LT3620B - Contrast media - Google Patents

Abstract

The physiologic suitability of contrast compositions, in particular those designed for angiography, may be increased by adding sodium and calcium subplasmic amounts and if required, those of kalium and/or magnesium, for example 30 mM NA, 0.15 mM Ca and 0.1 mM Mg.

Description

The present invention relates to contrast compositions, in particular radiographic contrast compositions, and in particular to so-called nonionic contrast compositions.

Contrast compositions are usually divided into two groups, so-called ionic and non-ionic contrast compositions. In these compositions, the contrast medium in the liquid carrier is present in ionic forms or molecular forms, or in a special form, respectively.

Contrast compositions can be used in medical image procedures such as X-rays, magnetic resonance imaging or ultrasound to highlight the contrast between images of the subject, usually the human body or the animal body. The resulting enhanced contrast allows for clearer observation or identification of various organs, tissue types, or body areas. The performance of an X-ray contrast composition is related to changes in the X-ray absorption characteristics of the parts of the body in which it is distributed; the operation of the magnetic resonance contrasting composition generally involves changes in the characteristic relaxation times Tj and T ₂ of the nuclei, as a rule, of the water protons from which the image is obtained; and the performance of the ultrasound contrast composition is related to changes in the speed or density of sound in the individual parts of the body in which they are distributed.

It is clear that the use of a substance as part of a contrasting composition depends largely on its toxicity and other undesirable effects it may have upon ingestion. Because such formulations are mainly used for diagnostic purposes rather than for direct therapeutic effect, there is a general belief in the need for compositions that minimize the impact on various cellular or body bioLT 3620 logic mechanisms, thereby reducing toxicity. and other adverse clinical effects.

The toxicity and undesirable effects of contrast compositions are determined by the components of the composition, such as solvent or vehicle, and the contrast agent and its components (e.g., ions if the material is ionic) and metabolites.

The following key factors determining the toxicity and undesirable effects of contrast compositions have been identified:

- contrast agent chemotoxicity,

- osmolarity of the contrasting composition,

- ionic (or non-ionic) composition of the contrast composition.

For example, in coronary angiography, the introduction of contrast compositions into the circulatory system has been associated with some serious effects on cardiac function, effects that were serious enough to limit the use of some contrast agents in angiography.

In this procedure, a certain amount of contrast medium, more than blood, circulates in the circulatory system for a short period of time, and differences in the chemical and physico-chemical nature of the contrast medium that may temporarily replace it may lead to undesirable effects such as arrhythmia, QT a reduction in the strength of the heart muscle, as well as the development of ventricular fibrillation. Numerous studies have been conducted on the reported adverse effects on cardiac function after administration of contrast compositions to the circulating system, such as during angiography, and extensive efforts have been made to reduce or eliminate these effects.

It should be clearly noted that modern non-ionic contrast compositions of low osmolality do not exhibit the usual higher toxicity or other undesirable effects and are fully suitable for most patients. However, there is a desire to use even more physiologically balanced contrast compositions where the tissue may be exposed to contrast media for a prolonged period, for example, when contrast media can be formed, such as stenosis, catheter embossing, PTCA (percutaneous transluminal coronary angioplasty) intervention.

most conventional X-ray contrast compositions include iodine-containing material as a contrast agent. (Iodine, which has a relatively high atomic weight, has a 'relatively large cross-section for X-rays').

Thus, contrast compositions used in angiography may contain iodine concentrations as high as 250450 mg J / ml, and at these concentration ranges, the osmolality of 1.5 ionic contrast agents (such as diatrizoate, iodothiamate, iodoxitalamate, iodamine and metrizoate) is 5-9 times higher. , than normal human plasma; an osmolality of a ratio 3 ionic contrast agent (e.g. iodoxaglate) or a ratio 3 nonionic contrast agent (e.g., metrizamide, iodopromide, iodopentol, iodopamidol and iodohexol) is approximately half that of a nonionic contrast agent 6 (e.g. iodotrolan and iodine). osmolality is about a quarter of the 1.5 osmolarity of ionic contrast media at the same centers of iodine konLT 3620 B. The ratio of 6 nonionic contrast media can be used at iodine concentrations that are hypotonic.

In the above paragraph, the ratio of 3 is that the ratio of iodine atoms to the delta of the contrast medium (ie, ions or molecules) is 3. The ratio of 1.5 ionic to 3 nonionic contrast media usually has one triodophenyl residue and the ratio of 3 ionic contrast media to non-ionic contrast agents generally contain two triiodophenyl residues.

Thus, at most iodine concentrations, such as 250 mg J / ml, the radiopaque compositions will be hypertonic. This hypertension causes osmotic effects such as removal of water from red blood cells, endothelial cells, and cardiovascular muscle cells. Water loss renders red blood cells inelastic, while hypertonicity, chemotoxicity, and suboptimal ionic composition, alone or in combination, reduce muscle cell contraction, causing small blood vessels to expand, and thereby lowering blood pressure.

Therefore, there is a general reluctance to add ions to an isotonic or already hypertonic contrast composition as this will cause or increase hypertonicity and thus the osmotic side effects.

However, as noted above, the ionic composition of the composition, or the total ions deficiency in the contrasting composition, contribute significantly to the toxicity and undesirable effects of the contrasting composition. Ionic contrast compositions necessarily contain counter-labeled ions, typically counter-labeled cations to iodine ions, which are usually anions. Many studies have been conducted on the composition of these ionic contrast compositions, and although commercial cations are predominantly sodium (Na ⁺ ) and / or Megluminium (Meg ⁺ ), plasma ions such as calcium, potassium, and magnesium may be included.

Although it is generally accepted that the decrease in cardiac muscle contraction force increases with increasing sodium ion concentration, Almen's results (see Act Radiolcgica Diagnosis, 17: 130-448 (1976)) using a bat wing vein model for contrast effect on smooth muscle the absence of normal ionic concentrations in plasma cations (ie sodium, potassium, magnesium and calcium) adversely affects muscle contraction. The work of Simon et al. AJR 114: 801-816 (1972), ionic contrast compositions based on diatrizoate, strongly suggest that coronary angiography carries the risk of ventricular fibrillation when sodium ion concentrations in the contrast composition fall significantly below normal plasma levels. Other studies also generally show that ventricular fibrillation occurs when the sodium ion concentration in the contrast composition drops below about 3.2 to 2.6 mM (see Morris, In Investigative Radiology 2_3: S127-S129 (1988)). Indeed, it has also been noted that the drop in ventricular fibrillation from nonionic contrast media may be unacceptably high (see Piao et al., Investigative Radiology 23: 466-470 (1988)).

The addition of calcium and magnesium ions to the ionic contrast medium containing sodium and noluminium cations has also been found to reduce the effects on the blood-encephalic barrier and that acute intravenous toxicity in animals can also be reduced.

However, now our studies have shown that the addition of magnesium or calcium plasma levels can lead to an unexpected increase in arrhythmia, particularly ventricular fibrillation, and this calcium level can also cause undesirable cardiac output.

Previous studies have also shown that the presence of sodium ions in the contrasting composition reduces the formation of red blood cell aggregates in human blood and also reduces the aggregation of red blood cells. Zucker et al. (see Investigative Radiology 23: S340-S345 (1988)) suggested that the non-ionic radiographic contrast composition of iodohexol should contain sodium added in the form of 15 mM NaCl to reduce red blood cell aggregation without, at the same time, significantly altering osmolality.

However, although studies have shown that the addition of plasma ions to a radiographic contrast composition may modify the biological effects of such a composition, it has been recognized, as noted above, that any addition of ions to a hypertonic composition will increase hypertonicity and thereby osmotic effects. Thus, although the literature suggests that contrast compositions can reduce ventricular fibrillation fall and red blood cell aggregation by incorporating 1 such composition in low sodium concentrations, and that undesirable changes in muscle cell contraction force can be reduced by adding normal plasma cations to normal plasma, the data are not fully compatible in this field of science, and indeed are more contradictory when it comes to the optimal amount of cations in the contrast composition.

However, we have found, as described in WO-A-90/11094, that certain adverse effects of non-ionic contrast media, particularly arrhythmias (e.g., ventricular fibrillation), red blood cell aggregation and reduction in heart rate may be reduced or even eliminated, introducing relatively low concentrations of sodium ions, e.g., about 30 mM; the improvement is such that this addition is justified, even when the contrast composition is initially hypertonic.

We now find that the undesirable effects of contrast compositions in angiography can be further reduced by the addition of certain salt concentrations to other plasma cations. For example, we have found that the negative effects of contrast media on cardiac contractility and red blood cell aggregation and similar to arrhythmia can be further reduced.

Thus, we have found in in vitro assays in human blood that the inhibitory effect of red blood cell aggregation upon addition of electrolytes to X-ray contrast media is greater when more than one plasma cation is used. In addition, in animal studies, we have found that the addition of calcium produces an additional undesirable effect on the cardiac contractile force greater than that obtained with sodium alone. Particularly when calcium is administered, the initial decrease in cardiac contractile force during coronary perfusion, which may occur with sodium-containing contrast compositions, may be reduced or substantially eliminated. However, relatively small amounts of calcium should be added (usually the calcium / sodium ratio should be lower than in plasma) to avoid undesirable increases in heart rate and an increase in arrhythmia. In animal studies, we have also found that cases of arrhythmia (e.g., ventricular fibrillation) can be further reduced by adding relatively small amounts of potassium and / or magnesium to such a contrast composition. We have also found that the addition of plasma cations to the contrast composition, particularly to the non-ionic X-ray contrast composition, reduces the effect of such a composition on decreasing serum levels of complementary blood proteins. We also found that the effect of the added plasma earth alkali metal cations on the reduction of red blood cell aggregation is more pronounced than that of the added plasma alkaline metal cations.

In one aspect, the present invention provides a contrast composition comprising a physiologically acceptable aqueous vehicle containing a contrast agent (preferably a nonionic contrast agent, preferably an iodine-containing radiographic contrast agent, most preferably a nonionic iodine-containing radiographic contrast agent) and a physiologically acceptable sodium compound. which produces concentrations of 15 to 75 mM sodium ions (preferably 20 to 70, especially 25 to 35 mM Na), characterized in that at least one salt selected from physiologically acceptable potassium and magnesium salts is present in the vehicle; said total calcium and potassium salts being up to 0.8 mM Ca (preferably 0.050.7, preferably 0.1-0.6 and especially 0.15-0.4 mM Ca) and up to 2 mM K (preferably 0, 2-1.5, preferably 0.3-1.2 and particularly good 0.4-0.9 mN K) and in this mixture the ratio of sodium ions to calcium ions is greater than 55, preferably greater than 60, particularly good 100- 250 (the ratio of sodium ions to potassium ions is also preferably greater than 15, more preferably greater than 20, especially greater than 30, such as 25 to 80).

Preferably, the contrast composition has an osmolality of at least 270, more preferably at least 280, preferably at least 290, and particularly good (especially atLT 3620 with a contrast ratio of 6 non-ionic X-ray contrast media) of 290-320 mosm / kg H ₂ O .

Preferably, the contrasting composition of the invention contains magnesium ions at concentrations up to 0.8 mM Mg, more preferably up to 0.6 mM Mg, preferably up to 0.5 mM Mg, e.g. 0.05 to 0 , 4 mM Mg, or particularly fine at 0.1 to 0.25 mM Mg. If the calcium and magnesium salts are present in the composition, it is preferable that the ratio of calcium to magnesium is at least about 1.4, preferably at least about 1.5, may even be as high as normal plasma (about 2.9) or slightly higher, e.g. , 3 to 8.

Balancing the ratio of sodium ions to calcium ions in the contrasting composition of the present invention is particularly important in cases where the composition contains a lower ratio non-ionic X-ray contrast agent and for compositions with low sodium concentrations. For example, it is best to have a sodium / calcium ratio greater than 300 / n for contrast media, particularly greater than 350 / n, preferably greater than 375 / n, and particularly well greater than 400 / n.

In general, the contrast compositions of the present invention contain the following concentration limits for sodium and other plasma cations:

Sodium 15-75 mM Calcium 0.05-0.6 mM Potassium 0.0-2.0 mM Magnesium 0.0-0.4 mM

Although preferably, the contrast composition of the present invention comprises a balanced mixture of all four plasma metal cations, sodium, calcium, potassium, and magnesium.

However, potassium may be used in combination with both sodium and calcium, or with one of potassium or magnesium, in particular sodium and calcium in concentrations such as those described above. Calcium has been found to counteract the initial decrease in cardiac contraction force caused by sodium-containing contrast media, and combinations of calcium with other plasma cations not only allow this neutralizing effect to be achieved with lower concentrations of calcium than if only one calcium is used, but also have surprisingly beneficial effects in reducing the occurrence of arrhythmia.

In general, if the concentration of sodium in the contrasting composition is close to the upper limit of the given concentration range, it is desirable that the minimum sodium / alkaline earth metal cation ratio be lower than at sodium concentrations close to the lower range indicated.

For contrast agents of a ratio of 6 or higher, the maximum ratios of other plasma cations to sodium will generally be close (e.g., within 30%) to those of normal plasma; for lower ratio contrast agents, the maximum values of these plasma cations to sodium ratios will be generally lower, such as 50 or even 60% lower than the values (for calcium, potassium and magnesium about 0.017, 0.026 and 0.006).

For lower ratio contrast agents, the following concentration limits are preferred for sodium ions in the range 25-35 mM Na and for other plasma cations:

Calcium 0.1 to 0.3 mM, e.g. 0.1-0.2 mM

0.0 to 1.2 nM, particularly 0.3 to -0 mM, e.g. 0.3 to 0.6 mM

Magnesium 0.0 to 0.2 mM, especially 0.05 to 0.2 mM, e.g. 0.1 mM

Thus, two particularly suitable compositions for lower ratio contrast agents have the following cation concentrations (or within 0.05 mM):

Sodium 30 mM

Calcium 0.15 rnM

Potassium 0.90 mM or 0.40 mM

Magnesium 0.10 mM

These concentrations and concentration ranges are generally desirable for lower ratio contrast agents at normal iodine concentrations, e.g., 140-350 mg J / ml.

For higher ratio contrast agents, compositions having a basic osmolality of less than 290 mosm / kg H ₂ 0 (i.e., compositions which are hypo-osmotic in the absence of salts) can preferably be converted to isotonic or hypertonic by the addition of a single metal salt or a combination of metal salts. and physiologically acceptable, preferably nonionic, osmotically active substances.

Non-ionic osmotic agents, such as polyols, especially saccharides or salt alcohols, especially hexitols, such as compounds such as mannitol, sorbitol, xylitol and glucose, can be used at concentrations up to 150 mM, preferably up to 100 mM, e.g. , 30-80 mM (e.g. osmolality corresponds to 150 mosm / kg H ₂ O and 1.1). If such osmotically active agents are used, the above concentrations of sodium, potassium, calcium and magnesium will be most suitable for lower ratio contrast agents, such as:

Well 25-35 mM, especially 30 mM

Ca. 0.1-0.3 mM, particularly 0.1-0.2 mM K 0.0-1.2 Mm, such as 0.3-0.6 mM Mg 0.0-0.2 mM, especially 0.05-0.2 mM.

In this case, an osmotic agent (e.g. up to 80 mM) will be used to make the contrast composition isotonic or slightly hypertonic (e.g. up to 320 mosm / kg K ₂ 0). The two best examples of such formulations use a ratio of 6 contrast agents (e.g. 150 mg J / ml) and contain the following cation concentrations (or within 0.05 mM):

Well 30 mM

Ca 0.15 mM

K at 0.0 mM and 0.4 mM

Mg 0.1 mM

Mannitol 80 mM.

If the basal osmolality of the higher ratio contrast agent com15 is sufficiently close to isotonic and the addition of metal salts is necessary only to raise the osmolality to isotonic (or slightly hypertonic), the following concentration limits are used:

Well. 65-75 mM

Ca 0.3-0.6 mM

K 0-2 mM, especially 0.5-2.0 mM

Mg 0-0.4 mM, especially 0.1-0.4 mM

In the most preferred examples of compositions containing a ratio of 6 contrast agents (e.g. 150 mg J / ml), the cation concentrations are as follows (or within 0.05 mM):

Na 7 0 mM

Ca 0.40 to 0.60 mM, e.g. 0.4, 0.5 or 0.0 mM

K 1.5 mM

Mg 0.25 mM

For higher ratios (e.g. iodixanol) of higher concentrations, such as 250-340 mg J / ml, or 270-320 mg J / ml, particularly about 320 mg J / ml, it is preferable to add metal salts in amounts of: smaller but still sufficient To make the composition isosmotic or slightly hyperosmotic, e.g.

Na 15-20 mM

Ca 0.1-0.3 mM

K 0.0-1.2 mM, e.g. 0.0 to 0.4 mM

Mg 0.0-0.2 mM (for example Na 18.8 mM, Ca 0.3 mM, KO mM, Mg 0 mM or Na 18.8 mM, Ca 0.3 mM, K 0.6 mM, Mg 0 , 15 mM). If the concentration of the contrast medium is close to the lower range (eg 250-300, especially 270 mg J / ml), the following cation concentration limits are more appropriate:

Na 25-35 mM

Ca 0.1-0.5 mM

K 0-1.2 mM, e.g. 0 -0.6 mM

Mg 0-0.2 mM '(e.g. Na 32.4 mM, Ca 0.5 mM, K 0 mM, Mg 0 mM).

In fact, the present invention has found that the negative effects of the increased hyperosmolarity resulting from the addition of metal cations to a nonionic radiographic contrast composition are outweighed by the resulting positive factors, such as reduction of ventricular fibrillation, reduction of blood cell aggregation, and contraction.

The present invention is particularly suitable for X-ray contrast compositions containing 3 to 6 ratio contrast agents, such as those listed below, in particular iohexol, jovoyoi, iopamidol, iotrolan, ioxagiat and especially iodixanol. (See GB-A-1548594, EP-A-83964, BE-A-836355, EP-A-33426 and EP-A-108638).

Other non-ionic X-ray contrast agents that may be used in the present invention include: metrizamide (see DE-A-2031724), iodecimol (see EP-A-49745), yoglucol (see US-A-4314055), yoglucamide (see BE-A846657), joglunide (see DE-A-2456685), yogulamide (see DE-A-882309), jomeprol (see EP-A-26281), iopentol (see EP-A-105752), jopromide (see DE-A-2909439), josarcol (see DE-A-3407473), josimide (see DE-A-3001292), jothasul (see EP-A-22056) and ioxylan (see WO- A-87/00757).

Particularly suitable compositions of the present invention are those containing at least 100 mg J / ml of these contrast agents. In addition, since the general requirement that isotonicity deviations must be minimized, it is desirable that the contrast composition has an osmolality of less than 1 osm / kg H ₂ O according to the present invention; 850 mosm / kg K ₂ O or less is particularly suitable.

Sodium, calcium, potassium and magnesium ions are conveniently included in the contrasting composition of the present invention using their salts with physiologically acceptable charge ions. Particularly suitable counter-charge ions are -yrapine anions such as chloride, phosphate and hydrocarbon ions. Alternatively, however, the cations may be incorporated, at least in part, in the form of salts containing a physiologically acceptable chelating agent, e.g., "sodium EDTA or calcium disodium EDTA. The contrast composition of the invention may be prepared by adding to the available contrast medium sodium, potassium, calcium and magnesium salts, both solid or already dissolved, and mixtures of salts or solutions of these mixtures.

Another aspect of the present invention is a process for the preparation of a contrast composition which comprises, if necessary, pre-dispersed in a physiologically acceptable carrier medium, a contrast agent, a source of sodium ions, a physiologically acceptable calcium salt, and, if necessary, an additional osmotic agent. , if necessary, at least one physiologically acceptable potassium or magnesium salt, and if necessary diluting the resulting mixture to provide a contrast medium according to the present invention.

The contrast compositions of the invention are particularly suitable for intravascular use, particularly for obtaining cardiac images. Thus, a further aspect of the present invention is the use of a contrast agent, physiologically acceptable sodium salt, physiologically acceptable calcium salt, optionally an additional osmotic agent, and optionally at least one physiologically acceptable potassium or magnesium salt contrast agent, for obtaining cardiac imaging.

Preliminary studies mentioned in WO-A-90/11094 have shown that compositions containing iodixanol or iohexol, as defined in the present application, containing from 0.3 to 0.6 mM Ca ² 'or about 0.2 mM Ca ²⁺ , atiLT 3620 B properly enhances the contrast media. Similarly, experimental results show that oxygenation of the medium, such as oxygen saturation, also effectively improves its properties.

Although mainly applicable to non-ionic contrast agents, the present invention also applies to ionic contrast agents, particularly ionic iodine-containing X-ray contrast agents, such as Ioxaglate (available from Guerbet SA, trade name Hexabrix).

Thus, another aspect of the present invention is a contrast composition comprising a physiologically acceptable aqueous carrier medium in which the ionic contrast agent (e.g., ioxaglate) is dissolved, said contrast composition comprising sodium and calcium and / or potassium ions and, if necessary, magnesium ions; the concentration of sodium ions is up to L60 mM (especially 130 to 150 mM), calcium ions up to 1.6 mM (especially up to 1.3, preferably about 1.2 mM) and potassium ions up to 4.5 mM (especially about 4 M). It is good that such a contrasting composition (e.g., ioxaglate at about 330 mg / ml, Na at about 140 mM, calcium at about 1.2 mM and K at about 4 M) also contains magnesium ions, e.g. up to 1 mM, especially about 0. , 8 mM.

The present invention will now be described with reference to the following non-limiting examples.

example

CONTRAST COMPOSITION

Composition:

Iohexol * (Ϊ40 mg J / ml)

Sodium chloride up to 30 mM Na ⁺

Calcium chloride to 0.15 mM Ca ²⁺

Potassium chloride up to 0.4 mM K ⁺

Magnesium chloride to 0.10 mM Mg ²⁺

The solid chlorides are dissolved in iohexol to give the desired cation concentration. Formulations containing 270, 300 and 350 mg J / ml iohexol and formulations containing potassium chloride up to 0.9 mM K ⁺ are prepared analogously. If dilution is required, water for injections should be used.

* Iohexol is obtained from Nycomed AS under the trade name OMNIPAQUE.

example

CONTRAST COMPOSITION

Composition:

Iodixanol * (150 mg J / ml)

Sodium chloride up to 30 mM Na ⁺

Calcium chloride to 0.15 mM Ca ²⁺

Potassium chloride up to 0.4 mM K ⁺

Magnesium chloride to 0.10 mM Mg ²⁺

Mannitol up to 80 mM

Chlorides and mannitol are dissolved in iodixanol (obtained from Nycomed AS). Formulations containing 180 mg J / ml iodixanol and formulations containing 0.9 mM K ^T potassium chloride are prepared analogously. If dilution is required, water for injections should be used.

example

CONTRAST COMPOSITION

Composition:

Iodixanol * (150 mg J / ml)

Sodium chloride up to 70 mM Na ⁺ Calcium chloride up to 0.4 mM Ca ²⁺ Potassium chloride up to 1.5 mM K ⁺ Magnesium chloride up to 0.25 mM Mg ²⁺

The chlorides are dissolved in iodixanol (obtained from Nycomed AS). A composition containing calcium chloride up to 0.5 mM K ⁺ is prepared analogously. If dilution is required, water for injections should be used.

example

CONTRAST COMPOSITION

Composition:

Iodixanol * (320 mg J / ml)

Sodium chloride to 30 mM Na ⁺

Calcium chloride up to 0.15 mM Ca

Potassium chloride to 0.40 mM K ⁺

Magnesium chloride to 0.10 mM Mg

The chlorides are dissolved in iodixanol (obtained from Nycomed AS). If dilution is required, water for injections should be used. Formulations containing 270 mg J / ml iodixanol and formulations containing potassium chloride up to 0.9 mM K ⁺ are obtained analogously.

pa vy z d y s

CONTRAST COMPOSITION

Composition:

Iodixanol * (270 mg J / ml)

Sodium chloride up to 32 mM Na ⁺

Calcium chloride up to 0.5 mM Ca ²⁺

The chlorides are dissolved in iodixanol (10 med AS is obtained). If dilution is required, use water intended for them. Compositions containing about 320 mg J / ml of nol are prepared analogously.

Example 15

CONTRAST COMPOSITION

Composition:

Iodixanol * (150 mg J / ml)

Sodium chloride up to 70 mM Na ⁺

Calcium chloride up to 0.6 mM Ca ²⁺

The chlorides are dissolved in iodixanol (obtained as med AS). If dilution is required, use water intended for them.

Example 7

CONTRAST COMPOSITION

Composition:

Iodixanol * (320 mg J / ml)

Sodium chloride to 18.8 mM Na ⁺

Calcium chloride up to 0.3 mM Ca ²⁺ from Nyco injections from Nyco injections

The chlorides are dissolved in iodixanol (obtained from Nycomed AS). If dilution is required, water for injections should be used. Formulations containing sodium ions up to 30 mM Na ⁺ are prepared analogously.

example

CONTRAST COMPOSITION

Composition:

Joversol (300 mg J / ml)

Sodium chloride up to 30 mM Na ⁺

Calcium chloride to 0.15 mM Ca ²⁺

Potassium chloride to 0.4 mM K ⁺

Magnesium chloride to 0.2 mM Mg ²⁺ .

Chlorides are dissolved in joversol (available from Mallinckrodt, Inc.) and water for injections is used if necessary. A composition containing potassium chloride up to 0.9 mM K ⁺ is prepared analogously.

ADDED PLASMA ION EFFECTS ON THE CHANGE OF HEART RELEASE POWER DUE TO INFLUENCE OF A CONTRASTIC COMPOSITION BOLUS

Calcium

Changes in heart rate after injection of a calcium ion-containing contrast medium with sub-plasma calcium levels and these plasma calcium levels were demonstrated by percentage change (compared to control values) during left ventricular pressure (ALVDP) exposure. seconds) and at the end of the exposure (45 seconds) 0.5 ml of a contrast formulation consisting of iodixanol (150 mg J / ml), sodium (70 mM,

NaCl) and O, 0.2, 0.4, 0.6, 0.9, and 2.4 mM Ca (CaCl ₂ ) bolus injected by Langendorff perfusion into isolated rat hearts.

Table 1

Plasma ion concentration ALVDP (%) * Na (mM) Ca (mM) During the exposition At the back of the exhibit 70 0 -49.4 ± 2.7 -52.2 ± 4.3 70 0.2 -31.3 ± 2.0 -4 8.3 ± 5.0 70 0.4 -24.6 ± 1.8 -24.3 ± 2.3 70 0, 6 -16.2 ± 1.8 -17.6 ± 2.9 70 0.9 -6.8 ± 1.8 +0.5 ± 1.7 70 2.4 + 31.2 ± 1.1 + 64.4 ± 4.7

* mean ± SVP, n = 6

The effect of 0, 0.1, 0.2, and 0.3 mM Ca (as CaCl ₂ ) in a contrast formulation containing iohexol 140 mg J / ml and sodium 30 mM (as NaCl) was similarly observed after the administration of a 1 ml bolus.

Table 2

Plasma ion concentration ALVDP (%) * Na (mM) Ca (mM) During the exposition At the back of the exhibit 30th 0 -24.3 ± 3.8 -29.8 ± 5.0 30th 0, - -11.5 ± 2.2 -3.9 ± 3.6 30th 0.2 -5.3 ± 2.2 +7.4 ± 4.4 30th 0.3 +3.1 ± 2.5 + 17.7 ± 3.5

* mean ± SVP, n ί

r> f *.

ZZ

The effect of calcium on higher concentration contrast formulations was similarly demonstrated by allowing 0.25 ml of a contrast composition containing iodixanol (300 mg J / ml), sodium (24 mM NaCl) and 0, 0, -2 and 0.4 mM Ca ( _{in the} form of CaCl ₂ ).

table

concentration A.LVDP (%) * Na (mM) Ca (mM) Exposure her hair At the back of the exhibit 24th 0 -25, 9 ± 1.8 -28.8 i 3.4 24th 0.2 -24.7 ± 1.5 -24.7 ± 2.6 24th 0.4 -14.3 ± 1.7 -7.3 ± 1.1 * average ± SVP, n = 6

The effect of calcium on the contrast composition in which the osmolality is enhanced by the addition of an osmolally active substance (mannitol) rather than by increasing the sodium concentrations is similarly demonstrated by allowing. 1 ml of contrast medium containing iodixanol (150 mg J / ml), sodium (in the form of 30 mM NaCl), mannitol (80 mosm / kg H ₂ O) and 0.1, 0.2 and 0.3 mM Ca (CaCl) ₂ ).

Table 4

Plasma ion concentration ALVDP (%) * Na (mM) Ca (mM) During the exposition At the back of the exhibit 30th 0 -22.1 ± 0.7 -39.6 ± 1.5 30th n i v t 1 -14.6 + 1.2 -16.3 + 2.2 30th 0.2 · -8.2 ± 0.3 -4.7 ± 2.4 30th 0.3 -3.8 ± 2.0 6.8 ± 3.6

* mean ± SVf, n = 6.

Other plasma cations

Using the same animal test, the effect of other plasma cations (chloride salts) on the sodium-containing contrast composition is demonstrated by the addition of 1 ml of iohexol (140 and 350 mg J / ml) and iodixanol (150 and 320 mg J / ml).

(Iohexol 140 mg J / ml) Table

Plasma ion concentration Δ LVDP (%) * Well (mM) Ca. (mM) K (mM) Mg (Mm) Exhibitions years Exhibitions In the end 30th 0 0 0 -23.0 ± 3.1 -28.4 ± 4.1 30th 0.1 0, 30 0.10 -11.5 ± 2.6 -10.0 ± 4.1 30th 0.15 0, 40 0, 10 -1.9 ± 0.7 +7.3 ± 2.0 30th 0.20 0, 60 0.20 -2.5 ± 2.4 + 6.0 ± 5.9 30th 0.25 0, 80 0, 12 +1.9 ± 2.7 + 20.4 ± 3.5

* mean ± SVP, n = 6 (Isoxol 350 mg J / ml) Table 6

Plasma ion concentration Δ LVDP (%) *** Well (mM) Ca. (mM) K (mM) Mg (Mm) Exhibitions years Exhibitions In the end 30th 0 0 0 * -63.0 ± 0.6 -84.0 ± 0.5 30th 0.15 0.4 0, 10 ** -46.7 ± 1.1 -62.8 ± 1.7

* n = 30, ** n = 6, *** Mean ± SVP (Iodixanol 150 mg J / ml) Table 7

Plasma ion concentration Δ LVDP (%) ** Well (mM) Ca. (mM) K (mM) Mg (Mm) Exhibitions years Exhibitions In the end 70 0 0 0 -49.9 ± 2.5 -74.9 ± 2.0 70 0, 60 0 0 -10.0 ± 1.9 -15.1 ± 1.4 70 0.40 1.5 0.25 -11.0 ± 0.8 -21.2 ± 2.0 30 * 0.15 0.4 0.1 -4.2 ± 1.1 -2.2 ± 2.0

* plus 80 mosm / kg H ₂ 0 mannitol, 8 * mean ± SVP, n = 6 (iodixanol 320 mg J / ml)

Plasma ion concentration Δ LVDP (%) * Well (mM) Ca. (mM) K (mM) Mg (Mm) Exhibitions years Exhibitions In the end 18.8 0 0 0 -31.6 ± 2.1 -49.9 ± 2.8 18, 8 0.3 0 -21.7 ± 1.4 -26.9 ± 2.5 30th 0.15 0.4 0.1 -33.8 ± 2.2 -45.8 + ± 2.2

* mean ± SVP, n = 6

THE IMPACT OF ADDED PLASMA CATIONS ON ARHYTHMIA

Calcium

The effect of adding sodium (as NaCl) or sodium and sub-plasma calcium to the contrast composition on the electrophysiological effects of b'olius injection (approximately one order of magnitude greater than the volume required for angiographic purposes) was measured using an isolated rabbit heart.

table

Contrast medium (mg J / ml) Well (mM) Ca. (mM) % SF % ES % BS Johannesburg (350) 30th 0 0 0 0 30th 0.1 0 0 0 30th 0.2 0 0 0 30th 1.2 50 21st 71 Iodixanol (320) 19th 0 0 0 0 19th 0.3 0 0 0

SF = ventricular fibrillation

ES = multiple extrasystoles

BS = Common Disorders

Injection volume = 7.5 ml

Other plasma cations

The desirability of adding plasma concentrations of calcium or magnesium to or close to plasma was demonstrated for iohexol (350 mg J / ml) (Table 9 above and tables 11 and 12 below) and iodixanol (320 mg J / ml) (below) given in Table 10) cases. In the studies presented in Tables 11 and 12, even greater amounts of contrast composition were injected to ensure arrhythmia challenge and thus to demonstrate clearly the cardioprotective effects of various cations.

table

Iodixanol (320 mg J / ml)

Well (mM) Ca. (mM) Mg (mM) % SF % ES % BS 28th 0 - 0 0 0 0 28th 2, 5 0, 95 67 33 100 19th 1.2 0, 6 30th 0 30th Injected volume = 15 ml 11th table Yohexol (350 mg J / ml) Well (mM) Ca. (mM) Mg (mM) K (mM) % SF 30th 0.15 0 0.4 20th 30th 0.15 1.2 0.4 90 Injected volume = 15 ml 12th table Yohexol (350 mg J / ml) Well (mM) Ca. (mM) Mg (mM) K (mM) % SF 30th 0.15 0 0 40 30th 0, 15 0.1 0 30th 30th 0.15 0 0.4 20th 30th 0.15 0 0.9 10th 30th 0.15 0.1 0.4 15th 30th 0.15 0.1 0.9 10th

Injection volume = 15 ml

In addition, the use of a very large contrast medium bolus demonstrated the cardioprotective effect of the addition of calcium, magnesium and potassium cations to the contrast formulation using 16 isolated rabbit hearts:

ml of iohexol (350 mg J / ml) induced ventricular fibrillation or asystoles in 14 of 16 hearts (87.5%).

ml of iohexol (350 mg J / ml) with 30 mM NaCl induced ventricular fibrillation or asystoles in 4 of 16 hearts (25.0%).

ml of iohexol (350 mg J / ml) with 30 mM NaCl, 0.15 mM CaCl ₂ , 0.4 mM KCl, and 0.1 mM MgCl ₂ induced ventricular fibrillation or asystoles in 1 of 16 hearts (6%).

Claims (13)

DEFINITION OF INVENTION 1. A contrasting composition comprising a physiologically acceptable aqueous carrier medium containing a contrast agent and a physiologically acceptable sodium compound having a sodium ion concentration of 15 to 75 mM Na, characterized in that said carrier medium is dissolved in a physiologically acceptable calcium salt and if desired, at least one salt selected from physiologically acceptable potassium and magnesium salts; said total calcium and potassium salts are up to 0.8 mM Ca and up to 2 mM K; and that the ratio of sodium to calcium is greater than 55. 2. The contrast composition of claim 1, wherein the concentration of calcium ions is 0.05 to 0.7 mM Ca ²⁺ . 3. The contrast composition of claim 1, wherein the concentration of calcium ions is from 0.1 to 0.6 mM Ca ²⁺ . The contrast composition of any one of claims 1 to 3, wherein the concentration of potassium ions is between 0.2 and 1.5 mM K ⁺ . 5. The contrast composition of any one of claims 1 to 3, wherein the concentration of potassium ions is between 0.3 and 1.2 mM K ⁺ . 6. Contrast composition according to any one of claims 1 to 5, characterized in that it has a magnesium ion concentration of up to 0.8 mM Mg ²⁺ . LT 3 t ϋ 3 7. The contrast composition according to any one of claims 1 to 5, characterized in that it has a magnesium ion concentration of 0.05 to 0.4 mM Mg ²⁺ . 8. The contrast composition according to any one of claims 1 to 7, characterized in that it contains an iodine-containing X-ray contrast agent. 9. The contrast composition of claim 8, wherein the contrast agent is selected from iohexol, ioversol, iopamidol, iotrolan, ioxaglate and iodixanol. 10. Contrast composition according to claim 8 or 9, characterized in that it contains 25-35 mM Na ⁺ , 0.1 to 0.3 mM Ca ²⁺ , 0.3 to 1 sodium, calcium, potassium and magnesium. 2 mM K ^+, and 0.05 to 0.2 mM Mg ²⁺ , and wherein, if said contrast agent is present in a ratio of 6 or greater, the composition further comprises a physiologically acceptable osmotically active agent. 11. Contrast composition according to claim 8 or 9, characterized in that it contains sodium, calcium, potassium and magnesium in concentrations of 65 - 75 mM Na ⁺ , 0.3 - 0.6 mM Ca ²⁺ , 0.5 - 2.0 mM K ⁺ and 0.1 to 0.4 mM Mg ²⁴ , wherein said contrast agent is in a ratio of 6 or greater. 12. The contrast composition of any one of claims 1 to 11, wherein said contrast composition has an osmolality of 290-320 mosm / kg H ₂ O. 13. A process for the preparation of a contrast composition comprising mixing, if necessary, a contrast agent, a source of sodium ions, a physiologically acceptable calcium salt, if desired, and at least one additional active agent, after dispersion in a physiologically acceptable aqueous vehicle. of physiologically acceptable potassium or magnesium salts and, if necessary, dilute the resulting mixture to 5 is obtained from a composition as defined in any one of claims 1 to 12.