CONTRAST MIXTURE AND USE THEREOF

Abstract

A contrast mixture with increased affinity and selectivity to neoplasms of the gastrointestinal tract, being of three components and consisting of 0.0005-0.01% by weight of low-molecular component, 0.05-6% by weight of high-molecular component and isotonic solution, wherein low-molecular component is a contrast substance, which is a colouring agent used in food industry and pharmacy and high-molecular component is a colloid modulator of velocity designed to decelerate diffusion of the contrast mixture into a tissue in such manner that the velocity of diffusion into healthy tissue of gastrointestinal tract and the velocity of diffusion into neoplasm tissue of gastrointestinal tract is different. In an embodiment, the colouring agent is the sodium and/or calcium salt of [4-(alpha-(4-diethylaminophenyl)-5-hydroxy-2,4-disulphophenylmethylidene)-2,5-cyclohexadiene-1-ylidene] diethylammonium hydroxide or 3,7-bis(Dimethylamino)-phenothia zin-5-ium chloride and the colloid modulator of velocity is a starch, pectin, agar-agar (agarose and agaropectins) and/or non-linearly branched amylopectins. A use of the contrast mixture for colour sharp distinction of the interface between healthy tissue and neoplasm tissue of gastrointestinal tract.

Claims

1. A contrast mixture with increased affinity and selectivity to neoplasms of the gastrointestinal tract, wherein the contrast mixture comprises three components and consists of 0.0005-0.01% by weight of a low-molecular component, 0.05-6% by weight of a high-molecular component and an isotonic solution, wherein the low-molecular component is a contrast substance comprising a sodium and/or calcium salt of [4-(-(4-diethylaminophenyl)-5-hydroxy-2,4-disulphophenylmethylidene)-2,5-cyclohexadiene-1-ylidene] diethylammonium hydroxide or 3,7-bis(Dimethylamino)-phenothiazin-5-ium chloride and the high-molecular component is a colloid modulator of velocity which is comprising a polysaccharide linear polymer.

2. The contrast mixture according to claim 1, wherein the polysaccharide linear polymer is starch, pectin, agar-agar (agarose and agaropectins), non-linearly branched amylopectins or combinations thereof, wherein the size of colloid particles is within the range of 1-1000 nm.

3. The contrast mixture according to claim 2, wherein the starch is hydroxymethyl starch and/or hydroxyethyl starch.

4. A method of utilizing the contrast mixture according to claim 1 for colour sharp distinction of interface between healthy tissue and neoplasm tissue of gastrointestinal tract in duration of 10-25 minutes, for enlargement of volume of a protruded neoplasm of the gastrointestinal tract in duration of 10-25 minutes, or for colour contrasting of healthy tissue and neoplasm tissue in duration of 10-25 minutes without repeated administration of the contrast mixture.

Description

OVERVIEW OF FIGURES

[0035] FIG. 1Endoscopic finding before submucosal injection of contrast mixture.

[0036] FIG. 2Endoscopic finding after submucosal injectioninjection site.

EXAMPLES OF EMBODIMENTS

[0037] The proposed invention is further explained by means of following non-restrictive examples. Even though a number of embodiments is further disclosed, it is obvious that a skilled person in the art will find other possible alternatives to these embodiments. Therefore the scope of the invention is not restricted to these embodiments disclosed in examples but is given by definition of patent claims.

Example 1

[0038] The prepared contrast mixture for diagnostics and surgical treatment of neoplasms of gastrointestinal tract according to this invention has following composition:

[0039] Low-molecular component, i.e. the contrast substance, which is in this example of embodiment the sodium salt of [4-(-(4-diethylaminophenyl)-5-hydroxy-2,4-disulphophenylmethylidene)-2,5-cyclohexadiene-1-ylidene] diethylammonium hydroxide in amount: 0.025 g, i.e. 0.0025% by weight.

[0040] High-molecular component, i.e. the colloid modulator of velocity, which is in this example hydroxyethyl starch in amount: 30.000 g, i.e. 3.0000% by weight.

[0041] Isotonic solution in amount: 969.975 g, i.e. 96.9975% by weight.

[0042] The content of the contrast substance in the range according to this invention can be adjusted to a morphologic type of finding in gastrointestinal tract so that the optimal visual contrast is obtained.

[0043] The colloid modulator of velocity provides deceleration of diffusion of the contrast mixture into tissue, wherein the velocity of diffusion into healthy tissue and the velocity of diffusion into neoplasm tissue of the gastrointestinal tract is different.

[0044] The contrast mixture according to this invention was used for diagnostics and surgical treatment of the neoplasm of large intestine.

[0045] By using the contrast mixture according to this invention for diagnostics and surgical treatment of neoplasms of gastrointestinal tract, the colour sharp distinction of interface between healthy tissue and neoplasm tissue of gastrointestinal tract was achieved in the visible area as well as increase in volume of the neoplasm of gastrointestinal tract and thus its protrusion from healthy tissue of gastrointestinal tract, namely in duration of typical 15 minutes. The colour sharp distinction of interface is achieved by a different velocity of diffusion of low-molecular component and high-molecular component diffusion into healthy tissue and neoplasm tissue.

[0046] The neoplasm of gastrointestinal tract forms a structure whose epithelial cells are interconnected, so macromolecular components permeate from lumen of gastrointestinal tract into the wall of neoplasm slower than low-molecular components.

[0047] Differences in permeating of high-molecular component of the mixture into tissue are quantitative, not qualitative, i.e. high-molecular component permeates into healthy tissue with different velocity than into neoplasm. Injection of the contrast substance is applied into healthy tissue (injected under neoplasm), thus initial diffusion of the contrast mixture occurs in the administration site (injection site) of healthy tissue. Diffusion is a dynamic process that results in an increased concentration of colouring agent in neoplasm tissue compared to the healthy one during therapeutic time window, i.e. colour distinction of neoplasm tissue from healthy tissue is achieved (dark blue-light blue) and contrasting is negative. Colour transition between healthy tissue and neoplasm tissue is formed by a different tissue which comprises elements of both tissues (cells and extracellular matrix) whereby a new turquoise coloured staining of this narrow interface is achieved.

[0048] By using the contrast mixture according to this invention, prolongation of timeframe of intervention for typical 15 minutes is achieved without repeated administration of the contrast mixture. At the same time, the sharp difference in colour of interface between healthy tissue and neoplasm tissue, as well as actual volume of protruded neoplasm, increases precision and quality of polypectomy. Better visual control during surgery enables more precise intervention even under complicated conditions (e.g. worse access for polypectomy loop or possible proximity of inoperable tumour).

[0049] This prolongation of an applicability period reduces time stress of the medical staff and comforts the patient (the intervention falls within an outpatient care, it is performed under local anaesthesia and patient is fully conscious). An improved visual feedback during endoscopic diagnostics and intervention itself decreases invasiveness of the intervention (less of the healthy tissue being removed), cognitive load for medical staff, shortens the duration of intervention, minimizes risks for the patient (perforation of intestine wall and duodenum wall) and improves surgeon's comfort during application of ligator and subsequent resection. The visual contrast enables to localize neoplasm more precisely and thus reduces resection of healthy tissue.

[0050] The contrast substance according to this invention is applicable for selective contrasting of neoplasms along the whole length of gastrointestinal tract.

[0051] In FIGS. 1 and 2 is shown documentation that is related to the polypectomy of large intestine neoplasm when using the contrast mixture according to this example of embodiment.

Example 2

[0052] The contrast mixture for diagnostics and surgical treatment of neoplasms of gastrointestinal tract according to this invention has similar composition as in Example of embodiment 1 with the difference that instead of the sodium salt of [4-(-(4-diethylaminophenyl)-5-hydroxy-2,4-disulphophenylmethylidene)-2,5-cyclohexadiene-1-ylidene] diethylammonium hydroxide, the calcium salt of [4-(-(4-diethylaminophenyl)-5-hydroxy-2,4-disulphophenylmethylidene)-2,5-cyclohexadiene-1-ylidene] diethylammonium hydroxide is used and instead of hydroxyethyl starch, the hydroxymethyl starch is used.

[0053] Other factors are the same as stated in the Example of embodiment 1.

Example 3

[0054] The contrast mixture for diagnostics and surgical treatment of neoplasms of gastrointestinal tract according to this invention has similar composition as in Example of embodiment 1 with the difference that instead of sodium salt of [4-(-(4-diethylaminophenyl)-5-hydroxy-2,4-disulphophenylmethylidene)-2,5-cyclohexadiene-1-ylidene] diethylammonium hydroxide, the mixture of sodium and calcium salt of [4-(-(4-diethylaminophenyl)-5-hydroxy-2,4-disulphophenylmethylidene)-2,5-cyclohexadiene-1-ylidene] diethylammonium hydroxide is used in 1:1 ratio, wherein the mixture is in amount of 0.0025% by weight.

[0055] Instead of hydroxyethyl starch the mixture of hydroxyethyl starch and hydroxymethyl starch in 1:1 ratio is used, wherein the mixture is in amount of 3.00% by weight.

[0056] Other factors are the same as stated in Example of embodiment 1.

Example 4

[0057] The contrast mixture for diagnostics and surgical treatment of neoplasms of gastrointestinal tract according to this invention has similar composition as in Example of embodiment 1 with the difference that instead of sodium salt of [4-(-(4-diethylaminophenyl)-5-hydroxy-2,4-disulphophenylmethylidene)-2,5-cyclohexadiene-1-ylidene] diethylammonium hydroxide, the mixture of sodium and calcium salt of [4-(-(4-diethylaminophenyl)-5-hydroxy-2,4-disulphophenylmethylidene)-2,5-cyclohexadiene-1-ylidene] diethylammonium hydroxide in 3:7 ratio is used, wherein the mixture is in amount of 0.0025% by weight.

[0058] Instead of hydroxyethyl starch the mixture of hydroxyethyl starch and hydroxymethyl starch in 1:1 ratio is used, wherein the mixture is in amount of 3.00% by weight.

[0059] Other factors are the same as stated in Example of embodiment 1.

Example 5

[0060] The contrast mixture for diagnostics and surgical treatment of neoplasms of gastrointestinal tract according to this invention has similar composition as in Example of embodiment 1 with the difference that instead of sodium salt of [4-(-(4-diethylaminophenyl)-5-hydroxy-2,4-disulphophenylmethylidene)-2,5-cyclohexadiene-1-ylidene] diethylammonium hydroxide, the mixture of sodium and calcium salt of [4-(-(4-diethylaminophenyl)-5-hydroxy-2,4-disulphophenylmethylidene)-2,5-cyclohexadiene-1-ylidene] diethylammonium hydroxide in 7:3 ratio is used, wherein the mixture is in amount of 0.0025% by weight.

[0061] And instead of hydroxyethyl starch, the mixture of hydroxyethyl starch and hydroxymethyl starch in 1:1 ratio is used, wherein the mixture is in amount of 3.00% by weight.

[0062] Other factors are the same as stated in Example of embodiment 1.

Example 6

[0063] The prepared contrast mixture for diagnostics and surgical treatment of neoplasms of gastrointestinal tract according to this invention has following composition:

[0064] Low-molecular component, i.e. the contrast substance, which is in this example of embodiment the sodium salt of [4-(-(4-diethylaminophenyl)-5-hydroxy-2,4-disulphophenylmethylidene)-2,5-cyclohexadiene-1-ylidene] diethylammonium hydroxide in amount: 0.025 g, i.e. 0.0025% by weight.

[0065] High-molecular component, i.e. the colloid modulator of velocity, which is in this case the mixture of agarose and agaropectin in 7:3 ratio in total amount: 1.5000 g, i.e. 0.15000% by weight.

[0066] Isotonic solution in amount: 998.745 g, i.e. 99.8745% by weight.

[0067] Other factors are the same as stated in Example of embodiment 1.

Example 7

[0068] The prepared contrast mixture for diagnostics and surgical treatment of neoplasms of gastrointestinal tract according to this invention has following composition:

[0069] Low-molecular component, i.e. the contrast substance, which is in this example of embodiment 3,7-bis(Dimethylamino)-phenothiazin-5-ium chloride in amount: 0.025 g, i.e. 0.0025% by weight.

[0070] High-molecular component, i.e. the colloid modulator of velocity, which is in this example of the embodiment the mixture of agarose and agaropectin in 7:3 ratio in total amount: 1.5000 g, i.e. 0.15000% by weight.

[0071] Isotonic solution in amount: 998.745 g, i.e. 99.8745% by weight.

[0072] Other factors are the same as stated in Example of embodiment 1.

Example 8

[0073] The prepared contrast mixture for diagnostics and surgical treatment of neoplasms of gastrointestinal tract according to this invention has following composition:

[0074] Low-molecular component, i.e. the contrast substance, which is in this example of embodiment the sodium salt of [4-(-(4-diethylaminophenyl)-5-hydroxy-2,4-disulphophenylmethylidene)-2,5-cyclohexadiene-1-ylidene] diethylammonium hydroxide in amount: 0.025 g, i.e. 0.0025% by weight.

[0075] High-molecular component, i.e. the colloid modulator of velocity, which is in this case the mixture of agarose and agaropectin in 1:1 ratio in total amount: 1.5000 g, i.e. 0.15000% by weight.

[0076] Isotonic solution in amount: 998.745 g, i.e. 99.8745% by weight.

[0077] Other factors are the same as stated in Example of embodiment 1.

Example 9

[0078] The prepared contrast mixture for diagnostics and surgical treatment of neoplasms of gastrointestinal tract according to this invention has following composition:

[0079] Low-molecular component, i.e. the contrast substance, which is in this example of embodiment the sodium salt of [4-(-(4-diethylaminophenyl)-5-hydroxy-2,4-disulphophenylmethylidene)-2,5-cyclohexadiene-1-ylidene] diethylammonium hydroxide in amount: 0.025 g, i.e. 0.0025% by weight.

[0080] High-molecular component, i.e. the colloid modulator of velocity, which is in this case the mixture of agarose and agaropectin in 3:7 ratio in total amount: 1.5000 g, i.e. 0.15000% by weight.

[0081] Isotonic solution in amount: 998.745 g, i.e. 99.8745% by weight.

[0082] Other factors are the same as stated in Example of embodiment 1.

Example 10

[0083] The prepared contrast mixture for diagnostics and surgical treatment of neoplasms of gastrointestinal tract according to this invention has following composition:

[0084] Low-molecular component, i.e. the contrast substance, which is in this example of embodiment the 3,7-bis(Dimethylamino)-phenothiazin-5-ium chloride in amount: 0.025 g, i.e. 0.0025% by weight.

[0085] High-molecular component, i.e. the colloid modulator of velocity, which is in this example of the embodiment the mixture of agarose and agaropectin in 1:1 ratio in total amount: 1.5000 g, i.e. 0.15000% by weight.

[0086] Isotonic solution in amount: 998.745 g, i.e. 99.8745% by weight.

[0087] Other factors are the same as stated in Example of embodiment 1.

Example 11

[0088] The prepared contrast mixture for diagnostics and surgical treatment of neoplasms of gastrointestinal tract according to this invention has following composition:

[0089] Low-molecular component, i.e. the contrast substance, which is in this example of embodiment the 3,7-bis(Dimethylamino)-phenothiazin-5-ium chloride in amount: 0.025 g, i.e. 0.0025% by weight.

[0090] High-molecular component, i.e. the colloid modulator of velocity, which is in this example of the embodiment the mixture of agarose and agaropectin in 3:7 ratio in total amount: 1.5000 g, i.e. 0.15000% by weight.

[0091] Isotonic solution in amount: 998.745 g, i.e. 99.8745% by weight.

[0092] Other factors are the same as stated in Example of embodiment 1.

Example 12

[0093] The prepared contrast mixture for diagnostics and surgical treatment of neoplasms of gastrointestinal tract according to this invention has following composition:

[0094] Low-molecular component, i.e. the contrast substance, which is in this example of embodiment the 3,7-bis(Dimethylamino)-phenothiazin-5-ium chloride in amount: 0.025 g, i.e. 0.0025% by weight.

[0095] High-molecular component, i.e. the colloid modulator of velocity, which is in this example of the embodiment the amylopectin: alpha-D-gluco-hexopyranosyl-(1->4)-alpha-D-gluco-hexopyranosyl-(1->6)-[alpha-D-gluco-hexopyranosyl-(1->4)]-alpha-D-gluco-hexopyranosyl-(1->4)-alpha-D-gluco- hexopyranose in amount: 1.5000 g, i.e. 0.15000% by weight.

[0096] Isotonic solution in amount: 998.745 g, i.e. 99.8745% by weight.

[0097] Other factors are the same as stated in Example of embodiment 1.

Example 13

[0098] The prepared contrast mixture for diagnostics and surgical treatment of neoplasms of gastrointestinal tract according to this invention has following composition:

[0099] Low-molecular component, i.e. the contrast substance, which is in this example of embodiment the sodium salt of [4-(-(4-diethylaminophenyl)-5-hydroxy-2,4-disulphophenylmethylidene)-2,5-cyclohexadiene-1-ylidene] diethylammonium hydroxide in amount: 0.025 g, i.e. 0.0025% by weight.

[0100] High-molecular component, i.e. the colloid modulator of velocity, which is in this case the pectin: (2S, 3R, 4S, 5R, 6R)-3,4,5,6-tetrahydroxyoxane-2-carboxylic acid in total amount: 1.5000 g, i.e. 0.15000% by weight.

[0101] Isotonic solution in amount: 998.745 g, i.e. 99.8745% by weight.

[0102] Other factors are the same as stated in Example of embodiment 1.

REFERENCE SIGNS

[0103] 1Gastrointestinal tract [0104] 2Neoplasm of gastrointestinal tract [0105] 3Interface between gastrointestinal tract and neoplasm of gastrointestinal tract [0106] 4Injection site

INDUSTRIAL APPLICABILITY

[0107] The contrast mixture according to this invention is characterized by selective contrasting of neoplasms along the whole length of gastrointestinal tract and thus it is possible to use it also for other neoplasms localised in other parts of gastrointestinal tract such as small intestine or duodenum.