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WO1995000156A1 - Compositions et procedes de traitement et de prevention des dysfonctionnements retiniens - Google Patents

Compositions et procedes de traitement et de prevention des dysfonctionnements retiniens Download PDF

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Publication number
WO1995000156A1
WO1995000156A1 PCT/IB1994/000192 IB9400192W WO9500156A1 WO 1995000156 A1 WO1995000156 A1 WO 1995000156A1 IB 9400192 W IB9400192 W IB 9400192W WO 9500156 A1 WO9500156 A1 WO 9500156A1
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WO
WIPO (PCT)
Prior art keywords
retinal
retilin
treatment
patients
dystrophy
Prior art date
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PCT/IB1994/000192
Other languages
English (en)
Inventor
Vladimir Khatskelevich Khavinson
Sergey Vladimirovich Sery
Andrey Leonidovich Kozhemyakin
Rustem Ilyasovich Valeyev
Original Assignee
Neopharm Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Neopharm Ltd filed Critical Neopharm Ltd
Priority to AU69795/94A priority Critical patent/AU6979594A/en
Publication of WO1995000156A1 publication Critical patent/WO1995000156A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4702—Regulators; Modulating activity
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans

Definitions

  • the invention relates to pharmaceutical methods for treating patients with retinal dysfunction using biologically active factors in preparations of mammalian retinal extracts.
  • vasodilators nicotinic acid, nitecsin, No-spa (also known as
  • DrotaveriumTM DrotaveriumTM
  • nicospan a mixture of No-spa and nicotinic acid
  • theophylline theophylline
  • EuphyllineTM, ComplaminTM, and sodium nitrate ii) agents which improve the condition of the vascular wall and microcirculation (ProdectinTM- aka AngininTM and
  • nucleinic acid preparations (DronuclideTM, EncadTM, and sodium nucleinate) (1, 2).
  • Nonspecific therapy suffers from the disadvantage that any therapeutic effects tend to be unstable and short-lived, i.e., with deterioration of visual function at the termination of treatment and the requirement for multiple courses of maintenance therapy delivered over a long period of time.
  • clinical efficacy has not been unequivocally demonstrated for many of the therapeutic agents listed above.
  • vasodilative preparations may also have systemic hypotensive action, and other agents may exhibit such side effects as allergic reactions, facial hyperemia, dizziness, paresthesia, fatty infiltration of the liver (e.g., nicotinic acid), and dyspeptic disturbances.
  • Complamin is contraindicated during acute myocardial infarction, and may have adverse cardiovascular effects and induce hemorrhage
  • biogenic stimulators are contraindicated in patients with cardiovascular disease, hypertonia, and acute gastrointestinal disturbance
  • heparin is contraindicated in many conditions including hemorrhagic diathesis, leukosis, anemia, polyps and malignant neoplasms of the gastrointestinal tract, and ulcerative ailments- Other difficulties may prevent combination therapy with one or more of the identified medicinal agents, e.g., Unithiol is not recommended for combination with other medicinal agents because it contains reactive thiol groups.
  • Encad Adverse reactions pose still another difficult, e.g., Encad may exhibit undesirable side effects such as parotic and cervical lymph node enlargement and tenderness which can produce a heightened sensitivity to the preparation, and allergic reactions in the form of rash and elevated temperature. Encad is also contraindicated during acute and chronic inflammatory and infectious diseases, pregnancy, central nervous system disorders, viral illnesses, renal illnesses, benign and malignant tumors, and severe cardiovascular disease.
  • MIAA monoiodoacetic acid
  • ERG electroretinography
  • microopthaloscopic and histologic examination revealed retinal edema, optic disc edema, and scomata within one hour after injection of MIAA.
  • Retilin treatment produced statistically significant (p ⁇ 0.05) restoration of ERG B-wave bioelectric amplitude at 15 day to values more than twice those of controls.
  • ERG B-wave amplitude in the retilin treatment group was >80% of normal (i.e. the recorded pre-MIAA values).
  • animals in the control group showed ERG B-wave values at day 35 that were only 45% of normal.
  • severe retinal toxicity was induced with 15 mg/kg MIAA iv, every animal in the control group had unmeasurable bioelectric activity.
  • retilin treatment (1 mg/kg daily starting at day 3) restored measurable bioelectric activity in 40% of the animals at day 15, and the values recorded in the treatment group at day 35 were 15% of normal.
  • MIAA severely toxic level
  • retilin treatment markedly reduced amorphous foci and retinal edema on day 5 (as compare with controls) and at day 22 retinal edema observed in the controls, was not observed in the retilin treated animals.
  • retilin In other retilin a 1 month pretreatment course of retilin completely prevented severe retinal toxicity induced by 35 mg/kg MIAA, as evidenced by a complete lack optic nerve disc edema and the failure to pretreated animals to develop amorphous foci on the retina, or other histologic of bioelectric indicators of toxicity. In other experimental animal studies of hereditary retinal dysfunction, retilin treatment administered post-natally to Campbell rats significantly delayed and ameliorated development of retinal abiotrophy. Preliminary clinical trials tested therapeutic efficacy of pharmaceutical grade
  • Retilin in patients with more than four different retinal dystrophies namely, central involutional chorioretinal dystrophy, hereditary central tapetoretinal abiotrophy of the Stargardt, Best or Franceschetti type, secondary central chorioretinal dystrophy, and retinitis pigmentosa.
  • Objective clinical measurements show retilin treatment remarkably effective- For example, in patients with hereditary abiotrophy Retilin treatment increased visual field in 15 patients to near normal values.
  • retilin treatment increased measured visual acuity in every patient; increased visual perception in the long and medium wavelength light with an average 25% improvement (over pretreatment values); eliminated scotomas in the central visual field; increased measured color perception; and, reduced dystrophic retinal changes visualized by fluorescent angiography.
  • retinitis pigmentosa retilin treatment increased ERG "B"-wave amplitude and values for Arden's light/dark coefficient were significantly increased.
  • the invention relates to the use a medicinal peptide preparation derived from extraction of mammalian retina and called "Retilin" for making pharmaceutical preparations for treating patients with retinal dysfunction.
  • the invention relates to use of the subject pharmaceutical preparations in treatment methods.
  • the subject methods find uses in therapeutic and prophylactic for treatment of patients with retinal dysfunction, e.g. hereditary or chemical or drug-induced toxic retinal diseases, or dysfunctions resulting as a complication of illness or disease.
  • retilin was found to have remarkable prophylactic and therapeutic effects in both preventing retinal damage induced by toxic chemicals, and inhibiting and treating hereditary diseases in experimental animals and humans.
  • Restoration of retinal function in restore damaged tissues was confirmed by visual testing, and by ophthalmoscopic and histologic observations, as disclosed in the EXAMPLES section, below).
  • Retilin improved visual function and reduced destructive processes in the retina during chemically induced and hereditary retinal dystrophies in experimental animals.
  • retilin treatment inhibited development of abiotrophic changes and restored visual function in cases of longstanding hereditary retinal disease; as evidenced using objective measurements of visual acuity, visual field, color perception, electroretinography, ophthalmoscopic examination, flourescent angiography and the like.
  • the following terms as used herein are intended to have meaning as follows: namely,
  • Retilin treatment is intended to mean a method of delivering to a subject in need thereof a pharmaceutical preparation of Retilin with the aim of treating or preventing one or more retinal dysfunctions in the subject.
  • the subject methods include delivering the preparation to a patient i) before the dysfunction has been diagnosed, e.g., prophylactic protocols delivered with the aim of preventing development of the dysfunction, as well as, ii) after the dysfunction has been diagnosed, e.g., therapeutic protocols.
  • the subject treatments have fulfilled the intended aim of treating or preventing the retinal dysfunction in the subject will be evident by a change (increase or decrease) or complete elimination of one or more clinical indicia of disease, e.g., diagnostic symptoms including but not limited electroretinography parameters, measurements of visual field or visual acuity, light sensitivity after visual disadaptation, color perception, Arden's light/dark index, and the like.
  • diagnostic symptoms including but not limited electroretinography parameters, measurements of visual field or visual acuity, light sensitivity after visual disadaptation, color perception, Arden's light/dark index, and the like.
  • Retinal dysfunction is intended to mean a pathologic condition of retinal tissue that changes visual perception in the subject so afflicted. Vision in the subject so afflicted is altered when compared with the vision of a normal healthy control subject.
  • the subject pathologic conditions include, but are not limited to, i) toxic retinal dystrophy, (e.g., chemical or drug-induced secondary chorioretinal dystrophy), ii) vascular retinal impairment, iii) macular degeneration and peripheral degeneration of the retina, iv) retinal detachment and defects; v) retinal lesions induced by physical trauma, vi) retinal complications of illnesses; vii) central involutional chorioretinal dystrophy, viii) hereditary central tapetoretinal abiotrophy of the Stargardt, Best, or Franceschetti type, ix) retinitis pigmentosa, and x) secondary central chorioretinal dystrophy.
  • toxic retinal dystrophy e
  • Representative illness, diseases, and conditions having retinal dysfunction have been classified and codified ("International Classification of Diseases; ICD-9-CM, Washington DC, 1989.
  • the subject pharmaceutical preparations and methods of the invention are useful for treating one or more of the following codified diseases: namely, 360. Disorders of the globe; 360.0. Purulent endophthalmitis; 360.00. Purulent endophthalmitis (no other specification); 360.01. Acute endophthalmitis; 360.02. Panophthalmitis; 360.03. Chronic endophthalmitis; 360.04. Vitreous abscess; 360.1. Other endophthalmitis; 360.11. Sympathetic uveitis; 360.12. Panuveitis; 360.13.
  • Parasitic endophthalmitis (no other specification); 360.19 Other Phacoanaphylactic endophthalmitis; 360.2. Degenerative disorders of globe; 360.20. Degenerative disorder of globe (NOS); 360.21. Progressive high (degenerative) myopia, Malignant myopia; 360.23. Siderosis; 360.24. Other metallosis; Chalcosis; 360.29. Other; 361. Retinal detachments and defects; 361.0. Retinal detachment with retinal defect, Rhegmatogenous retinal detachment; 361.00. Recent detachment with retinal defect (NOS); 361.01. Recent detachment, partial, with single defect; 361.02. Recent detachment, partial, with multiple defects; 361.03.
  • Serous retinal detachment Retinal detachment without retinal defect
  • 361.3 Retinal defects without detachment
  • 361.30 Retinal defect (NOS), Retinal break(s) (NOS); 361.31. Round hole of retina without detachment;
  • Exudative retinopathy Coats' syndrome; 362.13. Changes in vascular appearance, Vascular sheathing of retina, Atherosclerosis of retinal vessels (440.8); 362.14. Retinal microaneurysms (NOS); 362.15. Retinal telangiectasia; 362.16. Retinal neovascularization (NOS), Neovascularization: choroidal subretinal; 362.17. Other intraretinal microvascular abnormalities, Retinal varices; 362.18. Retinal vasculitis, Eales' disease Retinal, Retinal: perivasculitis arteritis, phlebitis, endarteritis; 362.2. Other proliferative retinopathy; 362.21.
  • Retrolental fibroplasia 362.29. Other nondiabetic proliferative retinopathy; 362.3. Retinal vascular occlusion; 362.30. Retinal vascular occlusion (NOS); 362.31. Central retinal artery occlusion; 362.32. Arterial branch occlusion; 362.33. Partial arterial occlusion, Hollenhorst plaque, Retinal microembolism; 362.34. Transient arterial occlusion, Transient blindness (amaurosis fugax); 362.35. Central retinal vein occlusion; 362.36. Venous branch occlusion; 362.37. Venous engorgement, Occlusion of retinal vein: incipient, partial; 362.4.
  • Retinal layer separation (NOS); 362.41. Central serous retinopathy; 362.42. Serous detachment of retinal pigment epithelium, Exudative detachment of retinal pigment epithelium; 362.43.Hemorrhagic detachment of retinal pigment epithelium; 362.5. Degeneration of macula and posterior pole; 362.50. Senile macular degeneration (NOS); 362.51. Nonexudative senile macular degeneration, Senile macular degeneration: atrophic dry; 362.52. Exudative senile macular degeneration Kuhnt-Junius degeneration; Senile macular degeneration: disciform wet; 362.53.
  • NOS Retinal layer separation
  • Cystoid macular degeneration 362.54. Macular cyst, hole, or pseudohole; 362.55. Toxic maculopathy; 362.56. Macular puckering, Preretinal fibrosis; 362.57. Drusen (degenerative); 362.6. Peripheral retinal degenerations; 362.60. Peripheral retinal degeneration (NOS); 362.61. Paving stone degeneration; 362.62. Microcystoid degeneration, Blessig's cysts, Ivanov's cysts; 362.63. Lattice degeneration, Palisade degeneration of retina; 362.64. Senile reticular degeneration, Pseudoretinitis pigmentosa; 362.65. Secondary vitreoretinal degenerations; 362.7.
  • Hereditary retinal dystrophies 362.70. Hereditary retinal dystrophy (NOS); 362.71. Retinal dystrophy in systemic or cerebroretinal lipidoses. Additional codes relating to complications and sequelae of diseases that may prove amenable to the subject therapy include: cerebroretinal lipidoses (330.1); systemic lipidoses (272.7); retinal dystrophy in other systemic disorders and syndromes (362.72); Bassen-Kornzweig syndrome (272.5); Refsum's disease (356.3); Vitreoretinal dystrophies and Juvenile retioschisis (362.73); Pigmentary retinal dystrophy, Retinal dystrophy, albipunctate, Retinitis pigmentosa (362.74); other dystrophies primarily involving the sensory layer of the retina, Progressive cone (rod) dystrophy, Stargardt's disease (362.75); Dystrophies primarily involving the retinal pigment epithelium, Fundus flavimaculat
  • Hereditary choroidal dystrophies Hereditary choroidal atrophy: partial (capillaries), total (all vessels); 363.50. Hereditary choroidal dystrophy or atrophy, unspecified; 363.51. Circumpapillary dystrophy of choroid, partial; 363.52. Circumpapillary dystrophy of choroid, total, Helicoid dystrophy of choroid; 363.53. Central dystrophy of choroid, partial Dystrophy, choroidal: central areolar, circinate; 363.54. Central choroidal atrophy, total Dystrophy, choroidal: central gyrate, serpiginous; 363.55. Choroideremia; 363.56.
  • Additional codes for underlying conditions in which the subject therapeutic method is useful as a candidate therapeutic agent include, but are not limited to: pigmentary retinal dystrophy (362.74); Visual disturbances (368); Visual field defects (368.4); Visual field defect, unspecified (368.40); Scotoma involving central area, Scotoma: central, centrocecal, paracentral (368.41); Scotoma of blind spot area, Paracecal scotoma, Enlarged: angioscotoma, blind spot (368.42); Sector or arcuate defects, Scotoma: arcuate, Bjerrum, Seidel (368.43); Other localized visual field defect, Scotoma, Visual field defect: NOS, nasal step, ring, peripheral (368.44); Color vision deficiencies, Color blindness (368.5); Protan defect, Protanomaly, Protanopia (368.51); Deutan defect, De
  • Subject in need thereof is intended to mean a mammal, e.g., humans, domestic animals and livestock, having one or more retinal dysfunctions.
  • Retilin preparation is intended to mean a preparation consisting of one or more peptides of less than 10,000 daltons, extractable from mammalian retina (e.g., cow, pig, and the like) in about 3% acetic acid in the presence of about 7 mM zinc chloride, e.g., under the conditions recited below; and further exhibiting biological activity in one or more of the animal models or clinical studies recited in the EXAMPLES section, below.
  • the subject preparation is preferably prepared by a stepwise process of: i) extracting in a 3% acetic acid solution in the presence of about 7 mM ZnCl 2 for about 48-56 hours, ii) precipitating materials from the extract solution by adding 9 volumes of acetone for each volume of the extract solution and cooling for about 20-24 hours to -1°C to -3°C, iii) drying the acetone-treated extract solution to a powder, iv) solubilizing the acetone powder by adding distilled water and agitating at room temperature for about 2 hours, v) adjusting the pH of the distilled water-extract solution to pH 4.0 with acetic acid, and vi) bringing the pH of the pH 4-extract solution to neutrality, e.g., by lyophilization to sublimate the acetic acid and form a white powder.
  • the neutralized extract solution is one illustrative form of the subject retilin preparation while the lyophilized white powder is another form that is dissolved in sterile saline prior to injection.
  • the subject retilin preparations are capable of treating or preventing toxic retinal dysfunction in a rabbit eyes that occurs as the result of intravenous administration of monoiodoacetic acid, as disclosed in EXAMPLES section, below.
  • Suitable retilin preparations are isolated from long or short horned cattle or pigs according to methods disclosed in Russian Federation Invention Certificate No. 1,436,305 (incorporated herein by reference).
  • surgically isolated animal retinas e.g., 0.5 kg retinas from long horned cattle fundus
  • acetic acid e.g., 5 kg
  • zinc chloride lgram/ liter of acetic acid homogenate solution
  • periodic mixing i.e., about 3 times/day for 1 hour each.
  • '5 extract is then centrifuged under conditions sufficient to remove tissue debris, (e.g., 20 min. at 3000 rpm).
  • the clear supernatant solution is decanted and 1:10-1:20 volumes (w/w) of acetone are added (e.g., 34 kg).
  • Acetone extraction is carried out at a temperature of -1°C to 3°C for 20-40 hours and the extract filtered.
  • the resulting acetone precipitate is dried resulting e.g. in about 0.03kg of a black powder.
  • the 0 acetone precipitate powder is dissolved in e.g. 0.6 kg distilled water, incubated for 2 hours at room temperature with agitation and filtered to obtain a yellow filtrate.
  • the pH of the filtrate is adjusted to pH 4.0 with acetic acid, sterile filtered through EKS plates, poured into bottles and preferably lyophilized at -27°C over 5 hours.
  • the sterile lyophilized filtrate is preferably vialed as a white powder, e.g. at 10 mg/vial.
  • the powder Prior to use the powder is resuspended in sterile saline.
  • the yield in the procedure is about 0.006 kg of Retilin from the illustrative 0.5 kg starting material.
  • EXAMPLE 8 show that retilin treatment was therapeutic in patients with secondary central chorioretinal dystrophy, i.e., as evidenced by increased visual acuity in every patient, improved visual perception to long and medium wavelength light, elimination of scotomas in the central visual field, a positive increase in color perception (distinction of blue color), and a significant reduction of dystrophic changes in the pigmented epithelium seen on fluorescent angiograms.
  • the retilin preparations of the invention are presently believed to be composed of natural biologically active peptides of a class termed "cytomedines".
  • the subject preparations offer advantages of providing therapeutic effects at very low dosages and without toxicity (as tested at the dosage ranges recited herein).
  • a purpose of therapy in an acute setting is to rapidly increase the concentration in a tissue, e.g., by bolus intravenous injection or infusion of a retilin preparation. Alternatively, in other cases it may desirable to deliver the retilin preparation over a longer period of time.
  • preparations themselves are water-soluble at the low concentrations at which they are usually employed, they may also be used in the form of their acid salts with pharmaceutically acceptable salts, e.g., acetic, citric, malic, or succinic acid.
  • Freely-soluble salts of retilin may also be converted to salts of low solubility in body fluids by modification with a slightly water-soluble pharmaceutically acceptable salt, e.g., tannic or palmoic acid, or by inclusion in a . time-release retilin formulation such as covalently coupled to a larger carrier protein or peptide, or in timed-release capsules and the like.
  • the acid addition salts of retilin with pharmaceutically acceptable acids will be biologically equivalent to the peptides themselves.
  • Pharmaceutically acceptable salts can be readily prepared from retilin by conventional methods.
  • such salts are, for example, prepared by treating an retilin with an aqueous solution of the desired pharmaceutically acceptable metallic hydroxide or other metallic base and evaporating the resulting solution to dryness, preferably under reduced pressure in a nitrogen atmosphere.
  • a solution of an retilin is mixed with an alkoxide to the desired metal, and the solution subsequently evaporated to dryness.
  • the pharmaceutically acceptable hydroxides, bases, and alkoxides include those with cations for this purpose, including (but not limited to), potassium, sodium, ammonium, calcium, and magnesium.
  • Other representative pharmaceutically acceptable salts include hydrochloride, hydrobromide, sulfate, bisulfate, acetate, oxalate, valarate, oleate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, furmarate, succinate, tartrate, and the like.
  • shelf life stability is improved by adding excipients such as: a) hydrophobic agents (e.g., glycerol); b) sugars (e.g., sucrose, mannose, sorbitol, rhamnose, xylose); c) complex carbohydrates (e.g., lactose); and/or d) bacteriostatic agents.
  • Pharmacokinetic half-life of the retilin preparations is modified by: a) encapsulation (e.g., in liposomes); b) controlling the degree of hydration (e.g.,. by controlling the extent and type of glycosylation of the peptide); and, c) controlling the electrostatic charge and hydrophobicity of the retilin preparation.
  • retilin preparations The route of delivery of the subject retilin preparations is determined by the particular disease. For topical application it is useful to apply retilin at the local site (e.g., by parabulbar injection, eye drops, or by placing an impregnated bandage over the eye while for other indications retilin is delivered by intravenous, intraperitoneal, intramuscular, subcutaneous, intranasal, and intradermal injection, as well as, by transdermal delivery (e.g., with a lipid-soluble carrier in a skin patch placed on the exterior of the eyelid), or even by gastrointestinal delivery (e.g., with a capsule or tablet).
  • transdermal delivery e.g., with a lipid-soluble carrier in a skin patch placed on the exterior of the eyelid
  • gastrointestinal delivery e.g., with a capsule or tablet.
  • the preferred therapeutic compositions for inocula and dosage will vary with the clinical indication.
  • the inocula is typically prepared from a dried retilin preparation (e.g., a lyophilized white powder) by suspending the preparation in a physiologically acceptable diluent such as water, saline, or phosphate-buffered saline.
  • a physiologically acceptable diluent such as water, saline, or phosphate-buffered saline.
  • retilin preparations were non-toxic when in rats, rabbits, and humans by gross pathologic examination and histologic examination during toxicology and pharmacology testing (in the disclosed dosage range).
  • Retilin preparations are administered alone or in combination with pharmaceutically acceptable carriers, in either single or multiple doses.
  • suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions, and various nontoxic organic solvents.
  • the pharmaceutical compositions formed by combining retilin with the pharmaceutically acceptable carrier are then readily administered in a variety of dosage forms such as tablets, lozenges, syrups, injectable solutions, and the like.
  • These pharmaceutical carriers can, if desired, contain additional ingredients such as flavorings, binders, excipients, and the like.
  • tables containing various excipients such as sodium citrate, calcium carbonate, and calcium phosphate are employed along with various disintegrants such as starch, and preferably potato or tapioca starch, alginic acid, and certain complex silicates, together with binding agents such as polyvinylpyrolidone, sucrose, gelatin, and acacia.
  • lubricating agents such as. magnesium sterate, sodium lauryl sulfate, and talc are often useful for tableting purposes.
  • Solid compositions of a similar type may also be employed as fillers in salt and hard-filled gelatin capsules. Prefe ⁇ ed materials for this purpose include lactose or milk sugar and high molecular weight polyethylene glycols.
  • aqueous suspensions of elixirs When aqueous suspensions of elixirs are ' desired for oral administration, the essential active retilin ingredient therein are combined with various sweetening or flavoring agents, colored matter or dyes, and if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, and combinations thereof.
  • diluents such as water, ethanol, propylene glycol, glycerin, and combinations thereof.
  • solutions of retilin in sesame or peanut oil or in aqueous polypropylene glycol are employed, as well as sterile aqueous saline solutions of the corresponding water soluble pharmaceutically acceptable metal salts previously described.
  • Such an aqueous solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal injection.
  • the sterile aqueous media employed are all readily obtainable by standard techniques well known to those skilled in the art. Additionally, it is possible to administer the aforesaid compounds topically (e.g., through a placed catheter) using an appropriate solution suitable for the purpose at hand.
  • the medicinal preparation "Retilin” is introduced parenterally, orally, retrobulbar introduction, peribulbar introduction, subconjunctivally, locally, and also in the form of eye instillation, dermal application, and during physical therapy in the structure of any medicinal form or composition. It is used as a solitary agent of medication or in combination with other medicinal preparations. Since the pharmacokinetics and pharmacodynamics retilin will vary in different patients, the most preferred method for achieving a therapeutic concentration in a tissue is to gradually escalate the dosage and monitor the clinical effects. The initial dose, for such an escalating dosage regimen of therapy, will depend upon the route of administration.
  • the optimal dosage range for the intramuscular or any other injection form of the preparation which is a lyophilized white powder store in vials and soluble in water for injection, goes from 0.02 to 2.0 mg per 1kg body weight in a single dose for adults (2-200 mg).
  • Retilin preferably is administered in the above-indicated dosages over a period of 1-30 days, depending on the character of the course and severity of the disease. The treatment course is repeated after 1 -6 months.
  • Retilin is compatible with preparations of various pharmacological groups and is used in combination with traditional therapy methods. Examples are given below, including testing in experimental animals and in human clinical trials, that illustrate the efficacy of the newly disclosed retilin treatments in ameliorating and eliminating retinal dystrophy.
  • EXAMPLE 1 The Effects of a Therapeutic Course of Retilin on the Function and Morphology of the Retina During Toxic Dystrophy
  • Retilin on the retina was investigated using an experimental animal model of dystrophy that occurs in the eyes of sexually mature chinchilla rabbits following intravenous injection of monoiodoacetic acid (MIAA).
  • MIAA monoiodoacetic acid
  • Experimental toxic retinal dystrophy was induced in 14 rabbits (each 2.5- 3.5 kg in mass) by the intravenous injection of a 4% solution of MIAA at doses of 15 mg/kg (i.e., inducing a severe degree of retinal damage) and 5 mg/kg (i.e., inducing a moderate degree of retinal damage).
  • the extent of the injury was assessed by measuring bioelectric activity of the retina using established electroretinography (ERG) procedures.
  • ERG recording was made under conditions of adaptation to darkness prior to injection of the monoiodoacetic acid (initial values) and again at 20 min., and 5, 10, 15 and 35 days after its injection.
  • the animals were divided into experimental and control groups.
  • each animal received daily, a single intramuscular injection of Retilin at a dose of 1 mg/kg; over the course of the entire experiment; and, starting on the 3rd day after the injection of the monoiodoacetic acid.
  • control group each animal was given an injection of sterile physiological solution using the same regimen of treatment as used with the experimental group (above).
  • MIAA 5mg/kg
  • Retilin 1 mg/kg
  • retilin treatment improves the function of an injured retina during dystrophic retinal disease induced by a toxic agent.
  • each animal received a corresponding injection of sterile physiological solution (i.e., according to the injection schedule of the experimental group).
  • sterile physiological solution i.e., according to the injection schedule of the experimental group.
  • the retinal edema observed microscopically at day 2 was still in evidence at day 7, and along the periphery of the retina there was an observed accumulation of pigment cells, i.e., situated closer to the corner of the eye.
  • a union of processes (i.e., one process with another) was observed in the ciliary body, along with the formation of "cavernous lacunae".
  • moderate retinal edema was still in evidence in the control (untreated) animals and amorphous foci were observed along the retinal periphery.
  • retilin treatment was consistent with those of a candidate therapeutic agent useful therapeutically for treating diseases with retinal sequelae leading to an impairment of retinal function, e.g., treatment of secondary chorioretinal dystrophy, retinopathies of various genesis, vesicular retinal impairment, macular degeneration and peripheral degeneration of the retina, retinal detachment and defects, retinal lesion induced by chemical or physical factors, and other chorioretinal disorders.
  • Retilin was prepared under sterile pharmaceutical good manufacturing process by homogenizing of surgically isolated animal retinas (e.g., 0.5 kg retinas from long horned cattle fundus) in 1:10-1:15 volumes (w/w) of 3% acetic acid (e.g., 5 kg) in the presence of zinc chloride ( lgram/ liter of acetic acid homogenate solution) and extracting the tissues in a cooled 4°C reactor vessel for 48-56 hours with periodic mixing (i.e., about 3 times/day for 1 hour each). The acetic acid extract was then centrifuged under conditions sufficient to remove tissue debris, (i.e., 20 min. at 3000 rpm).
  • tissue debris i.e., 20 min. at 3000 rpm
  • the clear supernatant solution was decanted and 1:10-1:20 volumes (w/w) of acetone were added (e.g., 34 kg).
  • Acetone extraction was carried out at a temperature of -1°C to 3°C for 20-40 hours and the extract was filtered.
  • the resulting acetone precipitate was dried resulting e.g. in about 0.03kg of a black powder.
  • the acetone precipitate powder was dissolved in e.g. 0.6 kg distilled water, incubated for 2 hours at room temperature with agitation and filtered to obtain a yellow filtrate.
  • the pH of the filtrate was adjusted to pH 4.0 with acetic acid, sterile filtered through EKS plates, poured into bottles and lyophilized at -27°C over 5 hours.
  • the sterile lyophilized filtrate was vialed as a white powder, e.g. at 10 mg/vial. Prior to use the powder was resuspended in sterile saline. The yield in the procedure was about 0.006 kg of retilin preparation from the 0.5 kg starting material.
  • Bioelectric activity was recorded by connecting a lead from the interior superior quadrant of the cornea using a contact lens-type electrode, to a BST-1 type electroencephalograph (GDR). Output signals from the electrode were transmitted to an F-37 analyzing unit for synchronous storage and averaging of results.
  • retilin was a candidate therapeutic agent potentially useful for in a variety of prophylactic regimens designed to inhibit development of retinal sequelae that are recognized to occur with high frequency in certain patient populations: e.g., secondary chorioretinal dystrophy, retinopathies of various genesis, vascular retinal impairment, macular degeneration and peripheral degeneration of the retina, retinal detachment and defects, retinal lesion induced by chemical or physical factors, and other chorioretinal disorders.
  • the animals of the control group (9 rats) were given corresponding injections of sterile physiological solution. Retinal function in the animals of both groups was evaluated using ERG recordings at day 30 and day 47 after birth. All the animals were kept under conditions of natural lighting. Just prior to the ERG recording, a rat was adapted to darkness for 2 hours. The ERG recording was taken under Nembutal anesthetic with the aid of a wick-type electrode in contact with the moistened cornea. The pupil was dilated by 1% atropine, and the cornea was anesthetized using a 0.25% solution of tetracaine hydrochloride. A white diffuser was used as a photostimulus.
  • retilin treatment in an experimental animal model were viewed to be highly supportive of retilin as a candidate therapeutic agent for use in clinical trials in medicinal preparations for treating such diseases as hereditary retinal dystrophy and congenital eye anomalies accompanied by impairment of retinal function.
  • Retilin Treatment Administered to Patients with Lesions of the Retina (362) and with Central Involutional Chorioretinal Dystrophy (Senile Macular Degeneration)
  • Group II patients treated in combination therapy with the pharmaceutical
  • Retilin (2 -3 mg daily for 10 days, peribulbar introduction) and the additional conventional therapy consisting of tissue extract, vitamin, and vasodilative therapy
  • Group m patients receiving only the tissue extract, vitamin, and vasodilative therapy but without Retilin treatment for 10 days (30 patients, 60 eyes) prior to evaluation.
  • the overall clinical presentation of the patients under observation in this study was characterized by the presence of dystrophic foci localized in the macular region and, in a number of cases, the foci were disseminated over the entire posterior pole of the eye. Visual acuity in all the patients was reduced to a significant degree; absolute and relative central scotomas were also observed within the visual field.
  • Prior to Retilin treatment the patients had in this study had received either single or repeat courses of support therapy, administered over a period of about 6 months, but they still evidenced a progressive clinical decline in visual function.
  • Retilin treatment was evaluated in 40 patients, all in the 50-60 year age group
  • Retilin treatment was administered by retrobulbar injections, i.e., into the thick part of the lower eyelid, at a dosage of .5 g for a single daily administration and repeated daily over a course of 5-10 days.
  • the control group consisted of 20 patients with central involutional chorioretinal dystrophy who were treated using traditional methods- In 25 of the 40 patients with central involutional chorioretinal dystrophy
  • Retilin Treatment of Other Retinal [362] as Illustrated by Treatment of Hereditary Central Tapetoretinal Abiotrophy of the Retina.
  • Retilin treatment was administered to 30 patients, 10 -35 years old (15 men, 15 women), all having diagnosed hereditary central tapetoretinal abiotrophy of Stargardt's type (362.75), Best's (vitellifo ⁇ n dystrophy; [362.76]) and Franceschenl's (fundus flavimaculatus; [362.76]) all in the developed and far advanced stage.
  • Retilin treatment was administered by retrobulbar injections, i.e., into the thick part of the inferior lid, in the involved eye at a dosage of 5 mg, given once daily over a period of 5-10 days.
  • the control group consisted of 20 patients with tapetoretinal abiotrophy who were treated using traditional methods.
  • a positive effect from retilin treatment wa-s also noted, as evidenced by: i) an elevation of visual acuity from 0.01 to 0.1, ii) widening of the peripheral boundaries of the visual field along various meridians from 5 to 10 degrees, iii) reduction of the dimensions of the central scotomas in the field of vision, and iv) a positive dynamic with respect to color perception.
  • Retilin treatment was administered to 103 patients, 13 -79 years of age (55 men, 48 women), having diagnosed pigmentary peripheral retinal abiotrophy (retinitis pigmentosa; [362.74]).
  • Retilin treatment was administered by peribulbar or intramuscular injections at a dosage of 10 mg, once daily over a period of 10 days (i.e., a retilin treatment course dose of 100 mg). The patients were given from 1 to 6 courses of retilin treatment.
  • a control group of 29 patients with diagnosed retinitis pigmentosa was treated using traditional methods (i.e., vasodilative agents, angio- protectors, anti-sclerotic preparations, vitamin and tissue therapy).
  • the patients in the control and experimental groups were examined in the clinic prior to treatment, and changes characteristic of pigmentary peripheral abiotrophy were confirmed in all patients: namely, i) a decline in visual acuity, ii) visual field disturbances (paracentral scotomas, circinate scotomas), i ⁇ ) color perception impairment, iv) dark adaptation impairment, v) pigmentation of the fundus ocuh, vi) characteristic "ceraceous" staining of the optic nerve; and, vii) in a number of cases, partial optic nerve atrophy and disruptions of the electrophysiological values (reduced "B" wave amplitude on an electroretinogram [ERG], reduced Arden's light/dark coefficient, abrupt rise in electrical sensitivity threshold).
  • ERP electroretinogram
  • TABLE 7 The results relating the number of patients (abs., absolute number) receiving 1, 2, 3, 4, 5 or 6 courses of Retilin treatment to the improvement in visual acuity, are summarized in TABLE 7, below.
  • the data in TABLE 7 are arranged so that the higher improvements acuity values appear first followed by poorer improvements, and both the number of eyes (abs.) having an acuity value falling within a particular range (abs.) and the percentage of eyes with that particular percentage increase are presented.
  • Rabkin's Before Treatment Injections Treatment Course table reads: abs. % abs. % abs. %
  • Rabkin's Control** 1 2 3 4 table reads: abs. % abs. % abs. % abs. % abs. %
  • results presented in TABLES 1 IA and 1 IB below show the pre- and post-treatment values, respectively, that were obtained by measuring the light sensitivity of patients with retinitis pigmentosa before and after Retilin treatment as a function of the length of time spent in darkness.
  • the results show that patients in the control group (treated using conventional methods) showed an insignificant improvement in light sensitivity in comparison with the pre-treatment values (by 0.3 - 0.4 optical density units).
  • Light sensitivity in patients receiving retilin either intramuscularly or by parabulbar administration, increased by more than 0.5 -1.9 optical density units (relative to the pretreatment values) and in certain cases were ore than two-fold greater than control values (shaded boxes in TABLE 1 IB). Consequently, light sensitivity values after retilin treatment were reliably greater in comparison with the control group.
  • Retilin treatment was administered to patients with secondary central chorioretinal dystrophy, the development of which was caused by the following disorders: namely, either (a) chorioretinal inflammation, scars, and other disorders of the choroid (363), in particular, posterior uveitis (363.20) and post-traumatic chorioretinal scars (363.3); (b) disorders of the optic nerve and visual pathways (377), in particular, optic neuritis (377.3); (c) retinal detachments and defects (361); or, (d) disorders of the globe (360), in particular, degenerative myopia (360.21). Forty patients having a diagnosed disease satisfying the study criteria of secondary central chorioretinal dystrophy were admitted into this clinical trial.
  • Retilin treatment was administered by retrobulbar injections into the thick part of the lower lid of the involved eye at a dosage of 5mg, once a day for 5 -10 days.
  • a control group consisted of 20 patients with secondary central chorioretinal dystrophy and the disease in these patients was treated using traditional methods.
  • SUBSTITUTE SHEET (RULE 2 ( . - 3. Mashkovskiy M. D. Medicinal agents. -- M., 1984, v. 1, pgs. 450, 456 - 457, 460; v. 2, pgs. 14, 75, 151.

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Abstract

Préparations pharmaceutiques destinées au traitement des dysfonctionnements rétiniens et consitutées d'une préparation de rétiline et d'un excipient pharamaceutiquement acceptable; utilisation de préparations de rétiline dans la fabrication de préparations pharmaceutiques destinées au traitement des dysfonctionnements rétiniens; et procédés de traitement des dysfonctionnements rétiniens par l'administration d'une préparation pharmaceutique de rétiline.
PCT/IB1994/000192 1993-06-17 1994-06-17 Compositions et procedes de traitement et de prevention des dysfonctionnements retiniens WO1995000156A1 (fr)

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US8946184B2 (en) 2005-02-14 2015-02-03 Archemix Llc Aptamer therapeutics useful in the treatment of complement-related disorders
RU2558976C2 (ru) * 2013-09-19 2015-08-10 Венера Айратовна Шаимова Способ прогнозирования развития витреоретинальной тракции при периферических дистрофиях сетчатки

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EP4159220A1 (fr) * 2006-03-08 2023-04-05 Archemix LLC Aptamères de liaison complémentaires et agents anti-c5 utiles dans le traitement des troubles oculaires
RU2301072C1 (ru) * 2006-06-22 2007-06-20 Общество С Ограниченной Ответственностью "Сиа Пептайдс" Средство, нормализующее функции кровеносных сосудов, и способ его получения

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DE2117057B2 (de) * 1971-04-07 1979-11-22 Biofarm Fabrica De Medicamente, Bukarest (Rumaenien) Verfahren zur Herstellung eines Arzneimittels zur Behandlung von Augenkrankheiten
EP0327769A2 (fr) * 1988-02-08 1989-08-16 FIDIA S.p.A. Facteur neuronotrophique
US5210185A (en) * 1988-03-18 1993-05-11 Fidia S.P.A. Human nerve growth factor
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V.B. DANILICHEV et al., "Lechenie Perifericheskoi Pigmentnoi Tapetorenalnoi Abiotrofii", 1992, OFTALMOLOGICHESKY ZHURNAL, KIEV, Agentstvo Semeinogo Vospitaniya, No. 3, p. 174-178. *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8946184B2 (en) 2005-02-14 2015-02-03 Archemix Llc Aptamer therapeutics useful in the treatment of complement-related disorders
US9617546B2 (en) 2005-02-14 2017-04-11 Archemix Llc Aptamer therapeutics useful in the treatment of complement-related disorders
US10947544B2 (en) 2005-02-14 2021-03-16 Archemix Llc Aptamer therapeutics useful in the treatment of complement-related disorders
US11913000B2 (en) 2005-02-14 2024-02-27 Iveric Bio, Inc. Aptamer therapeutics useful in the treatment of complement-related disorders
RU2558976C2 (ru) * 2013-09-19 2015-08-10 Венера Айратовна Шаимова Способ прогнозирования развития витреоретинальной тракции при периферических дистрофиях сетчатки

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