JP2016034285A - Intraocular pressure measuring method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an intraocular pressure measuring method capable of measuring an intraocular pressure continuously in a state closer to the nature over a long term, and an animal capable of performing the measurement.SOLUTION: In the animal, a pressure sensor or at least a pressure sensing portion thereof is fixed in an eye by inserting a plurality of parallel gaps in a biological membrane and by passing a catheter into the gaps. Alternatively, for another of the animal, a pressure measuring transmitter containing the pressure sensor and a transmission part is disposed in an eye.SELECTED DRAWING: None

Description

  The present invention relates to a method for measuring intraocular pressure in a natural state or continuous, and further, novel animals (including human and non-human animals) useful as model animals for diseases (especially glaucoma) in which fluctuations in intraocular pressure are involved. The present invention relates to a manufacturing method and various methods using the same.

  Glaucoma is a disease characterized by functional structural abnormalities of the eye that has characteristic changes in the optic nerve and visual field, and can usually improve or suppress optic nerve damage by sufficiently lowering intraocular pressure. Academic guidelines (second edition)]. Conventionally, it has been understood as a disease in which the optic nerve is impaired by an increase in intraocular pressure, but in recent years, the existence of normal-tension glaucoma that exhibits glaucomatous optic neuropathy in spite of normal intraocular pressure has been revealed. Epidemiological studies have revealed that normal intraocular pressure is the mainstream in Japan. At present, the only treatment that can be confirmed for normal-tension glaucoma is a decrease in intraocular pressure. Intraocular pressure measurement is important in the diagnosis and treatment of glaucoma and in the development of drugs for treating glaucoma.

  As an intraocular pressure measurement method used for diagnosing glaucoma in humans, a contact-type intraocular pressure measurement method and a non-contact-type intraocular pressure measurement method are known. The contact-type intraocular pressure measurement method measures the intraocular pressure by bringing the tip of a tonometer built in a slit lamp microscope into contact with the cornea, and it is necessary to instill an anesthetic before the measurement. On the other hand, the non-contact type intraocular pressure measurement method measures the intraocular pressure by blowing compressed air onto the cornea, and does not require instillation of an anesthetic, but has a problem in that the measurement error is large. There are circadian variations in intraocular pressure as well as blood pressure. Measurements only during the examination or examination are not sufficient. In addition, different values are shown depending on the posture and posture of the subject. It is important that measurements be obtained in any state. Each method is premised on a single measurement, and is not suitable for the purpose of continuously measuring intraocular pressure and tracking changes over time.

  Further, in the screening of glaucoma therapeutic drugs or evaluation of candidate compounds for glaucoma therapeutic drugs, experimental animals are often used, but it is required to monitor intraocular pressure continuously over a long period of time. Furthermore, both the contact-type intraocular pressure measurement method and the non-contact-type intraocular pressure measurement method may affect the intraocular pressure by the measurement operation itself, and the intraocular pressure in the animal's original physiological environment is more natural. It is also required to measure in a stable state. It is known that anatomical differences such as corneal thickness affect the measurement values in both measurement methods. An apparatus created for the human eyeball cannot accurately measure the intraocular pressure of anatomically different animals. <Invention at the 30th Annual Meeting of the Comparative Ophthalmology Society (August 2010) Announced by the authors>.

As a model animal for solving these problems, an attempt was made to continuously measure intraocular pressure over a long period of time by embedding a pressure sensor in a predetermined location of a rabbit eyeball and receiving a telemetric signal. (Non-patent documents 1 to 3).
In Non-Patent Document 1, a commercially available transmitter for pressure measurement (model TA11PA-C40; Data Sciences International, St. Paul, MN) is used, and the transmitter part (length 25 mm, diameter 15 mm, weight 9 g) is: A sensor catheter (length 15 cm, diameter 0.7 mm) that is implanted subcutaneously between the scapulae of the back of the neck of the rabbit and extends from the transmitter is inserted through the limbal opening into the anterior chamber after passing through the skin. Thus, it is disclosed that intraocular pressure could be measured over 180 to 370 days.
Non-Patent Document 2 uses the same transmitter for pressure measurement as Non-Patent Document 1, and the transmitter part (length 25 mm, thickness 12 mm, weight 9 g) is implanted under the neck and inserted from the head. The catheter (15 cm long, 0.7 mm wide) is passed subcutaneously until it reaches the conjunctival sac and into the midvitreous (position 3-4 mm behind the coronoscleral junction). It has been disclosed that intraocular pressure could be measured over at least two months by insertion.
Non-Patent Document 3 discloses cutting a rabbit cornea and fixing a pressure sensor to the iris. The pressure sensor used in Non-Patent Document 3 includes a curved tube or a spiral tube whose shape is deformed by pressure, and determines intraocular pressure by observing the shape change from the outside (outside the eyeball). It is.

Moreover, the technique which embeds a pressure sensor in a patient's eyeball not for a model animal but for the purpose of treatment is disclosed by patent documents 1-3, for example.
Patent Document 1 discloses embedding a pressure sensor in the patient's cornea, Patent Document 2 in the patient's cornea (under the conjunctiva), and Patent Document 3 in the patient's cornea or sclera. Yes. Patent Document 3 has a description (Claim 6) that a pressure sensor is arranged so as not to come into contact with vitreous humor.

International Publication No. 2009/081031 Pamphlet US Pat. No. 6,579,235 US Patent Application Publication No. 2003/0078487

McLaren JW et al. Invest Ophthalmol Vis Sci 1996; 37: 966-975. Schnell CR et al. Invest Ophthalmol Vis Sci 1996; 37: 958-965. Chen P-J et al. J Micromech Microeng 2007; 17: 1931-1938.

  Unlike the widely used contact-type intraocular pressure measurement method or non-contact-type intraocular pressure measurement method, the model animals described in Non-Patent Documents 1 to 3 can measure intraocular pressure continuously in a natural state. is there. In addition, by providing an appropriate rest period after implantation surgery, the animal itself is not affected by the intraocular pressure due to the measurement operation itself, which is a concern in contact-type tonometry or non-contact-type tonometry. It is also possible to measure the intraocular pressure in the physiological environment in a more natural state.

  However, in the model animal described in Non-Patent Document 1 or 2, it is necessary to embed the transmitter part outside the eyeball, for example, subcutaneously on the back of the neck, which is not only uncomfortable for the model animal but also scratches the surgical track. May damage your health or cause damage to your transmitter. In addition, since the catheter connected to the external transmitter is inserted into a predetermined area of the eyeball, the eye movement is restricted, and in this respect as well, the model animal is stressed. Further, the catheter bends as the eye moves, which affects the pressure in the catheter and makes it impossible to accurately measure the intraocular pressure.

The present inventor has intensively studied to solve these drawbacks, and as a result, it is possible to eliminate all of these drawbacks by implanting the pressure measurement transmitter in the eye, for example, the vitreous cavity or the lens capsule of the eyeball. noticed.
Surprisingly, as is apparent from the disclosures of the prior art documents described in the background art section, only Non-Patent Document 2 has disclosed that insertion of a sensor catheter into the vitreous body has been disclosed so far. Measuring the pressure in the vitreous or lens has not been performed.
On the contrary, Patent Document 3 describes that the pressure sensor is disposed in the cornea or sclera “without contact” with vitreous humor, and from this description, those skilled in the art can also embed it in the eye. You can imagine how surprising the idea is.
In addition, the pressure sensor described in Non-Patent Document 3 (fixed to the iris) determines the intraocular pressure by observing the shape change from the outside (outside of the eyeball), and observation from the outside is not possible. As long as it is essential, there is a drawback that it is possible to measure only in an observable posture and under open eyelids (thus, measurement at bedtime is impossible). Implantation in the vitreous body or lens located behind the iris is not easily conceivable for those skilled in the art who know the existence of Non-Patent Document 3.

In addition to the above-described solution, the present inventor has examined a method for fixing the sensor catheter, so that the accurate intraocular pressure can be obtained regardless of whether the transmitter of the pressure measurement transmitter is provided inside or outside the eye. It was also found that it is possible to measure.
As in Non-patent Document 1, the catheter is usually secured by suture, as is sutured to the sclera with nylon thread. However, when the sensor catheter is sutured and fixed, if the catheter is weakly tied, the catheter moves, and if it is tied tightly, the catheter may be broken or kinked. Furthermore, since the cornea and sclera are thin tissues, the sutured part may tear and the catheter may come off. These problems are particularly serious in animals that perform eye movements for tracking, and have contributed to hindering accurate intraocular pressure measurements.

  An object of the present invention is to provide a novel intraocular pressure measurement method capable of continuously measuring intraocular pressure over a long period of time in a more natural state, and a novel animal capable of the measurement Is to provide.

Said subject is according to the invention,
[1] A non-human animal (hereinafter sometimes referred to as the first animal of the present invention), characterized in that a pressure measuring transmitter including a pressure sensor and a transmitter is installed in the eye.
[2] The pressure sensor or at least the pressure sensing part of the pressure sensor is fixed in the eye by inserting a plurality of parallel cuts into the biological membrane and passing the catheter through the cuts. A human animal (hereinafter sometimes referred to as the second animal of the present invention),
[3] The non-human animal according to [1] or [2], wherein the non-human animal is a dog, a pig, or a monkey,
[4] The non-human animal according to any one of [1] to [3], which is a model animal of a disease associated with fluctuations in intraocular pressure,
[5] A method for measuring intraocular pressure using the non-human animal of any one of [1] to [4],
[6] Measurement of intraocular pressure, wherein a pressure measurement transmitter including a pressure sensor and a transmission unit is installed in the eye, and the intraocular pressure is determined from information transmitted from the pressure measurement transmitter. Method,
[7] A plurality of parallel cuts are placed in the biological membrane, and a catheter is passed through the cuts to fix the pressure sensor or at least the pressure sensing site in the eye, and information obtained from the pressure sensor is stored in the eye or A method of measuring intraocular pressure, characterized by determining intraocular pressure by transmitting to a receiver outside the living body from a transmitter installed outside the eye;
[8] Treatment of a disease associated with fluctuation of intraocular pressure, comprising the step of administering a test substance to the non-human animal of any one of [1] to [4] and measuring the intraocular pressure of the animal or Screening methods for preventive drugs,
[9] The above-mentioned provision for a disease involving fluctuation of intraocular pressure, comprising the step of administering a test substance to the non-human animal of any one of [1] to [4] and measuring the intraocular pressure of the animal. Evaluation method of the test substance,
[10] A method for evaluating the safety of the test substance, comprising the steps of administering the test substance to the non-human animal of any one of [1] to [4] and measuring the intraocular pressure of the animal ,
[11] The method for producing a non-human animal according to [1], wherein a pressure measurement transmitter including a pressure sensor and a transmitter is installed in the eye.
[12] The non-human animal according to [2], wherein a plurality of parallel cuts are put in a biological membrane, and a catheter is passed through the cuts to fix a pressure sensor or at least a pressure sensing part thereof in the eye. Manufacturing method,
Can be solved.

  The animal of the present invention (including both the first animal of the present invention and the second animal of the present invention), particularly the non-human animal of the present invention, is a disease in which fluctuations in intraocular pressure are involved, for example, a model animal of glaucoma Can be used as According to the animal of the present invention, it is possible to continuously measure intraocular pressure over a long period of time. In addition, measurement errors based on the effects on the intraocular pressure due to the measurement operation itself or the difference in the eyeball structure with humans, which is a concern with the contact-type tonometry or non-contact-type tonometry methods that have been widely used in the past. In addition, it is possible to measure the intraocular pressure in the animal's original physiological environment in a more natural state. Furthermore, the discomfort and stress (for example, the discomfort of the transmitter embedded under the neck of the back of the neck or the restriction of eye movements) and the change in the internal pressure of the catheter accompanying the eye movement, which have been a problem in conventional model animals, are observed. It can be avoided.

  In particular, in the first animal of the present invention, since there is no cannulation outside the eyeball, (1) it is possible to measure the intraocular pressure closer to nature, (2) it is not affected by eye movement, (3 ) It has effects such as not affecting the eye movement and not causing a foreign body sensation.

It is a graph which shows the result of having measured the time-dependent change (intraocular pressure fluctuation accompanying an external pressure load) at the time of applying a physical pressure to the eye from the outside in the 1st model animal of this invention. It is a graph which shows the result of having measured the time-dependent change of the intraocular pressure (a) and blood pressure (b) at the time of administering the dimorphamine which is a respiration promoter in the 2nd model animal of this invention. It is a graph which expands and shows the graph shown in FIG. 2 in the horizontal axis (elapsed time) direction. In the 2nd manufacturing method of this invention, it is explanatory drawing which shows the state which cut the sclera, formed the band, and fixed the catheter.

  The first animal of the present invention is characterized in that the entire pressure measurement transmitter including the pressure sensor and the transmission unit is installed in the eye. Accordingly, the model animal as described in Non-Patent Document 2, that is, only a part of the transmitter for pressure measurement (tip of the sensor catheter) is inserted into the vitreous body, and the remaining part (sensor catheter excluding the tip) The model animal in which the most part and the transmitter part) are arranged outside the eyeball are not included in the first animal of the present invention.

  According to the second animal of the present invention, a plurality of parallel cuts are placed in a biological membrane, and a catheter is passed through the cuts, so that at least the pressure sensor or the pressure measurement transmitter including the pressure sensor and the transmission unit, or The pressure sensor has at least a pressure sensing portion fixed in the eye. Therefore, in the second animal of the present invention, the transmitting unit can be provided either inside or outside the eye.

  The animal in the present invention is not particularly limited as long as it is an organism having a structure called an eyeball. For example, mammals (for example, humans, dogs, monkeys, cows, pigs, sheep, cats, rabbits, rats, Vertebrates such as mice, guinea pigs), birds, reptiles, amphibians and fish, and invertebrates, and animals other than humans, that is, non-human animals are preferable.

  The transmitter for pressure measurement is not particularly limited as long as it includes at least a pressure sensor capable of measuring intraocular pressure and a transmitter capable of transmitting information obtained from the pressure sensor to an external receiver. For example, a commercially available transmitter for pressure measurement can be used. Examples of such pressure measuring transmitters include mouse transmitter PA-C10 (manufactured by Data Sciences International, sold by Prime Tech), and small animal transmitter PA-C40 [the company MLE1024 TR / Miller blood pressure transmitters (ADINSTRUMENTS), solid state pressure transducers (Konigsberg Instruments, Inc.) are commercially available.

For example, the transmitter PA-C10 incorporates a biological amplifier, an amplifier, a transmission circuit, a pressure sensor body, and a battery in a transmitter body portion (weight: 1.4 g, volume: 1.1 cm ³ ). A sensor catheter (filled with an antithrombogenic gel of about 2 mm on the tip side) extends from the portion. The tip of the sensor catheter is a pressure sensing part, and the pressure sensed here is detected by the sensor body built in the transmitter body portion through the catheter filled with the gel transmitting pressure.
The transmitter PA-C40 incorporates a biological amplifier, an amplifier, a transmission circuit, a pressure sensor body, and a battery in the transmitter body (weight: 7.6 g, volume: 4.4 cm ³ ). The sensor catheter (the tip side is filled with an antithrombotic gel of about 2 mm) extends.
The MLE1024 TR / mirror blood pressure transmitter is composed of a transmitter body (7 cm ³ ) and a solid state sensor catheter (tip diameter 0.66 mm). Since this is a solid state sensor, the pressure sensor is located at the tip of the catheter. There is no need to fill with liquid or gel. It can be charged in vivo with a wireless power supply.

  In a pressure measuring transmitter with a catheter extending from the main body, the measurement site and main body are fixed regardless of whether the catheter has a pressure sensing part at the tip or a catheter at the tip of the catheter. It can be placed in the eye so that the parts to be done are different. By using the catheter with the minimum necessary length, or by winding the catheter around the main body portion, the measurement site and the fixing site of the main body portion can be made to coincide. When pressure measurement and transmission are performed by the main body itself without a catheter, the installation site and the measurement site can be matched.

Hereinafter, the first animal of the present invention will be described, and then the second animal of the present invention will be described.
In the first animal of the present invention, the transmitter for pressure measurement can be installed in an arbitrary portion as long as it is in the eye, that is, a portion that is not outside the eye. It is preferable to install it in a part of the eye that does not hinder eye movement. For example, the transmitter for pressure measurement may be installed in an intraocular tissue (for example, in the anterior chamber or vitreous cavity) in which a large amount of body fluid occupies, between eyeball constituent tissues, or in an eyeball constituent tissue. And installation at the same site after removal of the eyeball constituent tissue.

  As in the case of installing in the anterior chamber or vitreous cavity, it is possible to fix a part of the device to a part of the intraocular tissue or place it in a floating state at the site where much of the body fluid occupies. . Examples of the fixing method to the intraocular tissue include, but are not limited to, adhesion and adhesion. For example, it can be attached to the iris, ciliary body, ciliary groove and placed in the vitreous, or can be attached to the cornea, iris, corner and placed in the anterior chamber. Further, it is possible to minimize the influence on the physiological mechanism of the eye and keep it floating in each part. The fixed / floating state is not limited to these methods.

In the case of placing between eyeball constituent tissues, for example, there can be mentioned between the retina and retinal pigment epithelial cells, between the retinal pigment epithelial cells and choroid, iris, ciliary body, and between choroid and sclera.
In the case of installation in the eyeball constituent tissue, examples thereof include the cornea, the sclera, the iris / ciliary body / choroid, the retina, and the crystalline lens.
When it is installed at the same site after removal of the ocular constituent tissue, it can be installed in the lens capsule after part or all of the lens, the cornea, or part of the sclera.

  The first animal of the present invention can be produced by the first production method of the present invention. The 1st manufacturing method of this invention includes the process of installing the transmitter for pressure measurement containing a pressure sensor and a transmission part in eyes. Hereinafter, a specific installation process will be described. However, the present invention is not limited to the following description as long as the pressure measurement transmitter can be installed in the eye and the intraocular pressure can be measured after the installation. .

  When a transmitter for pressure measurement is installed in the vitreous body, it can be carried out according to the retinal vitreous surgery method. As an example, after anesthetizing the animal to be inserted, the pupil is opened by instilling a mydriatic agent. The conjunctiva is incised to expose the scleral incision site. An incision is made vertically to a depth of 1/2 layer of the sclera at a position 1.5 mm outside from the limbus. The incision distance at this time depends on the size of the device to be installed, but in general, the incision is in the direction from 3 o'clock to 9 o'clock, that is, 180 degrees. Subsequently, a horizontal incision of 1.5 mm is made in the direction of the cornea center. Viscoelastic material is added to maintain the anterior chamber. Hereinafter, the viscoelastic substance is appropriately added as necessary. Further, a vertical incision toward the center of the eyeball is entered into the anterior chamber, and partial excision of the anterior lens capsule, removal of the lens, partial excision of the posterior lens capsule, and partial excision of the vitreous body are sequentially performed. The degree of each partial excision can be appropriately determined according to the size of the device. The device is inserted into the vitreous cavity secured by partial resection.

  As a method for fixing / floating the device inserted into the vitreous cavity, in the type in which the catheter extends from the main body portion, for example, the catheter can be installed in a ring shape at its ciliary root using its own restoring force. A catheter can be attached or adhered as required. The main body can be floated at any position within the vitreous cavity without contacting the tissue such as the retina by the mounting angle, length, and restoring force of the catheter. In addition to the ciliary root, the catheter can be placed in the ciliary groove, in the lens capsule, between the tin body and the ciliary body, between the anterior lens capsule and the ciliary root, etc. Absent. The catheter itself is processed and the body can be suspended at a free position within the vitreous cavity.

  In the case of being integrated with the main body without having a catheter, for example, it is possible to pass through the main body from at least two directions of the ciliary flat portion and suspend it in the vitreous cavity. Alternatively, it can be installed in the vitreous body in a floating state with a magnet and metal installed on the eyeball side or main body side. Also, a method in which a plurality of loops processed in the main body itself spreads the legs in the eyeball and the main body is fixed is also possible. It is rich in biocompatibility like wrapping the main body and has high water content, and it is possible to prevent contact with intraocular tissue with a gel that reflects intraocular pressure in the detection part, but it is limited to this method Absent.

  When installing a pressure measurement transmitter in the anterior chamber, it is possible to perform the procedure until the anterior chamber is reached and insert the device into the anterior chamber, except that no mydriasis is required .

  When replacing the lens in the lens capsule and installing a transmitter for pressure measurement, after partial excision of the lens capsule of the above-mentioned surgical procedure, partial or complete excision of the lens may be performed, and the device may be installed in the lens capsule Is possible.

In the second animal of the present invention, at least the pressure sensor or at least the pressure sensing part of the pressure sensor is fixed in the eye by a specific method among the pressure measurement transmitters including the pressure sensor and the transmitter. . That is, a plurality of parallel cuts are made in the biological membrane, and the catheter is passed through the cuts, thereby fixing the pressure sensor or its pressure sensing site in the eye.
Specifically, a single band is formed by making a cut perpendicular to the biological membrane, making a similar cut parallel to the cut, and then horizontally incising the bottom of the two cuts. Can do. In the present invention, after passing the catheter through the band, the catheter can be easily fixed with an appropriate strength by suturing the surplus portion as necessary.
According to the fixing method, not only the rabbit but also animals such as dogs, monkeys, and pigs that perform eye movements for tracking can be prevented from being displaced or pulled out. As a result, it is possible to suppress ocular tissue damage and continuously measure intraocular pressure over a long period of time.

The biological membrane may be any connective tissue that is strong enough to fix the catheter, and examples thereof include the sclera, conjunctiva, and subcutaneous tissue.
The length of the cut line depends on the size of the catheter to be placed. If the length is too short, it is difficult to pass the catheter, and if it is too long, stitching after passing the catheter becomes complicated. Further, the interval between the cuts, that is, the width of the band can be appropriately determined depending on the size of the catheter to be placed. For example, in the case of PA-C40, good fixing is possible with a length of about 1 mm and a width of about 2 mm.
The number of bands can be appropriately determined depending on the size of the eyeball of the animal. Two to three are preferable because the catheter can be more stably fixed when the number is large.

  A catheter provided with options such as beads generally used for fixing to a tissue or the like may be used. If necessary, by applying an adhesive to the exposed portion of the catheter between the bands, it is possible to prevent the catheter from being laterally displaced or pulled out. The adhesive is not particularly limited as long as it is biocompatible. For example, bioadhesive (3M Vetbond), medical bioadhesive (Dermabond, Johnson & Johnson) And instant medical adhesives (Aronalpha A manufactured by Sankyo Co., Ltd.) and adhesives that can adhere resins such as silicon and polyurethane. It is preferable to use an adhesive suitable for the material of the catheter because it can be bonded better.

The second animal of the present invention can be produced by the second production method of the present invention. The second production method of the present invention includes a step of fixing a pressure sensor in the eye by placing a plurality of parallel cuts in a biological membrane and passing a catheter through the cuts. Hereinafter, a specific installation process will be described.
After general anesthesia of the animal to be inserted, the pupil is opened by instilling a mydriatic agent. The conjunctiva is incised to expose the scleral incision site. The sensor catheter is preferably placed in a site with few blood vessels. Examples of the right eye include 2 o'clock to 3 o'clock direction, and left eye includes 9 o'clock to 10 o'clock direction. Further, the pressure sensor can be stabilized by forming the band on the sclera in the vicinity of the corneal ring portion that is the pressure sensor insertion portion. That is, as shown in FIG. 4, two perpendicular cuts 2a and 2b are made in parallel to a depth of about 1/2 layer of the sclera 1 at a position about 1.5 mm outside from the corneal limbus. A single band 3 is formed by horizontally incising approximately 1/2 layer (2c shown in FIG. 4) of the sclera with the two cuts. Two similar bands are formed and the catheter 9 is passed through. Next, a hole is made in the corneal limbus with a needle, a viscoelastic substance is injected into the anterior chamber, a catheter is inserted into the anterior chamber, and the incised portion is sutured. The viscoelastic substance is not particularly limited as long as it is biocompatible. For example, an ophthalmic viscoelastic substance (Provisc sodium hyaluronate manufactured by Nippon Alcon Co., Ltd.) or an eye viscoelastic agent (Discobisque manufactured by Nihon Alcon Co., Ltd.). (Discovisc) sodium hyaluronate / chondroitin sulfate sodium ester).

  The installation position of the transmission unit may be any place that is not affected by the movement of the animal and can suppress the feeling of foreign matter given to the animal. For example, in the orbit, it is embedded under the conjunctiva, between the eye muscles, and in the vicinity of the back eye muscle adhesion portion. If it is outside the orbit, it may be embedded in the vicinity of the eyelids such as the corners of the eyes and the eyes and under the frontal bone. Alternatively, it can be installed in the gap between the skull and the dura, which is generated by scraping the inside of the skull. Since it is possible to suppress noise as the catheter is shorter, it is particularly preferable to install it at the corner of the eye. If necessary, the catheter can be more firmly fixed by forming bands at a plurality of sites from the pressure sensor insertion site to the transmitter installation site.

Although the first and second animals of the present invention have been described above, the animal of the present invention (whether it is the first animal or the second animal) transmits from the pressure measurement transmitter. Intraocular pressure can be determined by receiving information to be received by a receiver installed outside the animal and performing predetermined information processing. Regarding each of the commercially available transmitters for pressure measurement, for example, receivers, converters, data analysis systems and the like are commercially available from the respective companies, and can be used in the present invention as appropriate.
In addition, since transmitter PA-C10 grade | etc., Has a transmission distance of 20 cm, there is a possibility that data cannot be received in a large breeding cage. In such a case, by attaching a relay antenna and an extracorporeal telemetry system to an animal using a jacket or a collar, it is possible to stably receive biological signals in anesthesia and non-restraint in a large cage. Become. Examples of the relay antenna include a JET-BP antenna (manufactured by Data Sciences International), and examples of the external telemetry system include an external jacket-type telemetry JET (transmission distance: 10 m, manufactured by the company). .

  The animal of the present invention (particularly a non-human animal) can be used as a model animal for diseases involving changes in intraocular pressure, such as glaucoma. Moreover, it can be used as a test animal for a pharmacological test or a safety pharmacology test by using a fluctuation (decrease or increase) in intraocular pressure as an index. More specifically, using the animal of the present invention, screening for a therapeutic or prophylactic agent (ocular pressure agonist) for a disease associated with fluctuations in intraocular pressure, and for the disease (particularly, the treatment or prevention of the disease) (Effectiveness) can be used for the evaluation of the test substance, the safety evaluation of the test substance, and the development of a device for measuring intraocular pressure indirectly from the outside. In addition, when the present invention is applied to a human, it is possible to monitor the therapeutic effect over time.

The screening method of the present invention includes a step of administering a test substance to the animal of the present invention and a step of measuring intraocular pressure of the animal. The evaluation method of the present invention includes a step of administering a test substance to the animal of the present invention and a step of measuring intraocular pressure of the animal.
If fluctuations in intraocular pressure in an animal are detected after administration of the test substance, the test substance can be selected as a candidate substance for an intraocular pressure agonist, and it can be used for diseases involving fluctuations in intraocular pressure. And can be evaluated as useful. For example, when a drop in intraocular pressure is detected after administration of a test substance, the test substance can be selected as a candidate substance for the treatment or prevention of glaucoma, and the test substance can be used for glaucoma. It can be evaluated that it is useful.
The administration method of the test substance is not particularly limited, but it is preferable to use an automatic dosing device such as a micro infusion pump iPRECIO (manufactured by Prime Tech). Since the test substance can be administered without anesthesia and without restraint, the intraocular pressure can be measured in a more natural state.
Further, by monitoring the behavior of the animal by video together with the biological information by telemetry, it is possible to check the noise due to the behavior of the animal, and it is possible to acquire more reliable data.

When the animal of the present invention is used as a model animal for glaucoma, the model animal of the present invention can be obtained by installing a transmitter for measuring pressure in the eye using a normal animal as a starting material. Alternatively, it can be combined with a known glaucoma model.
Examples of known glaucoma models include those caused by spontaneous onset, those obtained by applying a predetermined load operation to normal animals, and those obtained by genetic manipulation.

As a load operation for causing glaucoma, for example, a method of causing normal-tension glaucoma causing optic nerve axonal damage by administering an aluminum compound (particularly, aluminum trichloride) (Japanese Patent Laid-Open No. 2004-313188). ), A method of inducing ocular hypertension and optic nerve damage by injecting a liquid containing a cross-linked polymer (particularly cross-linked carboxyvinyl polymer or cross-linked polyvinyl alcohol) into the anterior chamber (Japanese Patent Laid-Open No. 2003-149236), Examples include a method of causing an osmotic pressure difference to allow water to flow into the eye, a method of sintering or ligating veins to increase aqueous humor outflow resistance, and a method of increasing the outflow resistance by irradiating a corner with laser. it can.
Naturally occurring beagle dogs (Gellatt, Florida univ.), Glaucoma-prone dog breeds, Shiba inu (Kato, University of Tokyo) (Kato, K., N. Sasaki, et al. (2007). "Cloning of canine myocilin cDNA and molecular analysis of the myocilin gene in Shiba Inu dogs. "Veterinary ophthalmology 10 Suppl 1: 53-62., Kato, K., N. Sasaki, et al. (2006)." Possible association of glaucoma with pectinate ligament dysplasia and narrowing of the iridocorneal angle in Shiba Inu dogs in Japan. "Veterinary ophthalmology 9 (2): 71-75.).

  Many glaucoma-related gene candidates are already known (e.g. Genome-wide association study of normal tension glaucoma: common variants in SRBD1 and ELOVL5 contribute to disease susceptibility. Meguro A, Inoko H, Ota M, Mizuki N, Bahram S. Ophthalmology. 2010 Jul; 117 (7): 1331-8.e5. Epub 2010 Apr 3.), manipulating these genes causes glaucoma be able to. For example, WO2004 / 092371 describes a normal-tension glaucoma model mouse that lacks the function of the endogenous glutamate transporter GLAST gene.

  EXAMPLES Hereinafter, the present invention will be specifically described by way of examples, but these do not limit the scope of the present invention.

Example 1
(1) Production of a model animal A telemetry transmitter for pressure measurement (PA) including a transmitter main body portion including a transmitter and a pressure sensor main body, and a sensor catheter that extends from the main body portion and senses pressure at a pressure sensing portion at the tip. -C10, manufactured by Data Sciences International). The size of the main body portion is 9.3 mm in diameter × 14.7 mm in length, and the size of the sensor catheter portion is 0.41 mm in diameter. Subsequently, the male beagle dog was incised in the horny limbus under anesthesia, and the telemetry transmitter was placed in the vitreous cavity. Subsequently, the catheter part of the telemetry transmitter was fixed to the ciliary flat part, and the incised part was sutured.

(2) Detection of intraocular pressure fluctuation due to external pressure load After the above operation, a recovery habituation period was provided, and a beagle dog with no general physical condition was observed. The transmitted pressure signal was received by the telemetry method, and the intraocular pressure was measured by a computer system for data acquisition analysis. In order to examine the influence of the external pressure of the beagle dog on the intraocular pressure abnormality, physical pressure from the outside was gradually applied to the eye of the beagle dog for about 10 seconds, and the change in the intraocular pressure was measured.
The results are shown in FIG. In addition, the vertical line shown in the graph of FIG. 1 shows the load start point of the physical pressure from the outside. From the results of FIG. 1, when an external physical pressure was applied to the eyes of a beagle dog, an increase in intraocular pressure was detected. On the other hand, when no external physical pressure was applied to the eyes of the beagle dog, no effect of abnormal intraocular pressure due to the external pressure of the beagle dog was observed.

Example 2
(1) Production of a model animal A telemetry transmitter for pressure measurement (PA) including a transmitter main body portion including a transmitter and a pressure sensor main body, and a sensor catheter that extends from the main body portion and senses pressure at a pressure sensing portion at the tip. -C40, manufactured by Data Sciences International). The size of the main body portion is 15 mm in diameter × 24 mm in length, and the size of the sensor catheter portion is 0.7 mm in diameter. Next, the male beagle dog was anaesthetized, and the tip of the catheter was inserted into the anterior chamber from the ear-side upper corneal ring. Subsequently, the catheter trunk was fixed to the sclera (see FIG. 4). The body portion of the telemetry transmitter was guided subcutaneously under the frontal bone and fixed by suturing, the incised portion was sutured, and the body portion was embedded subcutaneously.

(2) Effect on blood pressure and intraocular pressure of anesthetized beagle dogs by drugs Dimorphoramine (9 mg / body) was intravenously administered to beagle dogs under anesthesia. Dimorphamine has the effect of promoting respiratory excitement and increasing blood pressure by acting directly on the respiratory center. Before and after administration, the pressure signal transmitted from the telemetry transmitter was received by the telemetry method, and the intraocular pressure was measured by a computer system for data acquisition analysis. In addition, a catheter-type pressure transducer (SPC-320, Millar Instruments) is inserted from the femoral artery, and the signal from the catheter-type pressure transducer is guided to a pressure processor signal conditioner (Gould Electronics). The blood pressure was also measured simultaneously.

  As a result, increases in mean blood pressure (from 82 mmHg to 95 mmHg) and mean intraocular pressure (from 29 mmHg to 40 mmHg) were observed 30 seconds after administration of dimorphoamine. The result is shown in FIG. Further, FIG. 3 shows the result of matching between the fluctuation of blood pressure and the fluctuation of intraocular pressure. FIGS. 2A and 3A are graphs showing waveforms due to intraocular pressure, and FIGS. 2B and 3B are graphs showing blood pressure. Moreover, the vertical line shown in the graph of FIG.2 and FIG.3 shows the time of intravenous administration of dimorphoamine.

  The animal of the present invention (especially a non-human animal) can be used as a model animal for glaucoma, and can be used for screening for a therapeutic or prophylactic agent for glaucoma or for evaluating a test substance.

Claims (12)

  A non-human animal, wherein a plurality of parallel cuts are placed in a biological membrane and a catheter is passed through the cuts, whereby the pressure sensor or at least the pressure sensing part of the pressure sensor is fixed in the eye.   A non-human animal, wherein a pressure measurement transmitter including a pressure sensor and a transmitter is installed in the eye.   The non-human animal according to claim 1 or 2, wherein the non-human animal is a dog, a pig, or a monkey.   The non-human animal according to any one of claims 1 to 3, which is a model animal for a disease involving fluctuation of intraocular pressure.   The measuring method of intraocular pressure using the non-human animal as described in any one of Claims 1-4.   By placing a plurality of parallel cuts in the biological membrane and passing the catheter through the cuts, the pressure sensor or at least the pressure sensing part thereof is fixed in the eye, and the information obtained from the pressure sensor is transferred into or out of the eye. A method for measuring intraocular pressure, wherein intraocular pressure is determined by transmitting from an installed transmitter to a receiver outside the living body.   A method for measuring intraocular pressure, wherein a pressure measurement transmitter including a pressure sensor and a transmission unit is installed in an eye, and an intraocular pressure is determined from information transmitted from the pressure measurement transmitter.   The treatment or prevention of the disease in which the fluctuation | variation of intraocular pressure is involved including the process of administering a test substance to the non-human animal as described in any one of Claims 1-4, and the process of measuring the intraocular pressure of the said animal. Drug screening method.   The test for a disease associated with fluctuations in intraocular pressure, comprising the steps of administering a test substance to the non-human animal according to any one of claims 1 to 4 and measuring the intraocular pressure of the animal. Substance evaluation method.   A method for evaluating the safety of the test substance, comprising the steps of administering the test substance to the non-human animal according to claim 1 and measuring the intraocular pressure of the animal.   The non-human animal according to claim 1, wherein the pressure sensor or at least the pressure sensing portion thereof is fixed in the eye by putting a plurality of parallel cuts in the biological membrane and passing the catheter through the cuts. Production method.   The method for producing a non-human animal according to claim 2, wherein a transmitter for pressure measurement including a pressure sensor and a transmitter is installed in the eye.

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