Milos Sovak

Contrast media as carriers for local drug delivery. Successful inhibition of neointimal proliferation in the porcine coronary stent model.

BACKGROUND Lipophilic taxanes can be dissolved in contrast media at significantly higher concentration than in saline. As contrast media have occasionally been observed to delineate the contour of coronary arteries for some seconds they may serve as a matrix for an antiproliferative drug aimed at preventing restenosis. The aim of this study was to test a novel taxane-contrast agent formulation for this new approach in the setting of coronary stenting. METHODS AND RESULTS In cell culture experiments (bovine vascular smooth muscle cells), 60-min incubation with contrast agent-taxane formulations (iopromide-paclitaxel, iopromide-protaxel) induced a significant, concentration-dependent inhibition of vascular smooth muscle cell (VSMC) proliferation over 12 days. Shorter incubation times of 10 and 3 min showed the same efficacy. For in vivo investigation, 16 stents were implanted into the coronary arteries of eight pigs using a 1.3 to 1 overstretch ratio. A control group received iopromide 370 alone while the treatment group was injected with a iopromide-protaxel formulation at a dose of 74 micromol/l, which is far below protaxel levels inducing systemic toxicity. Quantitative angiography and histomorphometry of the stented arteries asserted statistic equality of the baseline parameters between the control and treatment groups. After 28 days, the treatment group showed a marked reduction of the parameters characterizing in-stent restenosis, especially a 34% reduction of the neointimal area. CONCLUSIONS First evidence is provided that using a contrast agent as solvent for a taxane constitutes a new drug delivery mechanism able to inhibit in-stent restenosis in the porcine restenosis model.

Uptake of contrast materials by experimental acute myocardial infarctions: a preliminary report.

The concentration of iodine within infarcted and normal myocardium after intravenous administration of contrast material was determined by fluorescence excitation analysis in seven dogs at 48 hours after coronary arterial ligation. The iodine concentration of infarcted myocardial tissue was several times greater than normal myocardium after administration of meglumine/sodium diatrizoate, iodipamide, and an experimental polymer of iothalamic acid.

Steroids: theoretical and experimental basis for utilization in prevention of contrast media reactions.

In vitro and in vivo studies were done to examine the effects of methylprednisolone on the adverse reactions induced by contrast media. At very high concentrations, the steroid potentiated the complement-activating effect produced in vitro by iodipamide, but inhibited the immune and nonimmune mechanisms of hemolysis. Rabbits pretreated for 3 days with intramuscular methylprednisolone (at high or low dosages) were significantly protected against an LD47 challenging dose of iodipamide. Those treated once with a low intravenous dose immediately prior to iodipamide challenge were protected to a lesser degree. Rabbits treated once with a very high intravenous dose of steroid evidenced no protection. A hyper-responsive dog was consistently protected against adverse reactions to injected sodium iothalamate by a 3-day steroid pretreatment.

Direct myocardial effects of intracoronary administration of new contrast materials with lost osmolality.

The effects of LV dynamics of the intracoronary administration of three new contrast materials with reduced osmolality were compared with those of a monomeric ionic material, sodium iothalamate, and the nonionic material, metrizamide. In eight anesthetized dogs, the monacid dimer, P286, caused increases in LV dimensions and decreases in LV systolic pressure and parameters of the contractile state. The changes were less than those caused by sodium iothalamte. The alterations in LV function tended to be greater, but not significantly so, during systemic hypoxemia compared to the normal state. The nonionic materials, P297 and iopamidol, like metrizamide, caused no deleterious effects on LV dynamics in either the normal or hypoxemic state. Nonionic materials actually caused a slight increase in parameters of the LV contractile state.

Differential accumulation of radiopaque contrast material in acute myocardial infarction

The differential accumulation of radiographic contrast materials in ischemically damaged and normal myocardium was assessed with direct measurement (fluorescent excitation analysis) of the iodine content of tissue samples from dogs with 48 hour old myocardial infarctions. Tissue samples were obtained 10, 30, 60 and 180 minutes after the intravenous administration of 2 ml/kg body weight of diatrizoate meglumine and sodium (Renografin-76). At all time intervals, the iodine concentration of infarcted tissue was at least threefold greater than that of normal myocardium. At 180 minutes the ratio between iodine concentration in infarcted myocardium and that in normal myocardium was 8.5 and between that in infarcted myocardium and that in blood was 2.6. The iodine concentration in the liver was similar to or greater than that in the infarcted area at time intervals after 10 minutes. These results suggest that the intravenous administration of contrast material may facilitate the identification of acutely infarcted myocardium with computerized X-ray transmission tomography.

Why does kidney size change during I.V. urography

Meglumine iothalamate (280 ml I/ml) and sodium iothalamate (400 mg I/ml) in doses of 700 mg I/kg bw, were injected i.v. as a bolus in dogs. Renal size, urine flow rate, arterial pressure, renal blood flow and mean transit time and renal blood volume were measured before and after injection. All changes were qualitatively and quantitatively identical for both drugs. They produced a small transient renal shrinkage followed by a greater and prolonged renal enlargement. During the period of renal enlargement, urine flow increased. The time course of the enlargement paralleled the increase of urine flow rate. Renal blood flow also increased but both the mean transit time and renal vascular volume decreased. Therefore, the kidney size increase after i.v. injection of large doses of urographic contrast media cannot be attributed to an increased volume of the vessels. Most likely it is caused by diuresis-induced increase in the volume of the tubules.

A new prodrug of paclitaxel: synthesis of Protaxel.

2′ and 7 Polyol carbonates of paclitaxel were synthesized and screened as potential paclitaxel prodrugs. Paclitaxel is released from 7-(2′′,3′′-dihydroxypropylcarbonato) paclitaxel (Protaxel) at rates inversely proportional to pH, by an intramolecular cyclization. Compared to paclitaxel, maximum tolerated i.v. or i.p. doses (MTD) of Protaxel are about 2.5- to 3-fold higher; its efficacy is substantially higher in human cancer line xenografts in athymic mice, especially in prostate PC-3, breast MDA-MB 468 and ovary OVCAR-1.

Release of serotonin from human platelets in vitro by radiographic contrast media.

Both ionic and nonionic, monomeric and dimeric contrast media were found to release serotonin from intact human platelets in vitro. The monomeric contrast media were compared at the concentration range of 25 mg I/ml. Iothalamate was the strongest and the statistically equal metrizamide iopamidol, and P-297 were the weakest releasers. Monomeric and dimeric contrast media were compared at concentration ranges of 50 and 100 mg I/ml. They ranked, in descending order of serotonin releasing potency: iodipamide, iothalamate, P-127, iopamidol, and a statistically indistinguishable group of the monoacid dimer P-286, the nonionic dimer ZK 74 435, and metrizamide. The capability of contrast media to release serotonin seems to be a composite result of their specific physical and molecular structural properties.

Development of Contrast Media Idiosyncrasy in the Dog

A laboratory dog exhibited an altered response to injections of sodium iothalamate. This idiosyncratic response may have been predicated on an earlier series of iothalamate injections. The overt manifestations of the reactions in this dog were vomiting, hypotension, and hyperreflexia. Significant changes in several electrolyte components and serum complement levels were noted when the dog reacted to the contrast material.

Acute cardiac tolerance of current contrast media and the new taxane protaxel using iopromide as carrier during porcine coronary angiography and stenting.

Scheller B, Speck U, Schmitt A, et al. Acute cardiac tolerance of current contrast media and the new taxane protaxel using iopromide as carrier during porcine coronary angiography and stenting. Invest Radiol 2002;37:29–34. rationale and objectives.The systemic tolerance thresholds of modern low-osmolar x-ray contrast media (CM) are similarly high, but their effects on the cardiovascular system and on the coagulation differ. The aim of this study was to comparatively evaluate the cardiovascular tolerability of iopromide, ioxaglate, and iosmin, and of a novel taxane protaxel, dissolved in iopromide, as a carrier, by coronary angiography and stenting. methods.Sixteen pigs were randomized into four groups: iosmin (350 mg iodine/mL, n = 4 , nonionic dimer), iopromide (370 mg iodine/mL, n = 4, nonionic monomer), ioxaglate (320 mg iodine/mL, n = 4, ionic dimer), and 70-&mgr;mol protaxel dissolved in iopromide 370 mg iodine/mL, intended to prevent restenosis. Coronary angiography was performed via the left carotid artery followed by implantation of stents into the left anterior descending and the circumflex arteries. About 80 mL per animal was used in each group. results.There were no thrombotic complications and no significant adverse events of electrocardiography, blood pressure, or contractility during or after CM injections. There were no differences among the CM tested except that ioxaglate was the only agent showing a significant reduction in dp/dt after 50 seconds compared to iosmin. The values of preinjection parameters were most rapidly regained after iosmin, compared with other CM tested. conclusions.The novel iso-osmolar nonionic CM iosmin is well tolerated in porcine coronary angiography and subsequent stenting. The cardiac tolerance of iopromide has not been adversely affected by addition of the cytostatic protaxel.