Screening method

Abstract

The invention relates to a method for identification of substances which are applicable for treatment or prevention of an insufficient longitudinal growth of the eye (hypermetropia) or for treatment or prevention of an excessive longitudinal growth of the eye (myopia); substances identified by the method for treating or preventing conditions related to the longitudinal growth of the eye; substances and mixtures of substances for the preparation of a pharmaceutical composition for the treatment or prevention of abnormal growth of the axial length of the eye. The identification involves measuring the effect of the substances on the retinal pigment epithelium of the eye, e.g. by detecting the metabolic effect of the substance on the retinal epithelium, the effect on the standing potential or the effect on the proteoglycanes of the scleral tissue of the eye, by way of EOG examination, by way on the size of the so-called c-wave in ERG-recordings, or by the state of the Ca 2+ -channels or on the [ 3 H]-ryanodine receptors of the retinal pigment epithelium.

1 . A method for screening substances effective of treating or preventing disorders of the eye related to the axial length of the eye comprising identifying substances based on an effect by the substance on the retinal pigment epithelium of an eye.  
     
     
         2 . The method according to  claim 1  further comprising administering the substance to an individual and measuring the effect of the substance on the retinal pigment epithelium of the individual upon administration.  
     
     
         3 . The method according to  claim 1  comprising administering the substance to an in vitro preparation of retinal pigment epithelium and measuring the effect of the substance on the retinal pigment epithelium therein.  
     
     
         4 . The method according to any of claims  1  and  2  wherein the effect on the retinal pigment epithelium is through an effect of the substance on the neuroretina.  
     
     
         5 . The method according to any of claims  1  and  2  wherein the substance further has an effect on the neuroretina.  
     
     
         6 . The method according to  claim 5  wherein the effect on the neuroretina also induces an effect on the retinal pigment epithelium.  
     
     
         7 . The method according to any of the preceding claims wherein the effect on the retinal pigment epithelium is on the ion exchange over the cell membrane of the retinal epithelium such as on the Ca 2+  exchange, e.g. through the receptors ryanodine receptor (RyR) and/or on the inositol trisphosphate (IP 3 ) receptor.  
     
     
         8 . The method according to any of the preceding claims wherein the effect on the retinal pigment epithelium is a metabolic effect.  
     
     
         9 . The method according to any of the preceding claims wherein the effect on the retinal pigment epithelium is an effect substantially directly on the retinal pigment epithelium compared to an effect through an effect on the neuroretina.  
     
     
         10 . The method according to any of the preceding claims wherein the effect of the substance on the retinal pigment epithelium is measured by means of the standing potential and/or on the amplitude of the c-wave by electro retinography (ERG).  
     
     
         11 . The method according to any of claims  9  and  10  wherein the effect on the retinal pigment epithelium is measured by means of the amplitude of the c-wave by electro retinography (ERG) and the effect on the neuroretina is measured by means of the amplitude of the a-wave and/or b-wave by electro retinography (ERG) upon administration of the substance.  
     
     
         12 . The method according to any of the preceding claims wherein the substance increases, upon administration or application of the substance, the standing potential and/or the amplitude of the c-wave measured by electro retinography (ERG) and/or increases ryanodine receptor (RyR) and/or inositol trisphosphate (IP 3 ) receptor binding.  
     
     
         13 . The method according to  claim 12  for identifying substances effective of inhibiting the longtitudinal growth of the eye.  
     
     
         14 . The method according to  claim 13  for identifying substances for the treatment or prevention of myopia.  
     
     
         15 . The method according to any of claims  1 - 11  wherein the substance decreases, upon administration or application of the substance, the standing potential and/or the amplitude of the c-wave measured by electro retinography (ERG) and/or decreases ryanodine receptor (RyR) and/or inositol trisphosphate (IP 3 ) receptor binding.  
     
     
         16 . The method according to  claim 15  for identifying substances effective of increasing the longtitudinal growth of the eye.  
     
     
         17 . The method according to  claim 16  for identifying substance for the treatment of hypermetropia.  
     
     
         18 . The method according to any of claims  12  and  15  wherein the increase or decrease, respectively, corresponds to at least 10% compared to the initial value, such as at least 20%, preferable at least 25%.  
     
     
         19 . The method according to any of the preceeding claims wherein the substance is a mixture of two or more substances.  
     
     
         20 . A method for screening substances effective of preventing or treating disorders of the eye related to the axial length of the eye comprising identifying substances having an effect on the composition of the proteoglycanes and/or the collagen specific amino acid present in the connective tissue of the sclera of the eye.  
     
     
         21 . The method according to  claim 20  comprising administering the substance to an animal and measuring the effect on the composition of the proteoglycanes and/or the collagen specific amino acid present in the connective tissue of the sclera upon administration.  
     
     
         22 . The method according to  claim 20  comprising administering the substance to an in vitro preparation of retinal pigment and scleral tissue and measuring the effect of the substance on the composition of the proteoglycanes and/or the collagen specific amino acid present in the tissue culture.  
     
     
         23 . The method according to  claim 20  comprising adding the substance to a tissue culture comprising fibroblasts and identifying the effect on the composition of the proteoglycanes and/or the collagen specific amino acid produced by the fibroblasts.  
     
     
         24 . The method according to any of claims  20 - 23  wherein the substance increases the content of proteglycanes of the sclera compared to the initial value.  
     
     
         25 . The method according to claims  22 - 24  wherein the substances effective of inhibiting the longtitudinal growth of the eye  
     
     
         26 . The method according to  claim 25  for identifying substances for the treatment of myopia.  
     
     
         27 . The method according to any of claims  20 - 23  wherein the substance decreases the content of proteglycanes of the sclera, in the tissue culture or in the in vitro preparation, respectively.  
     
     
         28 . The method according to  claim 27  for identifying substances effective of increasing the longtitudinal growth of the eye.  
     
     
         29 . The method according to  claim 28  for identifying substances for the treatment of hypermetropia.  
     
     
         30 . The method according to any of claims  21 - 29  wherein the effect of the substance is detectable within a period from about 1 week to about 12 weeks from the start of the treatment.  
     
     
         31 . The method according to any of claims  21 - 30  wherein the animal is a mammal, the tissue culture or the in vitro preparation is derived from an mammal, respectively.  
     
     
         32 . The miethod according to any of the preceeding claims wherein the substance is selected from the group consisting of prostaglandine and analogues thereof; and compounds of the general formula I, II or III  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 3 , R 7 , and R 9  are independently selected from the group consisting of hydrogen, optionally substituted C 1-20 -alkyl, optionally substituted C 2-20 -alkenyl, optionally substituted C 4-20 -alkadienyl, optionally substituted C 6-20 -alkatrienyl, optionally substituted C 2-20 -alkynyl, optionally substituted C 1-20 -alkoxycarbonyl, optionally substituted C 1-20 -alkylcarbonyl, formyl, optionally substituted aryl, optionally substituted aryloxycarbbnyl, optionally substituted arylcarbonyl, optionally substituted heteroaryl, optionally substituted heteroaryloxycarbonyl, optionally substituted heteroarylcarbonyl, carbamoyl, mono- and di(C 1-20 -alkyl)aminocarbonyl, mono- and di(C 1-20 -alkyl)amino-C 1-20 -alkyl-aminocarbonyl, and halogen such as fluoro, chloro, bromo or iodo, and 
 R 8  is selected from the group consisting of hydrogen, optionally substituted C 1-20 -alkyl, optionally substituted C 2-20 -alkenyl, optionally substituted C 4-20 -alkadienyl optionally substituted C 6-20 -alkatrienyl, optionally substituted C 2-20 -alkynyl, optionally substituted C 1-20 -alkoxy, optionally substituted C 2-20 -alkenyloxy, carboxy, hydroxy, optionally substituted C 1-20 -alkoxycarbonyl, optionally substituted C 1-20 -alkylcarbonyl, formyl, optionally substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted aryloxy, optionally substituted arylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroaryl, optionally substituted heteroaryloxycarbonyl, optionally substituted heteroaryloxy, optionally substituted heteroarylcarbonyl, amino, mono- and di(C 1-20 -alkyl)amino, carbamoyl, mono- and di(C 1-20 -alkyl)aminocarbonyl, amino-C 1-20 -aminocarbonyl, mono- and di(C 1-20 -alkyl)amino-C 1-20 -alkylaminocarbonyl, optionally substituted C 1-20 -alkylcarbonylamino, guanidino, carbamido, optionally substituted C 1-20 -alkanoyloxy, sulphono, optionally substituted C 1-20 -alkylsulphonyloxy, nitro, sulphanyl, optionally substituted C 1 20 -alkylthio, and halogen such as fluoro, chloro, bromo or iodo.  
 
     
     
         33 . Method according to  claim 32 , wherein R 1 , R 3 , R 7 , and R 9  are independently selected from the group consisting of hydrogen, optionally substituted C 1-6 -alkyl, optionally substituted C 2-6 -alkenyl, optionally-substituted C 2-6 -alkynyl, optionally substituted C 1-6 -alkylcarbonyl, formyl, optionally substituted aryl, optionally substituted arylcarbonyl, optionally substituted heteroaryl, and optionally substituted hetetoarylcarbonyl, and 
 R 8  is selected from the group consisting of hydrogen, optionally substituted C 1-6 -alkyl, optionally substituted C 2-6 -alkenyl, optionally substituted C 2-6 -alkynyl, optionally substituted C 1-6 -alkoxy, optionally substituted C 2-6 alkenyloxy, carboxy, hydroxy, optionally substituted C 1-6 -alkoxycarbonyl, optionally substituted C 1-6 -alkylcarbonyl, formyl, optionally substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted aryloxy, optionally substituted aryicarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroaryl, optionally substituted heteroaryloxycarbonyl, optionally substituted heteroaryloxy, optionally substituted heteroarylcarbonyl, amino, mono- and di(C 1-6 -alkyl)amino, carbamoyl, mono- and di(C 1-6 -alkyl)aminocarbonyl, optionally substituted C 1-6 -alkylcarbonylamino, guanidino, carbamido, optionally substituted C 1-6 -alkanoylpxy, sulphono, optionally substituted C 1-6 -alkylsulphonyloxy, nitro, sulphanyl, optionally substituted C 1-6 -alkylthio, and halogen such as fluoro, chloro, bromo or iodo.    
     
     
         34 . The method according to  claim 33 , wherein R 1 , R 3 , R 7  and R 9  are independently selected from the group consisting of hydrogen, optionally substituted C 1-6 -alkyl, optionally substituted C 2-6 -alkenyl, optionally substituted C 2-6 -alkynyl, optionally substituted aryl, and 
 R 8  is selected from the group consisting of hydrogen, optionally substituted C 1-6 -alkyl, optionally substituted C 2-6 -alkenyl, optionally substituted C 2-6 -alkynyl, optionally substituted C 1-6 -alkoxy, optionally substituted C 2-6 alkenyloxy, carboxy, hydroxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heteroarylcarbonyl, amino, nitro, sulphanyl, and halogen such as fluoro, chloro, bromo or iodo.    
     
     
         35 . Use of a substance having an effect on the retinal pigment epithelium identified according to the method described in any of the claims  1 - 34  for the preparation of a medicament for treating or preventing disorders of the eye related to the axial length of the eye.  
     
     
         36 . Use according to  claim 35  for the preparation of a medicament for topical application in the form of a preparation suitable for application on mucosa e.g. for application on eye mucosa e.g. eye drops, eye salve, eye gel, or an eye insert; or for application on nasal mucosa e.g. a nasal insert, a nasal drop or spray, a nasal ointment or gel.  
     
     
         37 . Use according to  claim 36  for the preparation of a medicament for topical application in the form of a powder, paste, ointment, lotion, gel, cream, emulsion, solution, suspension, spray, sponge, strip, plaster, pad, or dressing; or for the preparation of a medicament for implantation.  
     
     
         38 . Use according to  claim 35  for the preparation of a medicament for injection or systemic administration, characterized in that the medicament is in a form suitable for injection or systemic administration, e.g. a solution or a suspension.  
     
     
         39 . Use according to any of claims  35 - 38  wherein the concentration of the substance or mixture of substances is present in the medicament in an amount of 0.001-99%, typically 0.01-75%, more typically 0.1-20%, especially 1-10% by weight of the medicament.  
     
     
         40 . Method for treating or preventing disorders of the eye related to the axial length of the eye comprising administering to an individual in need thereof a therapeutically effective amount of one or more substances selected from the group of compounds of the general formula I, II or III  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 3 , R 7 , and R 9  are independently selected from the group consisting of hydrogen, optionnally substituted C 1-20 -alkyl, optionally substituted C 2-20 -alkenyl, optionally substituted C 4-20 -alkadienyl, optionally substituted c 6-20 -alkatrienyl, optionally substituted C 2-20 -alkynyl, optionally substituted C 1-20 -alkoxycarbonyl, optionally substituted C 1-20 -alkylcarbonyl, formyl, optionally substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroaryl, optionally substituted heteroaryloxycarbonyl, optionally substituted heteroarylcarbonyl, carbamoyl, mono- and di(C 1-20 -alkyl)aminocarbonyl, mono- and di(C 1-20 -alkyl)amino-C 1-20 -alkyl-aminotarbonyl, and halogen such as fluoro, chloro, bromo or iodo, and 
 R 8  is selected from the group consisting of hydrogen, optionally substituted C 1-20 -alkyl, optionally substituted C 2-20 -alkenyl, optionally substituted C 4-20 -alkadienyl, optionally substituted C 6-20 -alkatrienyl, optionally substituted C 2-20 -alkynyl, optionally substituted C 1-20 -alkoxy, optionally substituted C 2-20 -alkenyloxy, carboxy, hydroxy, optionally substituted C 1-20 -alkoxycarbonyl, optionally substituted C 1-20 -alkylcarbonyl, formyl, optionally substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted aryloxy, optionally substituted arylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroaryl, optionally substituted heteroaryloxycarbonyl, optionally substituted heteroaryloxy, optionally substituted heteroarylcarbonyl, amino, mono- and di(C 1-20 -alkyl)amino, carbamoyl, mono- and di(C 1-20 -alkyl)aminocarbonyl, amino-C 1-20 -alkylaminocarbonyl, mono- and di(C 1-20 -alkyl)amino-C 1-20 -alkylaminocarbonyl, optionally substituted C 1-20 -alkylcarbonylamino, guanidino, carbamido, optionally substituted C 1-20 -alkanoyloxy, sulphono, optionally substituted C 1-20 -alkylsulphonyloxy, nitro, sulphanyl, optionally substituted C 1-20 -alkylthio, and halogen such as fluoro, chloro, bromo or iodo.  
 
     
     
         41 . Method according to  claim 40 , wherein R 1 , R 3 , R 7 , and R 9  are independently selected from the group consisting of hydrogen, optionally substituted C 1-6 -alkyl, optionally substituted C 2-6 -alkenyl, optionally substituted C 2-6 -alkynyl, optionally substituted C 1-6 -alkylcarbonyl, formyl, optionally substituted aryl, optionally substituted arylcarbonyl, optionally substituted heteroaryl, and optionally substituted hetergarylcarbonyl, and 
 R 8  is selected from the group consisting of hydrogen, optionally substituted C 1-6 -alkyl, optionally substituted C 2-6 -alkenyl, optionally substituted C 2-6 -alkynyl, optionally substituted C 1-6 -alkoxy, optionally substituted C 2-6 -alkenyloxy, carboxy, hydroxy, optionally substituted C 1-6 -alkoxycarbonyl, optionally substituted C 1-6 -alkylcarbonyl, formyl, optionally substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted aryloxy, optionally substituted arylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroaryl, optionally substituted helteroaryloxycarbonyl, optionally substituted heteroaryloxy, optionally substituted heteroarylcarbonyl, amino, mono- and di(C 1-6 -alkyl)amino, carbamoyl, mono- and di(C 1-6 -alkyl)aminocarbonyl, optionally substituted C 1-6 -alkylcarbonylamino, guanidino, carbamido, optionally substituted C 1-6 -alkanoyloxy, sulphono, optionally substituted C 1-6 -alkylsulphonyloxy, nitro, sulphanyl, optionally substituted C 1-6 -alkylthio, and halogen such as fluoro, chloro, bromo or iodo.    
     
     
         42 . The method according to  claim 41 , wherein R 1 , R 3 , R 7  and R 9  are independently selected from the group consisting of hydrogen, optionally substituted C 1-6 -alkyl, optionally substituted C 2-6 -alkenyl, optionally substituted C 2-6 -alkynyl, optionally substituted aryl, and 
 R 8  is selected from the group consisting of hydrogen, optionally substituted C 1-6 -alkyl, optionally substituted C 2-6 -alkenyl, optionally substituted C 2-6 -alkynyl, optionally substituted C 1-6 -alkoxy, optionally substituted C 2-6 -alkenyloxy, carboxy, hydroxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted hetero-arylcarbonyl, amino, nitro, sulphanyl, and halogen such as fluoro, chloro, bromo or iodo.    
     
     
         43 . Method for treating and/or preventing myopia of a human eye comprising administering to an individual in need thereof a therapeutically effective amount of one or more substances selected from caffeine; 1,7-dimethylxanthine (paraxanthine), 7-methylxanthine (heteroxanthine), 3-methylxanthine; 1-methylxanthine, isobutylmethylxanthine (IBMX) and derivatives; 1-Hexyl-3,7-dimethylxanthine (pentifylline); 1,7-Dimethyl-xanthine; 1,3-Dipropyl-7-methyl-xanthine; 7-Propylxanthine; 7β-Chloroethyl-1,3-dimethylxanthine; 3,7-Dimethyl-1-propargyl-xanthine; 3-Propylxanthine; 1-(5-Oxohexyl)-3,7-dimethylxanthine (pentoxyfylline); 3-Isobutyl-1-methylxanthine; 3,9-Dimethylxanthine 8-Cyclopentyl-1,3-dimethylxanthine; 1,3-Bis(3-methylbut-2-butenyl-7-methylxanthine; 3,7-Dihydro-7-methyl-1,3-dipropyl-1H-purine-2,6-dione; 7-Methyl-1,3-diprenylxanthine(7-methyl-1,3-dipropyl-xanthine; 7-Ethoxymethyl-1-(5-hydroxy-5-methylhex-methylxanthine (Torbafylline, “HWA 448”); 1-(5 hydoxy-5-methylhexyl)-3-methyl-7-propylxanthine (A 80.2715); 3,7-Dimethyl-1-(5-oxyhexyl)-xanthine (Pentoxifylline, “Trental”); 3,7-Dimethyl-1-(5-hydroxyhexyl)-xanthine (Hydroxypentoxifylline); 1-Hexyl-3,7-dimethylxanthine (Pentifylline, “Cosaldon”); 3,7-Dimethyl-1-proparglyxanthine (DMPX); (E)-8-(3,4-Dimethoxystyryl)-1,3-dipropyl-7-methylxanthine (KF 17837)(Lisofylline); 1-(5-Hydroxy-5-methylhexyl)-3-methylxanthine (Albifylline, “HWA 138”): 3-Methyl-1-(5′-oxohexyl)-7-propylxanthine (Propeptofylline, “HWA 285”); 1-(5-Hydroxyhexyl)-3,7-dimethylxanthine (BL 194); (E)-1,3-dipropyl-8-(3,4-dimethoxystyryl)-7-methylxanthine (KF 17.837); 1,3-di-n-butyl-7-(2′oxopropyl)-xanthine (Denbufylline); 1-n-butyl-3-n-propylxanthine (XT-044); 7-(2,3-dihydroxypropyl)-theophylline (Dyphylline); 7-Methyl-8-(2-hydroxy-N-methylethylamino)-theophylline (Cafaminol); 7-(1,3-Dioxolan 2-ylmethyl)-theophylline (Doxofylline); 7-(2-Hydroxyethyl)-1,3-dimethylxanthine (Etofylline); 7-(2-Hydroxypropyl)-1,3-dimethylxanthine (Proxyphylline); Pyridoxine-O-(theophyllin-7-ylethyl)sulphate (Pyridofylline); 7-(2-(3-diethylcarbamoylpropionyloxy)ethyl)theophylline (Suxamidofylline); Piperazine bis (theophyllin-7-ylacetate)(Acepifylline); 8-benzyl-7-(2-(N-ethyl-N-2-hydroxyethylamino)ethyl)theophylline (Bamifylline); 2-amino-2-methylpropan-1-ol theophyllinate (Bufylline); 7-(2,3-Dihydroxypropyl)-1,3-dimethylxanthine (Diprophylline); 7-(2-diethylamoinoethyl)-1,3-dimethylxanthine camphor 10 sulphonate (Etamiphylline Camsylate); 3-Propylxanthine (Enprofylline); 4-amino-8-chloro-1-phenyl-(1,2,4)-triazolo (4,3-a)quinoxaline (CP 71366);  
       cysteine/cystine; glycine; forskoline; alpha-2-adrenergic agonist such as brimonidine (UK-14,304), clonidine, apraclonidine, dapiprazole, moxonidine (4-chloro-N-(4,5dihydro-1H-imidasol-2yl)-6-methoxy-2-methyl-5-pyridinamine), medetomidine, oxymetazoline, or derivatives thereof; peptides such as bradykinin, arginine vasopressin including V2 agonists, bombesine, substance P, pituitary adenylate cyclase activating polypeptide; somatostatftin analogues: such as tyril-somatostatin-14, Leu8,D-Trp22, and Tyr25-somatostatin-28 including agonists of somatostatin sst2 receptors, neuropeptide Y including agonists of Y2 receptors, and anlogues of these peptides; calcitriol or analogues of calcitriol or Vitamin D; muscarine receptor agonists such as the Carbachol, acetylincholine or analogues thereof; nonsteroidal anti-inflammatory drugs such as niflumic acid; prostaglandine and analogues thereof such as F2-alpha analogues inciuding PhXA41 (latanoprost), prostaglandin receptor agonists including PGF 2 alpha, 17-phenyl trinor PGE2, and U46619 FP, EP1, and TP receptor agonists), UF 021, 16-phenoxy-PGF2 alpha, cloprostenol, 17-phenyl-PGF2 alpha, fluprostenol, and PhXA85; Thapsigargin, A23187, Phosphodiesterase inhibitors including rolipram and Zaprinast, 4-chloro-3-ethylphenol and Bastidin, veratridine, esterogens including analogues thereof; Bay K 8644 (1,4-Dihydro-2,6-dimethyl-5-nitor-4-(2(triflouromethyl)-phenyl)-3-pyridinencarboxylic acid methyl ester; angiotensin converting enzyme inhibitors, in particular captopril (SQ 14225); adenosine A2-receptor agonists such as 5(N-ethyl)-.carboxamido adenosine -and-8-phenylaminoadenosine (CV-1808); Candoxatril (neutral endopeptidase 24.11 (NEP) inhibitor) Met-enkephalin, alphaendorphin or derivatives; and mixtures thereof.  
     
     
         44 . The method for treating or preventing myopia according to  claim 43  comprising a mixture of two or more substances having a synergistic effect on the myopia.  
     
     
         45 . The method for treating or preventing myopia according to any of claims  43  and  44  comprising caffeine or derivative thereof wherein the caffeine or the derivative thereof is administered in a dosage of 7.5-750 mg 1-4 times daily.  
     
     
         46 . The method for treating or preventing myopia according to any of claims  43 - 44  comprising cystein/cystin wherein the cystein/cystin is administered in a dosage of 20-2000 mg 1-4 times daily.  
     
     
         47 . The method for treating or preventing myopia according to any of claims  43 - 44  comprising forskoline wherein the forskoline is administered in a dosage of 5-560 mg 1-4 times daily.  
     
     
         48 . Method for treating and/or preventing hypermetropia of a human eye comprising administering to an individual in need thereof a therapeutically effective amounts of one or more substances selected from-theophylline; 3,7-dimethylxanthine (theobromine), xanthine; 1,9-dimethylxanthine; 1,3-Dipropyl-8-(2-(5,6-epoxynorbonyl)-xanthine; 8-Cyclopentyl-l,3-dipropylxanthine (CPDPX); 8-Sulphophenyltheophylline; 1,3-Dipropyl-8-(4-acrylate)phenylxanthine (BW-A1433); (1-Propyl-11C)8-dicyclopropylmethyl-1,3-dipropylxanthine (11C)KFP15372 and 11C-ethyl and 11C-methyl derivatives thereof; 8-Benzyl-7, (2-(ethyl(2-hydroxyethyl)amino)ethyl)theo-phylline (Bamiphylline); 8-Cyclopentyl-3-(3-((4-(flourosulfonyl)benzoyl)oxyl)pro-pyl)-1-propylxanthine; 1,3-Dipropyl-8-(4-((2-aminoethyl)amino)carbonylmethyl-oxyphenyl)xanthine; 8-(3-chlorostyryl)caffeine; 8-cyclopentyltheophylline; 8-(noradamantan-3 yl)-1,3-dipropylxanthine (KW-3902); 1,3-Dipropyl-8-(3-noradamantyl)-xanthine; 1,3-Dipropyl-8-(4-sulphpphenyl)-xanthine; 1,3-Dipropyl-8-(2-amino-4-chlorophenyl)-xanthine; 7β-Hydroxyethyl-1,3-dimethylxanthine; 7-(2,3-Dihydroxypropyl)-1,3-dimethylxanthine; 8-Chloro-1,3-dimethylxanthine; 1,3,9-Trimethylxanthine; 8-Propionic acid-1,3-dimethylxanthine; 7,9-Dimethylxanthine; 8-Phenyl-1,3-dimethylxanthine; 7-Acetic acid-1,3-dimethylxanthine; 9-Propylxantine; 9-Methlxanthne; 8-Methylxanthine; 8-(p-Sulfophenyl)-1,3-dimethylxanthine; 1,9-Dimethylxanthine; hypoxanthine; ethylendiamin; fluoxetine; L-ornithine; azetazolamid; bumetanide; Tamoxifen and other estrogen antagonists, the calmodulin antagonist J8, calcium antagonists including nimodipine and nicardipine, Endothelin agonist, in particular sarafotoxin S6c (selective ETB receptor agonist); Dorzolamide (MK-507), sezolamide and MK-927 (thienothiopyran-2-sulfonamide derivatives carbonic anhydrase inhibitors), methazolamide, ethoxzolamide, leuenkephalin or dervatives; and mixtures thereof.  
     
     
         49 . Method according to  claim 48  comprising a mixture of two or more substances having a synergistic effect on the hypermetropia.  
     
     
         50 . The method for treating or preventing hypermetropia according to any of claims  48 - 49  comprising L-orhinthine wherein the L-ornithine is administered in a dosage of 20-2000 mg 1-4 times daily.  
     
     
         51 . The method for treating or preventing hypermetropia according any of claims  48 - 49  comprising fluoxetin wherein the fluoxetin is administered in a dosage of 0.1-20 mg 1-4 times daily.  
     
     
         52 . The method for treating or preventing hypermetropia according any of claim  43 - 46  comprising azetozolamid wherein the azetazolamid is administered in a dosage of 5-500 mg 1-4 times daily.  
     
     
         53 . The method for treating or preventing hypermetropia according to any of claims  48 - 52  wherein theophylline and/or the 3-methylxanthin and/or 1-methylxanthine and/or xanthine is/are administered in a dosage of 7.5-750 mg 1-4 times daily.  
     
     
         54 . A method according to any of the preceeding claims wherein the substance is administered systemically.  
     
     
         55 . Pharmaceutical preparation for treating and/or preventing myopia of a human eye comprising a therapeutically effective amount of one or more substances selected from caffeine; 1,7-dimethylxanthine (paraxanthine), 7-methylxanthine (heteroxanthine) isobutylmethylxanthine (IBMX) and derivatives; 3-methylxanthine, 1-methylxanthine; 1-Hexyl3,7-dimethylxanthine (pentifylline); 1,7-Dimethyl-xanthine; 1,3-Dipropyl7-methyl-xanthine; 7-Propylxanthine; 7β-Chloroethyl-1,3-dimethylxanthine; C 3,7-Dimethyl-1-propargyl-xanthine, 3-Propylxanthine; 1-(5-Oxohexyl)-3,7-dimethylxanthine (pentoxyfylline); 3-Isobutyl-1-methylxanthine; 3,9-Dimethylxanthine 8-Cyclopentyl-1,3-dimethylxanthine; 1,3-Bis(3-methylbut-2-butenyl-7-methylxanthine; 3,7-Dihydro-7-methyl-1,3-dipropyl-1H-purine-2,6-dione; 7-Methyl-1,3-diprenylxanthine(7-methyl-1,3-dipropyl-xanthine; 7-Ethoxymethyl-1-(5-hydroxy-5-methylhex-methylxanthine (Torbafylline, “HWA 448”); 1-(5 hydoxy-5-methylhexyl)-3-methyl-7-propylxanthine (A 80.2715); 3,7-Dimethyl-1-(5-oxyhexyl)-xanthine (Pentoxifylline, “Trental ”); 3,7-Dimethyl-1-(5-hydroxyhexyl)-xanthine (Hydroxypentoxifylline); 1-Hexyl-3,7-dimethylxanthine (Pentifylline, “Cosaldon”); 3,7-Dimethyl-1-proparglyxanthine (DMPX); (E)-8-(3,4-Dimethoxystyryl)-1,3-dipropyl-7-methylxanthine (KF 17837)(Lisofylline); 1-(5-Hydroxy-5-methylhexyl)-3-methylxanthine (Albifylline, “HWA 138”): 3-Methyl-1-(5′-oxohexyl)-7-propylxanthine (Propentefylline, “HWA 285”); 1-(5-Hydroxyhexyl)-3,7-dimethylxanthine (BL 194); (E)-1,3-dipropyl-8-(3,4-dimethoxystyryl)-7-methylxanthine (KF 17.837); 1,3-di-n-butyl-7-(2′oxopropyl)-xanthine (Denbufylline); 1-n-butyl-3-n-propylxanthine (XT-044); 7-(2,3-dihydroxypropyl)-theophylline (Dyphylline); 7-Methyl-8-(2-hydroxy-N-!methylethylamino)-theophylline (Cafaminol); 7-(1,3-Dioxolan 2-ylmethyl)-theophylline (Doxofylline); 7-(2-Hydroxyethyl)-1,3-dimethylxanthine (Etofylline); 7-(2-Hydroxypropyl)-1,3-dimethylxanthine-(Pyoxypylline); Pyridoxine-O-(theophyllin-7-ylethyl)sulphate (Pyridofylline); 7-(2-(3-diethylcarbamoylpropionyloxy)ethyl)theophylline (Suxamidofylline); Piperazine bis (theophyllin-7-ylacetate)(Acepifylline); 8-benzyl-7-(2-(N-ethyl-N-2-hydroxyethylamino)ethyl)theophylline (Bamifylline); 2-amino-2-methylpropan-1-ol theophyllninate (Bufylline); 7-(2,3-Dihydroxypropyl)-1,3-dimethylxanthine (Diprophylline); 7-(2-diethylamoinoethyl)-1,3-dimethylxanthine camphor 10 sulphonate (Etamiphylline Camsylate); 3-Propylxanthine (Enprofylline); 4-amino-8-chloro-1-phenyl-(1,2,4)-triazolo (4,3-a)quinoxaline (CP 71366); cysteine/cystine; glycine; forskoline; alpha-2-adrenergic agonist such as brimonidine (UK-14,304), clonidine, apraclonidine, dapiprazole, moxonidine (4-chloro-N-(4,5 dihydro-1H-imidasol-2yl)-6-methoxy-2-methyl-5-pyridinamine), medetomidine, oxymetazoline, or derivatives thereof; peptides such as bradykinin, arginine vasopressin including V2 agonists, bombesine, substance P, pituitary adenylate cyclase activating polypeptide; somatostatin analogues such as Tyril-somatostatin-14, Leu8,D-Trp22, and Tyr25-somatostatin-28 including agonists of somatostatin sst2 receptors, neuropeptide Y including agonists of Y2 receptors, and anlogues of these peptides; calcitriol or analogues of calcitriol or Vitamin D; muscarine receptor agonists such asgthe Carbachol, acetylincholine or analogues thereof; nonsteroidal anti-inflamtmatory drugs such as niflumic acid; prostaglandine and analogues thereof such as F2 alpha analogues including PhXA41 (latanoprost), prostaglandin receptor agonists including PGF 2 alpha, 17-phenyl trinor PGE2, and U46619 FP, EP1, and TP receptor agonists), UF 021, 16-phenoxy-PGF2 alpha, cloprostenol, 17-phenyl-PGF2 alpha, fluprostenol, and PhXA85; Thapsigargin, A23187, Phosphodiesterase inhibitors including rolipram and Zaprinast, 4-chloro-3-ethylphenol and Bastidin, veratridine, esterogens including analogues thereof; Bay K 8644 (1,4-Dihydro-2,6-dimethyl-5-nitor-4-(2(triflouromethyl)-,Phenyl)-3-pyridinencarboxyllc acid methyl ester; angiotensin converting enzyme inhibitors, in particular captopril (SQ 14225); adenosine A2-receptor agonists such as 5′(N-ethyl)-carboxamido adenosine and 8-pheniylaminoadenosine (CV-1808); Candoxatril (neutral endopeptidase 24.11 (NEP) inhibitor); Met-enkephalin, alphaendorphin or derivatives; and mixtures thereof. and mixtures thereof together with a pharmaceutically acceptable carrier or excipient.  
     
     
         56 . Pharmaceutical preparation for treating and/or preventing hypermetropia of a human eye comprising a therapeutically effective amount of one or more substances selected from theophylline; 3,7-dimethylxanthine (theobromine); xanthine; 1,9-dimethylxanthine; 1,3-Dipropyl-8-(2-(5,6-epoxynorbonyl)-xanthine; 8-Cydlopentyl-1,3-dipropylxanthinle (CPDPX); 8-Sulphophenyltheophylline; 1,3-Dipropyl-8-(4-acrylate)phenylxanthine (BW-A1433); (1-Propyl-11C) 8-dicyclopropylmethyl-1,3-dipropylxanthine (11C)KF15372 and 11C-ethyl and 11C-methyl derivatives thereof; 8-Benzyl-7,(2-(ethyl(2-hydroxyethyl)amino)ethyl)theo-phylline (Bamiphylline); 8-Cyclopentyl-3-(3-((4-(flourosulfonyl)benzoyl)oxyl)pro-pyl)-1-propylxanthine; 1,3-Dipropyl-8-(4-((2-aminoethyl)amino)carbonylmethyl-oxyphenyl)xanthine; 8-(3-chlorostyryl)caffeine; 8-cyclopentyltheophylline; 8-(noradamantan-3 yl)-1,3-dipropylxanthine (KW-3902); 1,3-Dipropyl-8-(3-noradamantyl)-xanthine; 1,3-Dipropyl-8-(4-sulphophenyl)-xanthine; 1,3-Dipropyl-8-(2-amino-4-chlorophenyl)-xanthine; ethylendiamin; xanthine; hypoxanthine; fluoxetine; L-ornithine; azetazolamid; bumetanide; Tamoxifen and other estrogen antagonists, the calmodulin antagonist J8, calcium antagonists including nimodipine and nicadipine, Endothelin agonist, in particular sarafotoxin S6c (selective -ETB receptor agonist); Dorzolamide (MK-507), sezolamide and MK-927 (thienothiopyran-2-sulfonamide derivatives carbonic anhydrase inhibitors), methazolamide, ethoxzolamide, leuenkephalin or dervatives; and mixtures thereof together with a pharmaceutically acceptable carrier or excipient.  
     
     
         57 . Pharmaceutical preparation according to any of claims  55  and  56  in the form suitable for application on mucosa e.g. for application on eye mucosa e.g. eye drops, eye salve, eye gel, or an eye insert; or for application on nasal mucosa e.g. a nasal insert, a nasal drop-or spray, a nasal ointment or gel.  
     
     
         58 . Pharmaceutical preparation according to any of claims  55  and  56  in the form suitable for topical application on skin e.g. a powder, paste, ointment, lotion, gel, cream, emulsion, solution, suspension, spray, sponge, strip, plaster, pad, or dressing.  
     
     
         59 . Pharmaceutical preparation according to any of claims  55  and  56  in a form suitable for implantation, injection or systemic administration.  
     
     
         60 . Pharmaceutical preparation according to any of claims  55  and  56  in a form suitable for injection or systemic administration, e.g. a solution or a suspension.  
     
     
         61 . Pharmaceutical preparation according to any of claims  55 - 60  wherein the concentration of the substance or the mixture of substances is present in the medicament in an amount of 0.001-99%, typically 0.01-75%, more typically 0.1-20%, especially 1-10% by weight of the medicament.  
     
     
         62 . Pharmaceutical preparation according to any of claims  55 - 61  wherein the substance or the mixture of substance are extracted from natural sources.  
     
     
         63 . Use of a compound of the general formula I, II or III  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 3 , R 7 , and R 9  are independently selected from the group consisting of hydrogen, optionally substituted C 1-20 -alkyl, optionally substituted C 2-20 -alkenyl, optionally substituted C 4-20 -alkadienyl, optionally substituted C 6-20 , alkatrienyl, optionally substituted C 2-20  alkynyl, optionally substituted C 1-20 -alkcxycarbonyl, optionally substituted C 1-20 -alkylcarbonyl, formyl, optionally substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted arylcarbonyl, optionallysubstituted he teroaryl, optionally substituted heteroaryloxycarbonyl, optionally substituted heteroarylcarbonyl, carbamoyl, mono- and di(C 1-20 -alkyl)aminocarbonyl, mono- and di(C 1-20 -alkyl)amino-C 1-20 -alkyl-aminocarbonyl, and halogen such as fluoro, chloro, bromo or iodo, and 
 R 8  is selected from the group consisting of hydrogen, optionally substituted C 1-20 -alkyl, optionally substituted C 2-20 -alkenyl, optionally substituted C 4-20 -alkadienyl, optionally substituted C 6-20 -alkatrienyl, optionally substituted C 2-20 -alkynyl, optionally substituted C 1-20 -alkoxy, optionally substituted C 2-20 -alkenyloxy, carboxy, hydroxy, optionally substituted C 1-20 -alkoxycarbonyl, optionally substituted C 2-20 -alkylcarbonyl, formyl, optionally substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted aryloxy, optionally substituted arylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroaryl, optionally substituted heteroaryloxycarbonyl, optionally substituted heteroaryloxy, optionally substituted heteroarylcarbonyl, amino, mono- and di(C 1-20 -alkyl)amino, carbamoyl, mono- and di(C 1-20 -alkyl)aminocarbonyl, amino-C 1-20 -alkylaminocarbonyl, mono- and di(C 1-20 -alkyl)amino-C 1-20 -alkylaminocarbonyl, optionally substituted C 1-20 -alkylcarbonylamino, guanidino, carbamido, optionally substituted C 1-20 -alkanoyloxy, sulphono, optionally substituted C 1-20 -alkylsulphonyloxy, nitro, sulphanyl, optionally substituted C 1-20 -alkylthio, and halogen such as fluoro, chloro, bromo or iodo for the preparation of a medicament for treating or preventing disorders of the eye related to the axial length of the eye.  
 
     
     
         64 . Use according to  claim 63 , wherein R 1 , R 3 , R 7 , and R 9  are independently selected from the group consisting of hydrogen, optionally substituted C 1-6 -alkyl, optionally substituted C 2-6 -alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 -alkylcarbonyl, formyl, optionally substituted aryl, optionally substituted arylcarbonyl, optionally substituted heteroaryl, and optionally substituted heteroarylcarbonyl, and 
 R 8  is selected from the group consisting of hydrogen, optionally substituted C 1-6 -alkyl, optionally substituted C 2-6 -alkenyl, optionally substituted C 2-6 -alkynyl, optionally substituted C 1-6 -alkoxy, optionally substituted C 2-6 -alkenyloxy, carboxy, hydroxy, optionally substituted C 1-6 -alkoxycarbonyl, optionally substituted C 1-6 -alkylcarbonyl, formyl, optionally substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted aryloxy, optionally substituted arylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroaryl, optionally substituted heteroaryloxycarbonyl, optionally substituted heteroaryloxy, optionally substituted heteroarylcarbonyl, amino, mono- and di(C 1-6 -alkyl)amino, carbamoyl, mono- and di(C 1-6 -alkyl)amninocarbonyl, optionally substituted C 1-6 -alkylcarbonylamino, guanidino, carbamido, optionally substituted C 1-6 -alkanoyloxy, sulphono, optionally substituted C 1-6 -alkylsulphonyloxy, nitro, sulphanyl, optionally substituted C 1-6 -alkylthio, and halogen such as fluoro, chloro, bromo or iodo.    
     
     
         65 . Use according to  claim 64 , wherein R 1 , R 3 , R 7  and R 9  are independently selected from the group consisting of hydrogen, optionally substituted C 1-6 -alkyl, optionally substituted C 2-6 -alkenyl, optionally substituted C 2-6 -alkynyl, optionally substituted aryl, and 
 R 8  is selected from the group consisting of hydrogen, optionally substituted C 1-6 -alkyl, optionally substituted C 2-6 -alkenyl, optionally substituted C 2-6 -alkynyl, optionally substituted C 1-6 -alkoxy, optionally substituted C 2-6 -alkenyloxy, carboxy, hydroxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heteroarylcarbonyl, amino, nitro, sulphanyl, and halogen such as fluoro, chloro, bromo or iodo.    
     
     
         66 . Use according to any of claims  63 - 65  wherein the preparation is in the form suitable for application on mucosa e.g. for application on eye mucosa e.g. eye drops, eye salve, eye gel, or an eye insert; or for application on nasal mucosa e.g. a nasal insert, a nasal drop or spray, a nasal ointment or gel.  
     
     
         67 . Use according to any of claims  63 - 65  wherein the preparation is in the form suitable for topical application on skin e.g. a powder, paste, ointment, lotion, gel, cream, emulsion, solution, suspension, spray, sponge, strip, plaster, pad, or dressing.  
     
     
         68 . Use according to any of claims  63 - 65  wherein the preparation is in a form suitable for implantation, injection or systemic administration.  
     
     
         69 . Use according to any of claims  63 - 68  wherein the substance or the mixture of substances is present in the medicament in an amount of 0.001-99%, typically 0.01-75%, more typically 0.1-20%, especially 1-10% by weight of the medicament.  
     
     
         70 . Use according to any of claims  63 - 68  wherein the xanthine or substituted xanthine is present in a dosage of 7.5-750 mg and is administered 1-4 times daily.  
     
     
         71 . Use according to any of claims  63 - 70  excluding an implantat of  claim 68  
 wherein the medicament is intended for administration 1-4 times daily.  
 
     
     
         72 . Use-according to any of claims  63 - 71  wherein the substance or the mixture of substances are extracted from natural sources.