General pharmacology in experimental animals of gadobenate dimeglumine (MultiHance), a new magnetic resonance imaging contrast agent.

OBJECTIVES: To assess in animals the pharmacological tolerability for intravascular gadobenate dimeglumine. RESULTS: Cardiovascular effects: In healthy animals no relevant effects were observed apart from slight and transient increases in cardiac output and decreases in systemic vascular resistance. In pigs with myocardial ischemia: doses up to 3.0 mmol/kg caused dose-dependent decreases in heart rate, systemic vascular resistance and mean arterial blood pressure along with transient increases in cardiac output. In vitro: Myocardial contractility was slightly depressed after direct exposure to a 30 mM solution. Respiratory effects in healthy pigs: no effects after 1.0 mmol/kg i.v. Effects on the central nervous system: In healthy animals: gadobenate dimeglumine, 1.0 mmol/kg i.v, did not penetrate nor impair the blood-brain barrier in rats and did not affect behavior, motor coordination or EEG. In pathological models: even in the presence of an osmotically disrupted blood-brain barrier, brain penetration of gadobenate was poor and no signs of epileptogenic potential were evident. Effects on blood: No hemolytic potential was observed. Plasma coagulation was slightly affected in vitro but not in vivo. Effects on kidney and liver function: Transient increases in diuresis, without effects on blood and urine enzymes were observed at doses of 1.25 and 2.5 mmol/kg. CONCLUSIONS: The clinical use of gadobenate dimeglumine as an intravascular magnetic resonance imaging contrast agent is strongly supported by the good tolerability of the product in healthy and pathological animal models.

Cardiac effects of contrast media in MR angiography: evaluation in an experimental model of myocardial ischemia.

RATIONALE AND OBJECTIVES: The authors evaluated the cardiac tolerability of paramagnetic contrast agents for magnetic resonance (MR) angiography in an in vitro model of ischemic rat heart. MATERIALS AND METHODS: The left anterior descending coronary artery was temporarily occluded in a perfused rat heart model to induce cardiac ischemia and reperfusion. A dose of 0.4 mL of gadobenate dimeglumine, of gadopentetate dimeglumine, or of D-mannitol was injected directly into the aorta both during the ischemia and during the reperfusion period. The left ventricular pressure and heart rate were recorded. RESULTS: Myocardial ischemia resulted in decreased cardiac activity, with a reduction in left ventricular pressure and heart rate. A further decrease in cardiac activity was temporarily induced by injection of contrast medium during both the ischemic and early reperfusion phases. Less marked responses were induced by a hyperosmolal solution of mannitol. CONCLUSION: These results suggest that the transient cardiac effects induced by bolus injection of paramagnetic contrast medium may be regarded as the combined effects of the osmotoxicity of the contrast medium solution and the chemotoxicity of the contrast medium molecule.

The haemodynamic effects of iodinated water soluble radiographic contrast media: a review.

All classes of iodinated water-soluble radiographic contrast media (RCM) are vasoactive with the iso-osmolar dimers inducing the least changes in the vascular tone. The mechanisms responsible for RCM-induced changes in the vascular tone are not fully understood and could be multifactorial. A direct effect on the vascular smooth muscle cells causing alterations in the ion exchanges across the cell membrane is thought to be an important factor in RCM-induced vasodilatation. The release of the endogenous vasoactive mediators adenosine and endothelin may also play a crucial role in the haemodynamic effects of RCM particularly in the kidney. In addition, the effects of RCM on blood rheology can cause a reduction in the blood flow in the microcirculation. The purpose of this review is to discuss the pathophysiology of the haemodynamic effects of RCM and to offer some insight into the biology of the endothelium and vascular smooth muscle cells as well as the pharmacology of the important vasoactive mediators endothelin and adenosine.

Brain penetration and neurological effects of gadobenate dimeglumine in the rat.

PURPOSE: The study aimed at measuring the amount of the gadobenate ion that crosses an experimentally disrupted blood-brain barrier (BBB) in rats following i.v. administration of gadobenate dimeglumine (GD). The intention was also to compare this amount with the minimally effective intrathecal dose that alters the cerebral function. METHODS: Sprague Dawley rats with an osmotically disrupted BBB received 0.3 mmol/kg of (153Gd) GD, i.v. Radioactivity was measured in plasma and brain parenchyma. The effect on the cerebral function was evaluated by means of a standard motor coordination test (Rota-rod test). RESULTS: Brain levels of the gadobenate ion were approximately 60 nmol/g tissue after i.v. injection of GD. In rats with an intact BBB, the lowest dose of GD able to slightly impair motor coordination was 0.01 mmol/kg following intracisternal injection. CONCLUSION: I.v. administration of GD to rats with a disrupted BBB results in brain levels of the gadobenate ion that are more than 20 times lower than those reached following intrathecal administration of the minimal effective dose, as determined by the Rota-rod test.

Effects of iodinated contrast media on pulmonary airway resistance in anesthetized guinea pigs.

RATIONALE AND OBJECTIVES: Bronchospasm is occasionally observed following iodinated X-ray contrast medium administration. We performed an in vivo study in guinea pigs to investigate the effects of a number of iodinated contrast media on pulmonary airway resistance and the mechanisms underlying the potential bronchoconstrictor effect. METHODS: The contrast media studied were the pharmaceutical formulations of iomeprol (400 mg I/ml), iopamidol (370 mg I/ml), and iohexol (350 mg I/ml), which are nonionic, triiodinated contrast media; diatrizoate (370 mg I/ml), an ionic, triiodinated contrast medium; iotrolan (300 mg I/ml), a nonionic, hexaiodinated contrast medium; and iocarmate (280 mg I/ml) and ioxaglate (320 mg I/ml), which are both hexaiodinated and ionic contrast media. Each contrast medium was administered intravenously at 2 g I/kg. Changes in pulmonary airway resistance were evaluated by measuring intratracheal pressure at the moment of maximum insufflation, or maximal insufflation pressure (MIP), in anesthetized guinea pigs submitted to forced ventilation. RESULTS: All contrast media except ioxaglate caused mean increases of MIP of no more than 20%. By contrast, ioxaglate caused a marked bronchoconstrictor effect, increasing MIP by 242% +/- 46%. Of the drugs tested for antagonistic action on this increase in MIP, salbutamol inhibited almost completely the increase in MIP for the first 40 min posttreatment. Similarly, lysine acetylsalicylate and indomethacin consistently reduced MIP after contrast media administration to levels only 30% and 14% above those of baseline precontrast media, respectively. Promethazine had only a minor inhibitory effect, and the response to prednisolone varied. CONCLUSION: There was no apparent relationship between the size of the increase in airway resistance and the charge or molecular weight of the contrast agent molecule or the pharmaceutical formulation. The increase induced by ioxaglate must be attributed to inherent molecular toxicity mediated through a direct action on the production of bradykinin and/or the prostanoid products of the cyclooxygenase pathway, rather than through a direct action on the release of histamine.

Pharmacodynamic effects of iomeprol for injection in experimental animals.

Iomeprol for injection is a new nonionic triiodinated contrast medium for diagnostic radiology, which combines low osmolality with low viscosity. The effects of iomeprol for injection on the cardiovascular system, blood parameters, renal function and the central nervous system were studied after intravascular administration to several animal species of doses at least as high as the highest presumed clinical doses. The following observations were made with respect to the central circulatory system: moderate and short-lasting increases of left ventricular end-diastolic pressure and cardiac output, no significant effects on heart rate either in vitro or in vivo, some episodes of arrhythmia and ventricular fibrillations only at doses far higher than the highest presumed clinical ones, no significant increases in diastolic and systolic coronary flow. The following observations were made with respect to peripheral circulation: no significant changes on blood pressure, moderate and short-lasting increases in renal and pulmonary arterial flow, together with a decrease in peripheral vascular resistance, no crossing of the blood-brain barrier in healthy animals. Cardiovascular and haemodynamic changes were all significantly milder than those induced by ionic contrast media (CM) and were similar to effects caused by some other nonionic contrast media. When injected into the femoral artery of rats, iomeprol was shown to be less algogenic than iopamidol and iohexol. In comparison with the same reference CM, iomeprol affected to a lesser extent the filterability of red blood cells in vitro and showed a less marked effect on their deformability. When administered intravenously at very high dosages, iomeprol had no effect on the glomerular filtration rate, but increased both renal blood flow and diuresis. Proteinuria and enzymuria were also increased, albeit more transiently. The neurotolerance of iomeprol for injection after intravenous administration was higher than or at worst equal to that of iopamidol and iohexol. Iomeprol is therefore a promising new contrast agent particularly suitable for intravascular use in humans.

Subarachnoid buprenorphine administered by implantable micropumps.

This report concerns 23 patients, the majority of whom are suffering from low back and chest pain caused by chest, urological or gynaecological cancer. These patients were treated with subarachnoid buprenorphine, administered in a single bolus or by slow infusion from micropumps, at a daily dose adapted to patients need (0.06-0.15 mg). The painful symptomatology was successfully controlled in all the cases treated, allowing the patients to live a virtually normal life. In no cases was respiratory depression or tolerance observed.

Synthesis and pharmacological study of 4,4a,5,6-tetrahydro-4a-substituted-benzo(h)cinnolin-3(2H)ones.

A series of 4,4a,5,6- tetrahydro-4a-substituted-benzo(h)cinnolin-3(2H)-one (II a-e) (III a) were synthesized and evaluated pharmacologically in comparison with the 4a-unsubstituted congeners (I), which were reported to be potent antithrombotic and antihypertensive agents. All the test compounds, apart from (II e) (R2 = OCH3) and (III a) (R1,R2 = H), displayed significant antihypertensive activity. In particular (II a) (R1,R2 = H) was more active than the unsubstituted analogue (I a). Moreover (II d) (R1 = OCH3), (II e) (R2 = OCH3) and (III a) showed antithrombotic activity comparable to or higher than that of ASA.

Dose-response decrease in plasma tryptophan and in brain tryptophan and serotonin after tryptophan-free amino acid mixtures in rats.

Rats fasted 15 hours were treated p.o. with increasing amounts (660 and 1320 mg/kg body weight) of a mixture containing a fixed proportion of seven essential amino acids (L-phenylalanine 13.6%, L-leucine 6.0%, L-isoleucine 12.1%, L-methionine 12.1%, L-lysine 30.3%, L-threonine 10.6%, L-valine 15.2%) and lacking tryptophan. The mixtures produced a dose-response decrease of free (by 34% after the lower dose and by 58% after the higher dose of the mixture) and total (by 10 and 31%) plasma tryptophan and of brain tryptophan (by 38 and 65%), serotonin (by 17 and 41%) and 5-hydroxyindole acetic acid (by 21 and 49%). The mechanisms of these changes are discussed.