WO2008066206A1 - Appareil de blocage d'une conduction électrique anormale par thérapie photodynamique (tpd) - Google Patents
Appareil de blocage d'une conduction électrique anormale par thérapie photodynamique (tpd) Download PDFInfo
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- WO2008066206A1 WO2008066206A1 PCT/JP2007/073628 JP2007073628W WO2008066206A1 WO 2008066206 A1 WO2008066206 A1 WO 2008066206A1 JP 2007073628 W JP2007073628 W JP 2007073628W WO 2008066206 A1 WO2008066206 A1 WO 2008066206A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/06—Radiation therapy using light
- A61N5/0613—Apparatus adapted for a specific treatment
- A61N5/062—Photodynamic therapy, i.e. excitation of an agent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
- A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
- A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
- A61B18/22—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor
- A61B18/24—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor with a catheter
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
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- A—HUMAN NECESSITIES
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- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/06—Radiation therapy using light
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/06—Radiation therapy using light
- A61N5/0601—Apparatus for use inside the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/06—Radiation therapy using light
- A61N5/0601—Apparatus for use inside the body
- A61N5/0603—Apparatus for use inside the body for treatment of body cavities
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/06—Radiation therapy using light
- A61N2005/0626—Monitoring, verifying, controlling systems and methods
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/06—Radiation therapy using light
- A61N2005/0635—Radiation therapy using light characterised by the body area to be irradiated
- A61N2005/0643—Applicators, probes irradiating specific body areas in close proximity
- A61N2005/0644—Handheld applicators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/06—Radiation therapy using light
- A61N2005/065—Light sources therefor
- A61N2005/0651—Diodes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/06—Radiation therapy using light
- A61N2005/0658—Radiation therapy using light characterised by the wavelength of light used
- A61N2005/0662—Visible light
- A61N2005/0663—Coloured light
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/06—Radiation therapy using light
- A61N5/067—Radiation therapy using light using laser light
Definitions
- Anomalous electrical conduction blocker using photodynamic therapy (PDT) is anomalous electrical conduction blocker using photodynamic therapy (PDT)
- the present invention relates to the fields of arrhythmia such as atrial fibrillation caused by abnormal electrical conduction of cells and abnormal excitement, and photodynamic therapy, and relates to an apparatus using photodynamic therapy.
- arrhythmia such as atrial fibrillation caused by abnormal electrical conduction of cells and abnormal excitement
- photodynamic therapy relates to an apparatus using photodynamic therapy.
- Tachyarrhythmia refers to the transmission of abnormal excitement to normal myocardial tissue.
- a swirling circuit reentry circuit
- heart excitation is controlled at a normal rate (sinus rhythm) by excitation from the sinoatrial node, but in the case of tachyarrhythmia, heart rate is higher than sinus rhythm due to abnormal excitation from some heart tissue. Will continue at a fast rate.
- the reentry circuit refers to the part where excitement swirls in a circuit form because normal electrical excitement transmission is not performed due to the presence of a transmission failure site in the myocardial tissue. This reentry circuit is involved in the persistence of tachyarrhythmia, while abnormal excitation and transmission cause seizures of tachyarrhythmia.
- Atrioventricular Nodal Reentry Tachycardia is an arrhythmia that is caused by an atrial premature contraction and is maintained by the formation of a reentry circuit in the atrioventricular node and part of the atrium. is there.
- Atrioventricular Nodal Reentry Tachycardia is an arrhythmia that is caused by an atrial premature contraction and is maintained by the formation of a reentry circuit in the atrioventricular node and part of the atrium. is there.
- a method of blocking a part of the reentry circuit with a catheter abrasion as a radical treatment is blocked.
- the cause of the attack exists in a specific site, and examples of tachyarrhythmia in which radical treatment to stop the attack is performed include atrial fibrillation (Atiral Fibrillation: AF).
- Atrial fibrillation is a type of cardiac arrhythmia. It is an arrhythmia caused by irregular atrial excitation and causes thrombotic obstruction such as cerebral infarction. Seizures of atrial fibrillation are caused by the presence of electrical signal strays from the left atrium (LA) to the pulmonary veins (PV) in myocardial tissue. During atrial fibrillation, the atrioventricular node receives electrical impulses not only from the sinoatrial node but also from many locations throughout the atrium. Atrioventricular node Will not be able to handle this and will produce irregular and fast heartbeats.
- Atrial fibrillation can be treated by stopping electrical conduction from the pulmonary vein of focal activity to the left atrium.
- a catheter may be inserted so as to reach a part of the left atrium, and the abnormal excitation conduction path may be cauterized using high frequency, ultrasound, etc., and treated with catheter abrasion that causes the cells of that part to die. Yes (see Patent Document 1 and Non-Patent Documents 1 to 4).
- Treatment methods using catheter ablation include balloon catheter ablation using a balloon catheter to treat with ultrasound and high frequency.
- Photodynamic therapy is used for cancer treatment and the like.
- Photodynamic therapy also referred to as PDT, photochemical therapy
- PDT is a photosensitizer such as a certain porphyrin derivative administered by intravenous injection or other method, and lesions such as cancerous tissue are observed. Absorption and accumulation selectively in tissue lesions to be treated. And then irradiating with a light beam such as a laser beam to destroy the tissue. It has the property that the photosensitizer is selectively accumulated in the lesion and that it is sensitized by light. It is used. However, there are some treatment methods that do not use accumulation.
- the photosensitizer taken into the lesion by light irradiation is excited, and the energy of the sensitizer is transferred to oxygen present in the lesion to generate active singlet oxygen, which is then activated by the cells in the lesion. It is based on the mechanism of killing by apoptosis or necrosis.
- Patent Document 1 Japanese Patent Application Laid-Open No. 2004-130095
- Patent Document 2 Japanese Patent No. 2961074
- Patent Literature 4 US Patent Application Publication No. US2002 / 0095197
- Non-patent literature 1 Carlo Pappone et al., Circulation 2000; 102; 2619-2628
- Non-patent literature 2 Mathaniel M. Fried et al., Lasers in Surgery and Medicine
- Non-Patent Literature 3 Kazushi Tanaka et al., Journal of American College of Cardiology, Vol. 38, No. 7. December 2001, 2079-2086
- Non-Patent Document 4 WALID SALIBA et al., Journal of Cardiovascular Electrophysiology, Volume 13, No. 10, October 2002, 957-961 Disclosure of the Invention
- An object of the present invention is to provide an apparatus and method for blocking abnormal conduction in the myocardium using photodynamic therapy or treating arrhythmia.
- the present inventors have found that by using photodynamic treatment by light irradiation, it is possible to accurately perform the overlay without damaging the target tissue where the abrasion should be performed.
- the present inventors used a water-soluble photodynamic therapeutic drug such as talaporfin sodium to be administered by intravenous injection or the like, so that the drug is administered to the treatment site in a short period after administration. It was found that the treatment can be started without having a long time after administration.
- the present inventors have developed a method for reducing the damage to the myocardial tissue and surrounding tissues and limiting the region where the electrical conduction is cut off in the treatment of tachyarrhythmia using the myocardial conduction blocking method. I found it.
- the present inventors can use the photodynamic therapy using a laser to cause the target site without causing damage to the abnormal electrical conduction site of the myocardium that is the target site or the surrounding tissue of the site of abnormal excitation.
- the depth of treatment necessary for complete cure It was found that can be obtained reliably.
- the present inventors have found a drug used in a method for treating arrhythmia such as atrial fibrillation by ablating by photodynamic therapy and blocking abnormal electrical conduction of the myocardium, optimal light irradiation conditions, etc.
- the present invention has been completed.
- the present invention is as follows.
- a catheter for guiding the light irradiation section to a site of abnormal electrical conduction or abnormal excitement in the myocardium where the photodynamic therapeutic agent of a subject to which a photodynamic therapeutic agent has been previously administered is present, Including a means for generating a light beam for irradiating a conduction site or an abnormal excitation occurrence site and a means for transmitting a light beam to the abnormal electrical conduction site, using a water-soluble chlorin drug as a photodynamic therapeutic agent, A catheter ablation device that blocks abnormal electrical conduction of the myocardium using photodynamic therapy, which uses a light beam having an excitation wavelength of the photodynamic therapeutic agent.
- the arrhythmia is selected from the group consisting of paroxysmal supraventricular tachycardia, atrial flutter, atrial tachycardia and ventricular tachycardia with atrioventricular recurrent tachycardia or atrioventricular nodal recurrent tachycardia, [2 ] Or
- a catheter abrasion device for treating arrhythmia using the photodynamic therapy [3] A catheter abrasion device for treating arrhythmia using the photodynamic therapy.
- a water-soluble chlorin agent as a photodynamic therapeutic agent comprising: a catheter for guiding to the abnormal electrical conduction site; a means for generating a light beam for irradiating the abnormal electrical conduction site; and a means for transmitting a light beam to the abnormal electrical conduction site Use the photodynamic as a ray -
- WO 2008/066206 A catheter ablation device for atrial fibrillation treatment using photodynamic therapy using a light beam having an excitation wavelength of a therapeutic agent.
- the photodynamic therapeutic agent is talaporfin sodium
- the irradiating light is a semiconductor laser light or LED light of 650 to 90 nm, and the category of any one of [1 ;! to [5:] Tel ablation device.
- [1 2] Means for monitoring the amount of photodynamic therapeutic agent present at the site of abnormal electrical conduction or abnormal excitability of the myocardium and / or the oxygen concentration of the site of abnormal electrical conduction or abnormal excitement of the myocardium A device according to any one of [1] to [1 1].
- [1 3] Monitor the amount of photodynamic therapeutic agent present at the irradiation means and the abnormal electrical conduction site or abnormal excitation occurrence site in the myocardium and the oxygen concentration in the abnormal electrical conduction site or abnormal excitation occurrence site in the myocardium.
- photodynamics obtained from means for monitoring the amount of the photodynamic therapeutic agent and the oxygen concentration at the site of abnormal electrical conduction or abnormal excitation in the myocardium [1] to [1 2], which changes the irradiation condition of the light to be irradiated according to the amount of the therapeutic agent and the oxygen concentration of Z or the abnormal electrical conduction site or abnormal excitation occurrence site of the myocardium .
- FIG. 1 is a graph showing the relationship between the drug concentration and the dead cell rate when the rat cardiac muscle cell line is treated with PDT.
- FIG. 2 is a graph showing the relationship between the total dose of laser irradiation and the dead cell rate when PDT treatment is performed on a rat cardiac muscle cell line.
- Fig. 3 is a graph showing the relationship between the laser intensity and the dead cell rate when a rat cardiac muscle cell line is treated with PDT.
- Fig. 4 is a photograph showing the state of cells when a rat cardiac muscle cell line is treated with PDT.
- Fig. 5 is a photograph showing an experimental apparatus for measuring the PDT effect on the isolated myocardial tissue.
- Figure 6 is an enlarged photograph of the area around the developed muscle tissue in the experimental device that measures the PDT effect on the isolated myocardial tissue.
- Fig. 7 is a photograph showing the laser irradiation region and the stimulation / potential deriving site in the tissue in the experimental device that measures the PDT effect on the isolated myocardial tissue.
- FIG. 8A is a diagram showing a potential change at the time of stability in the isolated myocardial tissue.
- FIG. 8B is a diagram showing a potential change immediately before laser irradiation in the isolated myocardial tissue.
- FIG. 8C is a graph showing the potential change 2 minutes after the start of laser irradiation in the isolated myocardial tissue.
- FIG. 8D is a graph showing the potential change 5 minutes after the start of laser irradiation in the isolated myocardial tissue.
- Figure 8E shows the potential change in the isolated myocardial tissue after 5 minutes of laser irradiation.
- Fig. 8F is a diagram showing the appearance of automatic ability (generating action potential by itself) at site 2 in the isolated myocardial tissue.
- Figure 9 is a photograph showing a tissue specimen at the PDT trial site.
- FIG. 10 is a graph showing the relationship between the total dose of laser irradiation and the dead cell rate when PDT treatment was performed on rat primary cultured cardiomyocytes on the third day of culture.
- FIG. 11 is a graph showing the relationship between the total dose of laser irradiation and the dead cell rate when PDT treatment was performed on rat primary cultured cardiomyocytes on day 7 of culture.
- Figure 1 2 is a photograph showing the state of the cells when subjected to PDT treatment by administering the cod porphyrin sodium concentration 10 ⁇ ⁇ / ⁇ 1, laser irradiation total dose 3 X / cm 2 conditions.
- FIG. 13 is a photograph showing the state of cells when PDT treatment was performed under the conditions of administered talaporbuillin sodium concentration of 20 Aig / ml and laser irradiation total dose 3 J7 cm 2 .
- Fig. 14A is a diagram showing an outline of a device for treating arrhythmia using PDT.
- the region to be treated exemplified in FIG. 14B is the myocardium near the connection between the left atrium and the pulmonary vein.
- FIG. 14B is a diagram showing an outline of an arrhythmia treatment device having a bare fiber using a PDT.
- the region to be treated exemplified in FIG. 14B is an arbitrary myocardium. '
- FIG. 14C is a diagram showing an outline of a device for treating arrhythmia using a PDT and having an optical fiber with a diffusion means.
- the region to be treated exemplified in FIG. 14C is an arbitrary myocardium.
- Fig. 15 is a graph showing the relationship between the total energy density of laser irradiation and the dead cell rate at each drug concentration when cardiomyocytes and talaporphyrin sodium are not contacted.
- Figure 16 shows the relationship between the total energy density of laser irradiation and the dead cell rate at each drug concentration when cardiomyocytes are contacted with sodium talaporphyrin for 30 minutes.
- Figure 17 shows the relationship between cardiomyocytes and talaporphyrin sodium.
- Figure 18 shows the relationship between the total energy density of laser irradiation at each drug concentration and the dead cell rate when the mouse is in contact for 60 minutes.
- Figure 18 shows the relationship between cardiomyocytes and talaporphyrin sodium for 120 minutes. Shows the relationship between the total energy density of laser irradiation and the dead cell rate at different concentrations
- Fig. 19 shows the relationship between the contact time between cardiomyocytes and talaporfin sodium and the death cell rate.
- FIG. 20 shows control (Fig. 20 E) and contact time 0 (Fig. 20 A), 30 (Fig. 20 B), 60 (Fig. 20 C) for talaporfin sodium 30 / g / ml 120 (FIG. 20D) is a photograph showing the cell morphology immediately after laser light irradiation (15 J / cm 2 ). The length of the scale par in the photo is lOO ⁇ m.
- FIG. 21 shows changes in intracellular Ca 2+ concentration when extracellular Ca 2+ concentration is normal.
- FIG. 22 shows changes in intracellular Ca 2+ concentration when the extracellular Ca 2+ concentration is free.
- Figure 23 is a photograph showing the cell morphology before and after PDT.
- the length of the scale bar in the photo is 10 ⁇ ⁇ .
- FIG. 24 is a photograph showing the positional relationship of electrodes and the like on the myocardial tissue surface in the method for deriving the extracellular potential of Example 6.
- FIG. 25 is a diagram showing an outline of the ex vivo experimental system used in Example 6.
- FIG. 26 is a graph showing changes in the extracellular potential before and after the PDT of the derived potential in Example 6, Experiment 1.
- FIG. 27 is a graph showing changes in the extracellular potential before and after the PDT of the derived potential in Example 6, Experiment 2.
- FIG. 28 is a graph showing changes in the extracellular potential before and after the PDT of the derived potential in Example 6, Experiment 3.
- FIG. 29 is a graph showing changes in the extracellular potential before and after the PDT of the derived potential in Example 6, Experiment 4.
- FIG. 30 is a photograph showing the positional relationship between each part of the heart and the laser irradiation end in the in vivo experiment of Example 7.
- FIG. 31 is a diagram showing an outline of the in vivo experimental system of Example 7.
- FIG. 32 is a diagram showing changes in the rat electrocardiogram before and after the PDT in the interval 5 minutes in the experiment 1 of Example 7.
- FIG. 33 is a graph showing changes in the rat electrocardiogram before and after the PDT during 60 minutes of Interpal in Experiment 1 of Example 7.
- FIG. 34 is a graph showing changes in the rat electrocardiogram before and after PDT during 30 minutes of Interpal in Experiment 2 of Example 7.
- FIG. 35 is a diagram showing a rat electrocardiogram after 2 weeks in Experiment 2 of Example 7.
- Figure 36 is a photograph showing an Azan-stained specimen observation image of the laser irradiation site in the heart tissue in Experiment 1.
- the length of the scale bar in the photo is 0.2 mm.
- Fig. 37 is a photograph showing an HE-stained specimen observation image near the boundary region between the myocardial tissue and scar tissue in Fig. 36.
- the length of the scale bar in the photo is 50 // m.
- FIG. 38 is a photograph showing a fluorescence observation image of the change in drug distribution in rat myocardial tissue over time, and shows the result of Experiment 1 of Example 8 (interval 5 minutes).
- the length of the scale bar in the photo is 0.5mm.
- FIG. 39 is a photograph showing a fluorescence observation image of the change in drug distribution in rat myocardial tissue over time, and shows the result of Experiment 2 of Example 8 (interval 30 minutes).
- the length of the scale bar in the photo is 0.5mm.
- FIG. 40 is a photograph showing a fluorescence observation image of the change in drug distribution in rat myocardial tissue over time, and shows the result of Experiment 3 of Example 8 (interval 60 minutes).
- the length of the scale par in the photo is 0.5mm.
- FIG. 41 is a photograph showing the result of further image processing of the fluorescence images of FIGS.
- A, B and C show results for intervals 5, 60 and 120 minutes, respectively.
- the length of the scale bar in the photo is 0.5mra.
- Fig. 42 is an enlarged photograph showing a fluorescence observation image of the time course of drug distribution in rat myocardial tissue.
- A, B and C show results for intervals 5, 60 and 120 minutes, respectively.
- the length of the scale par in the photo is 0.1mm.
- FIG. 4 3 A is a photograph showing a thermal image when laser irradiation is performed under condition 1 of Example 1.
- FIG. 43B is a diagram showing a temperature rise when laser irradiation is performed under condition 1 of the first embodiment.
- FIG. 44A is a photograph showing a thermal image when laser irradiation is performed under condition 1 in Example 1.
- FIG. 44B is a diagram showing a temperature rise when laser irradiation is performed under condition 1 of Example 1.
- Figure 4 5 shows pharmacological studies of talaporfin sodium and data from clinical trials. When intravenously injected into rats at various doses (10, 5, 2, lmg / kg), humans were intravenously injected with lmg / kg. It is a figure which shows the time-dependent change of the plasma concentration at the time of shooting.
- Fig. 46 shows the concentration of drugs in the rat heart and the changes in rat and human plasma concentrations for doses of 5 mg / kg and 2 mg / kg.
- Figure 47 shows the ratio of drug concentration in rat and human plasma and heart.
- the apparatus using the PDT of the present invention can permanently block abnormal electrical conduction in cell tissues.
- treatment is performed by permanently stopping abnormal electrical conduction (electrical entry) of the tissue.
- PDT photodynamic therapy, photochemical therapy
- PDT drug photodynamic therapy drug
- light that can excite the PDT drug.
- One aspect of the device of the present invention is a catheter-like device in which a light irradiation part is disposed at the tip, and the catheter is inserted through the main vein or artery to the heart and a photosensitizer is applied. A part of the target myocardial tissue is irradiated with a laser to kill the tissue.
- the “catheter” refers to a thin tube that can be inserted into a blood vessel.
- an optical transmission means is inserted into the thin tube, or an optical transmission means is provided inside. ing.
- abnormal electrical conduction in the myocardial tissue includes reentry (excitation swirling) in which the electrical excitement that occurs in the myocardium swirls rather than in one direction.
- reentry excitation swirling
- an anatomical reentry caused by a specific structure of the heart tissue, a decrease in myocardial conductivity in the local area, and a refractory period (once the electrical stimulation of the myocardial cells occurs,
- An example of the former is a reentry that occurs when an atrioventricular node has a fast conduction path and a slow conduction path, and maintains atrioventricular nodal reentry tachycardia (AVNRT).
- APNRT atrioventricular nodal reentry tachycardia
- Another typical anatomy is the reentry caused by the existence of a sub-conduction pathway that passes through the Kent bundle different from the original conduction pathway between the atrium and the ventricle, which is the cause of Wolff- Parkinson-White syndrome (WPW syndrome) Reentry is one.
- Abnormal electrical excitement includes, for example, abnormal automatic ability and triggered activity.
- the atrial and ventricular cardiomyocytes (working myocardium) originally have spontaneous stimulating function (automated function), but usually the higher-order sinoatrial node and atrioventricular node (which are called special myocardium) Excitement is controlled. When the resting potential becomes shallow for some reason, automatic ability may occur in the working myocardium. This is called abnormal automatic ability.
- WO 2008/066206 can cause various arrhythmias. Abnormal excitement from the left atrium to the entrance of the pulmonary veins, which is said to be the main cause of atrial fibrillation, is thought to be both abnormal autoactivity and triggered activity. This is called excitement.
- an abnormal electrical conduction site of the myocardium can be treated by abrasion.
- Abnormal treatment of myocardial electrical conduction by ablation, blocking (blocking) abnormal electrical conduction, blocking (blocking) abnormal electrical conduction path, blocking (blocking) reentry (sub-conduction path), abnormal In some cases, it is used to create an electrical conduction block.
- the site may be referred to as a site having abnormal excitement or a site having abnormal automatic ability.
- the site of abnormal excitation is also the site that generates extra electrical signals in the stimulus transmission system.
- abnormal electrical conduction in the myocardium is blocked by killing the abnormal excitation occurrence site.
- abnormal electrical conduction may be interrupted.
- the disease that can be treated with the device of the present invention is an arrhythmia caused by the presence of the above-mentioned abnormal electrical conduction site or abnormal excitation occurrence site, particularly tachyarrhythmia.
- tachyarrhythmias include atrioventricular reentrant tachycardia (AVW: WPW syndrome) and atrioventricular nodal reentrant tachycardia (AVNRT).
- Ventricular tachycardia such as paroxysmal supraventricular tachycardia (PSVT), atrial flutter, atrial tachycardia, atrial fibrillation (AF) (upper ventricular tachyarrhythmia) and ventricular tachycardia Arrhythmia may be mentioned.
- PSVT paroxysmal supraventricular tachycardia
- AF atrial fibrillation
- ventricular tachycardia ventricular tachycardia
- Arrhythmia ventricular tachycardia
- atrioventricular recurrent tachycardia in addition to the atrioventricular nodules and hiss bundles, there is a secondary conduction path that connects the ventricle and the atrium, so the electrical signal once transmitted to the ventricle returns to the atrium again.
- atrioventricular nodal recurrent tachycardia there is no secondary conduction path, but there is a difference in the speed with which the electrical signal travels within one atrioventricular nodule.
- the conduction path is formed.
- the electrical signal continues to pass through the atrioventricular node and stimulates the atria and ventricles alternately, resulting in a tachyarrhythmia. Atrial flutter circles the right atrium , resort...
- WO 2008/066206 Caused by abnormal electrical activity in which the electrical signal continues to rotate in the form. Atrial tachycardia is always present in the atria. In Atrial Fibrillation -O! /, Abnormal excitatory conduction at the left atrial-pulmonary vein junction is the cause. Ventricular tachycardia is caused by abnormal electrical signal transmission in the form of a loop around the heart muscle damaged by myocardial infarction.
- the scope of application of abrasion is determined by the Japanese Circulation Society (Guidelines for the diagnosis and treatment of cardiovascular diseases, non-pharmacological guidelines for arrhythmia. Jpn Circulation J 65 (Suppl V): 1127, 2001),
- the target treatment can also be selected based on the regulations.
- the site to be ablated using the apparatus of the present invention is an abnormal electrical conduction site or abnormal excitation occurrence site of the myocardium that causes the arrhythmia, a part of the myocardium, and an atrium such as an atrial septum
- an atrium such as an atrial septum
- the site to be abraded can be determined as appropriate depending on the type of arrhythmia, and the abnormal electrical conduction site or abnormal excitable site that causes arrhythmia may be determined by mapping, and an abrasion may be performed on that site. .
- Ablation may be performed linearly or dottedly, and can be determined as appropriate depending on the target site of ablation.
- the target part of the abnormal left atrial tissue is a tissue in a region that conducts electrical excitement that causes an atrial fibrillation attack to the left atrium.
- a region include the vicinity of the myocardial portion at the connection between the pulmonary vein (PV) and the left atrium of the heart.
- the myocardium at the junction of the pulmonary vein and the left atrium corresponds to the vicinity of the entrance of the pulmonary vein. Preferably, it is in the vicinity of the connection between the pulmonary vein and the left atrium of the heart.
- the electrical connection between the left atrium and the pulmonary vein disappears, that is, a conduction block is formed, and the pulmonary vein is electrically connected. Atrial premature contractions originating from the pulmonary veins that cause isolation and excitement of the atrial fibrillation disappear.
- a part of the connection between the pulmonary vein and the left atrium of the heart may be killed, but preferably, the entire circumference is treated with the device of the present invention, so that a considerable portion of the circumferential region of the tissue is treated. The part is killed.
- the two pulmonary veins of the upper and lower pulmonary veins and the organization of the connection portion of the left atrium may be individually killed, or the two may be killed so as to surround them.
- the pulmonary veins and the left atrial junction were all killed so as to surround the tissue. It may be destroyed. When isolating the pulmonary veins, it is preferable to kill the tissue continuously in a linear fashion. E -Use this PDT. -Suitable for brazing.
- the left atrial canopy and the mitral annulus canal may be killed on the line.
- stopping the electrical conduction from the pulmonary vein to the left atrium is sometimes referred to as “creating a conduction block between the left atrium and the pulmonary vein”, and “electric lung vein (PV) ) “Isolation Ablation”. Box isolation is sometimes referred to as killing the above four pulmonary veins and the left atrial joint so as to surround them.
- An abnormal electrical conduction site or an abnormal excitation occurrence site that is killed by using the apparatus of the present invention can be monitored using an electrode or the like, and the electrical activity can be mapped and recorded.
- the electrode used for mapping is provided at the distal end of the catheter of the device of the present invention. In this case, for example, a plurality of electrodes may be provided at intervals.
- the catheter is placed so that the electrode portion is in contact with the myocardial tissue, and the potential is detected by the electrode.
- an electrode for electrical stimulation is also arranged, and electrical excitation is induced by electrical stimulation, and it can be seen whether the conduction stops at the place where the conduction block seems to be blocked.
- an electrode catheter with a ring-shaped tip is used in order to examine the potential around the pulmonary vein-left atrial junction.
- the CART0 system Johnson & johnson
- the CARTO system simultaneously records the intracardiac potential using a catheter electrode and the position of the catheter electrode (anatomical information-anatomical) obtained using magnetism, thereby rendering a three-dimensional heart image in real time on a computer display. It is also possible to display the excitation propagation process and potential wave height during tachycardia.
- the site of abnormal electrical conduction or abnormal excitement may be identified by monitoring the electrical signal and used as the target site.
- mapping can also be performed by applying a potential-sensitive dye (VSD) to a site that is suspected of having an abnormal electrical conduction site or an abnormal excitation site, and measuring the potential by potential imaging. Can be. Various methods can be used as the mapping method.
- VSD potential-sensitive dye
- abnormal electrical-conduction 'part ⁇ or whether abnormal treatment was performed properly, for example, whether a conduction probe was created. Can also be monitored.
- the examination of electrical conduction in the myocardium using electrodes is also referred to as taking an intracardiac electrocardiogram. That is, the device of the present invention includes an electrode that is a means for monitoring an abnormal electrical conduction site or an abnormal excitation occurrence site, or monitoring whether or not a treatment has been performed at an abnormal electrical conduction site or an abnormal excitation effort site. Or includes means for mapping or includes means for taking an intracardiac electrogram.
- the electrical potential of the myocardial tissue is monitored with the electrode of the catheter, the site of abnormal electrical conduction or the site of occurrence of abnormal excitation is identified, and the site is irradiated with light.
- a mapping pattern of electrical activity and X-rays are used.
- the position of the catheter can be accurately determined by seeing through the catheter position and superimposing the mapping pattern and the catheter position.
- a means for detecting contact of the catheter with cardiac tissue such as the inner wall of the atrium may be included.
- the means for detecting the contact is, for example, an electrode, and can detect the electrical conduction of the heart tissue by the contact.
- the PDT drug used in combination with the device of the present invention is not limited, and a known PDT drug may be used in combination with light of the absorption wavelength. Yes, the PDT drug and the light species can be selected as appropriate.
- the PDT drug to be used any drug having an absorption wavelength in the vicinity of 630 ⁇ and a drug having an absorption wavelength on the longer wavelength side can be used.
- water-soluble PDT drugs are suitable for treating arrhythmias.
- PDT drugs for example, ATX-S10 (670nm) (Iminochlorin aspartic acid derivative, which is a chlorin pharmacological IJ having a chlorin skeleton, (Toyo Hikaru Co., Ltd. Rights transfer, JP-A-6-80671), NPe6 (664nm) (Taraporfin sodium, Rezaphyrin (registered trademark), mono-L-aspartyl chlorin e6, Japanese Patent No.
- talaporfin sodium is preferred.
- Additives include solubilizing agents such as organic solvents, pH adjusters such as acids and bases, stabilizers such as ascorbic acid, excipients such as glucose, and isotonic agents such as sodium chloride.
- the device of the present invention includes a PDT drug supply means.
- the PDT drug supply means includes, for example, means for storing the PDT drug, means for feeding the PDT drug to the target site, and means for administering the PDT drug to the target site. In this way, by administering the PDT drug, the PDT drug is present at the target site, and by irradiating the target site with light, the abnormal electrical conduction site or the abnormal excitement generation site is damaged by necrosis or the like. Can be given.
- the dose of the PDT drug is not limited, and for example, several ⁇ g / ml to several mg / ml, preferably 10 mg / ml to 100 mg / ml of the prepared drug is several / 1 to several ml, preferably 1 ml to 10 ml.
- Administer by intravenous injection is from 0.1 mg / kg; L0 mg / kg, preferably from 0.5 mg / kg to 5 mg / kg. Alternatively, it may be administered directly by injection into the target site.
- Light irradiation can be started immediately after PDT drug administration or in a short time. For example, 0.5 hours after administration to within 10 hours after administration, preferably 0.5 hours after administration to after administration.
- a drug suitable for treatment has accumulated at the treatment site can be determined using the drug concentration in blood as an index.
- the dose of the above PDT drug and the time from the administration of the PDT drug to the irradiation of the light were determined using animals such as pigs, rats, and mice. It can be determined based on conditions.
- photodynamic therapy in which a PDT drug is administered followed by light, cell damage is caused by reactive oxygen. Photodynamic therapy does not generate heat and allows local treatment. Accordingly, protein denaturation due to heat does not occur, and the target site and the surrounding tissue of the target site do not die, so that only the target site can be reliably damaged.
- a light beam such as a laser
- heat can be generated at the site irradiated with the laser, and the surrounding tissue can be damaged. Therefore, the method and apparatus using the photodynamic therapy of the present invention have an excellent effect even with respect to a method or apparatus for irradiating only a laser without using a PDT drug.
- the type of light beam irradiated for treatment is not limited, but continuous light beam can be used.
- these rays may be collectively referred to as laser rays.
- the irradiation wavelength is 600 nm to 800 nm, and a light beam having a wavelength close to the absorption wavelength of the PDT drug to be used may be used.
- the light beam used in the apparatus of the present invention is preferably a continuous laser and a semiconductor laser.
- light emitted from a light emitting diode (LED) can be used as a light beam.
- LED light emitting diode
- an LED chip may be used as the light source.
- wavelength 650 to 690 nm, good Mashiku is 660 ⁇ 6 80nm, preferably it is preferable to use a semiconductor laser having a wavelength of 664 workers 2Nra.
- red LEDs with a wavelength of around 660 nm are preferred.
- the intensity of the irradiated light is the intensity, and the unit is expressed in W / cm 2 .
- the total energy density irradiation dose, J / cm 2
- the intensity or total energy density depends on the size of the abnormal part to be treated, etc. As appropriate. High intensity range for the intensity of light r
- WO 2008/066206 and low intensity range is not limited, the kind of light, Ri come depth such ⁇ abnormal portion to be cane treatment - Wataru & ⁇ to - this - and can - Ru - 0 irradiation - morphism
- irradiation time 10 seconds to 1000 seconds, preferably 50 seconds to 500 seconds, more preferably 50 seconds to 200 seconds.
- the total energy density 1 at the surface of the irradiated portion 10000 J / cm 2, preferably 10 ⁇ 2000J / cm 2, more preferably 50 ⁇ 2000J / cm 2, more preferably 100 ⁇ 1000J / cm 2 can be exemplified.
- blood artificial erythrocytes input Ri liquid myocardial tissue In this case, the light absorption coefficient is preferably 10 to 500 J / cm 2 .
- the target is the myocardium at a depth of 3 to 5 mm from the light irradiation position.
- the above-mentioned light irradiation conditions can be determined based on conditions determined using animals such as pigs, rats and mice.
- the tissue around the target site can be damaged by the conduction of heat.
- the method or apparatus of the present invention since the light that can limit the reaching area is used without using the heat that can be conducted, the localized treatment is possible. For example, even when the region of the abnormal electrical conduction site or abnormal excitation occurrence site of the myocardium is small, localized treatment can be performed without damaging the surrounding normal tissue.
- the temperature increase change from before irradiation to irradiation of the target site is within 20 ° C, preferably within 10 ° C, more preferably within 5 ° C,
- the maximum temperature is within 60 ° C, preferably within 50 ° C, more preferably within 45 ° C.
- a myocardial abnormal electrical conduction blocking device, an arrhythmia treatment device or an atrial fibrillation treatment device using the PDT of the present invention comprises at least a catheter 1, a light generation means (light generation apparatus) 2, and a means for transmitting light to an abnormal part.
- Catheter 1 is a bare fiber, that is, an optical transmission fiber with the tip cut open, or the tip of the optical transmission fiber.
- WO 2008/066206 A fiber with a diffusing means having a light diffusing function with a scattering material in the vicinity of the part is provided inside
- a scattering material such as alumina which scatters light rays can be used, and the light irradiation portion may be applied by coating or the like.
- the optical transmission fiber may be used out of the catheter, or it may be used as it is.
- an LED is used as the light beam to be irradiated, it has an LED chip as a means for generating light and a transparent chip as a means for transmitting the light.
- the tip of the catheter has an LED chip and a transparent chip.
- a means for supplying the PDT drug to an abnormal electric conduction site or an abnormal excitement generation site may be provided.
- Electrodes or the like which are means for electrophysiological examination, may be disposed in a catheter equipped with an optical transmission fiber for ablation, or electrophysiological examination may be performed separately from the catheter for ablation.
- a diagnostic electrode catheter may be provided.
- an ablation catheter and a diagnostic electrode catheter may be inserted from the left and right femoral veins.
- the catheter tip must have a flexible structure.
- a tension wire can be provided in the catheter, and the tip can be bent by a pulling operation of the tension wire.
- the tip may be bent in advance to match the shape of the treatment site.
- FIG. 14 shows a block diagram of the device of the present invention that can be used for treating atrial cells.
- Fig. 14A shows the whole apparatus
- Fig. 14B shows an apparatus having an optical fiber
- Fig. 14C shows an apparatus having an optical fiber with diffusion means. Since the apparatus of the present invention does not have a balloon and has only a diffusion fiber and a barrier, it is possible to treat a narrow or complex part that cannot be treated with a balloon-equipped device.
- the apparatus of the present invention does not have a balloon and has only a diffusion fiber and a barrier, it is possible to treat a narrow or complex part that cannot be treated with a balloon-equipped device.
- Nite / the kife end has a free-bending-bending structure—that is, the child—V, —.
- a catheter that is usually used as a cardiac catheter can be used.
- the device of the present invention may include a guide sheath or a guide wire for allowing the catheter to be inserted into the target site.
- the catheter may be inserted into the body from the femoral artery or brachial artery by a standard method.
- a method of inserting from the femoral vein to reach the right atrium and to reach the left heart tissue via the transatrial septum by the Brockenbrough method is generally performed.
- a light beam generator capable of generating the above-mentioned light beam can be used.
- the means for transmitting the light beam to the abnormal electrical conduction site or the abnormal excitement generation site includes an irradiation unit for irradiating the light beam near the distal end of the force tail 1 toward the abnormal part and the light beam from the light generator.
- An optical transmission fiber 3 for transmission to the light irradiation unit is included.
- the optical transmission fiber may be a quartz fiber or a plastic fiber.
- near the distal end means a portion near the end opposite to the end (proximal end) connected to the light generating device, and the distal end and the distal end. It refers to the part of the tens of centimeters from the part.
- the optical transmission fiber 3 is included in the catheter 1, and is connected to the light generator at one end and connected to the light irradiation unit at the other end.
- a fiber having a diameter of about 0.05 to 0.6 mm may be used in a wide variety of diameters as long as it can be accommodated in the force tape 1 and transmit the energy of the light beam.
- the catheter 1 includes, for example, a PDT drug supply means, the diameter can be appropriately changed.
- a beam splitter 5, a filter 7 and the like are appropriately provided between the light generating device and the optical transmission fiber 3 or in the middle of the optical transmission fiber 3 in order to transmit information to a monitor device or the like that can be included in the device. May be.
- the light beam irradiation unit is for irradiating the laser to the abnormal electrical conduction site or the abnormal excitation occurrence site, and the light transmitted through the optical transmission fiber 3 is directed to the abnormal electrical conduction site or the abnormal excitation generation site.
- the beam irradiator is provided all around the distal end of the catheter.
- a prism may be provided so that the light beam is irradiated laterally near the distal end portion of the optical transmission fiber 3, or the light beam is laterally disposed near the distal end portion of the optical transmission fiber 3.
- the surface may be roughened so as to be irradiated, and a scattering material such as alumina or silica that scatters light may be applied near the distal end of the optical transmission fiber 3.
- the catheter may be rotated to irradiate light around the entire circumference
- the area range in which the light irradiated from the vicinity of the distal end of the optical transmission fiber 3 irradiates the abnormal electric conduction site or abnormal excitement generation site is as follows.
- the catheter 1 is rotated according to the size of the abnormal electrical conduction site or abnormal excitement occurrence location, etc.
- the target tissue can be completely killed by applying multiple irradiations, and when irradiating with light, it can be deepened by irradiating with high intensity light or irradiating with low intensity light for a long time.
- the device of the present invention has transmurality, where transmurality means that the atrial muscle can be processed from the inside to the outside.
- the distance from the inside to the outside is about 3 to 5.
- the abnormal electrical conduction site or abnormal excitation site should be killed at a depth of 3 to 5 mm. .
- the means of monitoring the PDT drug and oxygen concentration present at the site of abnormal electrical conduction or abnormal excitement are the PDT drug-derived fluorescence, phosphorescence or oxygen-derived fluorescence at the site of abnormal electrical conduction or abnormal excitement. It is a device to monitor. These fluorescence or phosphorescences travel back through the optical transmission fiber.
- the fiber 1 for monitoring the fluorescence or phosphorescence may be the fiber 3 that transmits the laser, or a separate fiber dedicated to the monitor may be provided in the catheter 1. If the fiber for fluorescent or phosphorescent monitoring is shared with the fiber for transmitting light, the fluorescent or phosphorescent light is changed by the beam splitter 5 installed between the light generating device and the light irradiating unit.
- the fluorescence-or-light-optical module is directly connected to the detector. In the meantime, one firefly-light-or light-light passes through the fiber and reaches the detector 8.
- the amount of PDT drug and the oxygen concentration can be monitored. For example, since the porphyrin ring of the PDT drug generates fluorescence when excited, the amount of the PDT drug can be measured by measuring the fluorescence. Also, phosphorescence is quenched according to the oxygen concentration, so the oxygen concentration can be measured by measuring phosphorescence.
- Local oxygen partial pressure is measured by JM Vanderkooi et al., The Journal of Biological Chemistry, Vol. 262, No. 12, Issue of April 25, pp. 5476-5482, 1987, The Chemical Society of Japan, Experimental Chemistry. Lecture (Spectroscopy II), pp. 275-194, 1998 and Lichini M et al., Chem. Coramun., 19, pp. 1943-1944, 1999.
- the detector is electronically connected to the light generation means. The amount of PDT drug and oxygen accumulated by the detection means is fed-packed, and the light irradiation conditions such as light intensity and irradiation time are changed as needed. It is possible to control it.
- the apparatus including the above-described catheter can be used as it is, but it is not necessary to include the catheter, and a simple optical transmission fiber may be included instead of the catheter.
- a simple optical transmission fiber may be included instead of the catheter.
- the apparatus of the present invention inserts the catheter 1 from the femoral artery, femoral vein, brachial artery or brachial vein into the heart or the vicinity thereof, and carries the light beam irradiation part to the abnormal electrical conduction site or abnormal excitement generation site, where the light beam is transmitted. This can be done by irradiation. It is also possible to perform thoracotomy or laparoscopic surgery and use the device of the present invention to irradiate the site of abnormal electrical conduction or abnormal excitement with light.
- the method of using the device of the present invention for treatment includes, for example, a step of inserting a catheter into a vein or artery, a step of guiding the catheter to the atrium by appropriate operation through the vein or artery, and a catheter to a target region.
- the force can be carried out by a known method, and an appropriate guide sheath or guide sheath may be used.
- the above-mentioned water-soluble PDT drug is administered to the subject to be treated in advance by intravenous injection or the like, so that the PDT drug is present in advance in the abnormal part.
- the tissue site can be damaged.
- the light beam may be irradiated continuously to the abnormal site in a linear manner, or may be irradiated in a dotted manner.
- PV electrical pulmonary vein
- Example 1 PDT effect on rat heart muscle cell line H9c2 (2-1)
- a semiconductor laser peak wavelength: 660.8 nm was irradiated under various conditions to a continuous area light of 0.5 cm 2 irradiation field well.
- Figure 1 shows the relationship between drug concentration and dead cell rate. As shown in Fig. 1, the dead cell rate increased as the drug concentration increased up to 30 g / ml, and the rate at 40 / ig / ml was the same as that at 30 ⁇ g / ml.
- Figure 2 shows the relationship between the total energy density of laser irradiation and the dead cell rate.
- Figure 3 shows the relationship between laser intensity and dead cell rate. As shown in FIG. 3, the range laser intensity N 50 to 200 mW of m 2, the rate of dead cells did not change.
- Fig. 4 shows a comparison of cell conditions under the above condition (ii).
- Upper left is normal condition
- upper right is condition 7.5 g / ml, 3j7cm 2 condition
- lower left is condition 15 g / ml
- lower right is condition 15 // Indicates the state in the case of g / ml, 12J m 2 .
- Example 2 Preparation of an electrical conduction block for isolated myocardial tissue
- An electrical conduction block was created by performing PDT using myocardial tissue.
- Myocardial tissue was removed from Wister rats and perfusate (Tyrode solution (0 2 : 95%, C0 2 : 5% air) Ventilate the body and keep it at 37 ° C with a thermostatic device))) and expand the tissue base with a tungsten wire (fixed) (-made by Shi-Lyo) -b -extracted specimen of the extracted ventricular muscle ( Vertical top " ⁇ — 5c 7 Yokocho: cm" Thick
- talaporfin sodium was dissolved in the perfusate at 4.3 / g / ml, and 300 cc was circulated and perfused.
- intravenously administered at a dose of about 2 mg / kg to a 300 g rat it can be considered that the drug is dissolved at this level in the body fluid.
- the level of the perfusate was lowered below the surface of the tissue, and the laser-developed tissue was irradiated. After laser irradiation, it was returned to normal perfusate without talaporfin sodium again.
- the irradiated laser was a semiconductor laser (peak wavelength: 670.8 nm) continuous light, and the tissue was irradiated in contact with the tissue at an intensity of 150 mW / m 2 from a fiber tip irradiation port of 0.0017 cm 2 .
- Laser irradiation was performed for 5 minutes while moving the fiber to a 0.1 cm 2 region (vertical 0.1 cm ⁇ width 1 cm) on the tissue surface. Irradiated with 3.5 J / cm 2 in terms of total energy density.
- the tissue action potential was measured as follows. Electric stimulation of 2Hz, 50mA was applied from the bipolar electrode (0.2 ⁇ silver wire) by the stimulator, and the potential on the tissue surface was derived by the bipolar lead electrode (0.25 ⁇ stainless wire).
- Figure 5 shows the entire experimental apparatus.
- Figure 6 shows an enlarged view of the area around the developed muscle tissue.
- Figure 7 shows the laser irradiation area and the stimulation / potential derivation site in the tissue.
- Figures 8A to 8F show changes in the potential of the developed tissue. 8A to 8F, the upper line shows the potential change at site 1 in FIG. 7, and the lower line shows the potential change at site 2 in FIG.
- the unit of the vertical axis is mV.
- Fig. 8A shows the potential change at the time of stability, and the peak portion that rises and falls around 5ms and 8ms represents the action potential of the tissue.
- Figure 8B shows the potential change just before laser irradiation. The drug-containing perfusate is below the surface of the tissue, and the potential state is changing. The sine wave seen at 2 indicates noise contamination.
- Figure 8C shows the potential change 2 minutes after the start of laser irradiation. There is no change at site 1, but at site 2, the peak position starts to lag compared to Fig. 8B.
- Figure 8D shows the potential change 5 minutes after the start of laser irradiation. In Fig. 8C, the peak at site 2 is delayed and the shape is broken. This suggests that the stimulation pathway is partially blocked.
- Fig. 8C shows the potential change at the time of stability, and the peak portion that rises and falls around 5ms and 8ms represents the action potential of the tissue.
- Figure 8B shows the potential change just before laser irradiation. The drug
- FIG. 8 E shows after laser irradiation Shows potential change at 5 minutes. The peak at site 2 disappeared. It seems that the electrical conduction path has been completely applied.
- - Figure - 8- F- is - .gamma.
- site 2 in the ⁇ - ability - is a diagram showing the appearance of (- own _ Chi - active - Tsutomu - f generated by - potential).
- Fig. 8F shows the change in potential after a few minutes from Fig. 8E.
- Site 1 generates an action potential due to the stimulation potential (large peak), while site 2 generates an action potential independently. This indicates that an electric conduction block is formed even on the back side of the tissue. At least for the next hour, the resumption of electrical conduction could not be confirmed.
- Figure 9 shows a tissue specimen of the PDT trial site.
- the length of the scale par in Fig. 9 is 0.05 mm.
- Primary cultured cardiomyocytes were purchased in suspension and seeded on 96-well microplates. Were cultured in 3 7 ° C, C0 2 concentration of 5% was used cultured for 3 and 7 days cells. Primary cultured cardiac muscle cells are beating and the beating between cells is synchronized.
- the experimental conditions were as follows.
- Figure 10 shows the relationship between the total energy density of laser irradiation and the dead cell rate under condition (i).
- the dead cell rate was higher as the total energy density of laser irradiation was higher.
- talaporfin sodium ⁇ untreated concentration
- the total energy one density 3 J / cm rate of dead cells in N 5 J m 2 than 2 of the laser irradiation was reduced.
- Figure 11 shows the relationship between the total energy density of laser irradiation and the dead cell rate under condition (ii). When cells from 7 days in culture were used, the dead cell rate was higher than when cells from day 3 were used.
- Figure 1 2 shows the cellular status of the condition 10 / g / ml, 3 J N m 2.
- the left side of Fig. 12 shows the state before PDT, and the right side of Fig. 12 shows the state one day after PDT.
- the length of the scale bar in the figure is 0.1 mm.
- Fig.12 no damage is seen in the cell state, but the pulsation actually stops immediately after the PDT.
- Table 1 pulsation was resumed and synchronized about 1 to 3 days after the experiment. table 1
- FIG. 13 shows the state of cells under conditions 20 ⁇ 1, 3 jVcm 2 .
- the left side of Fig. 12 shows the state before PDT, and the right side of Fig. 12 shows the state one day after PDT.
- the connected cells are parabolic, and the individual cells themselves are contracted. The pulsation does not resume permanently.
- Example 4 PDT effect on cultured cardiomyocytes (Dead cell rate vs drug concentration, Total Dose)
- SD rat-derived cultured cardiomyocytes were used to examine the drug concentration, the relationship between drug contact time and dead cell rate, and the laser power required to cause cell death.
- SD rat-derived cultured cardiomyocytes were obtained from Cell Garage. As a medium, D-MEM / F12 + 10% FBS was used.
- Suspended cardiomyocytes 2 ⁇ 2 ⁇ 2 ⁇ 3 ⁇ 10 5 cells / ml are seeded at 0. lml / well (2.2 to 2.3 ⁇ 10 4 cells / well) on a collagen-coated 96-well plate, and cultured for 6-7 days in incubator base one coater (37 ° C, C0 2 concentration of 5%).
- talaporfin sodium as a PDT drug was dissolved in the medium so as to be 5, 15 or 30 g / ml.
- Cardiomyocytes were contacted with talaporfin sodium for 0, 30, 60, or 120 minutes, and then irradiated with laser.
- a semiconductor laser peak wavelength: 60.8 nm, power density: 150 mW m 2
- a continuous field of 0.5 cm 2 ( well area) under each condition 5, 10 and 15 J / cm 2 ).
- Figure 1 5-18 show cardiomyocytes and talaporphyrin sodium 0, 30, 60 or 120, respectively , memo...
- WO 2008/066206 Total energy density of laser irradiation at each drug concentration and contact at 2 o'clock when contacted for minutes However, no significant effect was observed at concentrations below ⁇ 5— / ⁇ g / ral. On the other hand, when the drug concentration was 30 g / ral, the increase in the dead cell rate after laser irradiation was markedly observed.
- Figure 19 shows the relationship between the contact time between cardiomyocytes and talaporfin sodium and the dead cell rate. Figure 19 shows that when the contact time is changed, 30 minutes of contact is the most effective, and the effect diminishes whether the contact time is shorter or longer than 30 minutes.
- FIG. 20D Control time (Fig. 20 E) and contact time 0 (Fig. 20 A), 30 (Fig. 20 B), 60 (Fig. 20 C) when talaporfin sodium is 30 ig / ml in OA to E ), 120 (FIG. 20D) shows the cell morphology immediately after laser light irradiation (15J / cra 2 ). After 30 minutes of contact, cell swells and marked cell shape changes such as contraction were observed.
- Example 5 Measurement of changes in intracellular calcium ion concentration in PDT for rat cardiomyocytes Changes in intracellular Ca 2+ concentration were measured for cells on day 1 of seeding by the following four protocols. SD rat-derived cultured cardiomyocytes were used. As a cell culture medium,
- D-MEM / F12 + 10% FBS was used. Before use in the experiment, float cardiomyocytes 1.6 ⁇ 10 5 cells / ml in a glass bottom 24 well plate at 0.5 ml / well (8.0 ⁇ 10 4 cells / well) and incubator (37 ° C, and cultured for 1 day in C0 2 5%).
- MEM + 10 o / o FBS containing 2.2 mM Ca 2+ was used as a normal medium
- SMEM + 10% FBS containing 364 M Ca 2+ was used as a Ca 2+ free medium.
- the intracellular Ca 2+ concentration was measured by Fluo-4 AM (Molecular Probe). Fluo-4 3 ⁇ 41 50 ⁇ 1 »30 (Dojindo Chemical Pure Solvent for Fluorescence Analysis) was added in 55 zl, 10 1 of which was added to 1 ml of medium for measurement (normal medium and Ca 2+ free medium) and 8 ⁇ And to myocardial cells
- Image J was used to calculate the amount of intracellular cumulative fluorescence change in each slide.
- the initial accumulated fluorescence F0 was set to 1, and the amount of fluorescence change was calculated from F / F0.
- Protocol 1 extracellular distribution of talaporfin sodium, extracellular normal Ca 2+ concentration
- fluo-4AM Normal medium solution
- the cod adjusted to each concentration in advance.
- porphinatorium normal medium
- Protocol 2 (Talaporfin sodium distribution, extracellular normal Ca 2+ concentration) Each well is contacted with fluo-4AM (normal medium) for 30 minutes at room temperature and then adjusted to each concentration in advance. (Normal medium) is administered at 0.5 uL / ml, and after 30 minutes of contact, the medium is replaced with normal medium before observation.
- fluo-4AM normal medium
- Protocol 3 Extracellular distribution of talaporfin sodium, extracellular Ca 2+ free
- fluo-4AM Ca 2+ free medium
- the talaporfin sodium (adjusted to each concentration in advance) Ca 2+ free medium) is administered at 0.5 well / ml, and observation is performed immediately after administration.
- Protocol 4 (Talaporfin sodium intracellular distribution, extracellular Ca 2+ free) Each well is contacted with fluo-4AM (Ca 2+ free medium) for 30 minutes at room temperature and then adjusted to each concentration in advance. (Ca 2+ free medium) is administered at 0.5 well / ml, and after contact for 30 minutes, the medium is replaced with Ca 2+ free medium.
- fluo-4AM Ca 2+ free medium
- Figures 21 and 22 show changes in intracellular Ca 2+ concentration in PDT.
- Figure 2 1 is the result of extracellular normal Ca 2+ concentration
- 2 2 are the result of extracellular Ca 2+ pretend one. A rapid increase in intracellular Ca 2+ concentration was observed immediately after PDT.
- Fig. 23 A and B show cell morphology before and after PDT.
- Fig. 23 A shows the cell morphology before PDT
- Fig. 23 B shows the cell morphology after PDT.
- Cell morphology was almost unchanged before and after PDT. From the above, it is considered that the increase in intracellular Ca 2+ concentration is mainly caused by Ca 2+ influx from outside the cell. Based on the above, it is considered that one of the causes of electrical conduction block by PDT is that the intracellular Ca 2+ concentration in the membrane due to cell membrane damage increased abnormally, leading to necrosis.
- Example 6 PDT electrical conduction block test on rat myocardial tissue in ex vivo system
- a developed specimen of the free right ventricular free wall of Wistar rat Oss, 8-10 weeks old
- the length (L) and thickness (d) of the light irradiation line for the samples in each experiment were as follows.
- Tyrode solution (0 2 : 95%, C0 2 : 5 ° / o gas was aerated and maintained at 37 ° C with a thermostat) was used as the perfusate.
- the right ventricular tissue was exfoliated by placing it in a perfusate warmed to about 37 ° C.
- the exfoliated tissue was fixed to a tissue bath silicon floor with a 0.2 mm diameter tungsten wire, and then a perfusate was poured.
- talaporfin sodium (Rezafilin (registered trademark); Meiji Seika) dissolved in physiological saline is ratted in about 0.5 ml.
- Intravenous injection was performed from the vena cava of the leg. After the heart is removed, the right ventricle group is used in normal Tyrode solution. ,
- Figure 25 shows a schematic diagram of the ex vivo experimental system.
- Fig. 2 6-29 shows changes in the extracellular potential before and after the PDT of the derived potential in each experiment-Fig. 2- -6- to 2 9-Hey-One-in the gap ⁇ ⁇
- the upper line (the red line and the ⁇ line (blue line) indicate the potentials at X and ⁇ in Fig. 24.
- the vertical axis indicates the port.
- the results of the potential measurement are shown: The upper panel (Fig. 26, 6) is immediately before light irradiation, the middle panel (Fig. 26, 6) is after light irradiation, and the lower panel (Fig. 26, C) is 3 hours later. The corrected results are shown.
- Figure 27 shows the potential measurement results of Experiment 2.
- the upper part (Fig. 27, 7) shows the result of the stimulating electrode re-appearing in the vicinity of ⁇
- the lower part shows the result after 2 hours after the end of light irradiation
- the middle part (Fig. 27, 7).
- Figure 28 shows the potential measurement results of Experiment 3.
- the upper part shows the result immediately after the irradiation
- the middle part shows the result of the stimulating electrode reappearing near the eye after 3 hours.
- Figure 29 shows the potential measurement results of Experiment 4.
- the upper part (Fig. 29-9) shows the result of automatic performance immediately before light irradiation, the middle part (Fig. 29. As shown in Fig. 29, it can be seen that an electric conduction block occurs after PDT. Further
- FIG. 31 shows the outline of the in vivo experimental system.
- the rat chest was closed and sutured. After that, they were fed with normal food and water, and anesthetized again after about 2 weeks, and an electrocardiogram was induced.
- the heart sample from Experiment 1 was removed after electrocardiogram induction 2 weeks later (extraction method was the same as in Example 6), and 4% paraformaldehyde was introduced from the coronary artery and perfusion-fixed. Soaked in about 40 ml of the same solution and left on a ⁇ mix roller.
- HE specimens and Azan-stained specimens at the laser irradiation site were prepared and observed with a microscope.
- the rat electrocardiogram before and after light irradiation in Experiments 1 and 2 and the state of the “electrocardiogram” after 2 weeks in Experiment 2 are shown below. Also,-An experiment image of HE and Azan stained specimens of the light irradiated part of the experiment ⁇ go ⁇ ⁇ tebo-2 MW ⁇ ⁇ '' is shown.
- Fig. 3 2 shows the changes in rat electrocardiogram before and after PDT at interval 5 minutes in experiment 1
- Fig. 3 3 shows the changes in rat electrocardiogram before and after PDT in interval 1 of experiment 1.
- Fig. 34 shows the changes in the rat ECG before and after PDT for 30 minutes in Experiment 2
- Fig. 35 shows the rat ECG after 2 weeks in Experiment 2.
- Fig. 36 shows the observation image of the Azan-stained specimen at the laser irradiation site in the heart tissue in Experiment 1 (scale par is 0.2 mm), and Fig. 37 shows the relationship between the myocardial tissue and scar tissue in Fig. 36. An image of HE-stained specimen observation near the boundary area is shown (scale bar is 50 111).
- the tissue used was a free right ventricular free wall from Wistar rats (Oss, 8-10 weeks old).
- heparin and nembutal 0.2 ml and 0.5 ml each
- resafirin Meiji Seika
- the sample for fluorescence observation is obtained by cutting the above tissue cross section with a freezing mouth tome at a thickness of 10 / m in the direction connecting the base to the apex, placing it on a slide glass, and drying for one or two days. .
- the light from the mercury lamp (Olympus) was attenuated by the ND filter (Olympus, 12%), and only the light in the 400 nm band was taken out by the Pandpass filter (Olympus) and applied to the sample as excitation light.
- the drug fluorescence was selectively extracted with a dichroic mirror (0MEGA, 636 nm ⁇ ) and a pan-pass filter (0MEGA, 695 nm half-value width 27.5 nm).
- the exposure time at the time of photographing was 5 seconds, and the excitation light was irradiated onto the photographing part at the same time as the photographing was started.
- Figures 38 to 40 are images taken with a 4x objective lens, and Figure 41 is the result of further image processing of the fluorescence images of Figures 38 to 40.
- Figure 42 shows a picture taken with a 20x objective lens.
- Figure 38 shows the result of Experiment 1 (interval 5 minutes), the left shows a fluorescent image, and the right shows an image with transmitted light.
- the upper layer structure is the endocardium
- the lower layer is the epicardium
- the scale bar is 0.5 mm.
- Figure 39 shows the results of Experiment 2 (interval 30 minutes), the left shows a fluorescence image, and the right shows an image with transmitted light.
- the layer structure on the left is the endocardium, the right is the epicardium, and the scale bar is 0.5 mm.
- Figure 40 shows the results of Experiment 1 (interval 5 minutes), the left shows a fluorescent image, and the right shows an image with transmitted light.
- the upper layer structure is the endocardium
- the lower layer is the epicardium
- Fig. 3 8-4 2 the brighter the white, the more the drug is present, and the portion where the bright streaks appear other than the membrane is the cell stroma.
- the brightness of the autofluorescence was subtracted from the tissue fluorescence image without the drug.
- Figures 3-8 to 40 and 42 are 2 times the maximum brightness value is displayed as the upper limit on the image).
- the intermediate color part between black and white is considered to be intracellular.
- Figure 41 shows the average of the brightness of the whole myocardial tissue excluding the endocardium and epicardium. The value is used as a threshold value, and the image is expressed in binary values of black and white. In other words, the part that appears white is the part where the drug is present above the average, and the black part is the part below the average.
- Example 7 Measurement of optical properties of rat myocardial tissue
- the right ventricular free wall tissue (with endocardium and epicardium) and the left ventricular tissue (endocardium and epicardial separation) exfoliated from the isolated rat heart were used.
- a spectrophotometer (Shimadzu Corporation) with an integrating sphere unit, diffuse transmittance, The diffuse reflectance was measured.
- the sample holder is sandwiched between two lcmX 4mm window curtains with a window and a sample in between.
- T ⁇ Anti-3 ⁇ 4 ⁇ —R—T
- the optical characteristic values of the left ventricle and right ventricle tissues are similar as described above, and when taking the average of these 6 samples, ⁇ is 1.3 ⁇ 0.1 mm.
- the amount of laser irradiation on the surface is I.
- the dose I at a certain depth d ( ⁇ ) is
- the light intensity becomes 0 ⁇ 37 times, 0.05 times, and 0.007 times at the depths of 1 mm, 3 mm, and 5 mm from the tissue surface.
- the total thickness of the epicardium and endocardium is about 0.1 mm, and if this is also included in the myocardial tissue, the laser irradiation dose at the deepest part in Experiments 1 to 4 of Example 4 is as follows: Become.
- the material used was the right ventricular tissue in which the rat thorax was opened in the same manner as in the in vivo experiment and the heart was exposed.
- Semiconductor laser (similar to i n vivo and ex vivo experiments) is transmitted by quartz fiber (core diameter 800 ⁇ m), intensity at irradiation end is 5 W m 2 , 10 W m 2 , irradiation time 100 s, irradiation dose 500J N m 2 (conditions 1), and laser irradiation in the right ventricular surface in m 2 (condition 2) N 1000J. Meanwhile, the temperature of the tissue surface was measured by thermography (Avio), and the surface temperature was measured by a thermocouple and digital pen recorder (Yokogawa Electric) before laser irradiation for temperature correction.
- Figures 4 3, 4 3 8, 4 4 and 4 4 B show thermal images and graphs of temperature rise under each laser irradiation condition.
- the display temperature of the thermal image in the figure is blue ⁇ yellow green ⁇ yellow and red. Under condition 1, the maximum temperature rise was about 5 ° C, and under condition 2, it was about 10 ° C. The temperature measurement result by thermocouple was around 30 ° C.
- Fig. 4 3A shows a thermal image under Condition 1
- Fig. 4 3 B shows a graph of temperature rise under Condition 1.
- Fig. 4 In the infrared image of 3A, the part enclosed by the dotted line is the fiber, and the circle is the temperature measuring point on the graph. The central yellow-green to yellow area is the heart. The scale bar is 2mm.
- the solid line arrow indicates the start of laser irradiation
- the dotted line arrow indicates the end of laser irradiation.
- Fig. 4 4 A and Fig. 4 4 B show the thermal image and the graph of temperature rise under condition 2, respectively.
- rats were intravenously injected at various doses (10, 5 , 2, lmg / kg ), and humans were intravenously injected at lmg / kg.
- the changes over time in the plasma concentration are shown as a graph in Fig. 45).
- the mean half-life of 10 minutes at 10 mg / kg between 2 and 60 minutes after intravenous injection was 47 minutes, and blood at 5 minutes.
- the concentration change from ⁇ 60 minutes was calculated using the average concentration in the serum as the true value.
- Fig. 45 shows the plasma drug concentration at each time after intravenous injection of sodium talapulphin.
- Fig. 46 shows a graph showing changes in drug concentration in the rat heart as well as changes in rat and human plasma concentrations for doses of 5 mg / kg and 2 mg / kg.
- the change in the concentration of the drug in the heart was calculated by calculating the half-life from 0 to 60 minutes with the true value of 5 minutes and 60 minutes (half-life 65 minutes). For 120 minutes, the ratio of the half-life in rat plasma to the heart up to 60 minutes is taken and multiplied by the half-life of the plasma concentration in 2 to 24 hours (half-life 13.3 hours). Using it, the concentration value in the heart at 24 hours was calculated as a true value, and the values at 60 minutes and 120 minutes were connected by a straight line.
- Figure 46 shows the results of comparison of drug concentrations in rat heart, plasma, and human plasma.
- the ratio between the drug concentration in rat plasma and the drug concentration in heart is shown.
- the drug concentration in the heart is calculated as the plasma / heart ratio of the initial drug distribution is the same as in the rat
- the half-life plasma and the ratio in the heart is the same as in the rat
- the plasma concentration is also calculated. I put something with a ratio.
- the calculated values for rats are somewhat reliable, but for humans they contain a lot of assumptions and cannot be said to be reliable.
- Figure 47 shows the ratio of drug concentration in rat and human plasma and heart. Reference Example 2 Examination of PDT implementation conditions in human
- the concentration of drugs in the heart is uncertain, it can be considered based on plasma concentrations.
- the distribution volume (representing the ease of drug transfer from the blood to the tissue) is similar in the rat and human in the steady state, and if the plasma concentration is similar (the dose administered) in not significantly different range.
- rats 10 mg / k g administered at intervals for 120 minutes, but becomes equivalent concentrations and human plasma the ratio of the cardiac in drug concentration in rats 2 mg / kg Upon administration, as compared with the time interval for 30 minutes, increased) drug concentration in heart also to draw.
- _ Ru _ the drug dose in humans can be estimated based on the concentration in summer and summer at a dose of about 2mi "/ 3 ⁇ 4T.
- the plasma drug concentration in humans is about 20 g / ml at ⁇ 6 hours when administered at lmg / kg.
- plasma concentrations were 24 ⁇ g / ml and 16 g / ml, respectively.
- the current dose of lmg / kg in humans is expected to be acceptable due to the successful PDT block.
- the dose may be further reduced by shortening the interval until light irradiation.
- the plasma concentration is 20 g / ml up to ⁇ 6 hours, so the upper limit of the interval is expected to be ⁇ 6 hours.
- the lower limit is not expected to be set too early. This is because the results of Example 5 and Example 6 predict that the drug distribution in the heart tissue is non-uniform immediately after intravenous injection and the desired therapeutic effect cannot be obtained.
- the lower limit for rats is considered to be several minutes or so, so it is necessary to take a longer interval for humans.
- it is predicted that 0.5 hours after intravenous injection will be the time for light irradiation.
- the laser irradiation dose at the deepest part in Experiments 3 and 4 is calculated as the minimum irradiation dose required under each condition. According to the study in Example 7, the plasma concentration is
- tissue thickness of the target site in atrial fibrillation treatment is
- the target part was irradiated with light for 60 to 90 seconds, and a sufficient necrosis layer could not be created at approximately 2500 J m 2.
- Transmural ablation There is a result that an irradiation dose of about 4800 J / cm 2 is necessary in the successful case (but this is based on a trial calculation, and it is considered that ablation is actually performed with a lower dose than this) .
- the wavelength is a wavelength having high permeability is used than 670 nm, required laser irradiation dose ⁇ 600J / C m 2 estimates results here is expected to sufficiently smaller than thermal damage Threading Scholl de. In consideration of safety, if the dose of laser is increased and the dose of drug is decreased, it should be suppressed to 2000 J / cm 2 at the maximum. It is appropriate to keep the dose of drug at the current clinical use level.
- the time required for treatment of one point in the target site is about 100 seconds at maximum compared with the current laser ablation method.
- 5W! II 2 , 13W m 2 output is required.
- the laser used in the above example has a wavelength of 670 nm, and if this is closer to 665 nm, which is the excitation wavelength band of talaporfin sodium, it is expected that the irradiation dose can be reduced (excitation efficiency is ⁇ 2 times). In this case, the drug dosage can be further reduced.
- the treatment device using the photodynamic treatment of the present invention When the treatment device using the photodynamic treatment of the present invention is used, an abrasion is applied to the abnormal electrical conduction site or abnormal excitement generation site of the myocardium by a photochemical reaction in which tissue cells are necrotized by active oxygen instead of heat. Since the abnormal conduction part of the myocardium is cut off, damage to the myocardial tissue and surrounding tissues is reduced. In addition, when used in the vicinity of veins for the treatment of atrial fibrillation, side effects such as stenosis caused by heat-induced destruction of surrounding tissues can be reduced.
- the apparatus of the present invention is intended for a subject to which a water-soluble photodynamic therapeutic agent such as Tarabolf innatrium is applied. Water-soluble photodynamic therapeutic drugs accumulate in the extracellular stroma of the myocardial treatment site in a short time
- the target site is cauterized by heat, so the heat conduction causes the cautery to a normal tissue around the target site, and the treatment site is limited to the target site only.
- the ablation is performed by the photochemical reaction using the light that can limit the reachable area without using the heat that can be conducted, so that the treatment site can be limited.
- the operation time can be shortened.
Description
Claims
Priority Applications (6)
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KR1020097013416A KR101454939B1 (ko) | 2006-11-30 | 2007-11-30 | 광선 역학적 치료(pdt)를 이용한 이상 전기 전도 차단 장치 |
JP2008547076A JP5346587B2 (ja) | 2006-11-30 | 2007-11-30 | 光線力学的治療(pdt)を利用した異常電気伝導遮断装置 |
US12/516,765 US8961580B2 (en) | 2006-11-30 | 2007-11-30 | Abnormal electrical conduction blocking apparatus using photodynamic therapy (PDT) |
CN2007800507052A CN101594827B (zh) | 2006-11-30 | 2007-11-30 | 利用光动力治疗(pdt)来阻断异常电传导的装置 |
EP07832984.4A EP2095775A4 (en) | 2006-11-30 | 2007-11-30 | Abnormal electrical conduction-blocking apparatus using photodynamic therapy (pdt) |
US14/591,178 US9724537B2 (en) | 2006-11-30 | 2015-01-07 | Abnormal electrical conduction blocking apparatus using photodynamic therapy (PDT) |
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JP2006324683 | 2006-11-30 | ||
JP2006-324683 | 2006-11-30 |
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US12/516,765 A-371-Of-International US8961580B2 (en) | 2006-11-30 | 2007-11-30 | Abnormal electrical conduction blocking apparatus using photodynamic therapy (PDT) |
US14/591,178 Continuation US9724537B2 (en) | 2006-11-30 | 2015-01-07 | Abnormal electrical conduction blocking apparatus using photodynamic therapy (PDT) |
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WO2008066206A1 true WO2008066206A1 (fr) | 2008-06-05 |
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PCT/JP2007/073628 WO2008066206A1 (fr) | 2006-11-30 | 2007-11-30 | Appareil de blocage d'une conduction électrique anormale par thérapie photodynamique (tpd) |
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US (2) | US8961580B2 (ja) |
EP (1) | EP2095775A4 (ja) |
JP (1) | JP5346587B2 (ja) |
KR (1) | KR101454939B1 (ja) |
CN (1) | CN101594827B (ja) |
WO (1) | WO2008066206A1 (ja) |
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WO2014185372A1 (ja) | 2013-05-13 | 2014-11-20 | 株式会社アライ・メッドフォトン研究所 | 治療進行度モニタ装置及びその方法 |
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JPWO2011105631A1 (ja) * | 2010-02-26 | 2013-06-20 | 学校法人慶應義塾 | 光化学反応により心筋組織の光線力学的アブレーションを行うカテーテル |
JP5598935B2 (ja) * | 2010-02-26 | 2014-10-01 | 学校法人慶應義塾 | 光化学反応により心筋組織の光線力学的アブレーションを行うカテーテル |
WO2011114652A1 (ja) * | 2010-03-15 | 2011-09-22 | ソニー株式会社 | 判別装置及び判別方法 |
WO2011114651A1 (ja) * | 2010-03-15 | 2011-09-22 | ソニー株式会社 | 算出装置及び算出方法 |
JP2011189019A (ja) * | 2010-03-15 | 2011-09-29 | Sony Corp | 判別装置及び判別方法 |
WO2014185372A1 (ja) | 2013-05-13 | 2014-11-20 | 株式会社アライ・メッドフォトン研究所 | 治療進行度モニタ装置及びその方法 |
KR20160015254A (ko) | 2013-05-13 | 2016-02-12 | 가부시키가이샤 아라이?메드포톤 겐큐쇼 | 치료 진행도 모니터링 장치 및 그의 방법 |
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JP5346587B2 (ja) | 2013-11-20 |
US8961580B2 (en) | 2015-02-24 |
EP2095775A4 (en) | 2017-11-22 |
EP2095775A1 (en) | 2009-09-02 |
US9724537B2 (en) | 2017-08-08 |
CN101594827A (zh) | 2009-12-02 |
JPWO2008066206A1 (ja) | 2010-03-11 |
US20100022998A1 (en) | 2010-01-28 |
US20150141902A1 (en) | 2015-05-21 |
KR101454939B1 (ko) | 2014-10-27 |
KR20090094331A (ko) | 2009-09-04 |
CN101594827B (zh) | 2012-09-05 |
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