A method of obtaining a magnetic resonance contrast agent and device for hydrogenation
The invention relates to a method for contrast agent for magnetic resonance research and device to implement the method. Carry out i) obtaining a solution in a solvent gidrirovannogo unsaturated compounds of the substrate and catalyst for the hydrogenation of compounds of the substrate, ii) the introduction of the solution in the form of droplets in a chamber containing gaseous hydrogen (H2rich parahydrogen (p-1H2and/or orthodeuterium (o2H2), for the hydrogenation of the substrate to form a hydrogenated agent image visualization, (iii) possible processing hydrogenated agent image visualization magnetic field having a lower field strength than the intensity of the ambient field of the Earth, iv) possible dissolution agent image visualization in the aquatic environment, (v) possible separation of the specified catalyst from the solution of the agent image visualization in the aquatic environment, (vi) the possible separation of the specified solvent from a solution of the agent visualization image specified in the aquatic environment, and (vii) the possible freezing of the solution agent image visualization in the aquatic environment. Device for hydrogenation includes camera hydrogenation with output is directed into the chamber to remove solvent. Luggage hydrogenation with an inlet opening for entry of the hydrogen to the inlet of the input solution is further provided with a generator of liquid droplets. The pipeline includes camera removal of the catalyst that is installed between the camera hydrogenation and camera removal of the solvent, and is equipped with an inlet for entry of the liquid. The camera metering removal of the solvent provided the outlet for the gas outlet and the outlet for the withdrawal of fluid. The invention allows to cause hyperpolarization of contrast agent. 2 N. and 11 C.p. f-crystals, 1 tab., 4 Il.
The present invention relates to a method of nuclear-spin polarization unsaturated compounds, parahydrogen-induced or orthodeuterium, and device for implementing this method, more preferably to a method for contrast agent for magnetic resonance research.
The hydrogen molecules (1H2) exist in two different forms, namely, in the form of prevodioca, when the nuclear spins are anti-parallel and shifted in phase (singlet state), and in the form of orthovalerate when they are parallel or antiparallel and match pagoda to orthovalerate is approximately 1:3. At 80K, this ratio is about 48:52, and at 20K it is close to 100:0 (actually about 99,8:0,2).
In contrast, deuterium (D2or2H2), in which the nucleus2N has a nuclear spin (S) 1, not 1/2, there are nine different forms in the three antisymmetric performax and six symmetric orthoformic. When the ambient temperature ratio Orchidaceae (o-D2) to paradeuterium (p-D2) in a mixture of ortho/parametere is approximately 2:1, at 60K is about 3:1, and at 20K - about 98:2 (deuterium freezes at about C).
In the patent application WO 99/24080, the content of which is given here as a reference, it is described the use of prevodioca for the catalytic hydrogenation of unsaturated compounds with the transfer of these compounds antiparallel proton spins of molecules prevodioca and the transfer of nuclear-spin polarization from protons produced from prevodioca to non-hydrogen nuclei with non-zero nuclear spin (i.e., S0) gidrirovaniem connection, for example, nuclei13With or15N. Thus, these nuclei with nonzero spin, you can ensure that the nuclear-spin polarization (hyperpolarization), equivalent to their hyperpolarizability cores, can be used to display magnetic resonance in approximately the same manner as it is carried out in case hyperpolarizing3Not.
A similar hyperpolarization of the nuclear spin can be obtained in the same way hydrogenation of deuterium, more preferably by orthodeuterium or mixtures of hydrogen (1H2) with deuterium (2H2), preferably a deuterium or mixtures of hydrogen with deuterium, in which the ratio of steam/artform hydrogen and the ratio of the ortho/paraform for deuterium exceed the equilibrium value (1:3 and 2:1) at ambient temperature, for example, have a relationship, the corresponding equilibrium values at temperatures below 80K, more preferably at temperatures below 40K, most preferably in the temperature range from the temperature of liquid helium (4K) up to 30K, and particularly preferably in the temperature range from the melting temperature of the hydrogen and/or deuterium to 25K.
Hydrogenation and/or deteriora, for example, bonds in the substrate molecule, caused by the introduction of the atom1H or2H associated with each of the atoms connected to the unsaturated bond is used to create a distribution of the spins of hydrogen/deuterium in the molecule is s. If the substrate molecule contains a nucleus with non-zero nuclear spin (in relation to the corresponding natural distribution of isotopes or exceeding it), especially if these nuclei with nonzero spin (S0) have a similar molecular structure hydrogenated substrate atoms1H or2N, introduced by hydrogenation, the introduction of atoms1H or2N may cause the distribution of nuclear spins in nuclei with S0 that is different from the equilibrium distribution at ambient temperature. Such non-equilibrium distribution of nuclear spins injected protons/deuterons and nuclei with S0 gidrirovaniem the substrate can be used for signal amplification in a variety of ways to display magnetic resonance, including display of magnetic resonance in vivo.
The term "hyperpolarization" is used here to describe the distribution of the population of nuclear spins of nuclei visualization with non-zero nuclear spins in gidrirovaniem the substrate, which is different from the equilibrium distribution of population in the range from ambient temperature to physiological temperature (e.g., 25-40°C), the new nuclear spins in gidrirovaniem the substrate, while in the specified distribution of the difference between the primary and the excited state of the nuclear spins is larger than the corresponding difference in the equilibrium population.
Under the "nuclei visualization understand the kernel gidrirovaniem the substrate responsible for the signal of magnetic resonance (Mr), which is used when displaying the magnetic resonance to generate images. So, for example, nuclei visualization can be kernel13With or15N, in the General case removed to a distance of 4 links from nuclei1N or2H, introduced by hydrogenation of the substrate, or it may be the nucleus1H or2H, introduced by asymmetric hydrogenation of unsaturated substrates. (Since the substrate is asymmetric, the resonance frequencies of two introduced hydrogens will not be the same).
At the same time as the patent application WO99/24080 describes the way in which you can perform parastacidae hydrogenation, the authors of the present invention have found that the hydrogenation for use in order to display magnetic resonance para-H2and/or ortho-D2induced hyperpolarization, the hydrogenation reaction is particularly preferably by mixing gaseous water is, is it 1:3, preferably more than 3:7, more preferably greater than 1:1, and/or the ratio of the ortho/paraform2H2more than 3:2, preferably more than 3:1, more preferably greater than 4:1), sprayed with a solution of unsaturated compounds and catalytic hydrogenation.
According to one of the objectives of the present invention provides a method of obtaining a MRI contrast agent, including:
i) obtaining a solution in a solvent gidrirovannogo unsaturated compounds of the substrate and catalytic hydrogenation of the compounds of the substrate,
ii) the introduction of this solution in the form of droplets in a chamber containing gaseous hydrogen (H2rich parahydrogen (p-1H2and/or orthodeuterium (o2H2), for the hydrogenation of a specified substrate to form a hydrogenated agent image visualization,
iii) possible processing the specified hydrogenated agent image visualization magnetic field having a lower tension than the tension of the surrounding field of the Earth,
iv) possible dissolution of the specified agent image visualization in the aquatic environment,
v) possible separation of the specified catalyst from the solution specified is from the solution of the specified agent rendering the image specified in the aquatic environment, and
vii) possible freezing of the solution of the specified agent rendering the image specified in the aquatic environment.
In possible operations (iii) of the method according to the invention, the agent visualization image is subjected to processing of a weak magnetic field - this operation is preferably performed when in a magnetic resonance study does not apply deuterium nuclei visualization images that enter deuteronomium ortho-D2(i.e. gas containing D2in which the ratio of ortho-D2: napa-D2more than 2:1). The processing of a weak magnetic field can be performed at any stage after the start of the hydrogenation, the method according to the invention can be implemented in its entirety in a weak field, however, it is desirable to process the weak field before adding water (possible operation (iv)), to avoid greater losses of hyperpolarization from the effects of a weak field, called paramagnetic materials that may be present in the water (such as minor impurities or dissolved oxygen), and also due to the fact that protons can be in the water relaksiruyushaya impact.
Accordingly, it is preferable to produce, and less the weak field) and/or in the reaction medium, coming out of the camera. The processing of a weak field (for example, in fields with less than 50 ILC, preferably less than 1 MT, most preferably less than 0.1 MT) can be secured using magnetic shielding, using commercially available materials such as mu-metal, and can be especially effective to manufacture, placing the device according to the invention fully or partially in the container with magnetic shielding, described in particular in patent application WO 99/17304.
In an alternative embodiment, the processing of a weak magnetic field can be performed using a transmission medium through a pipe with a double layer of mu-metal, inside which you can create a field of less than 1 MT, more preferably less than 0.5 MT, most preferably less than 0.1 MT.
It is preferable to carry out the processing of a weak magnetic field by passing through the zone with magnetic shielding with special profile of the magnetic field. Magnetic shield is a magnetic multi-layer tube made of mu-metal layers which are arranged in such a way that the sample came out of the Earth's magnetic field and are included in the zone with a field of less than 0.1 MT in a few microseconds. The sample was then gradually return in mania. This ensures an efficient transfer of polarization from protons to heteroatom.
This cyclic action of an external magnetic field from the "field" field to less than 1 ILC, preferably about 0.1 MT, with a gradual return to the Earth's field enables the transfer of polarization from protons in just gidrirovaniem contrast agent to the nucleus in the same molecule with a longer duration of polarization, preferably atom13With or15N. the Duration of this process is critical. As for the method provides maximum efficiency, the sample must immediately leave the field of the Earth, and then gradually return to field of the Earth. In this context, the term "immediately" means the procedure1 MS, and the term "gradually" means the order 10-10000 MS, preferably 100-1000 MS.
The shielding of the magnetic field can be made mu-metal and may consist of three concentric tubes, for example, with diameters of 80, 25 and 12 mm, respectively. At one end of the screen, all three layers overlap, creating maximum shielding, and the glass tube is straight and has an inner diameter of, for example, 1 mm. From the middle of the screen is saved only the outer is usually used to provide a more gradual increase of the field. The spiral continues behind the screen a few inches.
Magnetic screen is also equipped with a demagnetizing windings, as mu-metal slowly magnetized by external fields, especially near magnets image visualization. The method of degaussing involves passing an alternating current size is about 5 And 50 Hz through a demagnetizing coil, and then a gradual decrease of the current to zero. The whole process should be done within one to several minutes, preferably daily. The winding can be made of copper wire with a thickness of 1 mm with a lacquer finish and can contain approximately 2000 turns.
System interrupt flow operates, when the newly formed parasitiology product through the resistive magnet (coil) located within the zone with magnetic shielding. Magnetic shield can be a two-layer tube made of mu-metal with such shielding ability to the residual field was less than 0.1 MT, in the absence of current flowing through the winding. Initially, when the sample enters the coil, include the current to create the magnetic field of the same order as the field of the Earth. Then the current should be switched off and again gradually at roadru.
The main part of the agent image visualization requires such treatment a weak magnetic field for one or two reasons, first, because it facilitates the transfer of polarization of the injected nucleus1N or2H nuclei visualization image (for example,13C,15N and so on) and, secondly, because this treatment converts the linear form of the MRI signal from antiphase multiplet with zero integral in the multiplet with the useful signal, is preferable to render the image.
Used GearWay the substrate can be a material that is described in particular in patent application WO 99/24080 as parasitiology substrate. For research with the rendered image in vivo substrate preferably is a material that are acceptable from the physiological point of view as in gidrirovannoe and negidrirovannah forms. For magnetic resonance research using2D substrate preferably should be asymmetric with respect to gidriruemyi bonds, especially preferably asymmetrical within 4 links relative to bonds (e.g., N3With2OOSN2CH=CH-CH3should races is To MRI in vitro or in vivo biological or quasi-biological processes or synthesis of synthetic polymers (for example, peptide poliolefinovoy acid and so on) the substrate is preferably hydronaut with the formation of molecules involved in these reactions, for example, amino acid, nucleic acid, the molecule that binds the receptor, and so forth, or such a natural molecule or equivalent.
The solvent used at the operation (i) of the method according to the invention can be any suitable material which is a solvent for the substrate and catalytic hydrogenation. However, preferably it is a volatile organic solvent (e.g. acetone), especially one that is miscible with water, especially preferably non-water (i.e., not1H2About), and most preferably it is perdetermined solvent (for example, With2H3OS2H3or d6-acetone). If the agent image visualization is intended for Mrs studies in vivo, the solvent is preferably a physiologically acceptable. Removal of the solvent (possible operation (vi) of the method according to the invention) is preferably carried out by means of vacuum, for example, by means of a single evaporation when sprayed. However, you can use other ways to quickly remove rastvoronasosom or close to the minimum, you want to save in the substrate solution, catalyst and agent image visualization during hydrogenation reactions.
Alternatively, the reaction can be performed directly in water using water-soluble substrate and a water-soluble catalyst. The method in this case is easier and faster is implemented as a delete operation of a solvent is not required.
The hydrogenation catalyst is preferably a catalyst is described in WO99/24080, for example a complex metal, in particular a complex of rhodium.
Enriched with hydrogen, which can be pure1H2or2H2or mix1H2or2H2(may contain some amount of HD), possibly containing other gases, but preferably does not contain oxygen or other reactive or paramagnetic gases, can be obtained by cooling hydrogen (for example,1H2,2H2etc.) preferably to a temperature below 80K, more preferably to a temperature below 30K, even more preferably to a temperature below 22K, and ensure equilibrium nuclear spin States, possibly in the presence of terrorist.D. After that enriched hydrogen is preferably removed from the promoter equilibrium and can be stored before use, preferably at reduced temperature, for example, 20-80K. Receiving and storing enriched hydrogen is described in patent application WO 99/24080, the content of which is given here as a reference.
For conducting hydrogenation reactions enriched hydrogen is introduced into the reaction chamber, possibly under pressure, for example, from 50 to 100 bar, and a solution of catalyst and substrate is introduced into the reactor in the form of drops, for example, by sprinkling or spraying. If desired, the solution can be obtained by mixing separate solutions of catalyst and substrate. To ensure adequate mixing can be used switchgear or a series of spray nozzles and can be mixed with the contents of the camera using, for example, agitator drive or by an appropriate shape of the chamber walls for admission into the chamber of the flow of the reaction mixture.
It is preferable to apply the spray nozzle of the pneumatic type using prevodioca as the spray gas. These nozzles provide better mixing of the gas and the liquid, the smaller drops and more bystrong reactor, for example, annular or tubular reactor, or in an alternative implementation, it can be a periodic process. However, preferably the flow in the reactor of a continuous or pulsed stream enriched in hydrogen and sprayed solution, continuous or periodic removal of slurry from the base of the reactor and a continuous or periodic release of unreacted gas from the reactor. It is preferable to regulate the temperature of the enriched hydrogen and solution entering the reactor to achieve a desired temperature of the gas-droplet phase in the reactor. With this purpose in the input highways, you can set the temperature sensors and the heating or cooling jacket.
After hydrogenation and any possible, although in General the preferred processing weak magnetic field, the agent visualization image preferably is mixed with water. For this purpose, preferably sterile water, and also preferably does not contain paramagnetic impurities. The resulting aqueous solution is preferably treated to remove the hydrogenation catalyst, for example, passing through the ion exchange column, preferably not containing paramin the AI image, can be adjusted to provide the appropriate temperature of the aqueous solution flowing in the ion exchange column. To remove a typical metal complexes hydrogenation catalysts can be used strongly acidic ion-exchange resin loaded with sodium ion, such as resin DOWEX 1x2-400 (Dow Chemicals) and Amberlite IR-120 (both resin supplied by Aldrich Chemicals). To ensure rapid ion exchange resin should have only a low degree of crosslinking, for example, from sulphonated polystyrene resin with 2% blended with divinylbenzene, loaded with sodium ion.
Removing the non-aqueous solvent is usually produced by a single evaporation when sprayed, for example, by spraying an aqueous solution in the chamber, creating a vacuum and displacement of an aqueous solution containing no organic solvent from the chamber using an inert, preferably neuraminidase gas, for example nitrogen. As a rule, the flow of liquid components through the hydrogenation miss with a preferred pressure of nitrogen, for example, from 2 to 10 bar.
The resulting aqueous solution of the agent image visualization can be frozen and stored, or alternatively, directly to spolia solutions additional components, for example, modifiers, pH, complexing agents, etc., Such direct application may include, for example, continuous infusion or in the alternative performed by infusion or injection of one or more unit doses. Of particular interest is the introduction of a bolus.
The entire process, starting with hydrogenation to remove the solvent, can be typically implemented in less than 100 seconds, you can actually receive a single dose in just 10-20 seconds, which is considerably less than the value of T1 for nuclei visualization image many agents render the image thus obtained contrasting environment.
It is desirable that the material surface, which contacts the agent image visualization in the process of obtaining method according to the invention, which is substantially free of paramagnetic materials and represented, for example, of glass, used for storing hyperpolarizing3Not as described in the patent application WO 99/17304, or gold or deuterated polymer. The materials surface, which contacts the nonaqueous solvent (e.g. acetone) should be resistant to the action of acetone, and the valves may be magnetic and contain de is meniu can easily be automated or managed to do using the computer.
According to the next task, the invention provides a device for hydrogenation camera including hydrogenation, which has an output hole for outputting the fluid in the pipe connected to the inlet of the generator liquid droplets (e.g., spray nozzle, which is aimed in the camera removal of the solvent, while in the specified camera hydrogenation has an inlet for entry of hydrogen and an inlet for entry of solution, supplied additional generator of liquid droplets, the pipeline includes between the specified camera hydrogenation and the specified camera removal of the solvent removal chamber catalyst (for example, containing ion-exchange resin), equipped with preferably the inlet opening for entry of the liquid (for example, a hole for the entry of water, located between the specified camera hydrogenation and the specified camera removal of the catalyst, and this camera removal of the solvent provided the outlet for the gas outlet (for example, communicates with the vacuum source and the outlet for the withdrawal of fluid (for example, you may set the camera preparation of the composition and further a means of introduction to dosing or priumnojnota shielding, the magnetic field in at least part of the specified camera hydrogenation and/or at least part of the pipeline (preferably in the portion which is located upstream of the flow relative to the openings for entry of liquid (water)) is <50 MT, more preferably <1 MT and most preferably <0,1 MT.
Obviously, when implementing the method according to the invention directly in the water and using the water-soluble substrate and a water-soluble catalyst Luggage solvent removal is not required.
The device according to the invention preferably also contains tanks and the mixing chamber, designed for input materials, such as reservoir enriched in hydrogen, water tank, tank for solutions of catalytic hydrogenation and/or gidrirovannogo substrate, tanks for additional components of a contrast medium, a mixing chamber for mixing the solutions of catalyst and substrate, the mixing chamber for mixing water with the solution coming from the camera, hydrogenation, etc. in the Same way the camera hydrogenation is preferably provided with an opening for the removal of hydrogen, and various camera and cut the th introduction of their content to the device or through the device. Particularly preferably, when the device includes a generator enriched hydrogen, valves, starters, valves, and a computer control system which controls the operation of the device.
Magnetic shielding is preferably made with the possibility of moving, so it can be removed if you want the rendered image using the2H.
The camera and the piping device according to the invention preferably has a capability of sealing to prevent the ingress of air, in addition, the device is preferably provided with valves and holes that allow degassing, in particular to remove surface-adsorbed oxygen.
Water is supplied to the device according to the invention, preferably is obeskislorozhennaja, for example, by treatment with nitrogen.
"Camera" in the device according to the invention may have a square internal cross-section greater than the area of the inner cross section of the inlet or outlet port (in the direction of flow), in an alternative implementation of the cross-sectional area in the direction of flow can be practically constant, i.e., the hydrogenation with homogeneous catalysis upon receipt of Mr contrast agents is novelty. Similarly, such hydrogenation upon receipt of amino acids and pharmaceuticals is also different novelty.
The method is fast and efficient, what is the next task of the invention.
In line with this purpose, the invention provides a method of obtaining amino acids, pharmaceutical or diagnostic agent in vivo, characterized in that the method includes the operation of the hydrogenation, in which the substrate solution and the hydrogenation catalyst is sprayed into a chamber containing hydrogen.
If the hydrogenation is carried out using gas in which the ratio2N:1H exceeds 9:1, with the use of para-D2, this also allowed the use of a heterogeneous catalyst, then the catalyst removal may include filtering or other methods of particle removal.
The content of all mentioned in this description of the publications is given here as a reference.
Below is a description of the variants of the method and device according to the present invention with reference to the following non-restrictive examples and figures.
Fig.1 is a schematic illustration of the device according to the invention.
Fig.2 - shemalecocktail, shown in Fig.1.
Fig.4 is a schematic representation of a device according to another object of the present invention.
As shown in Fig.1, hydrogen (1H2) is supplied from the cylinder 1 through the pipe 2 in the steam generator is1H2and then the camera 3 hydrogenation. The solution of hydrogenation catalyst from the reservoir 4 and the solution gidrirovannogo substrate from the tank 5 is served by pipes 6 and 7 to the spray nozzle in the chamber 3. The liquid remaining in the chamber 3, passes through the pipe 8 through a pipe 9, which is made of two layers of mu-metal and represents a magnetic shield with an internal field of less than 0.1 MT, ion-exchange column 10 and then to a spray nozzle installed in the chamber 11 remove solvent. Before the liquid will enter the ion-exchange column, but after she leaves the magnetic shielding, the pipe 13 from the tank 12, water is added. The camera 11 solvent removal are connected by a pipe 14 to a vacuum pump 15, which serves to remove non-aqueous solvent, for example acetone. The liquid remaining in the chamber 11, is removed through outlet pipe 16.
As shown in Fig.2, a nitrogen pressure of 3 bar) is used for the displacement solutions of the catalyst and the substrate is t be pneumatic) in the chamber 3 hydrogenation, which is equipped with a valve hole 19 for the production of hydrogen. In an alternative embodiment, the dosing and mixing of substrate and catalyst can adjust the pumps with computer control (not shown). Nitrogen can be used to displace through the magnetic shielding 9 of the liquid collected in the chamber hydrogenation to mix it with water, which is displaced by nitrogen from the tank 12. As shown in Fig. 3, the mixture of solution/water passes into the mixing chamber 20 with the water jacket and then through the ion exchange column 10 in length from 2 to 4 cm, containing particles from sulphonated polystyrene size 400 mesh/ 2% divinylbenzene, and then to the spray nozzle 21 in the chamber 11 remove solvent. To ensure complete removal of nonaqueous solvent chamber 11 bufferinput using a cooling trap (not shown) with subsequent supply of the second volume before the vacuum pump is reset sudden load that otherwise would fall on the pump. After exiting the chamber 11 of the water "contrast medium" ready-to-use, alternatively you can sauteriot its pH and adjust ion profile (for example, add the cations plasma).
They are the Itza, which is then taken out and injected contrast medium to the patient. In the second mode, the device continuously generates a small dose of a contrast medium into the catheter to the patient. The second mode provides a simple visualization of the image, since the operator can regulate the flow of the MRI agent to obtain a satisfactory image.
In Fig. 4 shows a device 30 which applies hyperpolarizability solution in the syringe 31. The device uses a three-way switching valve 32. The syringe must be installed vertically with upward handle of the piston to ensure that no air bubbles in the solution. When the switching valve 32, the solution can be entered into the transition tube 33. The syringe or cavity 34 with a certain volume and low friction is placed directly before injection target 35, and the syringe 34 absorbs the amount of dead zone and possible gas bubbles.
The solution tetrathiocarbonate (bicyclo[2.2.1]hepta-2,5 diene)-[1,4-bis(diphenylphosphino)butane] rhodium (I) (93,5 mg) in barbotirovany argon acetone (5 ml) were loaded into a camera, And a solution of 2-ecotoxicology acid (110 mg, of 0.85 mmole) in barbotirovany argon acetone (5 ml) into the chamber C. the Chamber filled With 2% of curing, swollen in water and charged sodium ions, loaded in the ion exchange column. In the system through shirts circulated water at a temperature of 42°C. the Experiment began with the launch of a computer program, which operated valves according to the scheme 1, as shown in the table. The program written in the LabView system. After finishing the program through the bottom of the chamber G with a syringe selected sample of an aqueous solution hyperpolarizing O-acetyl-lactic acid.
Two-stage diaphragm pump with a capacity of 3 m3/h used to create vacuum and nitrogen pressure of 3 bar to create the displacing pressure.
The spray nozzle was a common nozzle for industrial oil burners, one in the chamber D with a capacity of 1.5 US gallons (5,678 l)/h with the cone angle of 60° and one in the chamber G with a capacity of 1.0 gallon US (there are 3,785 l)/h with the cone angle of 80°.
Magnetic valves 8 Tue, 24 VDC with strips of ethylene-propylene-diene copolymer (EPDM).
Magnetic shield was made of two concentric tubes made of mu-metal.
Hyperpolarizing the solution was applied using the device to obtain paramotoring contrast agent to cotn and syringe. The syringe was mounted vertically with the piston upward, to ensure there is no air in the solution. When the bubbles pop up up and remained in the top. When switching valve solution was to enter into the transition tube, for example, a length of 3200 mm and a diameter of 0,76 mm This created a dead zone with a volume of 1.5 ml Immediately prior to cannula "injection-target" (for example, venflon or exhaust valve) for a three-way tube attached to a syringe with a certain volume and low friction. This syringe absorbed amount of dead zone and possible gas bubbles of the transition pipe. To prevent the piston of the syringe cylinder used locking screw. After filling the syringe to inject the solution was directed by cannula to the target. For such a system is suitable syringes with ground cylinder and piston.
Using the above device, it was possible to enter into the tail vein of rats saline solution with a speed of 0.33 ml/s
1. A method of obtaining a magnetic resonance contrast agent, comprising (i) obtaining a solution in a solvent gidrirovannogo unsaturated compounds substra the eh in the camera, containing hydrogen (H2rich parahydrogen (p-1H2and/or orthodeuterium (o2H2), for the hydrogenation of a specified substrate to form a hydrogenated agent image visualization, (iii) possible, processing the specified hydrogenated agent image visualization magnetic field having a field intensity lower than the intensity of the ambient field of the Earth, (iv) the possible dissolution of the specified agent image visualization in the aquatic environment, (v) possible separation of the specified catalyst from the solution of the specified agent rendering the image specified in the aquatic environment, (vi) possible, the Department specified solvent from a solution of the specified agent rendering the image specified in the aquatic environment, and (vii) may freezing solution specified agent rendering the image specified in the aquatic environment.
2. The method according to p. 1, in which the field strength in the operation (iii) is less than 50 MT.
3. The method according to p. 1, in which the field strength in the operation (iii) is less than 1 MT.
4. The method according to p. 1, in which the field strength in the operation (iii) is less than 0.1 MT.
5. The method according to p. 1, in which particular field of less than 0.1 MT, and then back to the tensions surrounding field of the Earth.
6. The method according to p. 5, in which the duration of the first part of the cycle is of the order of1 MS, and the second part - the order 10-10000 MS.
7. The method according to any of paragraphs.1-6, wherein said method implemented directly in the water, as specified substrate, and the catalyst are soluble in water.
8. Device for hydrogenation camera including hydrogenation with the outlet for withdrawal of fluid in the pipe connected to the inlet of the generator drops of fluid directed into the chamber to remove solvent, with this camera hydrogenation with an inlet opening for entry of the hydrogen to the inlet of the input solution is further provided with a generator of liquid drops, the pipeline includes camera removal of catalyst installed between the specified camera hydrogenation and the specified camera removal of the solvent, and is equipped with an inlet for entry of the liquid, and this camera removal of the solvent provided the outlet for the gas outlet and the outlet for the withdrawal of fluid.
9. The device under item 8, in which said device for Hijiri specified camera hydrogenation and/or within at least part of the pipeline is <50 MT.
10. The device under item 9, in which the specified magnetic field is <1 MT.
11. The device according to p. 10, in which the specified magnetic field is <0,1 MT.
12. Device according to any one of paragraphs.8-11, wherein said pipeline is equipped with inlet for entry of the fluid located between the specified camera hydrogenation and the specified camera removal of the catalyst.
13. The method according to p. 1 to obtain amino acids, pharmaceutical preparation or in vivo diagnostic agent.
FIELD: coordination compounds synthesis.
SUBSTANCE: invention provides complex comprising calcium and [[(4R)-4[bis[carboxy.kappa.O)methyl]amino-.kappa.N]-6,9-bis[carboxy-.kappa.O)methyl]-1-[(4,4-diphenylcyclohexyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-phosphaundecane-11-ylic acid-.kappa.N6,.kappa.N9,-kappa.011]-oxydato(6-)]-,6H, (MS-325) or its salt with physiologically acceptable cation in each case containing essentially no Gf-MS-325. Also described are pharmaceutical agent based on compounds according to claim 1 and a method for preparing galena composition, complex or its salt with physiologically acceptable cation according to claim 1 intended for preparation of pharmaceutical agent reducing effect produced by heavy metals as well as complex or its salt with physiologically acceptable cation according to claim 1 intended for preparation of pharmaceutical agent suitable for NMR diagnostics and/or diagnostic radiology, a method for amplifying patient's image in NMR tomography based on compounds according to claim 1 and above defined complex or its salt with physiologically acceptable cation in each case containing essentially no visualizing metal chelates and MS-325.
EFFECT: increased assortment of complexes with useful medicine-destination properties.
14 cl, 4 dwg, 30 ex
SUBSTANCE: method involves carrying out X-ray examination with radiopaque substance being used. Biologically inert flexible cups for porolon inlay to be placed congruently to gingiva contour. The inlay is impregnated with Dimexid and left in oral cavity for 30-40 min before making X-ray examination.
EFFECT: high accuracy of diagnosis.
FIELD: pharmaceutical engineering; medical engineering.
SUBSTANCE: method involves carrying out nuclear magnetic resonance tomography of human or animal blood circulation system containing chelating ion complexes of bivalent and valence three paramagnetic metals of (I)X-L-Y formula, where X is the polyamide carbonyl ligand residue and Y is the gallic acid derivative, .
EFFECT: high accuracy of diagnosis.
FIELD: medicine, radiology, pharmacy.
SUBSTANCE: invention relates to an agent used in contrasting in carrying out the diagnostic radiology that comprises tantalite of at least one element taken among the group including yttrium, lanthanum, cerium, praseodymium, neodymium, samarium, europium, gadolinium, terbium, holmium, erbium, thulium, ytterbium, lutecium or bismuth, organic additive and water wherein the natural polysaccharide with acid functional groups is used as an organic additive in the definite ratio of components. Invention provides preparing an agent exhibiting uniform distribution of insoluble particles, high effectiveness of absorption in the low dose given to a patient, and high degree of contrasting, the combination of high adhesion to mucosa tissue of organs and good fluidity in applying the external stress that results to increasing reliability of results in carrying out the diagnosis. Invention can be used as X-ray contrast agent in X-ray assay of different organs.
EFFECT: valuable properties of agent.
3 cl, 9 ex
FIELD: veterinary science.
SUBSTANCE: the present innovation deals with performing anesthesia, slow injection of roentgenocontrast preparation as trasograph pre-diluted with water for 50% with the help of catheter into trachea at the quantity of 10% against poultry body weight, and roentgenoscopy to be carried out 10 min after injection, not later. The innovation provides the chance to study thoracic air sacs without lancing for putting postmortem diagnosis and for research objectives.
EFFECT: higher efficiency of studying.
SUBSTANCE: method involves introducing a mixture into purulent cavities or fistula path. The mixture contains 10 ml of 76% Urografin alcohol solution and 2 ml of 1% brilliant green alcohol solution to enable one to carry out following visual and X-ray estimation of surgical treatment quality.
EFFECT: objective estimation of bone and soft tissue volume and injury degree.
FIELD: pharmaceutical industry, in particular medicine X-ray contrast diagnosis agent.
SUBSTANCE: claimed pellet-shaped agent contains oxymethyl uracil, barium sulfate for fluoroscopy and potato starch in ratio of 4:1 or 6:1, wherein corn is coated with 5 % alcohol/acetone acetylphthalylcellulose solution, 10 % low molecular polyethylene solution in hexane and medical adhesive. Agent of present invention provides disintegration ability of active ingredient in intestine for 2, 4, 6 hours.
EFFECT: system for intestinal diagnosis with treating action, improved convenience and sanitary effect.
FIELD: medicine, gastroenterology.
SUBSTANCE: one should study motor-evacuation activity of gastroduodenal transition, carry out ultrasound investigation including the introduction of a contrast followed by scanning a longitudinal section of antroduodenal area. On registering the onset of contrast evacuation out of stomach into the upper-horizontal duodenal part one should start counting the number of peristaltic waves in antral gastric department for 180 sec, then a pick-up unit should be replaced under the lower hepatic edge into projection area of the upper-horizontal duodenal part to count the number of peristaltic waves in duodenum during 180 sec at subsequent detection of the coefficient for antroduodenal coordination by the following formula: C=Pa/Pd, where C - coefficient of antroduodenal coordination, Pa - the number of peristaltic waves in antral gastric department, Pd - the number of peristaltic waves in duodenum, and at coefficient value of antroduodenal coordination being 0.25-0.33 one should detect the norm, at the value being above 0.33 one should detect hypokinetic variant of disorders in antroduodenal coordination and at the value being below 0.25 it is possible to detect hyperkinetic variant of disorders in antroduodenal coordination.
EFFECT: higher efficiency for differential diagnostics.
SUBSTANCE: method involves carrying out irrigoscopy examination under artificial hypotonia of large intestine with single-stage double opacification of large intestine done with fine peptized aqueous barium cocktail heated to 36°C composed of water - 100 ml, sodium citrate - 1.5 g, sugar - 8 g, barium sulfate - 200 g, carboxymethyl cellulose 0.5 g, raw hen eggs - 2 eggs. Irrigoscopy examination is repeatedly carried out in 24 h. Ribbon-like shadows being observed, intestinal heminthiasis is to be diagnosed.
EFFECT: high reliability in determining shape and localization of helminth even in the cases of negative coprological and serological examination results.