IT201900002913A1 - Compound useful for the treatment of glaucoma - Google Patents
Compound useful for the treatment of glaucoma Download PDFInfo
- Publication number
- IT201900002913A1 IT201900002913A1 IT102019000002913A IT201900002913A IT201900002913A1 IT 201900002913 A1 IT201900002913 A1 IT 201900002913A1 IT 102019000002913 A IT102019000002913 A IT 102019000002913A IT 201900002913 A IT201900002913 A IT 201900002913A IT 201900002913 A1 IT201900002913 A1 IT 201900002913A1
- Authority
- IT
- Italy
- Prior art keywords
- melatonin
- agomelatine
- glaucoma
- treatment
- concentration
- Prior art date
Links
- 208000010412 Glaucoma Diseases 0.000 title description 16
- 150000001875 compounds Chemical class 0.000 title 1
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 claims description 29
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 claims description 29
- 229960003987 melatonin Drugs 0.000 claims description 28
- 229960002629 agomelatine Drugs 0.000 claims description 24
- YJYPHIXNFHFHND-UHFFFAOYSA-N agomelatine Chemical compound C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 YJYPHIXNFHFHND-UHFFFAOYSA-N 0.000 claims description 23
- 239000003889 eye drop Substances 0.000 claims description 12
- 229940012356 eye drops Drugs 0.000 claims description 12
- 230000002265 prevention Effects 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000006196 drop Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000013589 supplement Substances 0.000 claims description 4
- 206010030348 Open-Angle Glaucoma Diseases 0.000 claims description 3
- 210000001742 aqueous humor Anatomy 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- 230000000699 topical effect Effects 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 241000700159 Rattus Species 0.000 description 3
- 230000001640 apoptogenic effect Effects 0.000 description 3
- 210000004560 pineal gland Anatomy 0.000 description 3
- 201000004569 Blindness Diseases 0.000 description 2
- 208000003098 Ganglion Cysts Diseases 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 2
- 208000005400 Synovial Cyst Diseases 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000027288 circadian rhythm Effects 0.000 description 2
- 238000011461 current therapy Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 206010022437 insomnia Diseases 0.000 description 2
- 230000004410 intraocular pressure Effects 0.000 description 2
- 210000001328 optic nerve Anatomy 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 1
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 1
- 102000006969 5-HT2B Serotonin Receptor Human genes 0.000 description 1
- 102000006902 5-HT2C Serotonin Receptor Human genes 0.000 description 1
- XYLJNLCSTIOKRM-UHFFFAOYSA-N Alphagan Chemical compound C1=CC2=NC=CN=C2C(Br)=C1NC1=NCCN1 XYLJNLCSTIOKRM-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 208000019838 Blood disease Diseases 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 101150013372 Htr2c gene Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010020864 Hypertrichosis Diseases 0.000 description 1
- 206010062530 Increased bronchial secretion Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000000913 Kidney Calculi Diseases 0.000 description 1
- 102100024930 Melatonin receptor type 1A Human genes 0.000 description 1
- 101710098568 Melatonin receptor type 1A Proteins 0.000 description 1
- 102100024970 Melatonin receptor type 1B Human genes 0.000 description 1
- 101710098567 Melatonin receptor type 1B Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- 206010029148 Nephrolithiasis Diseases 0.000 description 1
- RDHQFKQIGNGIED-QMMMGPOBSA-N O-acetyl-D-carnitine Chemical compound CC(=O)O[C@@H](CC([O-])=O)C[N+](C)(C)C RDHQFKQIGNGIED-QMMMGPOBSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 229960000571 acetazolamide Drugs 0.000 description 1
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000036626 alertness Effects 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 229940006133 antiglaucoma drug and miotics carbonic anhydrase inhibitors Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 208000008784 apnea Diseases 0.000 description 1
- 229960002610 apraclonidine Drugs 0.000 description 1
- IEJXVRYNEISIKR-UHFFFAOYSA-N apraclonidine Chemical compound ClC1=CC(N)=CC(Cl)=C1NC1=NCCN1 IEJXVRYNEISIKR-UHFFFAOYSA-N 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229960004324 betaxolol Drugs 0.000 description 1
- NWIUTZDMDHAVTP-UHFFFAOYSA-N betaxolol Chemical compound C1=CC(OCC(O)CNC(C)C)=CC=C1CCOCC1CC1 NWIUTZDMDHAVTP-UHFFFAOYSA-N 0.000 description 1
- 235000019611 bitter taste sensations Nutrition 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 231100001015 blood dyscrasias Toxicity 0.000 description 1
- 230000036471 bradycardia Effects 0.000 description 1
- 208000006218 bradycardia Diseases 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229960003679 brimonidine Drugs 0.000 description 1
- 229960000722 brinzolamide Drugs 0.000 description 1
- HCRKCZRJWPKOAR-JTQLQIEISA-N brinzolamide Chemical compound CCN[C@H]1CN(CCCOC)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 HCRKCZRJWPKOAR-JTQLQIEISA-N 0.000 description 1
- 229960004484 carbachol Drugs 0.000 description 1
- AIXAANGOTKPUOY-UHFFFAOYSA-N carbachol Chemical compound [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 description 1
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 description 1
- 229960001222 carteolol Drugs 0.000 description 1
- LWAFSWPYPHEXKX-UHFFFAOYSA-N carteolol Chemical compound N1C(=O)CCC2=C1C=CC=C2OCC(O)CNC(C)(C)C LWAFSWPYPHEXKX-UHFFFAOYSA-N 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 239000000064 cholinergic agonist Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000004452 decreased vision Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 229960003933 dorzolamide Drugs 0.000 description 1
- IAVUPMFITXYVAF-XPUUQOCRSA-N dorzolamide Chemical compound CCN[C@H]1C[C@H](C)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 IAVUPMFITXYVAF-XPUUQOCRSA-N 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 210000002745 epiphysis Anatomy 0.000 description 1
- 201000004949 exfoliation syndrome Diseases 0.000 description 1
- 210000004709 eyebrow Anatomy 0.000 description 1
- 210000000720 eyelash Anatomy 0.000 description 1
- 210000000744 eyelid Anatomy 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 208000018706 hematopoietic system disease Diseases 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 101150075901 htr2 gene Proteins 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 210000000554 iris Anatomy 0.000 description 1
- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 description 1
- 229960001160 latanoprost Drugs 0.000 description 1
- 229960000831 levobunolol Drugs 0.000 description 1
- IXHBTMCLRNMKHZ-LBPRGKRZSA-N levobunolol Chemical compound O=C1CCCC2=C1C=CC=C2OC[C@@H](O)CNC(C)(C)C IXHBTMCLRNMKHZ-LBPRGKRZSA-N 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 229960004083 methazolamide Drugs 0.000 description 1
- FLOSMHQXBMRNHR-DAXSKMNVSA-N methazolamide Chemical compound CC(=O)\N=C1/SC(S(N)(=O)=O)=NN1C FLOSMHQXBMRNHR-DAXSKMNVSA-N 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 208000001491 myopia Diseases 0.000 description 1
- 230000004379 myopia Effects 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 208000035824 paresthesia Diseases 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000007180 physiological regulation Effects 0.000 description 1
- 201000000041 pigment dispersion syndrome Diseases 0.000 description 1
- 230000019612 pigmentation Effects 0.000 description 1
- 229960001416 pilocarpine Drugs 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000010344 pupil dilation Effects 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000000862 serotonergic effect Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000008454 sleep-wake cycle Effects 0.000 description 1
- 235000019637 sour taste sensation Nutrition 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000019640 taste Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
Description
Breve descrizione dell’invenzione Brief description of the invention
La presente invenzione si riferisce ad un supplemento fisiologico o un medicamento per la prevenzione o il trattamento del glaucoma. In particolare la presente invenzione si riferisce alla agomelatina in combinazione con melatonina, in cui in detta combinazione i due principi attivi pur essendo a dosi molto basse (e quindi privi di controindicazioni fastidiose) mantengono una significativa attività terapeutica per la prevenzione o il trattamento del glaucoma ad angolo aperto. The present invention relates to a physiological supplement or medicament for the prevention or treatment of glaucoma. In particular, the present invention refers to agomelatine in combination with melatonin, in which in said combination the two active ingredients, despite being at very low doses (and therefore free of troublesome contraindications), maintain a significant therapeutic activity for the prevention or treatment of glaucoma open angle.
Sfondo dell’invenzione Background of the invention
Il glaucoma è la seconda causa di cecità nel mondo e può presentarsi in diverse età. Il glaucoma viene classificato in congenito, ad angolo aperto e ad angolo chiuso, in accordo alle cause sottostanti la diminuzione dell'efflusso di umor acqueo. Ogni categoria è poi suddivisa in forme primarie e secondarie (Coleman A.L., Glaucoma, Lancet 1999; 354: 1803-10). Queste ultime si presentano comunemente in corso di sindrome da esfoliazione, sindrome da dispersione del pigmento, infiammazione oppure neo vascolarizzazione. Glaucoma is the second leading cause of blindness worldwide and can occur at different ages. Glaucoma is classified into congenital, open angle and closed angle, according to the underlying causes of the decrease in the outflow of aqueous humor. Each category is then divided into primary and secondary forms (Coleman A.L., Glaucoma, Lancet 1999; 354: 1803-10). The latter commonly occur during exfoliation syndrome, pigment dispersion syndrome, inflammation or neo vascularization.
L'obiettivo della terapia del glaucoma è quello di prevenire l'ulteriore perdita di visione e di evitare un impatto negativo sulla qualità della vita del paziente. Le terapie attuali inducono una riduzione della pressione oculare tale da prevenire danni ulteriori a carico del nervo ottico. Infatti, la progressione del danno è determinata dai cambiamenti del nervo ottico o del campo visivo che sono consistenti con la perdita di più cellule gangliari o di assoni. The goal of glaucoma therapy is to prevent further vision loss and to avoid a negative impact on the patient's quality of life. Current therapies induce a reduction in ocular pressure such as to prevent further damage to the optic nerve. In fact, the progression of damage is determined by changes in the optic nerve or visual field that are consistent with the loss of multiple ganglion cells or axons.
Le classi di farmaci utilizzati nella terapia del glaucoma sono: The classes of drugs used in the treatment of glaucoma are:
-agonisti colinergici ad uso topico (es., pilocarpina, carbacolo), i quali incrementano l'efflusso di umor acqueo; gli effetti collaterali consistono in: incremento di secrezione bronchiale, nausea, vomito, diarrea, incremento della miopia, dolore oculare o del sopracciglio, riduzione della visione, apnea; -cholinergic agonists for topical use (eg pilocarpine, carbachol), which increase the outflow of aqueous humor; side effects consist of: increased bronchial secretion, nausea, vomiting, diarrhea, increased myopia, eye or eyebrow pain, decreased vision, apnea;
-antagonisti beta-adrenergici ad uso topico (es., timololo, carteololo, levobunololo, betaxololo), i quali riducono la produzione di umor acqueo; gli effetti collaterali consistono in: scompenso cardiaco congestizio, broncospasmo, bradicardia, depressione, confusione, impotenza, peggioramento della miastenia gravis, incremento ematico del colesterolo; - beta-adrenergic antagonists for topical use (eg, timolol, carteolol, levobunolol, betaxolol), which reduce the production of aqueous humor; side effects consist of: congestive heart failure, bronchospasm, bradycardia, depression, confusion, impotence, worsening of myasthenia gravis, blood cholesterol increase;
-agonisti adrenergici ad uso topico (es., epinefrina, apraclonidina, brimonidina), i quali riducono sia la resistenza all'efflusso che la produzione di umor acqueo; gli effetti collaterali consistono in: incremento della pressione sanguigna, tachiaritmie, tremori, ansia, dolor di testa, dilatazione della pupilla, reazioni allergiche; -adrenergic agonists for topical use (eg, epinephrine, apraclonidine, brimonidine), which reduce both resistance to efflux and the production of aqueous humor; side effects consist of: increased blood pressure, tachyarrhythmias, tremors, anxiety, headache, pupil dilation, allergic reactions;
-inibitori dell'anidrasi carbonica ad uso topico o per via orale (es., dorzolamide e brinzolamide topici; acetazolamide e metazolamide orali), i quali riducono la produzione di umor acqueo; gli effetti collaterali consistono in: malessere, anoressia, depressione, parestesie, anomalie degli elettroliti serici, calcoli renali, discrasie ematiche, reazioni allergiche; alterazioni del gusto (sensazione di gusto amaro o acido); - carbonic anhydrase inhibitors for topical or oral use (eg, topical dorzolamide and brinzolamide; oral acetazolamide and metazolamide), which reduce the production of aqueous humor; side effects consist of: malaise, anorexia, depression, paraesthesia, abnormalities of serum electrolytes, kidney stones, blood dyscrasias, allergic reactions; taste changes (bitter or sour taste sensation);
-analoghi delle prostangladine (es., latanoprost), i quali incrementano l'efflusso di umor acqueo per la via uveosclerale; gli effetti collaterali consistono in aumento di pigmentazione da parte dell'iride, delle ciglia, della cute palpebrale e ipertricosi. - analogues of prostangladins (eg latanoprost), which increase the efflux of aqueous humor through the uveoscleral path; side effects consist of increased pigmentation of the iris, eyelashes, eyelid skin and hypertrichosis.
Si comprende da quanto esposto finora che la terapia attuale è principalmente, se non esclusivamente, rivolta al controllo della pressione oculare mediante un'azione sull'umor acqueo, sia per quanto riguarda la sua produzione, sia il suo efflusso. It can be understood from what has been said so far that current therapy is mainly, if not exclusively, aimed at controlling ocular pressure through an action on aqueous humor, both as regards its production and its efflux.
Nel glaucoma vi è una progressiva degenerazione delle cellule gangliari, legata per alcune di esse all’evento apoptotico (N. Pescosolido e al. Acta Ophtalmologica Scandinavica, 1988, Supplement 227, 20-21). La morte cellulare per apoptosi è accompagnata anche da necrosi, per la quale non vi è ancora alcun mezzo per impedirla. Di converso, si può pensare di agire sul fenomeno apoptotico, esercitando di fatto una neuroprotezione (McKinnon, 1997, Curr. Op. Ophthalmol. 8: 28-37). Per quanto riguarda il modello di glaucoma basato sul meccanismo dell’apoptosi, si veda il summenzionato lavoro di Pescosolido e al. e la Tesi Sperimentale di Specializzazione Università degli Studi di Roma “La Sapienza”, Istituto di Oftalmologia, di Renata Rosa, Anno Accademico 2000-2001. In glaucoma there is a progressive degeneration of ganglion cells, linked for some of them to the apoptotic event (N. Pescosolido and al. Acta Ophtalmologica Scandinavica, 1988, Supplement 227, 20-21). Cell death from apoptosis is also accompanied by necrosis, for which there is still no means to prevent it. Conversely, one can think of acting on the apoptotic phenomenon, effectively exercising a neuroprotection (McKinnon, 1997, Curr. Op. Ophthalmol. 8: 28-37). As for the glaucoma model based on the mechanism of apoptosis, see the aforementioned work by Pescosolido et al. and the Experimental Thesis of Specialization University of Rome "La Sapienza", Institute of Ophthalmology, by Renata Rosa, Academic Year 2000-2001.
L'agomelatina è un farmaco di recente approvazione con una struttura molecolare molto simile a quella del neurotrasmettitore endogeno melatonina, da cui differisce per un solo atomo, utilizzato nel trattamento della depressione. Agomelatine is a recently approved drug with a molecular structure very similar to that of the endogenous neurotransmitter melatonin, from which it differs by only one atom, used in the treatment of depression.
L’agomelatina è metabolicamente più stabile rispetto alla melatonina e possiede perciò una più lunga durata d’azione. La molecola si lega da agonista ai recettori MT1 e MT2 della melatonina che sono coinvolti nella regolazione fisiologica del ritmo circadiano. Si lega inoltre da antagonista ai recettori 5-HT2C e 5-HT2B della serotonina. In studi sperimentali condotti sul ratto, induce una maggiore secrezione di noradrenalina e dopamina nella corteccia cerebrale frontale. Si ritiene che l'azione combinata sui recettori melatoninergici e serotoninergici sia, con ogni probabilità, alla base dell'effetto antidepressivo. In studi condotti su volontari sani l’agomelatina ha dimostrato di non alterare la vigilanza diurna e la memoria. Agomelatine is metabolically more stable than melatonin and therefore has a longer duration of action. The molecule agonist binds to the MT1 and MT2 receptors of melatonin which are involved in the physiological regulation of the circadian rhythm. It also binds as an antagonist to the 5-HT2C and 5-HT2B receptors of serotonin. In experimental studies in rats, it induces increased norepinephrine and dopamine secretion in the frontal cerebral cortex. It is believed that the combined action on the melatonergic and serotonergic receptors is, in all likelihood, the basis of the antidepressant effect. In studies conducted on healthy volunteers, agomelatine has been shown not to alter daytime alertness and memory.
La melatonina (chimicamente N-acetil-5-metossitriptammina) è un ormone prodotto dalla ghiandola pineale (o epifisi), ghiandola posta alla base del cervello. Agisce sull'ipotalamo e ha la funzione di regolare il ciclo sonno-veglia. Oltre che negli esseri umani, essa è prodotta anche da animali, piante (fitomelatonina) e microorganismi. Melatonin (chemically N-acetyl-5-methoxytryptamine) is a hormone produced by the pineal gland (or epiphysis), a gland at the base of the brain. It acts on the hypothalamus and has the function of regulating the sleep-wake cycle. In addition to humans, it is also produced by animals, plants (phytomelatonin) and microorganisms.
La melatonina fu isolata nel 1958 dall'urina di topo, dal professore di dermatologia Aaron B. Lerner, insieme a suoi colleghi della Università Yale, in ricerche mosse dall'aspettativa che la sostanza presente nella ghiandola pineale potesse essere utile nel trattamento di affezioni della pelle. Gli stessi ricercatori coniarono il nome melatonina. Melatonin was isolated from mouse urine in 1958 by dermatology professor Aaron B. Lerner, along with his colleagues at Yale University, in research driven by the expectation that the substance present in the pineal gland could be useful in the treatment of diseases of the skin. The same researchers coined the name melatonin.
Verso la metà degli anni settanta, Lynch et al. Dimostrarono che la produzione di melatonina da parte della ghiandola pineale umana segue un ritmo circadiano. La scoperta delle proprietà antiossidanti della melatonina è del 1993. In the mid-1970s, Lynch et al. They showed that the production of melatonin by the human pineal gland follows a circadian rhythm. The discovery of the antioxidant properties of melatonin dates back to 1993.
La melatonina è nota anche come regolatore sonno-veglia ed è utilizzata anche per il trattamento a breve termine dell'insonnia, in individui adulti. Melatonin is also known as a sleep-wake regulator and is also used for the short-term treatment of insomnia in adults.
Tecnica nota Known technique
Nel brevetto statunitense US 7.960.438 viene descritto l’uso della agomelatina nel trattamento dei disturbi di tipo “ansioso”. US Patent 7,960,438 describes the use of agomelatine in the treatment of "anxious" type disorders.
Nel brevetto statunitense US 5.449.683 viene descritto l’uso della melatonina, a basse dosi, nel trattamento dell'insonnia. In US Patent US 5,449,683 the use of melatonin, in low doses, in the treatment of insomnia is described.
Nel brevetto statunitense US 5.145.871 viene descritto l’uso della l’acetil D-carnitina nel trattamento del glaucoma. In US patent 5,145,871 the use of acetyl D-carnitine in the treatment of glaucoma is described.
In Opthalmic & Physiological Optics 35 (2015) 201-205 viene descritto l’uso dell’agomelatina, da sola, in pazienti con glaucoma. The use of agomelatine alone in patients with glaucoma is described in Opthalmic & Physiological Optics 35 (2015) 201-205.
In Advances in Pharmacological Sciences, Volume 2017, “Article ID 4320408”, viene descritto l’uso di numerosi agenti attivi, compresa l’agomelatina, utili nel trattamento del glaucoma. In Advances in Pharmacological Sciences, Volume 2017, "Article ID 4320408", the use of numerous active agents, including agomelatine, useful in the treatment of glaucoma is described.
Descrizione delle figure Description of the figures
In figura 1 viene mostrato il grafico relativo alla variazione della pressione intraoculare, nel tempo (ore) dopo somministrazione di un collirio/gocce oculari comprendenti lo 0,05% di agomelatina e lo 0,05% di melatonina; lo 0,075% di agomelatina e lo 0,075% di melatonina; o lo 0,1% di agomelatina e lo 0,1% di melatonina; in tre gruppi di ratti sani (ratti maschi SpragueDawley di 250 g; 10 ratti per gruppo). In questa figura viene mostrato che la combinazione secondo l’invenzione, alle dosi indicate, una goccia per occhio sia la mattina che la sera, riduce in modo rapido e significativo la pressione intraoculare. Figure 1 shows the graph relating to the variation in intraocular pressure over time (hours) after administration of eye drops / eye drops comprising 0.05% agomelatine and 0.05% melatonin; 0.075% of agomelatine and 0.075% of melatonin; o 0.1% agomelatine and 0.1% melatonin; in three groups of healthy rats (250 g SpragueDawley male rats; 10 rats per group). This figure shows that the combination according to the invention, at the indicated doses, one drop per eye both in the morning and in the evening, rapidly and significantly reduces intraocular pressure.
Alla data odierna ancora esiste la necessità di disporre di un farmaco o di un dispositivo medico che agisca sul fenomeno apoptotico delle cellule nervose, preservandole o almeno ritardando la loro morte, quindi la neurodegenerazione oculare. To date, there is still a need to have a drug or a medical device that acts on the apoptotic phenomenon of nerve cells, preserving them or at least delaying their death, hence ocular neurodegeneration.
Nel contempo è anche sentita l'esigenza di disporre di un farmaco/dispositivo medico che presenti ridotti effetti collaterali. At the same time, the need is also felt to have a drug / medical device with reduced side effects.
Descrizione dell’invenzione Description of the invention
È stato ora sorprendentemente trovato che l’agomelatina in combinazione con melatonina, in forma di collirio, ed a basse dosi, è utile per la prevenzione o il trattamento del glaucoma ad angolo aperto. It has now been surprisingly found that agomelatine in combination with melatonin, in the form of eye drops, and in low doses, is useful for the prevention or treatment of open-angle glaucoma.
È pertanto un oggetto della presente invenzione una composizione farmaceutica somministrabile per via oftalmica, in forma di collirio o gel, comprendente come principi attivi agomelatina in combinazione con melatonina, ed opzionalmente uno o più diluenti e/o eccipienti oftalmologicamente accettabili. Therefore, an object of the present invention is a pharmaceutical composition which can be administered by ophthalmic route, in the form of eye drops or gel, comprising as active ingredients agomelatine in combination with melatonin, and optionally one or more diluents and / or ophthalmologically acceptable excipients.
È un ulteriore oggetto della presente invenzione l’agomelatina in combinazione con melatonina, somministrabile per via oftalmica, ed opzionalmente uno o più diluenti e/o eccipienti oftalmologicamente accettabili, per uso per la prevenzione o il trattamento del glaucoma ad angolo aperto. A further object of the present invention is agomelatine in combination with melatonin, which can be administered by ophthalmic route, and optionally one or more diluents and / or ophthalmologically acceptable excipients, for use for the prevention or treatment of open-angle glaucoma.
È un ulteriore oggetto della presente invenzione l’agomelatina in combinazione con melatonina, in forma di gel o gocce oculari, per uso per la prevenzione o il trattamento del glaucoma in cui l’agomelatina e la melatonina sono presenti in un rapporto compreso tra 0,5:1 e 1:0,5, preferito è un rapporto compreso tra 0,75:1 e 1:0,75; particolarmente preferito è un rapporto di 1:1; in cui la concentrazione dell’agomelatina nel gel/collirio è preferibilmente dallo 0,05 allo 0,5%; preferita è una concentrazione dallo 0,075 allo 0,25%; molto preferita è una concentrazione dello 0,1%; mentre la concentrazione della melatonina nel collirio è preferibilmente dallo 0,05 allo 0,5%; preferita è una concentrazione dallo 0,075 allo 0,25%; molto preferita è una concentrazione dello 0,1%; ed opzionalmente uno o più diluenti e/o eccipienti oftalmologicamente accettabili. A further object of the present invention is agomelatine in combination with melatonin, in the form of gel or eye drops, for use for the prevention or treatment of glaucoma in which agomelatine and melatonin are present in a ratio between 0, 5: 1 and 1: 0.5, a ratio of 0.75: 1 to 1: 0.75 is preferred; particularly preferred is a ratio of 1: 1; in which the concentration of agomelatine in the gel / eye drops is preferably from 0.05 to 0.5%; preferred is a concentration of 0.075 to 0.25%; most preferred is a concentration of 0.1%; while the concentration of melatonin in the eye drops is preferably from 0.05 to 0.5%; preferred is a concentration of 0.075 to 0.25%; most preferred is a concentration of 0.1%; and optionally one or more ophthalmologically acceptable diluents and / or excipients.
È un ulteriore oggetto della presente invenzione l’agomelatina in combinazione con melatonina, in forma di gocce oculari, per uso per la prevenzione o il trattamento del glaucoma, in cui detta composizione è somministrata per via oftalmica in forma di collirio una goccia per occhio per due volte al giorno. A further object of the present invention is agomelatine in combination with melatonin, in the form of eye drops, for use for the prevention or treatment of glaucoma, in which said composition is administered by the ophthalmic route in the form of eye drops, one drop per eye for twice daily.
È un ulteriore oggetto della presente invenzione l’agomelatina in combinazione con melatonina, in forma di gocce oculari, per uso per la prevenzione o il trattamento del glaucoma, in cui detta composizione è somministrata per via oftalmica forma di supplemento fisiologico o di medicamento. A further object of the present invention is agomelatine in combination with melatonin, in the form of eye drops, for use for the prevention or treatment of glaucoma, in which said composition is administered by the ophthalmic route as a physiological supplement or medicine.
Per gli scopi della presente invenzione l’agomelatina in combinazione con melatonina saranno convenientemente formulati in una convenzionale composizione farmaceutica. For the purposes of the present invention, agomelatine in combination with melatonin will be conveniently formulated in a conventional pharmaceutical composition.
Tale composizione può essere preparata secondo le normali conoscenze del tecnico del ramo, ad esempio consultando il ben noto "Remington's Pharmaceutical Sciences, Mack Publishing and Co.". Such a composition can be prepared according to the usual knowledge of the person skilled in the art, for example by consulting the well known "Remington's Pharmaceutical Sciences, Mack Publishing and Co.".
La via di somministrazione preferita della composizione secondo l’invenzione è quella oculare/oftalmica, preferibilmente in forma di collirio. The preferred route of administration of the composition according to the invention is ocular / ophthalmic, preferably in the form of eye drops.
Le dosi e la posologia saranno determinate dal medico curante, secondo la propria esperienza, lo stato della patologia e le condizioni del paziente. A titolo indicativo, una dose di 1 goccia per occhio, per due volte al giorno (mattina e sera) è quella preferita. The doses and posology will be determined by the attending physician, according to his experience, the state of the pathology and the patient's condition. As an indication, a dose of 1 drop per eye, twice a day (morning and evening) is the preferred one.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT102019000002913A IT201900002913A1 (en) | 2019-03-01 | 2019-03-01 | Compound useful for the treatment of glaucoma |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT102019000002913A IT201900002913A1 (en) | 2019-03-01 | 2019-03-01 | Compound useful for the treatment of glaucoma |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IT201900002913A1 true IT201900002913A1 (en) | 2020-09-01 |
Family
ID=67002118
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IT102019000002913A IT201900002913A1 (en) | 2019-03-01 | 2019-03-01 | Compound useful for the treatment of glaucoma |
Country Status (1)
| Country | Link |
|---|---|
| IT (1) | IT201900002913A1 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5145871A (en) | 1988-12-01 | 1992-09-08 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Use of acetyl d-carnitine in the therapeutic treatment of glaucoma, and pharmaceutical compositions useful in such treatment |
| US5449683A (en) | 1992-10-01 | 1995-09-12 | Massachussetts Institute Of Technology | Methods of inducing sleep using melatonin |
| US7960438B2 (en) | 2006-04-07 | 2011-06-14 | Les Laboratoires Servier | Use of agomelatine in obtaining medicaments intended for the treatment of generalized anxiety disorder |
| ES2597827A1 (en) * | 2015-07-21 | 2017-01-23 | Ocupharm Diagnostics, Sl | Use of melatoninergic compounds to treat the ocular surface (Machine-translation by Google Translate, not legally binding) |
-
2019
- 2019-03-01 IT IT102019000002913A patent/IT201900002913A1/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5145871A (en) | 1988-12-01 | 1992-09-08 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Use of acetyl d-carnitine in the therapeutic treatment of glaucoma, and pharmaceutical compositions useful in such treatment |
| US5449683A (en) | 1992-10-01 | 1995-09-12 | Massachussetts Institute Of Technology | Methods of inducing sleep using melatonin |
| US7960438B2 (en) | 2006-04-07 | 2011-06-14 | Les Laboratoires Servier | Use of agomelatine in obtaining medicaments intended for the treatment of generalized anxiety disorder |
| ES2597827A1 (en) * | 2015-07-21 | 2017-01-23 | Ocupharm Diagnostics, Sl | Use of melatoninergic compounds to treat the ocular surface (Machine-translation by Google Translate, not legally binding) |
Non-Patent Citations (9)
| Title |
|---|
| "Remington's Pharmaceutical Sciences", MACK PUBLISHING AND CO. |
| A. CROOKE ET AL: "Update in Glaucoma Medicinal Chemistry: Emerging Evidence for the Importance of Melatonin Analogues", CURRENT MEDICINAL CHEMISTRY, vol. 19, no. 21, 1 June 2012 (2012-06-01), NL, pages 3508 - 3522, XP055529555, ISSN: 0929-8673, DOI: 10.2174/092986712801323234 * |
| ALMUDENA CROOKE ET AL: "Melatonin and Its Analog 5-Methoxycarbonylamino- N -Acetyltryptamine Potentiate Adrenergic Receptor-Mediated Ocular Hypotensive Effects in Rabbits: Significance for Combination Therapy in Glaucoma", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 346, no. 1, 16 April 2013 (2013-04-16), US, pages 138 - 145, XP055634021, ISSN: 0022-3565, DOI: 10.1124/jpet.112.202036 * |
| CHESNOKOVA N B ET AL: "Novel agonists of melatonin receptors as promising hypotensive and neuroprotective agents for therapy of glaucoma", BIOCHEMISTRY (MOSCOW). SUPPLEMENT SERIES B: BIOMEDICAL CHEMISTRY, MAIK NAUKA - INTERPERIODICA, RU, vol. 11, no. 3, 18 August 2017 (2017-08-18), pages 272 - 278, XP036300317, ISSN: 1990-7508, [retrieved on 20170818], DOI: 10.1134/S1990750817030039 * |
| COLEMAN A. L., GLAUCOMA, LANCET, vol. 354, 1999, pages 1803 - 10 |
| CURR. OP OPHTHALMOL, vol. 8, 1997, pages 28 - 37 |
| N. PESCOSOLIDO, ACTA OPHTALMOLOGICA SCANDINAVICA, 1988, pages 20 - 21 |
| NICOLA PESCOSOLIDO ET AL: "Oral treatment with the melatonin agonist agomelatine lowers the intraocular pressure of glaucoma patients", OPHTHALMIC AND PHYSIOLOGICAL OPTICS., vol. 35, no. 2, 1 March 2015 (2015-03-01), GB, pages 201 - 205, XP055529605, ISSN: 0275-5408, DOI: 10.1111/opo.12189 * |
| OPTHALMIC & PHYSIOLOGICAL OPTICS, vol. 35, 2015, pages 201 - 205 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6266674B2 (en) | Formulation of quinones for the treatment of eye diseases | |
| Sambhara et al. | Glaucoma management: relative value and place in therapy of available drug treatments | |
| DK2442647T3 (en) | Dithiolforbindelser, derivatives thereof, and the uses of these | |
| DE69911620T2 (en) | MUSCARINE ANTAGONISTS FOR TREATING PRESBYOPIA | |
| US6225348B1 (en) | Method of treating macular degeneration with a prostaglandin derivative | |
| Enyedi et al. | The effectiveness of latanoprost for the treatment of pediatric glaucoma | |
| JP2006503913A5 (en) | ||
| Martínez-Águila et al. | Melatonin analogue agomelatine reduces rabbit's intraocular pressure in normotensive and hypertensive conditions | |
| JP2016128523A (en) | Formulations of tocotrienol quinones for treatment of ophthalmic diseases | |
| Novack et al. | New glaucoma medications in the geriatric population: efficacy and safety | |
| CN104411678A (en) | Methods for the treatment of diabetic retinopathy and other ophthalmic diseases | |
| JP2008502724A (en) | Ophthalmic formulation containing a selective α1 antagonist | |
| Moore et al. | Pharmacologic management of glaucoma in childhood | |
| CN103338758A (en) | Folic acid - ramipril combination: cellprotective, neuroprotective and retinoprotective ophtalmologic compositions | |
| WO2005072066A2 (en) | Preventive or therapeutic agent for diabetic maculopathy | |
| Stine et al. | The effects of intravenous romifidine on intraocular pressure in clinically normal horses and horses with incidental ophthalmic findings | |
| JP2013520406A (en) | Citicoline for the treatment of glaucoma and ocular hypertension | |
| IT201900002913A1 (en) | Compound useful for the treatment of glaucoma | |
| IT9020968A1 (en) | PHARMACEUTICAL COMPOUND BASED ON AN ANOCYANIDINE FOR THE TREATMENT OF OPHTHALMIC DISEASES | |
| IT201800004380A1 (en) | Composition useful for the treatment of open angle glaucoma. | |
| Lewis et al. | Topical therapies for glaucoma: what family physicians need to know | |
| Day et al. | Timolol 0.5%/dorzolamide 2% fixed combination vs timolol maleate 0.5% and unoprostone 0.15% given twice daily to patients with primary open-angle glaucoma or ocular hypertension | |
| Weinreb et al. | Latanoprostene bunod, a dual-acting nitric oxide donating prostaglandin analog for lowering of intraocular pressure | |
| Sharif | Degeneration of retina-brain components and connections in glaucoma: Disease causation and treatment options for eyesight preservation | |
| WO2021003393A1 (en) | Method, composition, and apparatus for treating headache |