Cationic Carrier Mediated Delivery of Anionic Contrast Agents in Low Doses Enable Enhanced Computed Tomography Imaging of Cartilage for Early Osteoarthritis Diagnosis.

Cartilage tissue exhibits early degenerative changes with onset of osteoarthritis (OA). Early diagnosis is critical as there is only a narrow time window during which therapeutic intervention can reverse disease progression. Computed tomography (CT) has been considered for cartilage imaging as a tool for early OA diagnosis by introducing radio-opaque contrast agents like ioxaglate (IOX) into the joint. IOX, however, is anionic and thus repelled by negatively charged cartilage glycosaminoglycans (GAGs) that hinders its intra-tissue penetration and partitioning, resulting in poor CT attenuation. This is further complicated by its short intra-tissue residence time owing to rapid clearance from joints, which necessitates high doses causing toxicity concerns. Here we engineer optimally charged cationic contrast agents based on cartilage negative fixed charge density by conjugating cartilage targeting a cationic peptide carrier (CPC) and multi-arm avidin nanoconstruct (mAv) to IOX, such that they can penetrate through the full thickness of cartilage within 6 h using electrostatic interactions and elicit similar CT signal with about 40× lower dose compared to anionic IOX. Their partitioning and distribution correlate strongly with spatial GAG distribution within healthy and early- to late-stage arthritic bovine cartilage tissues at 50-100× lower doses than other cationic contrast agents used in the current literature. The use of contrast agents at low concentrations also allowed for delineation of cartilage from subchondral bone as well as other soft tissues in rat tibial joints. These contrast agents are safe to use at current doses, making CT a viable imaging modality for early detection of OA and staging of its severity.

Effect of Ioxaglate on the cutaneous microcirculation in patients with coronary artery disease: Randomized, double blind, placebo-controlled study.

Radiographic contrast media (RCM) can initiate microcirculatory disorders. This study was performed to investigate effects of Ioxaglate on the cutaneous microcirculation. The investigation was carried out as prospective randomized double-blind comparison in parallel-group design on two groups of n = 10 patients each who had to undergo a diagnostic coronary angiography.The confirmatory parameter of the study was mean erythrocyte capillary velocity [vRBC in mm/sec]. VRBC in the ipsilateral nail-fold capillaries was recorded continuously for 3 min before and 6 min after injection of RCM or isotonic saline solution in the A. axillaris respectively, and was evaluated off-line.VRBC in nailfold capillaries was found to be decreased by Ioxaglate by 34% 150 seconds after injection, while isotonic NaCl solution immediately induced a slight increase of 14%.

In vivo comparative antithrombotic effects of ioxaglate and iohexol and interaction with the platelet antiaggregant clopidogrel.

RATIONALE AND OBJECTIVES: Experiments were designed to (1) compare the effects of iodinated contrast media (CM) on a rat model of arterial thrombosis, (2) evaluate which element of the ioxaglate solution supports its antithrombotic activity, and (3) investigate the interaction of ionic and non-ionic CM with the antiplatelet agent clopidogrel. MATERIALS AND METHODS: Carotid thrombosis was induced in rats by extravascular application of a filter paper soaked in FeCl3 (35% vol/wt), proximal to an ultrasonic flow probe. (1) The antithrombotic potential of low-osmolar ionic (ioxaglate Na/meglumine) or nonionic contrast media (iohexol and iodixanol) (all 1600 mg iodine/kg, IV) was assessed by measuring the time to occlusion (TTO) of the carotid artery and the thrombus weight (TW). (2) Isotonic saline and iso-osmolar (280 mOsm/kg) and hyperosmolar (560 mOsm/kg) solutions of meglumine hydrochloride, meglumine ioxaglate (560 mOsm/kg), sodium ioxaglate (600 mOsm/kg) and sodium and meglumine ioxaglate (commercial solution) were tested under similar conditions. (3) Interaction with clopidogrel was tested by injecting lower dose of CM (960 mg iodine/kg) 2 hours after clopidogrel (2 mg/kg per os). RESULTS: (1) Ioxaglate prolonged TTO when compared with saline (30.0 +/- 1.1 minute vs. 19.6 +/- 2.4 minutes, P< 0.001), whereas iohexol had no effect (21.3 +/- 1.3 minutes). Ioxaglate's effect was associated with a reduction in TW with ioxaglate versus saline (2.6 +/- 0.4 mg and 4.7 +/- 0.7 mg, respectively, P< 0.05) whereas TW remained unchanged in the iohexol group (4.2 +/- 0.4 mg). The nonionic dimer iodixanol induced a direct vasoconstrictor effect on the carotid artery and was consequently excluded from the study. (2) Neither iso-osmolar nor hyperosmolar solutions of meglumine had any effect on TTO whereas both sodium and meglumine salts of ioxaglic acid prolonged TTO, suggesting that the antithrombotic effect of ioxaglate is mediated by the ioxaglic acid moiety alone as neither meglumine, osmolality or sodium played a significant role. (3) A synergistic effect on TTO was found when ioxaglate was associated with clopidogrel whereas no such effect was observed with iohexol. CONCLUSIONS: These data show a greater in vivo antithrombotic potential for the ionic contrast medium ioxaglate than for the non-ionic contrast medium iohexol and, for the first time, a synergistic effect between a contrast medium and a platelet antiaggregant drug in vivo.

A randomized prospective trial of ioxaglate 320 (Hexabrix) vs. iodixanol 320 (Visipaque) in patients undergoing percutaneous coronary intervention.

We performed a randomized, prospective, double blind trial comparing the use of the ionic dimer contrast agent ioxaglate 320 (Hexabrix) with the nonionic dimer contrast agent iodixanol 320 (Visipaque) in 618 patients undergoing percutaneous coronary intervention (PCI) for stable or unstable coronary artery syndromes. The aim was to determine whether the different anticoagulant and antiplatelet properties of these two contrast agents resulted in a significant difference in the incidence of a combined endpoint comprising the major complications of PCI. Procedural success rates were marginally higher in the Visipaque group compared to the Hexabrix group, although this did not reach statistical significance (96.7% vs. 93.9%; P = 0.09). There was a borderline statistically significant higher requirement for bailout stenting in the Visipaque group compared to the Hexabrix group (6.8% vs. 3.2%; P = 0.05), although this was not a predefined endpoint. The incidence of the combined primary endpoint of failed catheter laboratory outcome/requirement for bailout stenting/requirement for abciximab/myocardial infarction/death before hospital discharge was higher in the Visipaque group compared to the Hexabrix group (17.9% vs. 14.8%), although this did not reach statistical significance (P = 0.29). When subgroup analysis was performed, the incidence of the combined endpoint in patients with stable coronary artery disease randomized to receive either Visipaque or Hexabrix was identical (13.7%). In patients with an acute coronary syndrome, there was a trend toward a reduced incidence of the combined endpoint in the Hexabrix compared to the Visipaque group, although this did not reach statistical significance (17.2% vs. 24.8%; P = 0.17). More adverse reactions occurred in the Hexabrix group compared to the Visipaque group (8.7% vs. 4.9%; P = 0.06). We conclude that there is no clear advantage with the use of an ionic contrast agent in a large population of patients undergoing PCI for both stable and unstable coronary artery disease. Although the study was underpowered to detect significant differences with the use of either agent when patients with either stable or unstable coronary disease were studied, it is highly unlikely that the ionicity of the contrast agent confers any advantage for patients with stable coronary disease. There remains a possibility that ionic agents do have advantages for patients with unstable coronary artery disease undergoing PCI, although a larger study than ours would be required to confirm or refute this.

Antithrombotic effects of ionic and non-ionic contrast media in nonhuman primates.

Thromboembolic complications have been attributed to the use of radiographic contrast media (CM) during interventional procedures for arterial revascularization. However, due to the low frequency of adverse events, comparisons between different CM have been difficult to perform, although it has been suggested that ionic (vs. non-ionic) CM may be associated with fewer thrombotic events. The present study was undertaken using well-characterized baboon thrombosis models in order to compare different CM under physiologically relevant and controlled conditions of blood flow, exposure time, and CM concentration. Three CM were studied: ioxaglate, iohexol, and iodixanol. CM were locally infused into the proximal segment of femoral arteriovenous shunts. Palmaz-Schatz stents (4 mm i.d.) and expanded tubular segments (9 mm i.d.), which exhibited venous-type flow recirculation and stasis, were deployed into the shunts distally. Saline was infused in identical control studies. Blood flow was maintained at 100 ml/min. Thrombosis was measured over a blood exposure period of 2 hours by gamma camera imaging of 111In-platelets and by gamma counting of deposited 125I-fibrin. CM concentrations within the flowfield were predicted using computational fluid dynamics. At infusion rates of 0.1 and 0.3 ml/min, the low-osmolar ionic CM ioxaglate reduced both platelet and fibrin deposition on the stents by 75-80% (p <0.005), while both iohexol and iodixanol reduced platelet deposition by 30-50% (p <0.05). In the regions of low shear flow, ioxaglate (0.3 ml/min) also reduced platelet deposition significantly (by 52% vs. control results; p <0.05). Thus the three agents evaluated--ioxaglate, iohexol, and iodixanol--all produced anticoagulant and antiplatelet effects and were inherently antithrombotic in vivo. The most striking effects were seen with the low osmolarity, ionic contrast agent ioxaglate.

Influence of a nonionic, iso-osmolar contrast medium (iodixanol) versus an ionic, low-osmolar contrast medium (ioxaglate) on major adverse cardiac events in patients undergoing percutaneous transluminal coronary angioplasty: A multicenter, randomized, double-blind study. Visipaque in Percutaneous Transluminal Coronary Angioplasty [VIP] Trial Investigators.

BACKGROUND: The potential merits and disadvantages of the use of ionic or nonionic contrast media in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) have been the subjects of controversy. The present study was designed to evaluate the possible influence of both types of contrast media on major adverse cardiac events (MACE) in patients undergoing PTCA. METHODS AND RESULTS: In a randomized, parallel-group, double-blind study, 1411 patients received either iodixanol (a nonionic, iso-osmolar contrast medium) or ioxaglate (an ionic, low-osmolar contrast medium) during PTCA. A standardized anticoagulation regimen was followed. Patients were monitored in the hospital for 2 days and followed-up at 1 month. The primary end point, a composite of MACE (death, stroke, myocardial infarction, coronary artery bypass grafting, and re-PTCA) after 2 days, occurred in 4.3% of the total population, with no statistically significant difference between groups (iodixanol, 4.7%; ioxaglate, 3.9%; P=0.45). Further, between 2-day and 1-month follow-ups, no significant difference (P=0.27) existed between the groups in the rates of MACE. Hypersensitivity reactions (P=0.007) and adverse drug reactions (P=0.002) were significantly less frequent in the iodixanol group. The only significant predicting factors for the occurrence of MACE were dissection/abrupt closure and country. CONCLUSIONS: No significant differences were observed between the iodixanol and ioxaglate groups with regard to MACE, although hypersensitivity and adverse drug reactions were significantly less frequent in patients who received iodixanol.

[Comparative thrombotic risk of two contrast agents in coronary angiography]. / Risque thrombotique comparatif de deux agents de contraste en coronarographie.

The thrombogenic risk of contrast agents in coronary angiography is still a topical issue, particularly in comparisons between ionic and nonionic contrast agents. As a complement to a preliminary study, the repercussions on sensitive markers of haemostasis were investigated in vivo in 38 patients undergoing a standard cardiac catheterisation. After randomization, an ionic low osmolality contrast agent (Ioxaglate 320) was used in 19 patients and a nonionic low osmolality contrast agent (Iopromide 370) was used in another 19 patients, according to an identical protocol. The following parameters were assayed in arterial blood samples obtained before and after the examination in each patient: platelet markers: beta-thromboglobulin (beta TG) and platelet factor IV (PF4); prethrombotic markers: thrombin-antithrombin 3 complex (TAT) and prothrombin fragments 1 and 2 (F1 + 2) as well as partial exploration of fibrinolysis: tissue plasminogen activator inhibitors (PAI). Comparison of the results demonstrated platelet activation and the presence of prethrombotic markers in both groups. No significant difference was detected between the two groups of patients. Consequently, there does not appear to be any difference in activation of coagulation between modern, low osmolality, ionic or nonionic contrast agents. This may suggest an equivalent thrombogenic risk.

Lack of myocardial perfusion immediately after successful thrombolysis. A predictor of poor recovery of left ventricular function in anterior myocardial infarction.

BACKGROUND: We investigated myocardial perfusion dynamics after thrombolysis and its clinical implications. METHODS AND RESULTS: We studied 39 patients with acute anterior myocardial infarction (AMI). Myocardial contrast echocardiography (MCE) was performed before and immediately after successful reflow with intracoronary injection of sonicated Ioxaglate. The average segmental score by two-dimensional echocardiography (graded 0, normal, to 3, akinetic/dyskinetic) and global ejection fraction (left ventricular ejection fraction, LVEF%) by left ventriculography were measured at 1 day and at 4 weeks after reflow. Hypokinesis in the infarct region was assessed by the centerline method and expressed in terms of standard deviations (regional wall motion [RWM]: SD/chord) of normal. Immediately after reflow, 30 of 39 patients (group A) showed significant contrast enhancement within the risk area. The other nine patients (23%, group B), however, showed the residual contrast defect in the risk area (myocardial no reflow). There were no significant differences in the elapsed time, angiographic collateral grade, and degree of residual stenosis between group A and group B. Before reflow, both groups exhibited similar levels of global and regional left ventricular function. Improvement in global (LVEF, average segmental score) and regional left ventricular function was greater in group A than in group B (average segmental score, 0.44 +/- 0.41 versus 0.97 +/- 0.36, p less than 0.01; LVEF, 56.4 +/- 13.4 versus 42.7 +/- 8.9, p less than 0.05; RWM, -1.87 +/- 0.85 versus -3.18 +/- 0.52, p less than 0.005). CONCLUSIONS: MCE demonstrates that angiographically successful reflow cannot be used as an indicator of successful myocardial reperfusion in AMI patients. The residual contrast defect in the risk area demonstrated immediately after reflow is a predictor of poor functional recovery of the postischemic myocardium.

Effect on thrombus growth and thrombolysis of two types of osmolar contrast media in rabbits.

Thromboembolic complications have been reported after diagnostic or interventional radiological procedures. However, contrast media inhibit platelet function and blood coagulation in vitro. To investigate these characteristics in vivo, we determined the effect of nonionic and ionic low osmolar contrast media on thrombus growth and thrombolysis in rabbits in a randomized study design. Rabbits received either ionic low osmolar contrast medium (ioxaglate), nonionic low osmolar contrast medium (iohexol) or saline. Thrombus growth was determined by the accretion of 125I-labeled fibrinogen on to autologous, nonradioactive, preformed thrombi in rabbit jugular veins. Thrombolysis was assessed by measurement of the decrease in radioactivity of standard sized preformed 125I-fibrinogen labeled thrombi. Ioxaglate significantly inhibited thrombus growth (60% inhibition, P less than 0.005 vs. saline), in contrast to iohexol, which had no significant effect (33% inhibition, P less than 0.2 vs. saline). Neither ioxaglate nor iohexol affected thrombolysis.