meios de Contraste , Gadolínio DTPA , Humanos , Falência Renal Crônica/terapia , Imageamento por Ressonância Magnética , Masculino
17.
Eur J Radiol ; 21(1): 1-10, 1995 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-8654452

RESUMO

The Gd(3+)-complex of 10-(2,3-dihydroxy-1-hydroxymethylpropyl)-1,4,7,10-tetraazacyclo dodecane-1,4,7-triacetic acid(gadobutrol) is a new, neutral Gd-chelate for use as an extracellular contrast agent in magnetic resonance imaging (MRI). The blood level in dogs after intravenous (i.v.) injection decreased with a terminal half-life of about 45 min, the clearance was about 3.75 ml/min per kg and the distribution volume of 0.23 l/kg suggested an extracellular distribution. Biodistribution experiments in rats revealed that only a very small amount (0.16%) of the dose was left in the body 7 days after i.v. injection. Measurable amounts of Gd could be detected only in the liver, kidneys and bones. The osmolality (0.57 osmol/kg at 0.5 mol/l and 1.39 osmol/kg at 1 mol/l) is in the range of other low osmolality contrast media for MRI. Only very little interaction with biologically relevant molecules was suggested by a histamine release test and a lysozyme inhibition test. An i.v.-LD50 of 23 mmol/kg in mice combined with a comparatively high T1-relaxivity (5.6 l/mmol per s at 0.47 T and 6.1 l/mmol per s at 2 T) in plasma promises a high margin of safety. In preliminary imaging experiments, gadobutrol caused high enhancement in different lesions (cerebral infarct, brain tumor) of the rat. Tripling of the typical clinical dose of 0.1 mmol/kg was shown to provide additional diagnostic gain in lesions of this type.


Assuntos
Meios de Contraste/farmacocinética , Imageamento por Ressonância Magnética , Compostos Organometálicos/farmacocinética , Animais , Encéfalo/patologia , Neoplasias Encefálicas/diagnóstico , Infarto Cerebral/diagnóstico , Meios de Contraste/toxicidade , Cães , Interações Medicamentosas , Espaço Extracelular/metabolismo , Feminino , Meia-Vida , Injeções Intravenosas , Dose Letal Mediana , Masculino , Taxa de Depuração Metabólica/fisiologia , Camundongos , Compostos Organometálicos/toxicidade , Ratos , Ratos Wistar , Distribuição Tecidual
18.
Rofo ; 166(1): 3-7, 1997 Jan.
Artigo em Alemão | MEDLINE | ID: mdl-9072100

RESUMO

PURPOSE: Comparison of a monomeric and a dimeric radiographic contrast medium in the visualisation of the coronary arteries via electron beam tomography (EBT). MATERIAL AND METHODS: In a total of 6 Göttingen minipigs the heart was examined by EBT (40 sections, ECG-triggering, 1.5 mm section thickness, 100 ms acquisition time) after injection of both iopamidol (monomer, 370 mg l/ml) and iotrolan (dimer, 320 mg l/ml) at a dose of 740 mg l/kg. Injection rate and scan delay were adjusted to heart rate and circulation time. RESULTS: The intravascular increase in density after intravenous injection of iotrolan was significantly higher and longer than after injection of iopamidol (> 300 HE: 28 +/- 4 versus 17 +/- 5 cardiac cycles; p < 0.05). Iotrolan attained a higher score in the visualisation of the coronary arteries in three-dimensional surface reconstructions (p < 0.05). CONCLUSION: The dimeric contrast medium iotrolan proved superior to the monomeric agent iopamidol for visualisation of the coronary arteries via EBT.


Assuntos
Meios de Contraste , Vasos Coronários/anatomia & histologia , Elétrons , Iopamidol , Tomografia/métodos , Ácidos Tri-Iodobenzoicos , Animais , Avaliação Pré-Clínica de Medicamentos , Masculino , Suínos , Porco Miniatura , Tomografia/instrumentação , Tomografia/estatística & dados numéricos
19.
Rofo ; 156(6): 523-6, 1992 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-1617171

RESUMO

MRT with gadolinium-DTPA (0.1 mmol/kg body weight) was performed in 10 patients with renal insufficiency requiring dialysis and the clearance of gadolinium-DTPA was studied. After 3 dialysis on 3 successive days more than 97% of the initial concentration of gadolinium-DTPA had been eliminated. Average half-life was 1.87 hours. There were no side effects in any of the patients. Close laboratory observation of liver function showed no significant changes during the period of study. No contra-indication for the use of this contrast medium in patients with renal insufficiency requiring dialysis was found during this study.


Assuntos
Meios de Contraste/farmacocinética , Falência Renal Crônica/metabolismo , Imageamento por Ressonância Magnética , Compostos Organometálicos/farmacocinética , Ácido Pentético/farmacocinética , Diálise Renal , Adulto , Idoso , Feminino , Gadolínio DTPA , Humanos , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade
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