(19)
(11)EP 1 600 766 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
26.06.2019 Bulletin 2019/26

(21)Application number: 04713993.6

(22)Date of filing:  24.02.2004
(51)International Patent Classification (IPC): 
G01N 27/404(2006.01)
A61B 5/1486(2006.01)
A61B 5/145(2006.01)
G01N 27/327(2006.01)
(86)International application number:
PCT/JP2004/002112
(87)International publication number:
WO 2004/074828 (02.09.2004 Gazette  2004/36)

(54)

ACTIVE OXYGEN SPECIES MEASURING DEVICE

MESSEINRICHTUNG FÜR AKTIVSAUERSTOFFSPEZIES

DISPOSITIF DE MESURE DES ESPECES ACTIVES DE L'OXYGENE


(84)Designated Contracting States:
AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

(30)Priority: 24.02.2003 JP 2003046392

(43)Date of publication of application:
30.11.2005 Bulletin 2005/48

(73)Proprietors:
  • Yuasa, Makoto
    Soka-shi, Saitama 340-0021 (JP)
  • Mizoguchi, Fumio
    Tokyo 1530063 (JP)

(72)Inventors:
  • YUASA, Makoto
    3400021 (JP)
  • MIZOGUCHI, Fumio
    1530063 (JP)
  • TAKEBAYASHI, Hitoshi
    3050045 (JP)
  • ABE, Masahiko
    2780017 (JP)
  • KOISHI, Masumi
    2280801 (JP)
  • KIDO, Shigeru
    shikawa-gun, Fukushima 9637808 (JP)
  • NAGAHAMA, Masamitsu
    Kitakatsushika-gun, Saitama 3430111 (JP)
  • KAWASAKI, Masayuki
    3400041 (JP)
  • YOKOSUKA, Masahiko
    3100847 (JP)
  • ISHIHARA, Takashi
    3360027 (JP)
  • IBRAHIM, Rizwangul
    Abiko-shi, Chiba 2701176 (JP)

(74)Representative: Murgitroyd & Company 
Scotland House 165-169 Scotland Street
Glasgow G5 8PL
Glasgow G5 8PL (GB)


(56)References cited: : 
EP-B1- 1 457 773
WO-A1-99/56613
JP-A- 02 001 537
JP-A- 2000 060 807
JP-A- 2003 024 285
US-A- 5 603 820
WO-A1-94/04507
WO-A1-03/054536
JP-A- 62 180 263
JP-A- 2002 245 177
JP-A- 2003 024 285
US-A- 5 806 517
  
  • BUETTEMEYER ROLF ET AL: "In vivo measurement of oxygen-derived free radicals during reperfusion injury" MICROSURGERY, vol. 22, no. 3, 2002, pages 108-113, XP002595027 ISSN: 0738-1085
  • SHIOZAWA ASAKO ET AL.: 'O2 sensor to shiteno kobunsika tetraaminophenylporphyrin shushoku denkyoku' POLYMER PREPRINTS vol. 51, no. 14, 18 September 2002, JAPAN, page 3717, XP002904068
  • YUASA MAKOTO ET AL.: 'Cobalt oyobi tetsu porphyrin o fukumu kobunshika fukugo sakutai-kei no sanso kangen shokubai kassei' MATERIAL TECHNOLOGY vol. 18, no. 6, 25 August 2000, pages 242 - 245, XP002904069
  • CHEN JIAN: 'Superoxide snsor based on hemin modified electrode' SENSORS AND ACTUATORS B vol. 70, no. 113, 2000, pages 115 - 120, XP004224589
  • BRUNET A.: 'Advantages and limits of the electrochemical method using Nafion and Ni-porphyrin-coated microelectrode to monitor NO release from cultured vascular cells' ANALUSIS vol. 2, no. 6, 2000, pages 469 - 474, XP002967704
  • KASANUKI TOMOHISA: 'Hydrogen peroxide sensor based on carbon paste electrode containing a metal porphyrin complex' CHEMICAL SENSORS vol. 17, no. SUPP B, 04 December 2001, pages 427 - 429, XP002967702
  • BARRY W. ALLEN: 'Electrode materials for nitric oxide detection' NITRIC OXIDE vol. 4, no. 1, 2000, pages 75 - 84, XP002967705
  • SHIOZAWA ASAKO ET AL: "O2 sensor to shiteno kobunsika tetraaminophenylporphyrin shushoku denkyoku/ SUPEROXIDE SENSOR BASED ON ELECTRODE MODIFIED WITH ELECTROPOLYMERIZED TETRAAMINOPHENYLPORPHYRIN", POLYMER PREPRINTS. JAPAN, SOCIETY OF POLYMER SCIENCE, JP, vol. 51, no. 14, 18 September 2002 (2002-09-18), page 3717, XP002904068, & Shiozawa Asako et al: "Superoxide Sensor Based on Electrode Modified with Electropolymerized Tetraaminophenylporphyrin", 51st SPSJ Symposium on Macromolecules , 18 September 2002 (2002-09-18), Retrieved from the Internet: URL:https://www.jstage.jst.go.jp/article/s psjppj/51m/0/51m_0_1589/_article/-char/en [retrieved on 2018-09-25]
  • W. Scheller ET AL: "Cytochrome C Based Superoxide Sensor for In Vivo Application", Electroanalysis, vol. 11, no. 10-11, 1 July 1999 (1999-07-01), pages 703-706, XP055202211, ISSN: 1040-0397, DOI: 10.1002/(SICI)1521-4109(199907)11:10/11<70 3::AID-ELAN703>3.0.CO;2-J
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description

TECHNICAL FIELD



[0001] The present invention relates to a reactive oxygen species measuring device for measuring reactive oxygen species such as an in vivo or in vitro superoxide anion radical (O2-.), hydrogen peroxide, .OH, NO, ONOO-.

BACKGROUND ART



[0002] In general, a superoxide anion radical (O2-.) which is a reactive oxygen species is produced in vivo by the oxidation of xanthine as well as hypoxanthine to uric acid by xanthine/xanthine oxidase (XOD) and the reduction of the enzyme by hemoglobin, and the like, and has an important role in association with the in vivo synthesis of a physiologically active substance, a sterilizing effect, an aging phenomenon and the like. On the other hand, it is alleged that various reactive oxygen species derived from the superoxide anion radical cause various diseases such as a cancer. Therefore, the measurement of a concentration of reactive oxygen species including an in vivo superoxide anion radical is considered to be important to specify the various diseases.

[0003] The superoxide anion radical, if no substrate exists, is converted into hydrogen peroxide and oxygen molecule (O2) by a disproportionating reaction, as indicated in an equation (1). The disproportionating reaction comprises the production of HO2. by the addition of proton to the superoxide anion radical, the production of hydrogen peroxide and oxygen molecule by the reaction of HO2. and oxygen molecule, and the production of hydrogen peroxide and oxygen molecule by the collision of HO2. and HO2. (equations (1) to (4)).

        2H+ + 2 O2-. → H2O2 + O2 ---     (1)

        H+ + O2-. → H2O. ---     (2)

        H2O. + O2-. + H+ → H2O2 + O2 ---     (3)

        H2O. + H2O-. → H2O2 + O2 ---     (4)



[0004] In this reaction system, the superoxide anion radical acts as an electron acceptor (an oxidizing agent), an electron donor (a reducing agent) and a hydrogen ion acceptor (a base), and an attempt has been made to measure a concentration of a superoxide anion radical, utilizing the natures of first two of the donor and the acceptor. For example, an attempt has been made to measure a concentration of a superoxide anion radical, utilizing the reaction of conversion from ferri-cytochrome c (trivalent) to ferro-cytochrome c (divalent), the reaction of production of formazane blue from nitro-tretrazolium blue (NBT) and the reducing reaction of tetranitromethane (TNM). All of these measurements have been made by an in vitro measuring process.

[0005] On the other hand, reviews have been made for a process for quantitatively detecting a concentration of an in vivo superoxide anion radical. For example, McNeil et al, Tatiov et al, Cooper et al and Scheller et al have reported that a concentration of a superoxide anion radical can be electrochemically detected by an enzyme electrode (cytochrome c-fixed electrode) fabricated by decorating a surface of an electrode of gold or platinum with N-acetyl cysteine, and S-Au bonding and fixing, to the resulting surface, a protein such as cytochrome c which is a metal protein based on an iron complex called heme for oxidation-reduction (see the following Documents 1 to 3).

Document 1
C.J. McNeil et al. Free Radical Res. Commun., 7, 89 (1989)

Document 2
M.J. Tariov et al. J. Am. Chem. Soc. 113, 1847 (1991)

Document 3
J.M. Cooper, K.R. Greenough and C.J. McNeil, J. Electroan al. Chem., 347, 267 (1993)

Document 4
W. Scheller et al. Electroanalysis, Vol.11, No.10, 703-706 (1999)



[0006] The measuring principle of this detecting method is as follows: Cytochrome c (trivalent) (cyt.c (Fe3+)) is reduced into cytochrome c (divalent) (cyt.c (Fe2+)) by reacting with a superoxide anion radical, as shown in an equation (5). Then, the cytochrome c (divalent) resulting from the reduction is re-oxidized electrochemically by O2-., as shown in an equation (6), and an oxidizing current at that time is measured, thereby quantitatively detecting a concentration of the superoxide anion radical indirectly.

        cyt.c (Fe3+) + O2-. → cyt.c (Fe2+) + O2 ---     (5)

        cyt.c (Fe2+) → cyt.c (Fe3+) + e- ---     (6)



[0007] However, the cytochrome c is an electron-transferring protein existing on a film of mitochondria within bio-cells and hence, to fabricate an electrode having the cytochrome c fixed thereon in an amount enough for the measurement, a large number of cells on the order of 105 - 106 are required, and there is a problem that the enzyme used is deactivated within several days. Therefore, it has been desired to develop an electrode which is capable of detecting active oxygen species such as a superoxide anion radical without need for a large amount of an enzyme and without the problem of the deactivation of the enzyme.

[0008] The applicant has found out (Shiozawa A. et al, Superoxide Sensor Based on Electrode Modified with Electropolymerized Tetraaminophenylporphyrin, Polymer Preprints, Japan, Vol.51, No.14 (2002), p.3717) that an electrode coated with a film of electropolymerized tetrakis(2-aminophenyl)iron porphyrin shows higher sensitivity for superoxide than a cytochrome c immobilized electrode. Therefore, the present applicant has proposed, in WO03/054536, a reactive oxygen species electrode comprising a polymerized film of a metalloporphyrin complex formed on a surface of a conductive member, an active oxygen species concentration measuring sensor including such an active oxygen species electrode, a counter electrode and a reference electrode, and a process for detecting reactive oxygen species in a sample by measuring an electric current produced between a metal in the polymerized film of the metalloporphyrin and reactive oxygen species by the sensor.

[0009] This is based on that the electrode assembly comprising the polymerized film of the metalloporphyrin complex having a metal ion introduced into the center of a porphyrin compound, which film has been formed on the surface of the conductive member, is capable of detecting the presence and concentration of the reactive oxygen species without need for a large amount of an enzyme and without the deactivation problem.

DISCLOSURE OF THE INVENTION



[0010] It is an object of the present invention to provide a reactive oxygen species measuring device with the present applicant's proposal further developed, which is capable of reliably measuring a concentration of a reactive oxygen species such as an in-vivo superoxide anion radical (O2-.), which can be small-sized in its entirety and can be always mounted to a living body, so that measured data can be transmitted to a remote location, and the health condition or the like of the living body provided in the remote location can be returned to a reactive oxygen species measuring location for information, thus monitoring the health condition of the living body by measuring and monitoring the reactive oxygen species.

[0011] To achieve the above object, a reactive oxygen species measuring device according to claim 1 is provided. The reactive oxygen species measuring device comprises a reactive oxygen species sensor provided with an electrode assembly having a working electrode and a counter electrode formed into a shape enabling the detection of the presence of an in vivo reactive oxygen species as an electric current, a power source means for applying a measuring voltage to the reactive oxygen species sensor, and a reactive oxygen species concentration measuring means for measuring a concentration of the reactive oxygen species from the current detected by the reactive oxygen species sensor. The arrangement of the reactive oxygen species measuring device as described above ensures that when an appropriate measuring voltage from the power source means is applied to the reactive oxygen species sensor, the electrode of the reactive oxygen species sensor can detect the presence of the reactive oxygen species in terms of the electric current, and the concentration of the reactive oxygen species can be determined from the electric current detected by the reactive oxygen species concentration measuring means.

[0012] The reactive oxygen species concentration measuring means includes an external output means for delivering the measured concentration of the reactive oxygen species to the outside, and comprises a remotely monitoring means adapted to monitor the concentration of the reactive oxygen species under the reception of the output from the external output means. Thus, the health condition of the living body can be monitored in a remote place, using the remotely monitoring means.

[0013] The remotely monitoring means may include a communication means for transmitting and receiving data to or from the reactive oxygen species measuring device, an arithmetic means adapted to perform a data processing for the concentration of the reactive oxygen species received from the external output means, and a display means for displaying the concentration of the reactive oxygen species and the result of the data processing obtained by the arithmetic means. In the reactive oxygen species measuring device, the external output means may be comprised of a communication means for transmitting and receiving the data to and from the remotely monitoring means, and a display means for displaying the concentration of the reactive oxygen species and the data received from the remotely monitoring means. With such arrangement, in the remotely monitoring means, the data processing for the concentration of the reactive oxygen species can be conducted by the arithmetic means to determine the health condition of a living body such as human being as a subject of measurement, and the health condition of the living body can be monitored by displaying them and the concentration of the reactive oxygen species by the display means. Further, the health condition and of the living body determined in the remote place can be returned to the active oxygen species measuring device through the communication means in both the remotely monitoring means and the active oxygen species measuring device, and displayed by the display means and thereby informed to a person. In addition, by using the remotely monitoring means as a base station, it is possible to make a simultaneous access to a plurality of reactive oxygen species measuring devices, to provide a centralized management of various data, and to carry out the data processing arithmetically inoperable in the reactive oxygen species measuring device to transmit necessary obtained data to the reactive oxygen species measuring device.

[0014] The present invention may have a feature that the delivery and reception of the data between the active oxygen species measuring device and the remotely monitoring means are carried out through a radio or wire propagation system. With such arrangement, when the radio propagation system is used, the monitoring of the concentration of the reactive oxygen species can be controlled remotely regardless of the magnitude of the distance between the remotely monitoring means and the reactive oxygen species measuring device, and particularly, even when the reactive oxygen species measuring device is moved, the operation always normal can be continued. For the radio propagation system, a known method employing an electric wave, infrared rays, ultraviolet rays or an ultrasonic wave, or any of various communication technologies such as an internet, a satellite communication and the like can be utilized. On the other hand, when the wire propagation system is used, the reliable transmission and reception of data are possible, and further, an electric wave interference cannot be exerted to other electronic equipments, and the wire propagation system can be used, for example, in a hospital or the like.

[0015] Another feature of the present invention is that the communication means and the display means in the reactive oxygen species measuring device may be formed in a mobile phone to deliver and receive the data to and from the remotely monitoring means through an internet. Thus, the measurement of reactive oxygen species can be achieved using the mobile phone excellent in portability or mobility and further by conducting the interchange of data through an internet, leading to a facilitated measuring operation. In addition, the measurement is possible at any time in any area if there is a telephone service in this area, and the reactive oxygen species can be measured in reliable correspondence to an emergency, whereby the monitoring of the health of a living body can be achieved.

[0016] The electrode of the active oxygen species sensor is formed into a shape capable of detecting the presence of an in-vivo active oxygen species in terms of an electric current. Thus, by attaching the electrode to a human body or an animal, an in vivo reactive oxygen species can be measured, and further can be continued to be measured constantly.

[0017] The power source means may be formed so that the measuring voltage to be applied to the reactive oxygen species sensor can be controlled variably. Thus, an appropriate measuring voltage corresponding to a reactive oxygen species to be measured can be applied to the reactive oxygen species sensor to measure a reactive oxygen species as a subject of measurement with a good accuracy.

[0018] The reactive oxygen species concentration measuring means may include at least one of a display means for displaying a concentration of reactive oxygen species determined based on an electric current detected by said reactive oxygen species sensor, and an external output means for delivering data to the outside. Thus, the measured concentration of the reactive oxygen species can be clearly displayed by the display means, and the concentration of the reactive oxygen species can be transmitted to a remote place or location by the external output means and monitored remotely.

[0019] More specifically, the working lectrode of the reactive oxygen species sensor is formed to have, on its surface, an element capable of detecting the presence of reactive oxygen species in terms of an electric current. Thus, by placing the element on the surface of the electrode assembly in a region where an in vivo reactive oxygen species exists, a concentration of the in vivo a reactive oxygen species can be measured reliably.

[0020] The element capable of detecting the presence of reactive oxygen species in terms of an electric current consists of a polymerized film of a metalloporphyrin complex. The element formed as described above ensures that a concentration of active oxygen species can be measured with a good accuracy and reliably.

[0021] The metalloporphyrin complex is represented by the following formula (II):

wherein M indicates a metal ion selected from the group consisting of iron, manganese, a cobalt, chromium and iridium; at least one of four Rs is any one of thiofuryl, pyrrolyl, furyl, mercaptophenyl, aminophenyl and hydroxyphenyl groups; and each of other Rs indicates any of the above-described groups, or alkyl group, aryl group or hydrogen; and

at least one of two Ls is an nitrogen-based axial ligand such as imidazole and its derivative, pyridine and its derivative, aniline and its derivative, histidine and its derivative, and trimethylamine and its derivative, a sulfur-based axial ligand such as thiophenol and its derivative, cysteine or its derivative, and methionine and its derivative, or an oxygen-based axial ligand such as benzoic acid and its derivative, acetic acid and its derivative, phenol and its derivative, an aliphatic alcohol and its derivative or water; and the other L indicates any of the above-described axial ligands or no ligand.



[0022] Thus, the metalloporphyrin complex can be formed reliably on the surface of the electrode assembly, thereby providing an electrode assembly excellent in sensitivity.

[0023] The porphyrin compound forming the metalloporphyrin complex may be one selected from the group consisting of 5,10,15,20-tetrakis(2-thienyl)porphyrin, 5,10,15,20-tetrakis(3- thienyl)porphyrin, 5,10,15,20-tetrakis(2-pyrrolyl)porphyrin, 5,10,15,20-tetrakis(3-pyrrolyl) porphyrin, 5,10,15,20-tetrakis(2-furyl)porphyrin, 5,10,15,20-tetrakis(3-furyl) porphyrin, 5,10,15,20-tetrakis(2-mercaptophenyl) porphyrin, 5,10,15,20-tetrakis(3-mercaptophenyl) porphyrin, 5,10,15,20-tetrakis(4-mercaptophenyl)porphyrin, 5,10,15,20-tetrakis(2-aminophenyl)porphyrin, 5,10,15,20-tetrakis(3-aminophenyl)porphyrin, 5,10,15,20-tetrakis(4-aminophenyl) porphyrin, 5,10,15,20-tetrakis(2-hydroxyphenyl)porphyrin, 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin, 5,10,15,20-tetrakis(4-hydroxyphenyl)porphyrin, [5,10,15-tris(2-thienyl)-20-mono(phenyl)]porphyrin, [5,10,15-tris(3-thienyl)-20-mono(phenyl)]porphyrin, [5,10-bis(2-thienyl)-15,20-di(phenyl)]porphyrin, [5,10-bis(3-thienyl)-15,20-di(phenyl)]porphyrin, [5,10-bis(2-thienyl)-10,20-di(phenyl)]porphyrin, [5,10-bis(3-thienyl)-10,20-di(phenyl)]porphyrin, [5-mono(2-thienyl)-10,15,20-tri(phenyl)]porphyrin, [5-mono(3-thienyl)-10,15,20-tri(phenyl)]porphyrin. Thus, the metalloporphyrin complex can be formed reliably on the surface of the electrode assembly, thereby providing an electrode assembly excellent in sensitivity.

[0024] The reactive oxygen species measuring device according to the present invention is constructed and operated as described above and hence, the following excellent effects can be exhibited: A concentration of reactive oxygen species such as in vivo superoxide anion radical (O2-.) can be measured reliably, and the entire device can be formed in a smaller size and always mounted to a living body. In addition, the measured data can be transmitted to a remote place or location, and further, the health condition of a living body determined in the remote place can be returned to a measuring place and informed, and thus, the health condition of the living body can be monitored by measuring and monitoring reactive oxygen species.

BRIEF DESCRIPTION OF THE DRAWINGS



[0025] 

Fig.1 is a circuit diagram showing one embodiment of a reactive oxygen species measuring device according to the present invention;

Fig.2(a) is a side view showing one embodiment of a reactive oxygen species sensor used in the active oxygen species measuring device according to the present invention, and Fig.2(b) is a left side view of the sensor shown in Fig.2(a);

Fig.3(a) is a side view showing another embodiment of a reactive oxygen species sensor used in the reactive oxygen species measuring device according to the present invention, and Fig. 3 (b) is a left side view of the sensor shown in Fig. 3 (a);

Fig.4 is a side view showing a further embodiment of an active oxygen species sensor used in the active oxygen species measuring device according to the present invention;

Fig.5 is a side view showing a yet further embodiment of a reactive oxygen species sensor used in the reactive oxygen species measuring device according to the present invention;

Fig. 6 (a) is a plan view showing a reactive oxygen species sensor used in the reactive oxygen species measuring device not according to the present invention with a cover removed, Fig.6(b) is a vertical sectional view of the embodiment in Fig.6(a), and a Fig.6(c) is an exploded perspective view with a cover removed; and

Fig.7 is a circuit diagram showing a yet further embodiment of an active oxygen species measuring device according to the present invention.


BEST MODE FOR CARRYING OUT THE INVENTION



[0026] An embodiment of the present invention will now be described with reference to Figs.1 to 7.

[0027] Fig.1 shows one embodiment of a reactive oxygen species measuring device according to the present invention.

[0028] The reactive oxygen species measuring device of the present embodiment includes a reactive oxygen species sensor 1 provided with an electrode assembly capable of detecting the presence of reactive oxygen species in terms of an electric current, a power source means 2 for applying a measuring voltage to the active oxygen species sensor 1, and an active oxygen species concentration measuring means for measuring a concentration of active oxygen species from the electric current detected by the reactive oxygen species sensor 1.

[0029] The reactive oxygen species sensor 1 in the present embodiment is formed in a two-electrode type and constructed by a working electrode 4, a counter electrode 5 and a shield. It should be noted that the reactive oxygen species sensor 1 may be formed in a three-electrode type including a reference electrode which is not shown.

[0030] The power source means 2 is constructed with a switch 8, a potential divider resistor R1, a variable resistor VR1, a potential divider resistor R2 connected in series to a DC power source 7 such a button battery and a potentiostat, so that a measuring voltage can be delivered in a variable manner from ends of the variable resistor VR1 and a potential divider resistor R2. The measuring voltage is intended to be measured by a voltmeter 9. The measuring voltage to be applied to the reactive oxygen species sensor 1 by the power source means 2 is controlled variably in accordance with reactive oxygen species to be measured by changing the resistance value of the variable resistor VR1. For example, the measuring voltage may be 0.5 V for a superoxide anion radical, -0.8 V for oxygen molecule (O2), -1.0 V for hydrogen peroxide (H2O2), and 0.6 V for nitrogen monoxide.

[0031] The measuring voltage from the power source means 2 is applied through a device resistor 3 to the counter electrode 5 and the working electrode of the reactive oxygen species sensor 1.

[0032] Further, a reactive oxygen species concentration measuring means 3 is connected to the reactive oxygen species sensor 1 for measuring the concentration of the reactive oxygen species through the amplification of a very weak current flowing between the counter electrode 5 and the working electrode 4 of the reactive oxygen species sensor 1 and corresponding to the concentration of the reactive oxygen species. The reactive oxygen species concentration measuring means 3 includes a display means 10 for displaying the concentration of the reactive oxygen species determined based on the electric current detected by the reactive oxygen species sensor 1, and an external output means 11 for delivering the measured concentration to the outside by transmission or the like. At least one of the display means 10 and the external output means 11 may be provided. When the external output means 11 is provided, a remotely monitoring means 12 including a receiving means 13 may be mounted to remotely monitor the concentration of the reactive oxygen species under the reception of the result of the detection of the concentration fed from the reactive oxygen species concentration measuring means 3. More specifically, the remotely monitoring means 12 includes the receiving means 13, and may be formed to remotely monitor the concentration of the active oxygen species by receiving the result of the detection of the concentration fed from the external output means 11 of the active oxygen species concentration measuring means to determine the health condition of a living body as a subject of measurement and the in vitro environmental condition by the arithmetic operation conducted based on the concentration of the reactive oxygen species by an arithmetic means (not shown), and displaying the concentration of the reactive oxygen species as well as the health condition of the living body as the subject of measurement and the in vitro environmental condition by a display means (likewise not shown).

[0033] The working electrode 4 as an electrode of the reactive oxygen species sensor 1 will be further described below.

[0034] The working electrode 4 is formed into a shape enabling the detection of the presence of an in-vivo active oxygen species in terms of an electric current, e.g., a fine needle-shape capable of being inset into the living body from the outside, a very small catheter-shape capable of being inserted into a blood vessel, or a shape capable of being bonded to a surface of a skin, e.g., a shaft portion of a pierce. Thus, the working electrode 4 can be mounted to a human body to measure reactive oxygen species in the human body or to measure an in vivo reactive oxygen species at all times. The specific construction of each of the working electrode 4 and the counter electrode 5 will be described below.

[0035] The working electrode 4 is formed to be provided, on its surface, with an element capable of detecting the presence of reactive oxygen species in terms of an electric current. Thus, it is possible to reliably measure a concentration of in vivo reactive oxygen species by placing the element in an area of a living body where reactive oxygen species exists.

[0036] The element of the working electrode 4 capable of detecting the presence of the reactive oxygen species in terms of the electric current of a polymerized film of a metalloporphyrin complex. By using the element formed as described above, the concentration of active oxygen species can be measured with a good accuracy and reliably.

[0037] The formation of the polymerized film of a metalloporphyrin suitable as a material for the working electrode 4 itself and a material for the surface film will be described below.

[0038] A conductive member constituting the working electrode 4 is particularly not limited, and any member can be used if it is a member commonly used for an electrode, and for example, the member which can be used includes carbons such as glassy carbon (GC), graphite, pyrolytic graphite (PG), highly oriented pyrolytic graphite (HOPG) and activated carbon; a rare metal such as platinum, gold and silver; or In2O3/SnO2 (ITO) or the like. Among them, particularly, it is preferable to use grassy carbon, taking an economy, a workability and a lightness into consideration. The shape of the conductive member is particularly not limited, and may be any shape if it can be used for the electrode. The conductive member can be any of various shapes such as a columnar shape, a prismatic shape, a needle-shape and a fiber-shape. For example, in order to measure a concentration of reactive oxygen species in a living body, it is preferable that the material is of a needle-shape, a catheter-shape or a pierce shaft-shape, as described above.

[0039] The metal porphyrin complex used for the formation of the metalloporphyrin complex polymerized film formed on the surface of the conductive member of the working electrode 4 are those represented by formula (II)

wherein M indicates a metal ion selected from the group consisting of iron, manganese, cobalt, chromium and iridium; at least one of four Rs is any one of thiofuryl, pyrrolyl, furyl, mercaptophenyl, aminophenyl and hydroxyphenyl groups; and each of other Rs indicates any of the above-described groups, or alkyl group, aryl group or hydrogen and at least one of two Ls is a nitrogen-based axial ligand such as imidazole and its derivative, pyridine and its derivative, aniline and its derivative, histidine and its derivative, and trimethylamine and its derivative, a sulfur-based axial ligand such as thiophenol and its derivative, cysteine and its derivative, and methionine and its derivative, or an oxygen-based axial ligand such as benzoic acid and its derivative, acetic acid and its derivative, phenol and its derivative, an aliphatic alcohol and its derivative or water; and the other L indicates any of the above-described axial ligands or no ligand.

[0040] The metalloporphyrin complex represented by the above formula (II) is a complex compound having a metal ion coordinated in a porphyrin compound. The porphyrin compound is a cyclic compound having four pyrrole rings alternately bonded to four methyl groups at α sites and four nitrogen atoms located to face to the center. The complex compound (metal porphyrin complex) can be formed by incorporating a metal atom at the center site. To form such complex compound, a metal atom may be introduced into the center of porphyrin using a metal complex forming method usually used, e.g., a method of metalation or the like. In the present invention, the metal ion which can be introduced into the center of the porphyrin compound includes various metal ions such as iron, manganese, cobalt, chromium and iridium.

[0041] Depending on the type of reactive oxygen species to be measured, suitable one of such metal ions may be used. Preferable examples are as follows: For example, if a superoxide anion radical is to be measured, iron, manganese or cobalt may be used. If oxygen in the state of a molecule is to be measured, iron, cobalt, manganese chromium or iridium may be used. If hydrogen peroxide is to be measured, iron or manganese may be used. Further, if OH, NO, ONOO- or the like is to be measured, iron or manganese may be used.

[0042] Preferable examples of the porphyrin compound forming said metal porphyrin complex include those in which at least one of four sites of site numbers 5, 10, 15 and 20 according to the IUPAC nomenclature in non-substituted porphyrin is substituted by any of thiofuryl, pyrrolyl, furyl, mercaptophenyl, aminophenyl and hydroxyphenyl groups, and each of other sites is any of the above-described substituting groups, or alkyl group, aryl group or hydrogen. Illustrative of particular examples are 5,10,15,20-tetrakis(2-thienyl) porphyrin, 5,10,15,20-tetrakis(3-thienyl) porphyrin, 5,10,15,20-tetrakis(2-pyrrolyl) porphyrin, 5,10,15,20-tetrakis(3-pyrrolyl) porphyrin, 5,10,15,20-tetrakis(2-furyl) porphyrin, 5,10,15.20-tetrakis(3-furyl) porphyrin, 5,10,15,20-tetrakis(2-mercaptophenyl) porphyrin, 5,10,15,20-tetrakis(3-mercaptophenyl) porphyrin, 5,10,15,20-tetrakis(4-mercaptophenyl) porphyrin, 5,10,15,20-tetrakis(2-aminophenyl) porphyrin, 5,10,15,20-tetrakis(3-aminophenyl) porphyrin, 5,10,15,20-tetrakis(4-aminophenyl) porphyrin, 5,10,15,20-tetrakis(2-hydroxyphenyl)porphyrin, 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin, 5,10,15,20-tetrakis(4-hydroxyphenyl)porphyrin, [5,10,15-tris(2-thienyl)-20-mono(phenyl)]porphyrin, [5,10,15-tris(3-thienyl)-20-mono(phenyl)]porphyrin, [5,10-bis(2-thienyl)-15,20-di(phenyl)]porphyrin, [5,10-bis(3-thienyl)-15,20-di(phenyl)]porphyrin, [5,10-bis(2-thienyl)-10,20-di(phenyl)]porphyrin, [5,10-bis(3-thienyl)-10,20-di(phenyl)]porphyrin, [5-mono(2-thienyl)-10,15,20-tri(phenyl)]porphyrin, [5-mono(3-thienyl)-10,15,20-tri(phenyl)]porphyrin, and the like.

[0043] Among the ligands indicated by L in the compound represented by the formula (II), examples of imidazole derivatives are methylimidazole, ethylimidazole, propylimidazole, dimethylimidazole, benzoimidazole or the like. Examples of pyridine derivatives are methylpyridine, methylpyridylacetate, nicotinamide, pyridazine, pyrimidine, pyrazine, triazine or the like. Examples of aniline derivatives are aminophenol, diaminobenzene or the like. Examples of histidine derivatives are histidine methyl ester, histamine, hippuryl-histidyl-leucine and the like. Examples of trimetylamine derivatives are triethylamine, tripropylamine and the like. Examples of thiophenol derivatives are thiocresol, mercaptophenol, mercaptobenzoic acid, aminothiophenol, benzene dithiol, methylbenzene dithiol and the like. Examples of cysteine derivatives are cysteine methyl ester, cysteine ethyl ester and the like. Examples of methionine derivatives are methionine methyl ester, methionine ethyl ester and the like. Examples of benzoic acid derivatives are salicylic acid, phthalic acid, isophthalic acid, terephthalic acid and the like. Examples of acetic acid derivatives are trifluoroacetic acid, mercaptoacetic acid, propionic acid, butyric acid and the like. Examples of phenol derivatives are cresol, hydroxybenzene and the like. Examples of aliphatic alcohol derivatives are ethyl alcohol, propyl alcohol and the like.

[0044] In the present invention, to form the polymerized film of the metal porphyrin complex on the surface of the conductive member of the working electrode 4, various polymerizing processes may be used such as an electrolytic polymerizing process, a solution polymerizing process, a heterogeneous polymerizing process and the like. Among them, the use of the electrolytic polymerizing process is preferred for forming the polymerized film. More specifically, a polymerized film of a metalloporphyrin can be formed on a surface of a conductive member by adding a suitable supporting electrolyte such as tetrabutyl ammonium perchlorate (TBAP:Bu4NCIO4), tetrapropyl ammonium perchlorate (TPAP:Pr4NCIO4) and tetraethyl ammonium perchlorate (TPAP:Et4NCIO4) into an organic solvent such as dichloromethane, chloroform and carbon tetrachloride, and subjecting the resulting mixture to a two-electrode (working electrode/counter electrode) electrolysis or a three-electrode (working electrode/counter electrode/reference electrode) constant-potential, constant-current, reversible potential sweep and pulse-type electrolysis using a conductive member as a working electrode, a rare metal electrode such as a platinum (Pt) electrode or an insoluble electrode such as a titanium electrode, a carbon electrode and a stainless steel electrode as a counter electrode and a saturated calomel electrode (SCE) or a silver-silver chloride electrode as a reference electrode, thereby polymerizing the mixture.

[0045] The particular arrangement of a reactive oxygen species sensor 1 including electrodes such as a working electrode 4 a counter electrode 5 and the like will be described below with reference to Figs.2 to 5.

[0046] Figs.2(a) and (b) show a reactive oxygen species sensor 1 including a working electrode 4 and a counter electrode 5 formed integrally with each other to form a needle-shaped electrode assembly taking the in vivo measurement, the combined measurement and the clinical diagnosis/therapy into consideration. In the active oxygen species sensor 1 shown in Fig.2, its outermost portion is formed as a counter electrode 5, and a conductive member forming the working electrode 4 is concentrically mounted within the counter electrode 5 with an electrically insulating material 14 interposed therebetween. Tip ends of the working electrode 4, the electrically insulating material 14 and the counter electrode 5 are cut obliquely to form a sharp needle point for finishing. A polymerized film of a metalloporphyrin as described above is formed on a portion of the working electrode 4 exposed to the outside from the tip end of the needle-shaped counter electrode 5. The working electrode 4 and the counter electrode 5 are formed so as to be electrically connected by lead wires 4a and 4a, respectively.

[0047] A material for forming the counter electrode 5 which can be used includes various materials, e.g. , a rare metal such as platinum, gold and silver, titanium, a stainless steel, a corrosion-resistant alloy such as an iron-chromium alloy, carbons and the like, but because the counter electrode may be inserted into a living body in many cases, it is preferable to form the counter electrode using a high safety material (for example, a rare metal such as platinum, gold and silver, titanium, a stainless steel, carbons and the like). If the needle-shape active oxygen species sensor 1 is desired to be inserted into a living body, then it is preferable that the sensor 1 is formed so that the contour of the counter electrode 5 is as thin as possible, for example, on the order of 0.2 to 1.5 mm. If a reference electrode (not shown) is desired to be employed, then any of various reference electrodes may be usually employed such as a silver/silver chloride electrode and a mercury/mercuric chloride electrode, and a solid reference electrode can be employed.

[0048] The thickness of the polymerized film of the metalloporphyrin complex may be determined properly depending on the types of the electrodes and the metalloporphyrin complex and the type of reactive oxygen species to be measured, but it is preferable that the thickness is equal to or smaller than 1 µm from the viewpoints of the activity of the electrodes and the decoration stability.

[0049] Figs.3(a) and (b) show another reactive oxygen species sensor 1a formed into a needle-shape as in Fig.2.

[0050] The reactive oxygen species sensor 1a of the embodiment shown in Fig.3 is an improvement in the reactive oxygen species sensor 1 shown in Fig.2 for the purpose of aiming to remove an unnecessary in vivo current, a current noise and the like and to enhance the sensitivity, the signal/noise ratio (S/N ratio) and the like. In an electrode assembly shown in Fig.3, a working electrode 4 comprised of a conductive member is placed into an electrically insulating material 14 (a two-layer structure), and they are placed into a counter electrode 5 (a three-layer structure). Further, they are placed into an electrically insulating material 14 (a four-layer structure), and finally, an outer surface of the resulting thin tube is coated with a material such as a metal serving as an earth to form an earth portion 15. Tip ends of the working electrode 4, the electrically insulating material 14, the counter electrode 5, the electrically insulating material 14 and the earth portion 15 are cut obliquely to form a sharp needle point for finishing. A polymerized film of a metal porphyrin is formed on an end face of the conductive member of the working electrode 4.

[0051] The thickness of the polymerized film of the metalloporphyrin complex may be determined properly depending on the types of the electrodes and the metalloporphyrin complex and the type of reactive oxygen species to be measured, but it is preferable that the thickness is equal to or smaller than 1 µm from the viewpoints of the activity of the electrodes and the decoration stability.

[0052] The reactive oxygen species sensor 1a having the structure shown in Fig.3 is also used for the combined measurement and hence, a multi-layer structure having about ten several layers can be constructed. A material for forming the earth which can be used includes various materials , e.g., a rare metal such as platinum, gold and silver, titanium, a stainless steel, a corrosion-resistant alloy such as an iron-chromium alloy, carbons and the like, but because the earth may be inserted into a living body in many cases, it is preferable to form the earth using a high safety material (for example, a rare metal such as platinum, gold and silver, titanium, a stainless steel, carbons and the like).

[0053] Each of the reactive oxygen species sensors 1 and 1a shown in Figs. 2 and 3 is capable of measuring reactive oxygen species by inserting the sharp tip end of the respective electrode section into a living body.

[0054] Fig.4 shows another reactive oxygen species sensor 1b formed into a catheter-shape.

[0055] The reactive oxygen species sensor 1b of the embodiment shown in Fig.4 is constructed as follows: A thin electrode section comprising a working electrode 4, an electrically insulating material 14 and a counter electrode 5 as in Fig.2 is formed in the sensor lb, and a tip end of the electrode section is cut perpendicular to an axial direction for finishing. Further, the electrode section is secured to a tip end of a pipe 16 made of a resin and having a counter length on the order of 1 mm along with connected lead wires 4a and 5a of the working electrode 4 and the counter electrode 5. The resinous pipe 16 is formed of a material which is safe even if it is inserted into a living body.

[0056] The reactive oxygen species sensor 1b shown in Fig.4 is capable of measuring reactive oxygen species or the like by inserting the thin electrode section into a living body, specifically, into a blood vessel, a lymphatic vessel, a digestive organ, any of internal organs and the like. A provision may be made for ensuring that the direction of advancement of the electrode section at the tip end can be freely changed by a remote manipulation. For example, the electrode section is mounted, slightly inclined with respect to an axial direction of the resinous pipe 16, so that the direction of advancement of the electrode section can be selected by rotating the resinous pipe 16 about an axis, or alternatively, a small-sized bimetal is mounted in the vicinity of the electrode section, so that the bimetal can be bent in any direction by controlling the supply of an electric current for the selection of the direction of advancement, or alternatively, a small-sized magnet is mounted on the electrode section, so that the direction of advancement of the small-sized magnet can be selected by applying a magnetic field from outside a living body.

[0057] Fig.5 shows another reactive oxygen species sensor 1c formed into a pierce shaft-shape.

[0058] The reactive oxygen species sensor 1c shown in Fig.5 is constructed as follows: A thin electrode section comprising a working electrode 4, an electrically insulating material 14 and a counter electrode as in Fig.2 is formed in the sensor lc, and the working electrode 4 inside the counter electrode 5is exposed to an axially intermediate portion of the electrode section, while the electrically insulating material 14 is exposed to an outer peripheral surface of the electrode section. Further, the working electrode 4 and the counter electrode 5 are connected to a small-sized power source means 2 and an active oxygen species concentration measuring means 3 within a decorative portion 17 of a pierce.

[0059] The reactive oxygen species sensor 1c shown in Fig.5 is capable of measuring reactive oxygen species or the like by inserting the thin electrode section through a pierce bore 19 in an ear 18.

[0060] Fig.6 shows a further reactive oxygen species sensor 1d formed into a chip-shape.

[0061] The reactive oxygen species sensor 1d, not according to the invention, shown in Fig.6 is adapted to measure a concentration of reactive oxygen in a liquid to be measured such as a small amount of blood removed from a living body. Fig.6 shows the reactive oxygen species sensor 1d in an exaggerated manner for convenience of the explanation, but the chip has a size of 5 mm x 20 to 30 mm in a planar shape with a thickness of on the order of 0.5 to 1.0 nm. The active oxygen species sensor 1d includes a working electrode 4 centrally formed on an insulting substrate 30 of a glass a resin, a ceramic or the like, and a counter electrode 5 and an earth portion 15 formed on opposite sides of the working electrode 4. A material for forming each of the working electrode 4, the counter electrode 5 and the earth portion 15, which can be used, includes gold, platinum, nickel, nickel-phosphorus plating material, a stainless steel, carbon or another conductive metal and the like. When such a material is used to form a pattern on the insulating substrate 30, any of an electroless treatment as a wet surface treatment and a vacuum deposition an ion-plating, a coating/baking by an ink jet and the like as a dry surface treatment may be selected. Further, as in the previous embodiments, a carbon layer 4c is formed thinly on a surface of a circular measuring portion 4b at an end of the central working electrode 4, and a polymerized film 4d of a metalloporphyrin complex is formed on the carbon layer 4c. The carbon layer 4c may be provided, as required, from the relation to a material or the like for the measuring portion 4b when the polymerized film 4d of a metal porphyrin complex on the carbon layer 4c is provided, but the carbon layer 4c may be omitted. The carbon layer 4c may be formed by a process similar to that for each of the working electrode 4, the counter electrode 5 and the earth portion 15. The polymerized film 4d of a metal porphyrin complex can be formed using any of various polymerizing processes such as an electrolytic polymerizing process, a solution polymerizing process and a heterogeneous polymerizing process as in each of the previous embodiments. The working electrode 4, the counter electrode 4 and the earth portion 15 are formed so that they are electrically connected by respective lead wires 4a, 5a and 15a. Alternatively, each of the lead wires 4a, 5a and 15a may be formed into an electrode-type capable of being plugged into a connection portion, so that the connection to the outside can be conducted simply in a snap-fitting manner. Further, an insulating cover 31 is secured to a surface of the insulating substrate 30 to cover the working electrode 4, the counter electrode 5 and the earth portion 15 from above, whereby a measuring space 32 having a function to draw a blood or the like into the measuring space by a capillary phenomenon is formed in a tip end of the working electrode 4 provided with the measuring portion 4b. The insulating substrate 30 is perforated with a small bore 33 for bringing the measuring space 32 into communication with the outside. It should be noted that the insulating substrate 30 and the cover 31 may be changed in their shape as required, and may be formed into shapes such that a liquid to be measured such as a blood can be introduced reliably and easily into the measuring space 32. Further, the surface of each of the insulating substrate 30 and the cover 31 may be formed in a state having a high affinity with a liquid to be measured, e.g., a blood, thereby facilitating the ingress of the liquid to be measured into the measuring space 32. The cover 31 may be omitted as required.

[0062] The reactive oxygen species sensor 1d, not according to the invention, shown in Fig.6 is capable of measuring reactive oxygen species by drawing a very small amount of a blood sampled from, for example, an earlobe into the measuring space 32 through an opening at a tip end of the measuring space 32 by a capillary phenomenon.

[0063] The operation of the sensors will be described below.

[0064] When any one of the reactive oxygen species sensors 1 and 1a shown in Figs.2 and 3 is used, the pointed tip end of the electrode is insetted into a living body, whereby the working electrode 4 and the counter electrode 5 are placed into the living body.

[0065] When the reactive oxygen species sensors 1b shown in Fig. 4 is used, the electrode section mounted at the tip end of the resinous pipe 16 is introduced into a blood vessel, a lymphatic a lymphatic vessel, a digestive organ or any of internal organs directly or utilizing a photo-fiberscope or the like, whereby the working electrode 4 and the counter electrode 5 are placed into a living body.

[0066] When the reactive oxygen species sensors 1c shown in Fig. 5 is used, the working electrode 4 and the counter electrode 5 of the electrode section mounted at the shaft portion with the pierce shaft inserted through the pierce bore 19 in the ear 18 are brought into contact with a living body portion of the pierce bore 19.

[0067] When the reactive oxygen species sensors 1d shown in Fig. 6 is used, a very small amount of a blood sampled, for example, from a earlobe is drawn into the measuring space 32 through the opening at the tip end of the measuring space 32 by the capillary phenomenon, whereby the working electrode 4 and the counter electrode 5 are brought into contact with the blood.

[0068] When the reactive oxygen species sensor 1, 1a, 1b, 1c or 1d is used in this manner in a measuring system in which a superoxide anion radical exists, the metal in the metalloporphyrin complex forming the polymerized film on the surface of the working electrode 4 is reduced by the superoxide anion radical. For example, if the metal ion is iron one, Fe3+ is reduced to Fe2+ by the superoxide anion radical (an equation (7)).

[0069] Then, the variable resistor VR1 is regulated to apply a voltage as large as enabling the oxidization of Fe2+ resulting from the reduction by the superoxide anion radical, from the power source means 2 to the working electrode 4 and the counter electrode 5, thereby electrochemically re-oxidizing Fe2+ resulting from the reduction (an equation (8)), and an electric current flowing at that time is measured.

        Por(Fe3+) + O2-. → Por(Fe2+) + O2 ---     (7)

        Por((Fe2+) → Por(Fe3+) + e- ---     (8)



[0070] In the equations (7) and (8), "Por" means porphyrin.

[0071] The electric current value detected by the working electrode 4 and the counter electrode 5 in the above manner corresponds to a concentration of the superoxide anion radical and hence, the concentration of the superoxide anion radical existing in a living body can be quantitatively detected based on the electric current value. Namely, the measurement of the concentration of the superoxide anion radical is enabled by a principle similar to the equations (5) and (6). According to the present embodiment, the electric current detected by the working electrode 4 and the counter electrode 5 can be determined quantitatively as the concentration of the superoxide anion radical by the reactive oxygen species concentration measuring means 3.

[0072] Further, in the present embodiment, the display means 10 of the reactive oxygen species concentration measuring means 3 displays the concentration of the reactive oxygen species determined based on the electric current detected by the reactive oxygen species sensor 1, 1a, lb, 1c or 1d, and the external output means 11 delivers the determined concentration toward the remotely monitoring means 12 by transmission or the like. The result of the detection of the concentration fed from the external output means 11 of the reactive oxygen species concentration measuring means 3 in the above manner is received by the receiving means 13 of the monitoring means 12, and the arithmetic operation is carried out based on the concentration of the active oxygen species by an arithmetic means (not shown) to determine the health condition of a living body as a subject of measurement. Then, the concentration of the reactive oxygen species and the health condition of the living body can be displayed by a display means (likewise not shown). In this manner, the remote monitoring of the concentration of the reactive oxygen species can be conducted.

[0073] Reactive oxygen species such as hydrogen peroxide and OH' and other radical active species such as NO and ONOO- can be likewise quantitatively detected by a principle similar to that described above.

[0074] In this way, when any of the reactive oxygen species sensors 1, 1a, 1b and 1c according to the present embodiments is used, reactive oxygen species such as superoxide anion radical, hydrogen peroxide and OH' and other radical active species (NO, OONOO-) can be detected and quantitatively measured in vivo.

[0075] Thus, in an in vivo environment, various diseases can be specified by in vivo reactive oxygen species. Therefore, the specification of a disease such as cancer can be achieved by measuring a concentration of reactive oxygen species in a blood.

[0076] Fig.7 shows an alternative embodiment of the present invention further realized to enable the remote monitoring.

[0077] In this embodiment, an active oxygen species concentration measuring means 3a of a reactive oxygen species measuring device and an arrangement of a remotely monitoring means 12a are formed further particularly, and an active oxygen species sensor 1 and a power source means 2 are formed as in the embodiment shown in Fig.1.

[0078] In this embodiment, data can be delivered and received in opposite directions between the reactive oxygen species measuring device and the remotely monitoring means 12a by utilizing an internet, and the control of the remote monitoring based on reactive oxygen species can be carried out with finer contents.

[0079] Further, in the reactive oxygen species concentration measuring means 3a of the reactive oxygen species measuring device, a mobile phone 21 is provided to serve as both of a communication means 22 for transmitting and receiving data to and from the remotely monitoring means 12a and a display means 23 for displaying the data. An arithmetic control means 24 including an amplifier, CPU and a memory (all not shown) is also provided in the reactive oxygen species concentration measuring means 3a to determine a concentration of reactive oxygen species under the reception of a detected voltage fed from a reactive oxygen species sensor 1 and to convert the data into data transmittable by the mobile phone 21. Data from the arithmetic control mans 24 is transmitted through an interface 25 to the mobile phone 21. A necessary software (program) is installed in the mobile phone 21, after being supplied from the remotely monitoring means 12a serving as a base station (a host side) for carrying out the overall control of a remotely controlled active oxygen species measuring system capable of being constructed based on the present invention, so that the communication means 22 and the display means 23 are operated. The communication means 22 is configured to transmit data concerning the concentration of active oxygen species received from the arithmetic control means 24 by a mail appended with such data to the remotely monitoring means 12a through an internet IN, on the one hand, and to receive data transmitted through the internet IN from the remotely monitoring means 12a, on the other hand. The display means 23 is configured to display the data concerning the concentration of reactive oxygen species received from the arithmetic control means 24, and to display data concerning the health condition of a living body received from the remotely monitoring means 12a.

[0080] In the remotely monitoring means 12 serving as the base station (the host side) for carrying out the overall control of the remotely controlled reactive oxygen species measuring system, there are a communication means 26 for transmitting and receiving data to and from the communication means 22 of the reactive oxygen species measuring device through the internet IN, an arithmetic means 27 including a CPU for carrying out a data processing for data concerning the concentration of reactive oxygen species and received from the reactive oxygen species measuring device and operating the various sections in association with one another and a memory (both not shown) and the like, and a display means 28 for displaying the concentration of reactive oxygen species and the result of the data processing provided by the arithmetic means 27.

[0081] The operation of the present embodiment will be described below.

[0082] An electric current in a living body as a subject of measurement, which has been detected as in the embodiment shown in Fig.1 using the reactive oxygen species sensor 1 and the power source means 2, is delivered into the reactive oxygen species concentration measuring means 3a. The arithmetic control means 24 conducts an arithmetic operation for the inputted electric current value to determine a concentration of reactive oxygen species, and further conducts a necessary data processing to transmit the result to the mobile phone 21 through the interface 25. The mobile phone 21 displays the concentration of reactive oxygen species as an image picture represented by numerical values or a graph on the display means 23 according to the instruction from the software already installed, and transmits data concerning the concentration of reactive oxygen species to the remotely monitoring means 12a by a mail through the internet IN by means of the communication means 22. In the remotely monitoring means 12a, the arithmetic means 27 carries out the data processing for the data concerning the concentration of reactive oxygen species and received by the communication means 27, thereby determining the health condition of a living body such as a person as a subject of measurement. Then, the concentration of reactive oxygen species as well as the health condition of the living body are displayed by the display means 28. Thus, the health condition of the living body and the like can be monitored from a remote location or place. Further, the data concerning the health condition of the living body and the like determined in the remotely monitoring means 12a are returned to the mobile phone 21e in the reactive oxygen species measuring device through the communication means 26 and 22 in the remotely monitoring means 12a and the reactive oxygen species measuring device and through the internet IN and then displayed on the display means 23. In this manner, it is possible to provide a service for informing a person in a reactive oxygen species concentration measuring filed of the data concerning the health condition of the living body and the like. In addition, a guideline for the subsequent health care can be obtained in the measuring field. By using the remotely monitoring means 12a as the base station, it is possible to make a simultaneously access to a plurality of reactive oxygen species measuring devices, to provide a centralized management for various data, and to diagnose the health condition or the diseased condition of a living body such as a person as a subject of measurement based on various data by a physician and inform a person in the concentration measuring field of the result of the diagnosis. Particular, if there is a need for the diagnosis provided based on the concentration of active oxygen species in an emergency operating field by a physician, then the diagnosis cab be conducted in real time by a physical specialist existing in a remote place, leading to a rapidness and a suitability in a lifesaving operation. Further, the data processing which is arithmetically inoperable in the reactive oxygen species measuring device can be carried out in the remotely monitoring means 12a, and necessary data provided by the arithmetic operation can be transmitted to the reactive oxygen species measuring device, which can contribute to a reduction in size of the active oxygen species measuring device. In addition, the arithmetic operation for determining the concentration of the active oxygen species based on the electric current value measured by the arithmetic control means 24 of the reactive oxygen species concentration measuring means in the reactive oxygen species measuring device may be omitted, and the measured electric current value received by the reactive oxygen species sensor 1 may be transmitted intact to the remotely monitoring means 12a, where the concentration of the reactive oxygen species may be determined arithmetically from the measured electric current value. This can contribute to a further reduction in size of the reactive oxygen species measuring device. In the present embodiment, the communication means 22 and the display means 23 for the reactive oxygen species measuring device are formed by the mobile phone 21, so that the transmission and reception of the data to and from the remotely monitoring means 12a are conducted through the internet IN. Therefore, the measurement of the reactive oxygen species and the remote monitoring control can be carried out very easily using the mobile phone 21 excellent in portability or mobility and the internet IN.


Claims

1. A reactive oxygen species measuring device comprising:

a reactive oxygen species sensor (1) provided with an electrode assembly having a working electrode (4) and a counter electrode (5) formed into a shape enabling the detection of the presence of an in-vivo active oxygen species as an electric current,

a power source means (2) for applying a measuring voltage to said reactive oxygen species sensor (1), and

a reactive oxygen species concentration measuring means (3, 3a) for measuring a concentration of the reactive oxygen species from said current detected by said reactive oxygen species sensor (1); and wherein

the working electrode (4) of said reactive oxygen species sensor (1) includes, on its surface, an element capable of detecting the presence of active oxygen species as an electric current;

characterized in that said element capable of detecting the presence of reactive oxygen species as an electric current consists of a polymerized film of a metal porphyrin complex;

said metal porphyrin complex is represented by the following formula (II):

wherein M indicates a metal ion selected from the group consisting of iron, manganese, a cobalt, chromium and iridium; at least one of four Rs is any one of thiofuryl, pyrrolyl, furyl, mercaptophenyl, aminophenyl and hydroxyphenyl groups; and each of other Rs indicates any of the above-described groups, or alkyl group, aryl group or hydrogen; and at least one of two Ls is an nitrogen-based axial ligand such as imidazole and its derivative, pyridine and its derivative, aniline and its derivative, histidine and its derivative, and trimethylamine and its derivative, a sulfur-based axial ligand such as thiophenol and its derivative, cysteine or its derivative, and methionine and its derivative, or an oxygen-based axial ligand such as benzoic acid and its derivative, acetic acid and its derivative, phenol and its derivative, an aliphatic alcohol and its derivative or water; and the other L indicates any of the above-described axial ligands or no ligand; and

said reactive oxygen species concentration measuring means (3, 3a) includes an external output means (11) for delivering the measured concentration of the reactive oxygen species to the outside of the measuring means, and the device further includes a remote monitoring means (12, 12a) separated from said external output means (11) and adapted to monitor the concentration of the active oxygen species under the reception of the output from said external output means (11).


 
2. A reactive oxygen species measuring device according to claim 1, characterized in that said remote monitoring means (12a) includes a communication means (26) for transmitting and receiving data to and from said reactive oxygen species measuring device, an arithmetic means (27) for conducting a data processing for the concentration of the reactive oxygen species received from said external output means, and a display means for displaying the concentration of the reactive oxygen species and the result of the data processing provided by said arithmetic means (27), and
said external output means in said reactive oxygen species measuring device is comprised of a communication means (22) for transmitting and receiving the data to and from the remote monitoring means (12a), and a display means (23) for displaying the concentration of the reactive oxygen species and the data received from said remote monitoring means (12a).
 
3. A reactive oxygen species measuring device according to claim 2, which is remotely controlled characterized in that the delivery and reception of the data between said measuring means and said remote monitoring means are carried out through a radio or wire propagation system.
 
4. A reactive oxygen species measuring device according to claim 2, which is remotely controlled characterized in that the communication means (22) and the display means (23) of said reactive oxygen species measuring device are formed in a mobile phone (21) to deliver and receive the data to and from said remote monitoring means (12a) through an internet.
 
5. A reactive oxygen species measuring device according to claim 1 or 2, characterized in that said power source means is formed so that the measuring voltage to be applied to said reactive oxygen species sensor can be controlled variably.
 
6. A reactive oxygen species measuring device according to claim 1 or 2, characterized in that said reactive oxygen species concentration measuring means includes at least one of a display means for displaying a concentration of reactive oxygen species determined based on the electric current detected by said reactive oxygen species sensor, and an external output means for delivering data to the outside.
 
7. A reactive oxygen species measuring device according to claim 1, characterized in that the porphyrin compound forming said metal porphyrin complex is one selected from the group consisting of

5,10,15,20-tetrakis(2-thienyl) porphyrin,

5,10,15,20-tetrakis(3-thienyl) porphyrin,

5,10,15,20-tetrakis(2-pyrrolyl) porphyrin,

5,10,15,20-tetrakis(3-pyrrolyl) porphyrin,

5,10,15,20-tetrakis(2-furyl) porphyrin,

5,10,15,20-tetrakis(3-furyl) porphyrin,

5,10,15,20-tetrakis(2-mercaptophenyl) porphyrin,

5,10,15,20-tetrakis(3-mercaptophenyl) porphyrin,

5,10,15,20-tetrakis(4-mercaptophenyl) porphyrin,

5,10,15,20-tetrakis(2-aminophenyl) porphyrin,

5,10,15,20-tetrakis(3-aminophenyl) porphyrin,

5,10,15,20-tetrakis(4-aminophenyl) porphyrin,

5,10,15,20-tetrakis(2-hydroxyphenyl)porphyrin,

5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin,

5,10,15,20-tetrakis(4-hydroxyphenyl)porphyrin,

[5,10,15-tris(2-thienyl)-20-mono(phenyl)]porphyrin,

[5,10,15-tris(3-thienyl)-20-mono(phenyl)]porphyrin,

[5,10-bis(2-thienyl)-15,20-di(phenyl)]porphyrin,

[5,10-bis(3-thienyl)-15,20-di(phenyl)]porphyrin,

[5,10-bis(2-thienyl)-10,20-di(phenyl)]porphyrin,

[5,10-bis(3-thienyl)-10,20-di(phenyl)]porphyrin,

[5-mono(2-thienyl)-10,15,20-tri(phenyl)]porphyrin,

[5-mono(3-thienyl)-10,15,20-tri(phenyl)]porphyrin.


 


Ansprüche

1. Eine Vorrichtung zur Messung reaktiver Sauerstoffspezies, die Folgendes beinhaltet:

einen Sensor für reaktive Sauerstoffspezies (1), der mit einer Elektrodenanordnung versehen ist, die eine Arbeitselektrode (4) und eine Gegenelektrode (5) aufweist,

welche zu einer Form gebildet sind, die das Erfassen des Vorhandenseins einer in vivo aktiven Sauerstoffspezies als elektrischen Strom ermöglicht,

ein Energiequellenmittel (2) zum Anlegen einer Messspannung an den Sensor für reaktive Sauerstoffspezies (1) und

ein Mittel zur Messung der Konzentration an reaktiven Sauerstoffspezies (3, 3a) zum Messen einer Konzentration der reaktiven Sauerstoffspezies aus dem Strom, der durch den Sensor für reaktive Sauerstoffspezies (1) erfasst wird; und wobei die Arbeitselektrode (4) des Sensors für reaktive Sauerstoffspezies (1) auf ihrer Oberfläche ein Element umfasst, welches das Vorhandensein von aktiven Sauerstoffspezies als elektrischen Strom erfassen kann;

dadurch gekennzeichnet, dass das Element, welches das Vorhandensein von reaktiven Sauerstoffspezies als elektrischen Strom erfassen kann, aus einem polymerisierten Film aus einem Metallporphyrinkomplex besteht;

wobei der Metallporphyrinkomplex durch die folgende Formel (II) dargestellt wird:

wobei M ein Metallion bezeichnet, ausgewählt aus der Gruppe, bestehend aus Eisen, Mangan, einem Kobalt, Chrom und Iridium; mindestens eines von vier Rs eine beliebige von einer Thiofuryl-, Pyrrolyl-, Furyl-, Mercaptophenyl-, Aminophenyl- und Hydroxyphenylgruppe ist; und jedes der anderen Rs eine beliebige der oben beschriebenen Gruppen oder eine Alkylgruppe, Arylgruppe oder Wasserstoff bezeichnet; und mindestens eines von zwei Ls ein axialer Ligand auf Stickstoffbasis, wie Imidazol und sein Derivat, Pyridin und sein Derivat, Anilin und sein Derivat, Histidin und sein Derivat und Trimethylamin und sein Derivat, ein axialer Ligand auf Schwefelbasis, wie Thiophenol und sein Derivat, Cystein oder sein Derivat und Methionin und sein Derivat, oder ein axialer Ligand auf Sauerstoffbasis, wie Benzoesäure und ihr Derivat, Essigsäure und ihr Derivat, Phenol und sein Derivat, ein aliphatischer Alkohol und sein Derivat oder Wasser ist; und das andere L einen beliebigen der oben beschriebenen axialen Liganden oder keinen Liganden bezeichnet; und

das Mittel zur Messung der Konzentration an reaktiver Sauerstoffspezies (3, 3a) ein externes Ausgabemittel (11) zum Abgeben der gemessenen Konzentration an reaktiven Sauerstoffspezies an die Außenseite des Messmittels umfasst, und die Vorrichtung ferner ein Fernüberwachungsmittel (12, 12a) umfasst, das von dem externen Ausgabemittel (11) getrennt ist und angepasst ist, um die Konzentration an aktiven Sauerstoffspezies beim Empfang der Ausgabe des externen Ausgabemittels (11) zu überwachen.


 
2. Vorrichtung zur Messung reaktiver Sauerstoffspezies gemäß Anspruch 1, dadurch gekennzeichnet, dass das Fernüberwachungsmittel (12a) Folgendes umfasst: ein Kommunikationsmittel (26) zum Übertragen und Empfangen von Daten zu und von der Vorrichtung zur Messung reaktiver Sauerstoffspezies, ein Rechenmittel (27) zum Durchführen einer Datenverarbeitung für die von dem externen Ausgabemittel empfangene Konzentration an reaktiven Sauerstoffspezies und ein Anzeigemittel zum Anzeigen der Konzentration an reaktiven Sauerstoffspezies und des Ergebnisses der Datenverarbeitung, die durch das Rechenmittel (27) bereitgestellt wird, und wobei das externe Ausgabemittel in der Vorrichtung zur Messung reaktiver Sauerstoffspezies ein Kommunikationsmittel (22) zum Übertragen und Empfangen der Daten zu und von dem Fernüberwachungsmittel (12a) und ein Anzeigemittel (23) zum Anzeigen der Konzentration an reaktiven Sauerstoffspezies und der von dem Fernüberwachungsmittel (12a) empfangenen Daten beinhaltet.
 
3. Vorrichtung zur Messung reaktiver Sauerstoffspezies gemäß Anspruch 2, die ferngesteuert ist, dadurch gekennzeichnet, dass die Abgabe und der Empfang der Daten zwischen dem Messmittel und dem Fernüberwachungsmittel durch ein Funk- oder Leitungssystem ausgeführt werden.
 
4. Vorrichtung zur Messung reaktiver Sauerstoffspezies gemäß Anspruch 2, die ferngesteuert ist, dadurch gekennzeichnet, dass das Kommunikationsmittel (22) und das Anzeigemittel (23) der Vorrichtung zur Messung reaktiver Sauerstoffspezies in einem Mobiltelefon (21) gebildet sind, um die Daten an das und von dem Fernüberwachungsmittel (12a) über ein Internet abzugeben bzw. zu empfangen.
 
5. Vorrichtung zur Messung reaktiver Sauerstoffspezies gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, dass das Energiequellenmittel derart gebildet ist, dass die an den Sensor für reaktive Sauerstoffspezies anzulegende Messspannung variabel gesteuert werden kann.
 
6. Vorrichtung zur Messung reaktiver Sauerstoffspezies gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, dass das Mittel zur Messung der Konzentration an reaktiven Sauerstoffspezies mindestens eines von einem Anzeigemittel zum Anzeigen einer Konzentration an reaktiven Sauerstoffspezies, bestimmt auf der Grundlage des von dem Sensor für reaktive Sauerstoffspezies erfassten elektrischen Stroms, und einem externen Ausgabemittel zum Abgeben von Daten nach außen umfasst.
 
7. Messvorrichtung für reaktive Sauerstoffspezies gemäß Anspruch 1, dadurch gekennzeichnet, dass die Porphyrinverbindung, die den Metallporphyrinkomplex bildet, eine ist, die ausgewählt ist aus der Gruppe, bestehend aus Folgendem:

5,10,15,20-Tetrakis(2-thienyl)porphyrin,

5,10,15,20-Tetrakis(3-thienyl)porphyrin,

5,10,15,20-Tetrakis(2-pyrrolyl)porphyrin,

5,10,15,20-Tetrakis(3-pyrrolyl)porphyrin,

5,10,15,20-Tetrakis(2-furyl)porphyrin,

5,10,15,20-Tetrakis(3-furyl)porphyrin,

5,10,15,20-Tetrakis(2-mercaptophenyl)porphyrin,

5,10,15,20-Tetrakis(3-mercaptophenyl)porphyrin,

5,10,15,20-Tetrakis(4-mercaptophenyl)porphyrin,

5,10,15,20-Tetrakis(2-aminophenyl)porphyrin,

5,10,15,20-Tetrakis(3-aminophenyl)porphyrin,

5,10,15,20-Tetrakis(4-aminophenyl)porphyrin,

5,10,15,20-Tetrakis(2-hydroxyphenyl)porphyrin,

5,10,15,20-Tetrakis(3-hydroxyphenyl)porphyrin,

5,10,15,20-Tetrakis(4-hydroxyphenyl)porphyrin,

[5,10,15-tris(2-Thienyl)-20-mono(phenyl)]porphyrin,

[5,10,15-tris(3-Thienyl)-20-mono(phenyl)]porphyrin,

[5,10-bis(2-Thienyl)-15,20-di(phenyl)]porphyrin,

[5,10-bis(3-Thienyl)-15,20-di(phenyl)]porphyrin,

[5,10-bis(2-Thienyl)-10,20-di(phenyl)]porphyrin,

[5,10-bis(3-Thienyl)-10,20-di(phenyl)]porphyrin,

[5-mono(2-Thienyl)-10,15,20-tri(phenyl)]porphyrin,

[5-mono(3-Thienyl)-10,15,20-tri(phenyl)]porphyrin.


 


Revendications

1. Un dispositif de mesure d'espèces réactives de l'oxygène comprenant :

un capteur d'espèces réactives de l'oxygène (1) pourvu d'un ensemble d'électrodes présentant une électrode de travail (4) et une contre-électrode (5) formées dans une configuration permettant la détection de la présence d'une espèce active in vivo de l'oxygène sous forme de courant électrique,

un moyen de source d'alimentation (2) pour appliquer une tension de mesure audit capteur d'espèces réactives de l'oxygène (1), et

un moyen de mesure de concentration d'espèces réactives de l'oxygène (3, 3a) pour mesurer une concentration des espèces réactives de l'oxygène d'après ledit courant détecté par ledit capteur d'espèces réactives de l'oxygène (1) ; et dans lequel l'électrode de travail (4) dudit capteur d'espèces réactives de l'oxygène (1) inclut, sur sa surface, un élément capable de détecter la présence d'espèces actives de l'oxygène sous forme de courant électrique ;

caractérisé en ce que ledit élément capable de détecter la présence d'espèces réactives de l'oxygène sous forme de courant électrique consiste en un film polymérisé d'un complexe métal porphyrine ;

ledit complexe métal porphyrine est représenté par la formule (II) suivante :

où M indique un ion métallique sélectionné dans le groupe constitué du fer, du manganèse, d'un cobalt, du chrome et de l'iridium ; au moins l'un de quatre R est n'importe quel groupe parmi des groupes thiofuryle, pyrrolyle, furyle, mercaptophényle, aminophényle et hydroxyphényle ; et chacun des autres R indique n'importe lesquels des groupes décrits ci-dessus, ou un groupe alkyle, un groupe aryle ou l'hydrogène ; et au moins l'un de deux L est un ligand axial à base d'azote tel que l'imidazole et son dérivé, la pyridine et son dérivé, l'aniline et son dérivé, l'histidine et son dérivé, et la triméthylamine et son dérivé, un ligand axial à base de soufre tel que le thiophénol et son dérivé, la cystéine ou son dérivé, et la méthionine et son dérivé, ou un ligand axial à base d'oxygène tel que l'acide benzoïque et son dérivé, l'acide acétique et son dérivé, le phénol et son dérivé, un alcool aliphatique et son dérivé ou l'eau ; et l'autre L indique n'importe lesquels des ligands axiaux décrits ci-dessus ou aucun ligand ; et

ledit moyen de mesure de concentration d'espèces réactives de l'oxygène (3, 3a) inclut un moyen de sortie externe (11) pour délivrer la concentration mesurée des espèces réactives de l'oxygène à l'extérieur du moyen de mesure, et le dispositif inclut en sus un moyen de surveillance à distance (12, 12a) séparé dudit moyen de sortie externe (11) et conçu pour surveiller la concentration des espèces actives de l'oxygène sous la réception de la sortie provenant dudit moyen de sortie externe (11).


 
2. Un dispositif de mesure d'espèces réactives de l'oxygène selon la revendication 1, caractérisé en ce que ledit moyen de surveillance à distance (12a) inclut un moyen de communication (26) pour transmettre et recevoir des données au et dudit dispositif de mesure d'espèces réactives de l'oxygène, un moyen arithmétique (27) pour réaliser un traitement de données pour la concentration des espèces réactives de l'oxygène reçue dudit moyen de sortie externe, et un moyen d'affichage pour afficher la concentration des espèces réactives de l'oxygène et le résultat du traitement de données fourni par ledit moyen arithmétique (27), et
ledit moyen de sortie externe dans ledit dispositif de mesure d'espèces réactives de l'oxygène est composé d'un moyen de communication (22) pour transmettre et recevoir les données au et du moyen de surveillance à distance (12a), et d'un moyen d'affichage (23) pour afficher la concentration des espèces réactives de l'oxygène et les données reçues dudit moyen de surveillance à distance (12a).
 
3. Un dispositif de mesure d'espèces réactives de l'oxygène selon la revendication 2, lequel est contrôlé à distance caractérisé en ce que la délivrance et la réception des données entre ledit moyen de mesure et ledit moyen de surveillance à distance sont effectuées par le biais d'un système de propagation radioélectrique ou filaire.
 
4. Un dispositif de mesure d'espèces réactives de l'oxygène selon la revendication 2, lequel est contrôlé à distance caractérisé en ce que le moyen de communication (22) et le moyen d'affichage (23) dudit dispositif de mesure d'espèces réactives de l'oxygène sont formés dans un téléphone mobile (21) afin de délivrer et recevoir les données au et dudit moyen de surveillance à distance (12a) par le biais d'internet.
 
5. Un dispositif de mesure d'espèces réactives de l'oxygène selon la revendication 1 ou la revendication 2, caractérisé en ce que ledit moyen de source d'alimentation est formé de sorte que la tension de mesure à appliquer audit capteur d'espèces réactives de l'oxygène puisse être contrôlée de manière variable.
 
6. Un dispositif de mesure d'espèces réactives de l'oxygène selon la revendication 1 ou la revendication 2, caractérisé en ce que ledit moyen de mesure de concentration d'espèces réactives de l'oxygène inclut au moins soit un moyen d'affichage pour afficher une concentration d'espèces réactives de l'oxygène déterminée sur la base du courant électrique détecté par ledit capteur d'espèces réactives de l'oxygène, soit un moyen de sortie externe pour délivrer des données à l'extérieur.
 
7. Un dispositif de mesure d'espèces réactives de l'oxygène selon la revendication 1, caractérisé en ce que le composé porphyrine formant ledit complexe métal porphyrine est un composé sélectionné dans le groupe constitué de

la 5,10,15,20-tétrakis(2-thiényl) porphyrine,

la 5,10,15,20-tétrakis(3-thiényl) porphyrine,

la 5,10,15,20-tétrakis(2-pyrrolyl) porphyrine,

la 5,10,15,20-tétrakis(3-pyrrolyl) porphyrine,

la 5,10,15,20-tétrakis(2-furyl) porphyrine,

la 5,10,15,20-tétrakis(3-furyl) porphyrine,

la 5,10,15,20-tétrakis(2-mercaptophényl) porphyrine,

la 5,10,15,20-tétrakis(3-mercaptophényl) porphyrine,

la 5,10,15,20-tétrakis(4-mercaptophényl) porphyrine,

la 5,10,15,20-tétrakis(2-aminophényl) porphyrine,

la 5,10,15,20-tétrakis(3-aminophényl) porphyrine,

la 5,10,15,20-tétrakis(4-aminophényl) porphyrine,

la 5,10,15,20-tétrakis(2-hydroxyphényl) porphyrine,

la 5,10,15,20-tétrakis(3-hydroxyphényl) porphyrine,

la 5,10,15,20-tétrakis(4-hydroxyphényl) porphyrine,

la [5,10,15-tris(2-thiényl)-20-mono(phényl)] porphyrine,

la [5,10,15-tris(3-thiényl)-20-mono(phényl)] porphyrine,

la [5,10-bis(2-thiényl)-15,20-di(phényl)] porphyrine,

la [5,10-bis(3-thiényl)-15,20-di(phényl)] porphyrine,

la [5,10-bis(2-thiényl)-10,20-di(phényl)] porphyrine,

la [5,10-bis(3-thiényl)-10,20-di(phényl)] porphyrine,

la [5-mono(2-thiényl)-10,15,20-tri(phényl)] porphyrine,

la [5-mono(3-thiényl)-10,15,20-tri(phényl)] porphyrine.


 




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Cited references

REFERENCES CITED IN THE DESCRIPTION



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Patent documents cited in the description




Non-patent literature cited in the description