CN1964734A - Enzymatic treatment of retinitis pigmentosa and relevant pharmaceutical composition therefor in form of a kit - Google Patents
Enzymatic treatment of retinitis pigmentosa and relevant pharmaceutical composition therefor in form of a kit Download PDFInfo
- Publication number
- CN1964734A CN1964734A CN200480043295.5A CN200480043295A CN1964734A CN 1964734 A CN1964734 A CN 1964734A CN 200480043295 A CN200480043295 A CN 200480043295A CN 1964734 A CN1964734 A CN 1964734A
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- enzyme
- physiological solution
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- eye
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
- A61K38/063—Glutathione
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Enzymes And Modification Thereof (AREA)
Abstract
A kit for the treatment of retinitis pigmentosa containing the coenzymes Reduced nicotinamide adenine dinucleotide (NADH), Reduced Nicotinamide adenine dinucleotide phosphate (NADPH) and Reduced Glutathione in aliquot parts and interactive quantities appropriate for administering said enzymes in accordance with a predefined time sequence.
Description
Technical field
The present invention relates to retinitis pigmentosa by enzyme therapy and be the pharmaceutical composition of the kit form that can be used for this therapy.
Background technology
Retinitis pigmentosa is the retinal diseases that presents many different pathological performances: when it influences amphiblestroid peripheral region, can cause the visual field limited and more and more be difficult to adapt to dark and penumbra, the retina peripheral region has most of staff cell, it is provided at the sensation of moving in vision possible in the penumbra and the outside band, or can cause the forfeiture of central vision when cone cell when regulating.This advancing of disease speed is different between different patients.Usually, retinitis pigmentosa displays at nonage, but also usually occurs in the child and show in the mode that is difficult for discovering.
Cause reason the unknown so far of this disease and therefore do not have any therapy that is used to suffer from this patient group.The well-determined information of using for the expert relates to the genetic origin of retinitis pigmentosa, and it is according to the known mechanism of geneticist, by partly heredity of generation heredity.Most of retinitis pigmentosa form is genetic and has identified three kinds of mode of inheritance so far: dominant autosomal, recessive autosomal and (X-is chain) that be closely related with sex.
The cardinal symptom of this disease is the dimness of vision and nyctalopia, promptly looks the thing difficulty when the lighting condition difference, and from good illumination to dark surrounds or the adjustment that vice versa.This phenomenon is that the outbreak of this early stage emergence period of disease concentrates on staff cell because at least in most of case.Other classical symptoms are for to the narrowing down gradually of the reaction (dazzling) of crossing high light, the visual field, and its form of expression trips for the difficulty of the object that perception is positioned at both sides or by step or other low obstacles, finally reaches the total blindness.
The process of this disease has the extremely indefinite persistent period, but progressive often and finally cause the maimed person.Described sx before in most of case, the visual field becomes more and more restricted and finally cannot see fully.The other diseases that wherein is easy to occur is the cataract of dazzling, achromatopsia and particular form.In most cases final result is as blind as a bat unfortunately.
In order to diagnose this disease, rely on usually as checks such as examination of ocular fundus, perimetry, electroretinogram, fluorescence angiography and examination of visual acuity:
-examination of ocular fundus is intended to assess the existence of peculiar pigment spot on amphiblestroid situation and the searching retinal surface, and it presents distinctive " osteoblast sample " profile in this disease.Though it presents identical symptom, yet some rare retinitis pigmentosa forms are not to characterize by the speckle on the optical fundus;
The inspection in-the visual field makes the sensitivity of assessment retina each several part photic stimuli become possibility.Its objective record to the difficulties in vision that has patient experience is useful;
-electroretinogram (ERG) is electroactive by the stimulation of record retinal responses specific light, therefore makes the functional definite evaluation of two kinds of dissimilar photoreceptors (being cone cell and staff cell) become and may and form.Electroretinogram is the very important inspection that is used to diagnose retinitis pigmentosa, even because-when this disease is in the starting stage-depiction that obtains normally very flat or lack fully;
-fluorescence angiography by the intravenous injection of fluorescent material with in different periods amphiblestroid photography is carried out subsequently.In fact, because blood circulation, fluorescent material arrives retina, therein its dyeing tremulous pulse, blood capillary and vein and therefore make that it is visible, also can reflect the functional status of its wall;
-examination of visual acuity allows the evaluation of visual acuity and is made up of the letter that the patient reads different sizes three meters distances.
Though identify and the retinitis pigmentosa of having classified about mid-term in last century greatly, so far to can curable prospect or understand prospect definite and that regulate the reason no less important of its process and almost do not have concrete progress.The international research at present method of extensive employing is a genetic method, it is managed to identify one or more genes that cause this disease and allows subsequently by modern gene engineering intervention, promptly, implantation method, its be intended to finish may carry out that retinal tissue is transplanted or at least healthy cell transplant the technology that enters in the ill retina, and immunological method, its be used to verify this disease of supposition be with immune some change into some theories on basis.
WO 2004/030693 (identical applicant) discloses the medicine box that is used for the retinitis pigmentosa treatment, and it comprises glutathion peroxidase, prolidase, glucose-6-phosphate dehydrogenase (G6PD) and predetermined administration time order.Use this Therapeutic Method, though still effective after the long-time slightly section, with regard to the response of patient with regard to the disappearance of pigment spot on the macula quite slow and even after injection in a very long time vision still keep smudgy.
Summary of the invention
Purpose of the present invention is for providing the pharmaceutical composition of kit form, and it makes retinitis pigmentosa than obtaining more effective treatment with the therapy according to WO 2004/030693.
Another object of the present invention is for providing a kind of method for the treatment of retinitis pigmentosa, it makes the visual acuity and the visual field enlarge, and the progressively recovery of image definition and colour vision is than using the faster and normal electroretinogram of last reconstruction of disclosed therapy among the WO 2004/030693.
According to the present invention, these purposes reach by the specific enzyme that utilization is used for mixing the pharmaceutical composition of kit form, this pharmaceutical composition is used for treating retinitis pigmentosa by being injected into retrobulbar tissue, just like illustrated in the claim 1.
More specifically, the enzyme that adopts is nicotinamide adenine dinucleotide reduced (NADH), hereinafter to be referred as enzyme A, NADPH (NADPH), hereinafter to be referred as enzyme B, and reduced glutathion, hereinafter to be referred as enzyme C, it is according to hereinafter further official hour order and form give.
The enzyme that is used for therapy of the present invention is commercially available lyophilized form and is dissolved in physiological solution so that it can be used for described therapy.
Every kind of enzyme-enzymatic solution form-method by retrobulbar injection fed in every eye continuous three days, and other is repeated described giving two opportunitys, each and the time (for every kind of enzyme) that last time separated one month.In fact described method is as follows: when described therapy begins the enzyme A of single dose is injected in the retrobulbar tissue of every eye continuous three days, repeats described therapy at second and three month then; At the 4th, the 5th and six month, the enzyme B of single dose is injected in the retrobulbar tissue of every eye continuous three days; At the 7th, the 8th and nine month, the enzyme C of single dose is injected in the retrobulbar tissue of every eye continuous three days.
The dosage of the different enzymes that per injection (for every eye) is used is as follows:
Enzyme A 0.25-0.35mg
Enzyme B 0.25-0.35mg
Enzyme C 0.9-1.1mg
The preferred dose of different enzymes is as follows during per injection:
Enzyme A 0.3mg
Enzyme B 0.3mg
Enzyme C 0.3mg
These dosage keep identical for all patients, and are irrelevant fully with the schema concept (typology) that changes.Especially, enzymatic solution prepares by the method that the above amount can be included in the 0.4ml injection.For example, be prepared as follows the enzymatic solution that is suitable for providing the 0.4ml injectable dosage that comprises the above preferred enzyme amount
Enzyme A:
Comprise the bottle of 10mg lyophozyme, add to 12.5ml with physiological solution.
Enzyme B:
Comprise the bottle of 10mg lyophozyme, add to 12.5ml with physiological solution.
Enzyme C:
Comprise the bottle of 25mg lyophozyme, add to 10ml with physiological solution.
Certainly be clear that very that if decision changes the dosage of any enzyme in the above dosage range, then these ratios also will change.
Described enzyme gives with said sequence and infusion cycles is a continuous uninterrupted.
The medicine box that the present invention is used for the treatment of retinitis pigmentosa comprises the equal portions that are suitable for administration and the above-mentioned enzyme of interaction amount:
A) be used for the enzyme A of concentration between continuous three days 0.4ml physiological solution 0.25 and the 0.35mg, every month once, continuous three days of every eye;
B) be used for the enzyme B of continuous three days 0.4ml physiological solution 0.25 to 0.35mg concentration next month after enzyme A administration last time, and every month once, every eye three months;
C) be used for the enzyme C of continuous three days 0.4ml physiological solution 0.9 to 1.1mg concentration next month after enzyme B administration last time, and every month once, every eye three months;
Especially, enzyme is included in each medicine box with lyophilized form and the amount that is enough to be used at least one complete serial administration, every kind of enzyme is further divided into to comprise and is enough to be used in a trimestral injection cycle, i.e. 18 injections, or be used for administration every day, be the equal portions of the amount of double injection, and the suitable dose that is used to constitute the physiological solution of described equal portions alternatively.Especially, different enzymes is further divided into one or more equal portions in each medicine box, and each comprises in the above preferred dose form, the enzyme C of enzyme B, the 1.0mg to 18mg of enzyme A, the 0.3mg to 5.4mg of 0.30mg to 5.4mg.The physiological solution that may also can have three or more equal portions of 0.4 to 7.2ml separately.
The patient's visual acuity of the present invention's treatment and the improvement gradually of the visual field, colour vision and image definition (decomposing force) are accepted in discovery.Its electroretinogram improves gradually, is rebuild at last.Especially, compare the therapy of WO 2004/030693, patient's response is faster aspect the disappearance of macula pigment spot.Opposite with the recurrent situation of WO 2004/030693 therapy, report injection 24-48 hour patient in back has vision and especially unambiguous vision more clearly.This therapy that gives produces positive response in all patients, though be to have passed through the different periods.Follow-up investigations behind the 2-3 show the side effect nonvolatil and that do not bring any character that is improved as that obtains.
Tabulate down and summarized the result of therapeutic therapy of the present invention in 1 23 patients suffering from retinitis pigmentosa.The meansigma methods and the standard deviation that have presented following parameters relevant with right eye and left eye before and after this treatment: visual acuity, the visual field and electroretinogram.
Table 1
| Visual acuity | The visual field (*) | Electroretinogram | |||||
| RE | LE | RE | LE | RE | LE | ||
| After treating before the treatment | Meansigma methods S.D. meansigma methods S.D. | 3,7/10 3,1/10 7,9/10 2,9/10 | 4,0/10 3,1/10 7,6/10 2,7/10 | 4,95％ 3,33％ 51,3％ 15,2％ | 4,74％ 3,32％ 47,7％ 17,3％ | Do not have or reduce greatly-increase- | |
(*) meansigma methods of corresponding temporo, nose, upper and lower isopter (isoptera).
The statistical analysis of every kind of parameter shows that the difference between the numerical value of treatment front and back is significant on the statistics.
Experimental data has confirmed that retinitis pigmentosa may be due to the hypothesis of enzyme defect, and it changes amphiblestroid metabolism, not only regulates vision process, also promotes the accumulation of pigment, and it is the characteristic feature of this disease.
Claims (10)
1. the medicine box that is used for retinitis pigmentosa treatment comprises the equal portions that are suitable for administration and enzyme nicotinamide adenine dinucleotide (enzyme A), nicotinamide-adenine dinucleotide phosphate (enzyme B) and the reduced glutathion (enzyme C) of interaction amount:
A) be used for the enzyme A of concentration between continuous three days 0.4ml physiological solution 0.25 and the 0.35mg, every month once, every eye three months;
B) next month after enzyme A administration last time, be used for the enzyme B of continuous three days 0.4ml physiological solution 0.25 to 0.35mg concentration, and every month once, every eye three months;
C) next month after enzyme B administration last time, be used for the enzyme C of continuous three days 0.4ml physiological solution 0.9 to 1.1mg concentration, and every month once, every eye three months.
2. according to the medicine box of claim 1, wherein the concentration of enzyme A is 0.3mg in the 0.4ml physiological solution, and the concentration of enzyme B is that the concentration of 0.3mg and enzyme C is 1.0mg in the 0.4ml physiological solution in the 0.4ml physiological solution.
3. according to the medicine box of claim 1 or claim 2, wherein said medicine box comprise lyophilized form, be enough to be used at least one time a) to c) amount of serial administration, for every kind of enzyme, be further divided into comprise be enough to be used in one time three months, every month once or every day dosage equal portions described enzyme and, selectively, be used to constitute the physiological solution of the suitable dose of described equal portions.
4. according to any one medicine box of claim 1 to 3, wherein said medicine box comprises the described enzyme of the lyophilized form that is further divided into one or more equal portions, each equal portions comprises 0.30 to 5.4mg enzyme A, 0.3 to 5.4mg enzyme B, 1.0 to 18mg enzyme C and optionally, the physiological solution of each three or more equal portions of 0.4 to 7.2ml.
5. enzyme nicotinamide adenine dinucleotide reduced (NADH), NADPH (NADPH) (enzyme B) and reduced glutathion (enzyme C) are used to prepare the purposes of the kit form pharmaceutical composition of the method treatment retinitis pigmentosa by being injected into retrobulbar tissue, and described medicine box comprises the equal portions that are suitable for administration and the described enzyme of interaction amount:
A) be used for the enzyme A of concentration between continuous three days 0.4ml physiological solution 0.25 and the 0.35mg, every month once, every eye three months;
B) next month after enzyme A administration last time, be used for the enzyme B of continuous three days 0.4ml physiological solution 0.25 to 0.35mg concentration, and every month once, every eye three months;
C) next month after enzyme B administration last time, be used for the enzyme C of continuous three days 0.4ml physiological solution 0.9 to 1.1mg concentration, and every month once, every eye three months.
6. according to the purposes of the enzyme of claim 5, wherein the concentration of enzyme A is 0.3mg in the 0.4ml physiological solution, and the concentration of enzyme B is that the concentration of 0.3mg and enzyme C is 1.0mg in the 0.4ml physiological solution in the 0.4ml physiological solution.
7. according to the purposes of the enzyme of claim 5 or 6, wherein said medicine box comprise lyophilized form, be enough to be used at least one time a) to c) amount of serial administration, for every kind of enzyme, be further divided into comprise be enough to be used in every eye one time three months, every month once or every day dosage equal portions described enzyme and, selectively, be used to constitute the physiological solution of the suitable dose of described equal portions.
8. according to the purposes of the enzyme of any one claim before, wherein said medicine box comprises the described enzyme of the lyophilized form that is further divided into one or more equal portions, comprise 0.3 to 5.4mg enzyme A, 0.3 to 5.4mg enzyme B, 1.0 to 18mg enzyme C and optionally, the physiological solution of each three or more equal portions of 0.4 to 7.2ml for each equal portions of every eye.
9. be used for the method for retinitis pigmentosa treatment, it is by following enzyme being injected into the method administration of retrobulbar tissue:
A) be used for the nicotinamide adenine dinucleotide reduced (NADH) (enzyme A) of concentration between continuous three days 0.4ml physiological solution 0.25 and the 0.35mg, every month once, every eye three months;
B) next month after enzyme A administration last time, be used for the NADPH (NADPH) (enzyme B) of continuous three days 0.4ml physiological solution 0.25 to 0.35mg concentration, and every month once, every eye three months;
C) next month after enzyme B administration last time, be used for the reduced glutathion (enzyme C) of continuous three days 0.4ml physiological solution 0.9 to 1.1mg concentration, and every month once, every eye three months.
10. according to the method for claim 9, wherein the concentration of enzyme A is 0.3mg in the 0.4ml physiological solution, and the concentration of enzyme B is that the concentration of 0.3mg and enzyme C is 1.0mg in the 0.4ml physiological solution in the 0.4ml physiological solution.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IT2004/000331 WO2005120544A1 (en) | 2004-06-08 | 2004-06-08 | Enzymatic treatment of retinitis pigmentosa and relevant pharmaceutical composition therefor in form of a kit |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1964734A true CN1964734A (en) | 2007-05-16 |
Family
ID=34957961
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200480043295.5A Pending CN1964734A (en) | 2004-06-08 | 2004-06-08 | Enzymatic treatment of retinitis pigmentosa and relevant pharmaceutical composition therefor in form of a kit |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP1753444A1 (en) |
| JP (1) | JP2008501783A (en) |
| CN (1) | CN1964734A (en) |
| AU (1) | AU2004320491A1 (en) |
| BR (1) | BRPI0418858A (en) |
| CA (1) | CA2567205A1 (en) |
| IL (1) | IL179479A0 (en) |
| RU (1) | RU2007100153A (en) |
| WO (1) | WO2005120544A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL2000008C2 (en) * | 2006-02-16 | 2007-08-17 | Apo Pharmaceuticals Internat B | Composition and dosage unit as a dietary supplement and for the treatment of retinis pigmentosa. |
| US20130225684A1 (en) * | 2012-02-28 | 2013-08-29 | Kyowa Hakko Bio Co., Ltd. | Methods and compositions for enhancement of vision performance |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5596011A (en) * | 1995-04-06 | 1997-01-21 | Repine; Karen M. | Method for the treatment of macular degeneration |
| US7445777B2 (en) * | 2002-10-01 | 2008-11-04 | Paola Ammannati | Enzymatic treatment of retinitis pigmentosis |
-
2004
- 2004-06-08 CA CA002567205A patent/CA2567205A1/en not_active Abandoned
- 2004-06-08 AU AU2004320491A patent/AU2004320491A1/en not_active Abandoned
- 2004-06-08 RU RU2007100153/15A patent/RU2007100153A/en not_active Application Discontinuation
- 2004-06-08 EP EP04745165A patent/EP1753444A1/en not_active Withdrawn
- 2004-06-08 WO PCT/IT2004/000331 patent/WO2005120544A1/en active Application Filing
- 2004-06-08 BR BRPI0418858-6A patent/BRPI0418858A/en not_active IP Right Cessation
- 2004-06-08 JP JP2007526708A patent/JP2008501783A/en active Pending
- 2004-06-08 CN CN200480043295.5A patent/CN1964734A/en active Pending
-
2006
- 2006-11-22 IL IL179479A patent/IL179479A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL179479A0 (en) | 2007-05-15 |
| RU2007100153A (en) | 2008-07-20 |
| CA2567205A1 (en) | 2005-12-22 |
| EP1753444A1 (en) | 2007-02-21 |
| BRPI0418858A (en) | 2007-11-20 |
| JP2008501783A (en) | 2008-01-24 |
| AU2004320491A1 (en) | 2005-12-22 |
| WO2005120544A1 (en) | 2005-12-22 |
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