WO2012080273A1 - N- acetyl - l - cysteine for treatment of polycystic ovary syndrome - Google Patents
N- acetyl - l - cysteine for treatment of polycystic ovary syndrome Download PDFInfo
- Publication number
- WO2012080273A1 WO2012080273A1 PCT/EP2011/072643 EP2011072643W WO2012080273A1 WO 2012080273 A1 WO2012080273 A1 WO 2012080273A1 EP 2011072643 W EP2011072643 W EP 2011072643W WO 2012080273 A1 WO2012080273 A1 WO 2012080273A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cysteine
- acetyl
- pcos
- pharmaceutical composition
- nac
- Prior art date
Links
- 201000010065 polycystic ovary syndrome Diseases 0.000 title claims abstract description 116
- 238000011282 treatment Methods 0.000 title claims abstract description 86
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 title claims description 155
- 210000001672 ovary Anatomy 0.000 claims abstract description 30
- 208000002874 Acne Vulgaris Diseases 0.000 claims abstract description 15
- 206010000496 acne Diseases 0.000 claims abstract description 15
- 230000027758 ovulation cycle Effects 0.000 claims abstract description 14
- 206010020112 Hirsutism Diseases 0.000 claims abstract description 12
- 230000035935 pregnancy Effects 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 61
- 239000000203 mixture Substances 0.000 claims description 22
- 238000009472 formulation Methods 0.000 claims description 11
- 206010014733 Endometrial cancer Diseases 0.000 claims description 9
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 9
- 201000006828 endometrial hyperplasia Diseases 0.000 claims description 9
- 208000000509 infertility Diseases 0.000 claims description 9
- 230000036512 infertility Effects 0.000 claims description 9
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 8
- 230000037396 body weight Effects 0.000 claims description 8
- 231100000535 infertility Toxicity 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 230000002496 gastric effect Effects 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 4
- 230000001737 promoting effect Effects 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 239000004554 water soluble tablet Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 25
- 208000024891 symptom Diseases 0.000 abstract description 15
- 238000011269 treatment regimen Methods 0.000 abstract description 4
- 241001465754 Metazoa Species 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 26
- 238000000034 method Methods 0.000 description 17
- 206010028980 Neoplasm Diseases 0.000 description 16
- 201000011510 cancer Diseases 0.000 description 15
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 14
- 238000010606 normalization Methods 0.000 description 12
- 230000006870 function Effects 0.000 description 11
- 230000004069 differentiation Effects 0.000 description 10
- 230000035755 proliferation Effects 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 9
- 102000001332 SRC Human genes 0.000 description 8
- 108060006706 SRC Proteins 0.000 description 8
- 229940088597 hormone Drugs 0.000 description 8
- 239000005556 hormone Substances 0.000 description 8
- 102000004877 Insulin Human genes 0.000 description 7
- 108090001061 Insulin Proteins 0.000 description 7
- 235000018417 cysteine Nutrition 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 229940125396 insulin Drugs 0.000 description 7
- 230000002611 ovarian Effects 0.000 description 7
- 206010022489 Insulin Resistance Diseases 0.000 description 6
- 230000001028 anti-proliverative effect Effects 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000035558 fertility Effects 0.000 description 6
- 230000036470 plasma concentration Effects 0.000 description 6
- 230000030833 cell death Effects 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 5
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 4
- 201000009030 Carcinoma Diseases 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 208000009956 adenocarcinoma Diseases 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 230000024245 cell differentiation Effects 0.000 description 4
- 230000001351 cycling effect Effects 0.000 description 4
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 4
- 230000016087 ovulation Effects 0.000 description 4
- 230000002035 prolonged effect Effects 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 4
- 102000009151 Luteinizing Hormone Human genes 0.000 description 3
- 108010073521 Luteinizing Hormone Proteins 0.000 description 3
- 206010027339 Menstruation irregular Diseases 0.000 description 3
- 206010033128 Ovarian cancer Diseases 0.000 description 3
- 239000003098 androgen Substances 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 208000031513 cyst Diseases 0.000 description 3
- 150000001945 cysteines Chemical class 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 210000005168 endometrial cell Anatomy 0.000 description 3
- 239000003163 gonadal steroid hormone Substances 0.000 description 3
- 230000003054 hormonal effect Effects 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 208000021267 infertility disease Diseases 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 229940040129 luteinizing hormone Drugs 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 208000012237 paracetamol poisoning Diseases 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000002062 proliferating effect Effects 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 230000003248 secreting effect Effects 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 2
- 201000009273 Endometriosis Diseases 0.000 description 2
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 2
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 2
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 2
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 2
- 206010020864 Hypertrichosis Diseases 0.000 description 2
- 206010033307 Overweight Diseases 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 2
- 229960004308 acetylcysteine Drugs 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000001548 androgenic effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000008238 biochemical pathway Effects 0.000 description 2
- 230000008512 biological response Effects 0.000 description 2
- 239000000090 biomarker Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000011712 cell development Effects 0.000 description 2
- 230000003915 cell function Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229940011871 estrogen Drugs 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000003172 expectorant agent Substances 0.000 description 2
- 238000010195 expression analysis Methods 0.000 description 2
- 229940028334 follicle stimulating hormone Drugs 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 2
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 2
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 2
- 201000008980 hyperinsulinism Diseases 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000003914 insulin secretion Effects 0.000 description 2
- 230000001788 irregular Effects 0.000 description 2
- 210000002510 keratinocyte Anatomy 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 229940066491 mucolytics Drugs 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 229960005489 paracetamol Drugs 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000001850 reproductive effect Effects 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 229960003604 testosterone Drugs 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 208000016261 weight loss Diseases 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- PYTMYKVIJXPNBD-OQKDUQJOSA-N 2-[4-[(z)-2-chloro-1,2-diphenylethenyl]phenoxy]-n,n-diethylethanamine;hydron;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(/Cl)C1=CC=CC=C1 PYTMYKVIJXPNBD-OQKDUQJOSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 208000007788 Acute Liver Failure Diseases 0.000 description 1
- 206010000804 Acute hepatic failure Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010011732 Cyst Diseases 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 241001492220 Echovirus E2 Species 0.000 description 1
- 208000017701 Endocrine disease Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 101600111816 Homo sapiens Sex hormone-binding globulin (isoform 1) Proteins 0.000 description 1
- 102000003746 Insulin Receptor Human genes 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- 208000037093 Menstruation Disturbances Diseases 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102000002727 Protein Tyrosine Phosphatase Human genes 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 108010089417 Sex Hormone-Binding Globulin Proteins 0.000 description 1
- 102100030758 Sex hormone-binding globulin Human genes 0.000 description 1
- 102300044179 Sex hormone-binding globulin isoform 1 Human genes 0.000 description 1
- 208000037063 Thinness Diseases 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 210000004198 anterior pituitary gland Anatomy 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 1
- 229960003608 clomifene Drugs 0.000 description 1
- 229940046989 clomiphene citrate Drugs 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000037416 cystogenesis Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 230000000667 effect on insulin Effects 0.000 description 1
- 208000030172 endocrine system disease Diseases 0.000 description 1
- 230000002357 endometrial effect Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 230000003325 follicular Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000003648 hair appearance Effects 0.000 description 1
- 230000003803 hair density Effects 0.000 description 1
- 230000003779 hair growth Effects 0.000 description 1
- 108091008039 hormone receptors Proteins 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 230000000910 hyperinsulinemic effect Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- 230000004066 metabolic change Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000000510 mucolytic effect Effects 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 210000002394 ovarian follicle Anatomy 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 108020000494 protein-tyrosine phosphatase Proteins 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000007944 soluble tablet Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003573 thiols Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 206010048828 underweight Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
Definitions
- the present invention relates to a pharmaceutical composition comprising N-acetyl-L- cysteine useful for the treatment of polycystic ovary syndrome and indications associated with polycystic ovary syndrome.
- PCOS Polycystic ovary syndrome
- PCOS is properly characterized as a hormonal disorder, associated with excessive amounts or effects of androgenic hormones, leading to a variety of symptoms: lack of regular ovulation and therefore lack of regular menstrual cycle, acne, hirsutism and hypertrichosis (increased hair growth and hair density) and infertility.
- PCOS is often associated with metabolic syndrome, i.e. type 2 diabetes, with resulting elevated body mass index, obesity and increased risk for cardiovascular diseases.
- PCOS The molecular mechanisms underlying PCOS is not fully understood.
- the ovaries of affected patients are stimulated to produce male (androgenic) hormones, in particular testosterone.
- This stimulation may be caused by e.g. excessive release of luteinizing hormone (LH) by the anterior pituitary gland or by the ovaries responding to high levels of insulin in the blood (hyperinsulinemia). Insulin resistance could be a leading cause.
- Hyperinsulinemia affects the pulsing of gonadotropin-releasing hormone (GnRH) and thus the balance between LH and follicle-stimulating hormone (FSH), the ovarian androgen production, follicular maturation and binding of sex hormones to sex hormone-binding globulin (SHBG).
- SHBG in turn, regulates the bioavailability of sex hormones.
- PCOS is thus associated with a complex hormonal imbalance, which leads to cyst formation and the other symptoms associated with PCOS.
- PCOS cardiovascular disease
- Treatments have been developed to alleviate symptoms, e.g. to lower insulin levels, normalize menstruation, improve fertility, promote weight loss, reduce the symptoms of hirsutism and acne and prevent endometrial hyperplasia and cancer.
- These therapies include hormonal therapies with suppression of ovulation, insulin- sensitizing drugs, diet and exercise, and, in the most severe cyst cases, surgery. Recurrence after surgery is quite common.
- the hormonal treatments commonly used for PCOS related symptoms are often associated with unwanted side effects and may also further aggravate the situation for infertile women wanting to become pregnant.
- NAC N-acetyl-L-cysteine
- NAC has been proposed for the treatment of insulin resistance and insulin imbalances in women with PCOS.
- the use of NAC for the treatment of or symptoms associated with PCOS has been proposed.
- No efficient long term dosage regimen has been proposed.
- NAC N-acetyl-cysteine
- a pilot study Reproductive Biomedicine online (2010)20, 403-409 describes where NAC is used for the treatment of clomiphene citrate resistant PCOS women during 5 days a month starting on day 3 of the cycle for 12 consecutive cycles.
- Pittaluga E.et al More than antioxidant: N-acetyl-cysteine in a murine model of endometriosis, Fertility and Sterility, 2010, 94(7), 2905-2908 describes the use of NAC for the treatment of endometriosis.
- N-acetyl-L-cysteine N-acetyl-L-cysteine
- An aspect of the object is to provide a pharmaceutical composition of N-acetyl-L-cysteine (NAC) with an effective dosage regimen for a long-term treatment of PCOS and of symptoms related to PCOS.
- NAC could be used in new therapeutic strategies for improving insulin sensitivity and insulin circulating levels in patients with PCOS.
- the inventors of the present invention show that NAC has a much wider effect in the patients diagnosed with PCOS. For example, in patients treated with NAC ovary size is reduced, the number of follicles is reduced and menstrual cycle is normalized.
- the inventors of the present disclosure have previously shown that NAC induces complex molecular and cellular changes mainly related to inhibition of proliferation and induction of differentiation in cancerous epithelial tissue towards normal tissue.
- the clinical outcome of pulsed or intermittent treatment with NAC includes a restoration of sex hormones balance, amelioration of ultrasonographic aspects of the ovaries, with reduction in the number of folllicles, more regular periods, ovulation restoration, improvement of fertility and amelioration of skin and hair problems.
- the prescribed treatment regimen may be used e.g. in order to achieve a normalization of the ovary cortex functions, through a more regular proliferation-differentiation cycling, with a consequent normalization of estrogen-secretory functions of ovarian cells and normalization of menstrual cycle.
- the prescribed treatment regimen may be used e.g. to reduce ovary volume, to reduce the number of follicles, to obtain regular menstrual cycle, to reduce hirsutism, to reduce acne and/or to reduce body weight and body mass index.
- the prescribed treatment regimen may be used e.g.
- the present invention provides a pharmaceutical composition comprising N-acetyl-L- cysteine for use in the treatment of a mammal, including a human, having polycystic ovary syndrome (PCOS), where the composition is for pulsed or intermittent, oral administration, for a time period of two months or more, at a dose of N-acetyl-L- cysteine that is between 20 and 90 mg/kg/day on days when administered.
- PCOS polycystic ovary syndrome
- the pharmaceutical composition comprising N-acetyl-L-cysteine is for administration for 1-3 consecutive days, followed by 1-2 days of interruption.
- the pharmaceutical composition is for administration at a dose of N-acetyl-L-cysteine that is between 30 and 45 mg/kg/day on days when administered.
- the invention provides a pharmaceutical composition comprising N- acetyl-L-cysteine for the use described above where the pharmaceutical composition is protected from light.
- the pharmaceutical composition is a water soluble tablet.
- the pharmaceutical composition contains sodium hydrogen carbonate.
- the pharmaceutical composition is a slow-release formulation and/or a gastric protected formulation .
- the invention provides a pharmaceutical composition comprising N- acetyl-L-cysteine for reducing ovary volume and/or follicles number in a subject with PCOS.
- the pharmaceutical composition is for achieving regular menstrual cycle in a subject with PCOS.
- the pharmaceutical composition is for reducing body weight and body mass index in a subject with PCOS.
- the pharmaceutical composition is for treating infertility or promoting a desired pregnancy in a subject with PCOS.
- the pharmaceutical composition is for reducing acne and/or hirsutism in a subject with PCOS.
- the pharmaceutical composition is for treating insulinemia in a subject with PCOS.
- the pharmaceutical composition is for reducing the risk for cardiovascular diseases in a subject with PCOS.
- the pharmaceutical composition is for reducing the risk for endometrial hyperplasia and endometrial cancer in a subject with PCOS.
- the invention provides a method for the treatment of a mammal having PCOS, comprising orally administering a pharmaceutical composition comprising N- acetyl-L-cysteine to said mammal in a pulsed or intermittent dosage regimen, for a time period of two months or more, at a dose of N-acetyl-L-cysteine that is between 20 and 90 mg/kg/day on days when administered.
- a pharmaceutical composition comprising N- acetyl-L-cysteine to said mammal in a pulsed or intermittent dosage regimen, for a time period of two months or more, at a dose of N-acetyl-L-cysteine that is between 20 and 90 mg/kg/day on days when administered.
- the pharmaceutical composition is administered for 3-5 consecutive days followed by 2-4 days of interruption.
- the pharmaceutical composition is administered for 1-3 consecutive days, followed by 1-2 days of interruption.
- the dose of N-acetyl-L-cysteine is between 30 and 60 mg/kg/day on administration days. In another embodiment of the method the dose of N- acetyl-L-cysteine is between 30 and 45 mg/kg/day on administration days.
- the method is for reducing ovary volume in a subject with PCOS.
- the method is for achieving regular menstrual cycle in a subject with PCOS, for reducing body weight and body mass index in a subject with PCOS, for treating infertility in a subject with PCOS, for reducing acne and/or hirsutism in a subject with PCOS, for reducing insulinemia in a subject with PCOS, for reducing the risk for cardiovascular diseases in a subject with PCOS or for reducing the risk for endometrial hyperplasia and endometrial cancer in a subject with PCOS.
- Fig. 1 shows a diagram of the effect of NAC treatment on ovary diameter after three months of treatment. The ratio between final (D3) and initial (DO) average ovary diameter is reported for the right ( ⁇ ) and left ( ⁇ ) ovary, and for their average ( ⁇ ).
- N-acetyl-L-cysteine is a well known low molecular weight pharmaceutical drug, with the chemical formula
- NAC tripeptide gluthation
- GSH tripeptide gluthation
- Cysteine is indeed among the three aminoacids composing GSH, so NAC is considered a precursor of GSH with its de-acetylated cysteine.
- NAC has been and still is largely used as a mucolytic agent, where the mode of action is generally attributed to the redox breakage of sensitive cysteine disulfur bridges in the mucus proteins.
- NAC participates to the complex redox cycling of thiol groups, where several enzymes acts. Indeed, of extreme physiological importance is the disulfide formation and breakage cycle, a common mechanism by which protein activity and cellular signaling is regulated.
- Enzymes such as protein tyrosine phosphatases and tyrosine kinases, for example, play pivotal roles in the control of the cell cycle, cell proliferation and differentiation, and many of them are regulated by the redox state of their cysteines.
- NAC appears to act in all biochemical pathways where GSH does. Enzymes and proteins whose activity is modulated by GSH, or by the redox enzymes utilizing GSH, operate in several processes either directly or through a net of signals transduction pathways. In this picture, NAC may either parallel GSH action, or may be even more effective than GSH.
- GSH is e.g. normally conjugated to reactive metabolites formed by paracetamol and helps detoxify them. When paracetamol is overdosed GSH is however depleted and the paracetamol metabolites start reacting with cellular proteins, eventually leading to cell death.
- NAC acts instead of GSH in the detoxification of paracetamol metabolites.
- NAC is believed to be virtually absent of undesired side effect, which is also indicated by the high NAC doses that are used in the treatment of paracetamol poisoning, estimated, for a 70 kg individual, of about 40 g/day.
- NAC as an antiproliferative, differentiating agent
- NAC N-acetyl-L-cysteine
- NAC treatment could lead to a normalization of the ovary cortex functions, through a more regular proliferation-differentiation cycling, and thereby also to a normalization of estrogen-secretory functions and consequent normalization of menstrual cycle.
- the observations made in cancer will here be presented as a background to the effects of NAC and as a likely mode of action also in PCOS.
- NAC was used to arrest proliferation and induce differentiation in two adenocarcinoma cell lines and in primary normal keratinocyte cells, all of epithelial origin. In these systems, the differentiation was characterized morphologically, biochemically and through gene expression analysis (the gene expression analysis extensively reported in BMC Cancer 2005, 5: 75).
- physiological differentiation pathway which can be regarded as a normalization of cell functions towards the tissue of origin.
- NAC -treated cancer cells In addition to the decreased proliferation, the morphology of NAC -treated cancer cells was also altered.
- epithelial cells under active proliferation display an irregular morphology - a mesenchymal morphology - and often form several multiple cell layers.
- cells undergo a differentiation process toward the structure and function of their final target tissue, they stop proliferation, their morphology becomes regularly polygonal, each cell sometimes thicker, and they form a single layer of adjacent cells. This process is accompanied by increased cell-cell and cell- sub stratum junctions, consistent with a shift from a proliferating mesenchymal to an adhesive, less motile and differentiated phenotype.
- c-Src activity is crucial in the proliferation/differentiation switch, and c-Src is indeed activated and over expressed in a number of human cancers, particularly in colon and ovary carcinoma. Conspicuous international drug design efforts are presently devoted to the search of specific c-Src inhibitors.
- a simple treatment of adenocarcinoma cells with NAC can reach the objective of c-Src inhibition, with a mechanism related to redox transitions in sensitive cysteine residues in c-Src, able to switch off this kinase and to deliver it to endo-lysosomes, where it is stored or degraded.
- the NAC induced terminal differentiation in adenocarcinoma cells was related to the inhibition of c-Src.
- NAC affects the modulation of the cysteine redox status of hormone receptors relatively fast
- a re-normalization of the proliferation/differentiation pathway requires longer periods of time, which highlights the need of prolonged treatments with an effective dosage regimen.
- NAC had some advantageous effects on epithelial cancer cells and that those effects could also be useful in the treatment of ovary cortex cells and endometrial cells in PCOS, if such cells should respond similarly.
- consequencies of above points include: ovulation restoration, regularization of menstrual cycle, improvement of fertility, weight loss, decreased hirsutism and hypertrichosis, amelioration of acne, finally an overall amelioration of the patients' quality of life.
- NAC indeed reduces ovary size and follicles number, normalizes menstrual cycle, reduced BMI and ameliorates acne.
- a dosage regimen of NAC for the treatment of PCOS was developed based on the following criteria:
- composition of the present invention comprising NAC for the treatment of PCOS or indications associated with PCOS is according to one embodiment to be administered at a dose between approximately 20 and 90 mg/kg/day.
- the lower limit is based on twice the dose used for mucolytic action, i.e. it is per se known to have a physiological effect.
- the upper limit is based on the consideration that higher doses have been found to cause gastric problems in many patients.
- the composition comprises NAC to be administered at a dose of
- composition comprises NAC to be
- Examples include repeated schemes with treatment for 4 days followed by interruption for 3 days each week or treatment for 2 weeks followed by interruption 1 week.
- regular intermittent treatment is pulsed treatment, i.e. with regular treatment and interruption duration, e.g. administration every other day or administration for two days followed by two days of interruption etc.
- Irregular intermittent treatment schemes that are not regularly repeated or have a more complex scheme that is repeated is also conceivable, e.g. dependent on response to treatment.
- the prescribed dose of NAC is administered for 3-5 consecutive days followed by 2-4 days of interruption, or administered for 1-3 consecutive days followed by 1-2 days of interruption.
- the NAC dose is in the range between 1.2 and 5.4 g/day, preferably between 1.8 and 3.6 g/day, on days when administered.
- the dose may be divided in two or more, preferably three or four, daily administrations of either one or two doses (e.g. pills) each, where each dose may comprise e.g. 0.15-2.7 g of NAC or preferably 0.6-1.2 g of NAC.
- dose may comprise e.g. 0.15-2.7 g of NAC or preferably 0.6-1.2 g of NAC.
- the daily dose needs to be adjusted accordingly.
- the pharmaceutical composition for treatment of PCOS or PCOS related symptoms comprises NAC in a dose of 150-5400 mg to be administered in two or more administrations per day, for a period of at least 2 months, such as at least 3 months.
- the pharmaceutical composition comprises NAC in a dose of 230-3600 mg to be administered in two or more administrations per day, for a period of at least 2 months, such as at least 3 months.
- the pharmaceutical composition for treatment of PCOS or PCOS related symptoms comprises NAC to be administered in a single or more administrations per day, 3-5 days per week, for a period of at least 2 months, such as at least 3 months.
- a pharmaceutical composition according to the present invention may be prepared in a manner per se known by a person skilled in the pharmaceutical art.
- the composition may comprise an effective amount of NAC, in accordance with the invention, as well as a suitable carrier or excipient that serves as a vehicle or medium for the active ingredient.
- suitable carrier or excipients are known in the art and include solid materials such as citric acid, natrium citrate, natrium (acid) carbonate plus flavoring.
- the pharmaceutical composition is preferably adapted for oral administration. Such compositions could be administered in different forms, at present preferably as tablets. Other forms, such as capsules, suppositories, solutions, suspensions, syrups or the like are also conceivable.
- NAC is not a stable molecule, its active thiol residue can be easily oxidized by oxygen, light and other radiations, so that the effective dose would not be reached.
- the preparation is thus preferably protected from light, e.g. by a light protecting package such as a blister foil package.
- Soluble tablets preferably comprise sodium hydrogen carbonate, which helps in a partial removal of oxygen from water during dissolution.
- NAC neuropeptide containing a gastric protected formulation
- suitable for preventing NAC release/solubility in the stomach may be provided.
- Such formulations are well known in the art and may be used with the present invention.
- tablet coatings that are resistant to gastric fluids and allow release of the drug only in the intestine, after its transit through the stomach, may be used.
- Commonly used formulations include polymers such as cellulose derivatives, methacrylate amino ester copolymers.
- the coating protects the tablet core from disintegration in the acidic environment of the stomach by employing a pH sensitive polymer, which swells or solubilises after having passed through the stomach, in response to the increase in pH, whereafter the drug is released.
- NAC neuropeptide
- Another option is to lower the dose of NAC entering the blood stream at any one time. Administration of NAC three or more times daily can be difficult to accomplish for the patient. Nevertheless, a repeated administration can be desirable to achieve a nearly constant serum concentration of NAC. To overcome these problems, a once or twice-a- day administration could be easier to handle for the patient, for instance morning and night.
- One option is to provide NAC in a slow-release formulation (also denoted sustained-release or controlled-release). By being able to reduce the rate of diffusion and uptake of NAC into the blood stream such a formulation enables administration of a larger dose at longer intervals. The dose is then distributed in the blood over a long time in small quantities, e.g.
- the present invention has been shown to have beneficial properties in many aspects related to PCOS and may be used both for the treatment of PCOS and for treatment of various indications associated with PCOS.
- treatment of various indications associated with PCOS is meant e.g. treatment to reduce the symptoms of the disease such as irregular menstruation, overweight, hirsutism and acne.
- Such treatment of various indications associated with PCOS also includes e.g. treatment to reduce ovary volume and number of follicles, treatment to increase the likelihood of getting pregnant, treatment to reduce insulinemia and treatment to reduce the risk of cardiovascular diseases, endometrial hyperplasia and endometrial cancer in subjects diagnosed with PCOS.
- NAC has been shown to improve the quality of life of the patient in the absence of undesired side effects; to reduce ovary size and number of follicles, to ameliorate acne, hirsutism to produce more regular menstrual cycles and to decrease body mass index.
- the pharmaceutical composition comprises NAC for the treatment of PCOS in order to convert ovary cortex function, including estrogen secretory function, towards normal.
- the pharmaceutical composition comprises NAC for the treatment of PCOS in order to reduce symptoms associated with PCOS.
- the pharmaceutical composition comprises NAC for treating infertility or promoting a desired pregnancy in a subject with PCOS.
- the pharmaceutical composition comprises NAC for reducing ovary volume in a subject with PCOS.
- the pharmaceutical composition comprises NAC for achieving a regular menstrual cycle in a subject with PCOS. In another embodiment of the present invention the pharmaceutical composition comprises NAC for reducing hirsutism in a subject with PCOS.
- the pharmaceutical composition comprises NAC for reducing acne in a subject with PCOS.
- the pharmaceutical composition comprises NAC for reducing body weight and body mass index in a subject with PCOS.
- the pharmaceutical composition comprises NAC for reducing insulinemia in a subject with PCOS.
- the pharmaceutical composition comprises NAC for reducing the risk for cardiovascular diseases in a subject with PCOS.
- the present invention provides a method for treating a subject having PCOS by oral administration of a pharmaceutical composition comprising N- acetyl-L-cysteine, using the dosage regimen of the present invention.
- the method is for achieving regular menstrual cycle in a subject with PCOS.
- the method is for reducing body weight and body mass index in a subject with PCOS.
- the method is for treating infertility or promoting a desired pregnancy in a subject with PCOS.
- the method is for reducing acne and/or hirsutism in a subject with PCOS.
- the method is for reducing insulinemia in a subject with PCOS. In another embodiment of the present invention the method is for reducing the risk for cardiovascular diseases in a subject with PCOS.
- the method is for reducing the risk for endometrial hyperplasia and endometrial cancer in a subject with PCOS.
- the prescribed NAC dose was 30 mg/kg/day, corresponding for an average body weight of 60 kg, to three oral doses of 600 mg NAC, three times a day, for three consecutive days each week, with four days of interruption. This resulted in 1.8 g of NAC per day, 5.4 g per week, 21.6 g per month.
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a new prescription of NAC in the treatment of polycystic ovary syndrome (PCOS)and of symptoms associated with PCOS, in a human or mammalian animal patient. In addition an effective dose range of NAC in the treatment of PCOS is proposed, wherein the patient is treated for at least two months in a pulsed or intermittent fashion. The prescribed treatment regimen may be used e.g. in order to reduce ovary volume and number of follicles, achieve regular menstrual cycle, promote a desired pregnancy, ameliorate acne and/or hirsutism and reduce body mass index (BMI) in a subject with PCOS. Side effects of this treatment are virtually absent and, in particular, this treatment does not hinder pregnancy.
Description
N - ACETYL - L - CYSTEINE FOR TREATMENT OF POLYCYSTIC OVARY SYNDROME
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising N-acetyl-L- cysteine useful for the treatment of polycystic ovary syndrome and indications associated with polycystic ovary syndrome.
BACKGROUND
Polycystic ovary syndrome (PCOS) is a relatively common disease, affecting 5-10 % of women of reproductive age and is a leading cause of infertility. It is a complex endocrine disorder whose first symptoms include multiple ovary cysts and increased ovary volume. The cysts are actually immature ovarian follicles that have developed from primordial follicles but have been arrested at an early stage due to disturbed ovarian function. PCOS is properly characterized as a hormonal disorder, associated with excessive amounts or effects of androgenic hormones, leading to a variety of symptoms: lack of regular ovulation and therefore lack of regular menstrual cycle, acne, hirsutism and hypertrichosis (increased hair growth and hair density) and infertility. PCOS is often associated with metabolic syndrome, i.e. type 2 diabetes, with resulting elevated body mass index, obesity and increased risk for cardiovascular diseases.
Women with PCOS also are at risk of developing endometrial hyperplasia (benign proliferation of endometrial cells) and endometrial cancer.
The molecular mechanisms underlying PCOS is not fully understood. The ovaries of affected patients are stimulated to produce male (androgenic) hormones, in particular testosterone. This stimulation may be caused by e.g. excessive release of luteinizing hormone (LH) by the anterior pituitary gland or by the ovaries responding to high levels of insulin in the blood (hyperinsulinemia). Insulin resistance could be a leading cause. Hyperinsulinemia affects the pulsing of gonadotropin-releasing hormone (GnRH) and thus the balance between LH and follicle-stimulating hormone (FSH), the ovarian androgen production, follicular maturation and binding of sex hormones to sex hormone-binding globulin (SHBG). SHBG, in turn, regulates the bioavailability of sex
hormones. PCOS is thus associated with a complex hormonal imbalance, which leads to cyst formation and the other symptoms associated with PCOS.
There is currently no cure for PCOS. Treatments have been developed to alleviate symptoms, e.g. to lower insulin levels, normalize menstruation, improve fertility, promote weight loss, reduce the symptoms of hirsutism and acne and prevent endometrial hyperplasia and cancer. These therapies include hormonal therapies with suppression of ovulation, insulin- sensitizing drugs, diet and exercise, and, in the most severe cyst cases, surgery. Recurrence after surgery is quite common. The hormonal treatments commonly used for PCOS related symptoms are often associated with unwanted side effects and may also further aggravate the situation for infertile women wanting to become pregnant.
N-acetyl-L-cysteine (hereinafter referred to as NAC) is a well-known drug, which has been used mainly as a mucolytic agent and in the treatment of paracetamol poisoning. In recent years it has also been acknowledged as having other beneficial properties, such as being anti-inflammatory and anti-proliferative, and has been suggested for the treatment of a variety of different disorders and symptoms such as diabetes and cancer.
NAC has been proposed for the treatment of insulin resistance and insulin imbalances in women with PCOS. The use of NAC for the treatment of or symptoms associated with PCOS has been proposed. No efficient long term dosage regimen has been proposed.
PRIOR ART
Following some earlier publications showing that NAC improves insulin secretion in response to glucose and affects the regulation of the insulin receptor in human erythrocytes Anna Maria Fulghesu et. al. set out to evaluate the effect of NAC on insulin secretion and peripheral insulin resistance in patients with PCOS (Fertility and Sterility 2002, Vol. 77, No.6, pages 1128-1135). It was shown that, by administering NAC to women with PCOS, at a dose of 1.8 g/day (normal weight persons) or 3 g/day (obese persons) for 5-6 weeks, peripheral insulin sensitivity as well as insulin circulating levels improved in hyperinsulinemic patients. The decrease in circulating insulin levels was also followed by a reduction in testosterone and androgen levels. No effect was seen in normoinsulinemic patients.
Other background art, describing the molecular effect of NAC in the treatment of cancer, include T. Parasassi, et. al. (Cell Death and Differentiation, 2005, Vol. 12, No. 10, pages 1285-1296); E. K. Krasnowska et. al. (Free Radicals Biology and Medicine 2008, 45(11): 1566-72) and A. C. Gustafsson et. al. (BMC Cancer, 2005, 5:75).Nasr A., Effect of N-acetyl-cysteine after ovarian drilliing in clomiphene citrate-resistent PCOS women: a pilot study, Reproductive Biomedicine online (2010)20, 403-409 describes where NAC is used for the treatment of clomiphene citrate resistant PCOS women during 5 days a month starting on day 3 of the cycle for 12 consecutive cycles. Pittaluga E.et al, More than antioxidant: N-acetyl-cysteine in a murine model of endometriosis, Fertility and Sterility, 2010, 94(7), 2905-2908 describes the use of NAC for the treatment of endometriosis.
OBJECTS OF THE INVENTION
The clinical outcome, other than the effect on insulin sensitivity and androgen levels, of NAC treatment in PCOS has, to the knowledge of the inventors, not been determined in the prior art, nor has an efficient long tern dosage regimen for the treatment of PCOS or the use of NAC for the treatment of indications associated with PCOS been proposed.
It is therefore a general object of the present invention to provide a solution to the problem of providing a pharmaceutical composition of N-acetyl-L-cysteine (NAC) for the treatment of PCOS and symptoms associated with PCOS. An aspect of the object is to provide a pharmaceutical composition of N-acetyl-L-cysteine (NAC) with an effective dosage regimen for a long-term treatment of PCOS and of symptoms related to PCOS.
SUMMARY OF THE INVENTION
It has previously been proposed that NAC could be used in new therapeutic strategies for improving insulin sensitivity and insulin circulating levels in patients with PCOS. The inventors of the present invention show that NAC has a much wider effect in the patients diagnosed with PCOS. For example, in patients treated with NAC ovary size is reduced, the number of follicles is reduced and menstrual cycle is normalized. The
inventors of the present disclosure have previously shown that NAC induces complex molecular and cellular changes mainly related to inhibition of proliferation and induction of differentiation in cancerous epithelial tissue towards normal tissue.
These findings have led the inventors of the present invention to propose a new prescription of NAC in the treatment of PCOS and of indications associated with PCOS, in a human or mammalian animal patient. In addition an effective dose range of NAC in the treatment of PCOS is proposed. Given a reported decreased plasma level of NAC after prolonged periods of treatment, the inventors propose a pulsed or intermittent treatment. The clinical outcome of pulsed or intermittent treatment with NAC includes a restoration of sex hormones balance, amelioration of ultrasonographic aspects of the ovaries, with reduction in the number of folllicles, more regular periods, ovulation restoration, improvement of fertility and amelioration of skin and hair problems.
In one embodiment of the present invention the prescribed treatment regimen may be used e.g. in order to achieve a normalization of the ovary cortex functions, through a more regular proliferation-differentiation cycling, with a consequent normalization of estrogen-secretory functions of ovarian cells and normalization of menstrual cycle. In aspects of the present invention the prescribed treatment regimen may be used e.g. to reduce ovary volume, to reduce the number of follicles, to obtain regular menstrual cycle, to reduce hirsutism, to reduce acne and/or to reduce body weight and body mass index. In still other aspects of the present invention the prescribed treatment regimen may be used e.g. to improve fertility and allow a desired pregnancy, to reduce insulinemia and to reduce the risk of cardiovascular diseases, endometrial hyperplasia and endometrial cancer. As opposed to the current hormone treatments, side effects of the treatment with the composition according to the invention are virtually absent, highly improving the quality of life for the treated patients. In particular, this treatment does not hinder pregnancy.
The present invention provides a pharmaceutical composition comprising N-acetyl-L- cysteine for use in the treatment of a mammal, including a human, having polycystic ovary syndrome (PCOS), where the composition is for pulsed or intermittent, oral
administration, for a time period of two months or more, at a dose of N-acetyl-L- cysteine that is between 20 and 90 mg/kg/day on days when administered.
In one embodiment the invention provides a pharmaceutical composition comprising N- acetyl-L-cysteine for the above mentioned use where the composition is for
administration for 3-5 consecutive days followed by 2-4 days of interruption. In another embodiment the pharmaceutical composition comprising N-acetyl-L-cysteine is for administration for 1-3 consecutive days, followed by 1-2 days of interruption.
In one embodiment the invention provides a pharmaceutical composition comprising N- acetyl-L-cysteine for the above mentioned use where the composition is for
administration at a dose of N-acetyl-L-cysteine that is between 30 and 60 mg/kg/day on days when administered. In another embodiment the pharmaceutical composition is for administration at a dose of N-acetyl-L-cysteine that is between 30 and 45 mg/kg/day on days when administered. In one embodiment the invention provides a pharmaceutical composition comprising N- acetyl-L-cysteine for the use described above where the pharmaceutical composition is protected from light. In another embodiment the pharmaceutical composition is a water soluble tablet. In still another embodiment the pharmaceutical composition contains sodium hydrogen carbonate. In one embodiment the pharmaceutical composition is a slow-release formulation and/or a gastric protected formulation .
In one embodiment the invention provides a pharmaceutical composition comprising N- acetyl-L-cysteine for reducing ovary volume and/or follicles number in a subject with PCOS. In another embodiment the pharmaceutical composition is for achieving regular menstrual cycle in a subject with PCOS. In still another embodiment the pharmaceutical composition is for reducing body weight and body mass index in a subject with PCOS. In one embodiment the pharmaceutical composition is for treating infertility or promoting a desired pregnancy in a subject with PCOS. In another embodiment the pharmaceutical composition is for reducing acne and/or hirsutism in a subject with PCOS. In still another embodiment the pharmaceutical composition is for treating insulinemia in a subject with PCOS. In one embodiment the pharmaceutical
composition is for reducing the risk for cardiovascular diseases in a subject with PCOS. In another embodiment the pharmaceutical composition is for reducing the risk for endometrial hyperplasia and endometrial cancer in a subject with PCOS.
In one aspect the invention provides a method for the treatment of a mammal having PCOS, comprising orally administering a pharmaceutical composition comprising N- acetyl-L-cysteine to said mammal in a pulsed or intermittent dosage regimen, for a time period of two months or more, at a dose of N-acetyl-L-cysteine that is between 20 and 90 mg/kg/day on days when administered. In one embodiment of the method the pharmaceutical composition is administered for 3-5 consecutive days followed by 2-4 days of interruption. In another embodiment the pharmaceutical composition is administered for 1-3 consecutive days, followed by 1-2 days of interruption.
In one embodiment of the method the dose of N-acetyl-L-cysteine is between 30 and 60 mg/kg/day on administration days. In another embodiment of the method the dose of N- acetyl-L-cysteine is between 30 and 45 mg/kg/day on administration days.
In one embodiment the method is for reducing ovary volume in a subject with PCOS. In other embodiments the method is for achieving regular menstrual cycle in a subject with PCOS, for reducing body weight and body mass index in a subject with PCOS, for treating infertility in a subject with PCOS, for reducing acne and/or hirsutism in a subject with PCOS, for reducing insulinemia in a subject with PCOS, for reducing the risk for cardiovascular diseases in a subject with PCOS or for reducing the risk for endometrial hyperplasia and endometrial cancer in a subject with PCOS.
BRIEF DESCRIPTION OF THE FIGURE
The invention will be explained in more detail in the following description, referring to the enclosed figure, where:
Fig. 1 shows a diagram of the effect of NAC treatment on ovary diameter after three months of treatment. The ratio between final (D3) and initial (DO) average ovary diameter is reported for the right (■) and left (·) ovary, and for their average (♦).
DETAILED DESCRIPTION OF THE INVENTION
NAC in general
N-acetyl-L-cysteine (NAC) is a well known low molecular weight pharmaceutical drug, with the chemical formula
MAC
The features of NAC are mainly related to its thiol group, which makes it effective in most biochemical pathways where the tripeptide gluthation (GSH), present in all human tissues at relatively high concentrations, even above 10 mM, acts. Cysteine is indeed among the three aminoacids composing GSH, so NAC is considered a precursor of GSH with its de-acetylated cysteine. NAC has been and still is largely used as a mucolytic agent, where the mode of action is generally attributed to the redox breakage of sensitive cysteine disulfur bridges in the mucus proteins. In fact NAC participates to the complex redox cycling of thiol groups, where several enzymes acts. Indeed, of extreme physiological importance is the disulfide formation and breakage cycle, a common mechanism by which protein activity and cellular signaling is regulated.
Enzymes such as protein tyrosine phosphatases and tyrosine kinases, for example, play pivotal roles in the control of the cell cycle, cell proliferation and differentiation, and many of them are regulated by the redox state of their cysteines.
Overall, although detailed mechanisms of action have not been finally elucidated, NAC appears to act in all biochemical pathways where GSH does. Enzymes and proteins whose activity is modulated by GSH, or by the redox enzymes utilizing GSH, operate in several processes either directly or through a net of signals transduction pathways. In this picture, NAC may either parallel GSH action, or may be even more effective than GSH.
GSH is e.g. normally conjugated to reactive metabolites formed by paracetamol and helps detoxify them. When paracetamol is overdosed GSH is however depleted and the paracetamol metabolites start reacting with cellular proteins, eventually leading to cell death. In the treatment of fulminant hepatic failure after paracetamol poisoning NAC acts instead of GSH in the detoxification of paracetamol metabolites. NAC is believed to be virtually absent of undesired side effect, which is also indicated by the high NAC doses that are used in the treatment of paracetamol poisoning, estimated, for a 70 kg individual, of about 40 g/day.
Contrary to the tripeptide GSH, which can be degraded already in the stomach, the simple NAC molecule freely diffuses in almost all tissues and cells. NAC
pharmacokinetic studies determined a peak concentration in plasma reached in about one hour, with a half-life of about three hours. Total clearance occurs between six and twelve hours.
NAC as an antiproliferative, differentiating agent
The inventors have recently found that N-acetyl-L-cysteine (NAC) possesses a marked antiproliferative effect on cancer cells of epithelial origin - the same origin as of ovarian and endometrial cells (Cell Death and Differentiation 2005, 12(10): 1285- 1296). This antiproliferative effect of NAC was due to the activation of a physiological differentiation pathway, associated with a normalization of cell function towards the tissue of origin. Although cancer and PCOS are principally unrelated diseases the observed effects of NAC eventually led the inventors to the idea that NAC might also be useful in the treatment of PCOS. In particular, in PCOS the abnormal secretory functions are possibly related to defects in the differentiation of ovarian cells. Therefore NAC treatment could lead to a normalization of the ovary cortex functions, through a more regular proliferation-differentiation cycling, and thereby also to a normalization of estrogen-secretory functions and consequent normalization of menstrual cycle. The observations made in cancer will here be presented as a background to the effects of NAC and as a likely mode of action also in PCOS.
NAC was used to arrest proliferation and induce differentiation in two adenocarcinoma cell lines and in primary normal keratinocyte cells, all of epithelial origin. In these
systems, the differentiation was characterized morphologically, biochemically and through gene expression analysis (the gene expression analysis extensively reported in BMC Cancer 2005, 5: 75).
As stated above, the antiproliferative effect of NAC, in the study of cancer, was not related to cell death or to toxicity but, instead, was due to the activation of a
physiological differentiation pathway, which can be regarded as a normalization of cell functions towards the tissue of origin.
In addition to the decreased proliferation, the morphology of NAC -treated cancer cells was also altered. In vitro, epithelial cells under active proliferation display an irregular morphology - a mesenchymal morphology - and often form several multiple cell layers. On the contrary, when cells undergo a differentiation process, toward the structure and function of their final target tissue, they stop proliferation, their morphology becomes regularly polygonal, each cell sometimes thicker, and they form a single layer of adjacent cells. This process is accompanied by increased cell-cell and cell- sub stratum junctions, consistent with a shift from a proliferating mesenchymal to an adhesive, less motile and differentiated phenotype.
On a whole, a complex series of metabolic changes were detected after NAC
supplementation to cancer cells, all converging in arresting the uncontrolled
proliferation and in inducing their terminal differentiation.
As an example of the ability of NAC to modulate signal transduction in cells through the redox status of sensitive cysteines, the enzyme non-receptor tyrosine kinase c-Src was studied in an in vitro model of colon carcinoma (CaCo-2) cells and ovary carcinoma (OVCAR-3) cells (Free Radicals Biology and Medicine 2008, 45(11): 1566- 72). c-Src activity is crucial in the proliferation/differentiation switch, and c-Src is indeed activated and over expressed in a number of human cancers, particularly in colon and ovary carcinoma. Conspicuous international drug design efforts are presently devoted to the search of specific c-Src inhibitors. Instead, it was found that a simple treatment of adenocarcinoma cells with NAC can reach the objective of c-Src inhibition, with a mechanism related to redox transitions in sensitive cysteine residues in c-Src, able to switch off this kinase and to deliver it to endo-lysosomes, where it is stored or
degraded. Thus, the NAC induced terminal differentiation in adenocarcinoma cells was related to the inhibition of c-Src.
The affinity of receptors for their ligand hormones is often modulated through the redox status of crucial cysteine residues, with the formation/breakage of disulfur bridges. The observation that NAC could alter the redox status of sensitive cysteines in c-Src lead to the idea that the effect of NAC in PCOS can be related to a restored proper affinity of receptors for their hormone ligands, including insulin, rather than or in addition to appropriate hormone levels for a normalized secretion.
In this respect, while NAC affects the modulation of the cysteine redox status of hormone receptors relatively fast, a re-normalization of the proliferation/differentiation pathway requires longer periods of time, which highlights the need of prolonged treatments with an effective dosage regimen.
NAC and PCOS
From the epithelial cancer studies described above the inventors of the present invention noticed that NAC had some advantageous effects on epithelial cancer cells and that those effects could also be useful in the treatment of ovary cortex cells and endometrial cells in PCOS, if such cells should respond similarly. In particular, it was hoped that the anti-proliferative and differentiating effects of NAC seen in cancer would also occur when NAC was used in the treatment of PCOS.
It was believed that if NAC had similar molecular effects on ovary cortex as those which had been observed in cancer, they would also be beneficial for the treatment of PCOS. It was hypothesized that NAC might have the following physiological effects on PCOS:
i) a normalization of the ovary cortex and of endometrial tissue functions, through a more regular proliferation-differentiation cycling;
ii) a normalization of estrogen secretory functions of ovarian cells;
iii) a normalization of hormone balance;
iv) consequencies of above points include: ovulation restoration, regularization of menstrual cycle, improvement of fertility, weight loss, decreased
hirsutism and hypertrichosis, amelioration of acne, finally an overall amelioration of the patients' quality of life.
On a whole, the hypothesized outcomes were verified either directly or indirectly through the patients' response in a pilot clinical study.In particular, the inventors have found that NAC indeed reduces ovary size and follicles number, normalizes menstrual cycle, reduced BMI and ameliorates acne.
Dosage regimen
From the study of NAC treatment on adenocarcinoma cell lines and primary normal keratinocyte cells (Cell Death and Differentiation 2005, 12(10): 1285-1296), it was concluded that the effective dose of NAC for induction of the antiproliferative- differentiating effect varied and was cell type dependent. The tissue of origin thus dictates the effective NAC concentration required to observe a complete block of proliferation, and has to be determined for each tissue. In addition, the NAC dose was also related to the cell malignancy. In detail, while normal cells required a low dose to stop proliferating and start differentiating, carcinoma cells with characteristic poorer prognosis required a higher NAC concentration.
For the purpose of the present invention a dosage regimen of NAC for the treatment of PCOS was developed based on the following criteria:
1) a dosage of NAC per day which is in agreement with other current clinical treatments and is considered without undesirable side effects;
2) a dose which is considered high enough to fulfill the requirement of abnormally proliferating cells, to switch them into the differentiation pathway;
3) a dose which is daily fractionated as to warrant an almost constant plasma level, in consideration of NAC pharmacokinetics and pharmacodynamics;
4) given a reported decrease in NAC plasma level after prolonged treatments
(Pendyala L, Creaven PJ. Cancer Epidemiol Biomarkers Prev. 1995; 4:245-51), the suspension of the treatment for about half of each week was considered for an optimal biological response in a two months or longer treatment.
The composition of the present invention, comprising NAC for the treatment of PCOS or indications associated with PCOS is according to one embodiment to be administered at a dose between approximately 20 and 90 mg/kg/day. The lower limit is based on twice the dose used for mucolytic action, i.e. it is per se known to have a physiological effect. The upper limit is based on the consideration that higher doses have been found to cause gastric problems in many patients. In another embodiment of the present invention the composition comprises NAC to be administered at a dose of
approximately 30-60 mg/kg/day. The lower limit has been shown to be effective in PCOS and the higher limit is known to have virtually no side effects. In still another embodiment of the present invention the composition comprises NAC to be
administered at a dose of approximately 30-45 mg/kg/day. This low dosage has surprisingly been shown to be effective in PCOS.
In one embodiment the composition is to be administered for a period of time which is two months or more, or preferably three months or more. To counteract a decrease in NAC plasma level after prolonged treatment NAC may be administered at the prescribed dosage in an intermittent fashion, i.e. intermittent dosage regimen/treatment. By intermittent administration or treatment is meant that the treatment is interrupted in periods, i.e. that the pharmaceutical composition is administered for a period of time, e.g. a few days, followed by an interruption in administration, where no pharmaceutical composition is administered for a period of time, e.g. for a few days. Intermittent treatment can be regular, e.g. treatment for a fixed number of days or weeks, followed by interruption for a fixed number of days or weeks. Examples include repeated schemes with treatment for 4 days followed by interruption for 3 days each week or treatment for 2 weeks followed by interruption 1 week. A special case of regular intermittent treatment is pulsed treatment, i.e. with regular treatment and interruption duration, e.g. administration every other day or administration for two days followed by two days of interruption etc. Irregular intermittent treatment schemes that are not regularly repeated or have a more complex scheme that is repeated is also conceivable, e.g. dependent on response to treatment. In different exemplifying embodiments of the present invention the prescribed dose of NAC is administered for 3-5 consecutive days followed by 2-4 days of interruption, or administered for 1-3 consecutive days followed by 1-2 days of interruption.
In one embodiment, by referring to a body weight of approximately 60 kg, the NAC dose is in the range between 1.2 and 5.4 g/day, preferably between 1.8 and 3.6 g/day, on days when administered. The dose may be divided in two or more, preferably three or four, daily administrations of either one or two doses (e.g. pills) each, where each dose may comprise e.g. 0.15-2.7 g of NAC or preferably 0.6-1.2 g of NAC. For patients with other weights, e.g. over- or underweight persons the daily dose needs to be adjusted accordingly.
In one embodiment of the present invention the pharmaceutical composition for treatment of PCOS or PCOS related symptoms comprises NAC in a dose of 150-5400 mg to be administered in two or more administrations per day, for a period of at least 2 months, such as at least 3 months. In a preferred embodiment of the present invention the pharmaceutical composition comprises NAC in a dose of 230-3600 mg to be administered in two or more administrations per day, for a period of at least 2 months, such as at least 3 months. In another embodiment of the present invention the pharmaceutical composition for treatment of PCOS or PCOS related symptoms comprises NAC to be administered in a single or more administrations per day, 3-5 days per week, for a period of at least 2 months, such as at least 3 months.
Pharmaceutical formulations
A pharmaceutical composition according to the present invention may be prepared in a manner per se known by a person skilled in the pharmaceutical art. The composition may comprise an effective amount of NAC, in accordance with the invention, as well as a suitable carrier or excipient that serves as a vehicle or medium for the active ingredient. Such carriers or excipients are known in the art and include solid materials such as citric acid, natrium citrate, natrium (acid) carbonate plus flavoring. The pharmaceutical composition is preferably adapted for oral administration. Such compositions could be administered in different forms, at present preferably as tablets. Other forms, such as capsules, suppositories, solutions, suspensions, syrups or the like are also conceivable.
The invention requires a strict assessment of the pharmaceutical quality of NAC preparation for obtaining the effective dose. Therefore, brand or certified generic
preparations have to be used. NAC is not a stable molecule, its active thiol residue can be easily oxidized by oxygen, light and other radiations, so that the effective dose would not be reached. The preparation is thus preferably protected from light, e.g. by a light protecting package such as a blister foil package. Soluble tablets preferably comprise sodium hydrogen carbonate, which helps in a partial removal of oxygen from water during dissolution.
It has been observed that high doses of NAC may cause abdominal pain. To overcome this, an option is to provide NAC in a gastric protected formulation , suitable for preventing NAC release/solubility in the stomach. Such formulations are well known in the art and may be used with the present invention. For example, tablet coatings that are resistant to gastric fluids and allow release of the drug only in the intestine, after its transit through the stomach, may be used. Commonly used formulations include polymers such as cellulose derivatives, methacrylate amino ester copolymers. The coating protects the tablet core from disintegration in the acidic environment of the stomach by employing a pH sensitive polymer, which swells or solubilises after having passed through the stomach, in response to the increase in pH, whereafter the drug is released.
Another option is to lower the dose of NAC entering the blood stream at any one time. Administration of NAC three or more times daily can be difficult to accomplish for the patient. Nevertheless, a repeated administration can be desirable to achieve a nearly constant serum concentration of NAC. To overcome these problems, a once or twice-a- day administration could be easier to handle for the patient, for instance morning and night. One option is to provide NAC in a slow-release formulation (also denoted sustained-release or controlled-release). By being able to reduce the rate of diffusion and uptake of NAC into the blood stream such a formulation enables administration of a larger dose at longer intervals. The dose is then distributed in the blood over a long time in small quantities, e.g. over 12+12 hours in the case of a twice-a-day regimen scheme. Many different technologies and formulations for slow-release are since long known in the art and may be applied with the present invention. In such technologies the active substance is for example encapsulated in a coating or matrix that is insoluble or less soluble in the body fluid where it is administered.
Formulations having a combined effect of slow-release and gastric protection is also possible and may be used within the present invention.
Use/medical indications of the present invention
The present invention has been shown to have beneficial properties in many aspects related to PCOS and may be used both for the treatment of PCOS and for treatment of various indications associated with PCOS. By treatment of various indications associated with PCOS is meant e.g. treatment to reduce the symptoms of the disease such as irregular menstruation, overweight, hirsutism and acne. Such treatment of various indications associated with PCOS also includes e.g. treatment to reduce ovary volume and number of follicles, treatment to increase the likelihood of getting pregnant, treatment to reduce insulinemia and treatment to reduce the risk of cardiovascular diseases, endometrial hyperplasia and endometrial cancer in subjects diagnosed with PCOS.
NAC, according to the present invention, has been shown to improve the quality of life of the patient in the absence of undesired side effects; to reduce ovary size and number of follicles, to ameliorate acne, hirsutism to produce more regular menstrual cycles and to decrease body mass index. Thus, in one embodiment of the present invention the pharmaceutical composition comprises NAC for the treatment of PCOS in order to convert ovary cortex function, including estrogen secretory function, towards normal.
In one embodiment of the present invention the pharmaceutical composition comprises NAC for the treatment of PCOS in order to reduce symptoms associated with PCOS.
In another embodiment of the present invention the pharmaceutical composition comprises NAC for treating infertility or promoting a desired pregnancy in a subject with PCOS.
In another embodiment of the present invention the pharmaceutical composition comprises NAC for reducing ovary volume in a subject with PCOS.
In still another embodiment of the present invention the pharmaceutical composition comprises NAC for achieving a regular menstrual cycle in a subject with PCOS.
In another embodiment of the present invention the pharmaceutical composition comprises NAC for reducing hirsutism in a subject with PCOS.
In another embodiment of the present invention the pharmaceutical composition comprises NAC for reducing acne in a subject with PCOS.
In still another embodiment of the present invention the pharmaceutical composition comprises NAC for reducing body weight and body mass index in a subject with PCOS.
In another embodiment of the present invention the pharmaceutical composition comprises NAC for reducing insulinemia in a subject with PCOS.
In another embodiment of the present invention the pharmaceutical composition comprises NAC for reducing the risk for cardiovascular diseases in a subject with PCOS.
In still another embodiment of the present invention the pharmaceutical composition comprises NAC for reducing the risk for endometrial hyperplasia and endometrial cancer in a subject with PCOS.
In other embodiments the present invention provides a method for treating a subject having PCOS by oral administration of a pharmaceutical composition comprising N- acetyl-L-cysteine, using the dosage regimen of the present invention.
In one embodiment of the present invention such method is used for reducing ovary volume in a subject with PCOS.
In another embodiment of the present invention the method is for achieving regular menstrual cycle in a subject with PCOS.
In still another embodiment of the present invention the method is for reducing body weight and body mass index in a subject with PCOS.
In a further embodiment of the present invention the method is for treating infertility or promoting a desired pregnancy in a subject with PCOS.
In another embodiment of the present invention the method is for reducing acne and/or hirsutism in a subject with PCOS.
In another embodiment of the present invention the method is for reducing insulinemia in a subject with PCOS.
In another embodiment of the present invention the method is for reducing the risk for cardiovascular diseases in a subject with PCOS.
In still another embodiment of the present invention the method is for reducing the risk for endometrial hyperplasia and endometrial cancer in a subject with PCOS.
EXAMPLE
The invention is further described and illustrated by reference to the following example. It should be noted, however, that this example should not be considered as limiting the invention in any way.
Example 1. Pilot clinical study on the effect of NAC to treat PCOS.
Aim and set up of the study. This pilot clinical study was designed to treat women with polycystic ovary syndrome (PCOS) with NAC as an alternative to other treatments, particularly those involving hormones. Five women, average age 25±5 years, diagnosed with PCOS through sonographic and clinical diagnosis, and having more than 10 ovary follicles, were enrolled.
Treatment. The prescribed NAC dose was 30 mg/kg/day, corresponding for an average body weight of 60 kg, to three oral doses of 600 mg NAC, three times a day, for three consecutive days each week, with four days of interruption. This resulted in 1.8 g of NAC per day, 5.4 g per week, 21.6 g per month. These precise modalities of treatment were based on the following considerations: 1) the dose of 1.8 g of NAC per day is in agreement with other current clinical treatments and is considered without undesirable side effects; 2) given NAC pharmacokinetics, the three daily doses of 0.6 mg approach a nearly constant plasma level, without discomfort of patients for a complex treatment; 3) given a reported decrease in NAC plasma level after prolonged treatments (Pendyala L, Creaven PJ. Cancer Epidemiol Biomarkers Prev. 1995; 4:245-51), the suspension of the treatment for about half of each week warrants an optimal biological response in a six-months or longer treatment.
Follow-up. Clinical outcome was evaluated after the first three months of treatment, with a planned follow-up evaluation at the end of the study after six months.
Results.
- Four cases presented a decrease in the average ovary diameter, with an average decrease of 20%, see table 1 and figure 1.
- Three cases having more than 10 follicles at the start of the study presented a decrease in follicle number, two of them achieving a completely normal ovary sonographic appearance.
- Three cases with irregular menstrual cycles, reported regularization.
- One case reported a decrease in body mass index from 26.5 to 25.2. The
remaining patients already had a low BMI. - One patient of the five suffered from acne before the start of the treatment. After treatment amelioration of acne and improvement of hair quality was reported by both patient and clinician.
Table !
In Table I results are summarized for each patient 1-5. Shown are: the average ovary diameter (D), in mm, for the right (dx) and left (sn) ovary, at the first sonographic evaluation at enrolment (0), and after three months (3). Also reported are cases starting with high follicle number and irregular menstrual cycle at enrolment (0) and the corresponding results after three months (3).
Claims
A pharmaceutical composition comprising N-acetyl-L-cysteine for use in the treatment of a mammal having polycystic ovary syndrome (PCOS), characterized in that the composition is for pulsed or intermittent, oral administration, for a time period of two months or more and wherein the administration takes place for 3-5 consecutive days followed by 2-4 days of interruption or alternatively for 1- 3 consecutive days followed by 1-2 days of interruption at a dose of N-acetyl-L- cysteine that is between 20 and 90 mg/kg/day on administration days.
A pharmaceutical composition comprising N-acetyl-L-Cysteine for use according to claim 1 characterized in that it is administered for 3-5 consecutive days followed by 2-4 days of interruption.
A pharmaceutical composition comprising N-acetyl-L-Cysteine for use according to claim 1 characterized in that it is administered for 1-3 consecutive days followed by 1-2 days of interruption
A pharmaceutical composition comprising N-acetyl-L-cysteine for use according to claim 1, characterized in that it is for administration at a dose of N-acetyl-L- cysteine that is between 30 and 60 mg/kg/day on administration days.
A pharmaceutical composition comprising N-acetyl-L-cysteine for use according to claim 1, characterized in that it is for administration at a dose of N-acetyl-L- cysteine that is between 30 and 45 mg/kg/day on administration days.
A pharmaceutical composition comprising N-acetyl-L-cysteine for use according to any of the previous claims, characterized in that it is protected from light.
A pharmaceutical composition comprising N-acetyl-L-cysteine for use according to any of the previous claims, characterized in that it is a water soluble tablet.
A pharmaceutical composition comprising N-acetyl-L-cysteine for use according to any of the previous claims, characterized in that it contains sodium hydrogen carbonate.
9. A pharmaceutical composition comprising N-acetyl-L-cysteine for use according to claims 1-6, characterized in that it comprises a formulation for slow-release and/or gastric protected formulation.
10. A pharmaceutical composition comprising N-acetyl-L-cysteine for use
according to claims 1-9 for reducing ovary volume and/or follicles number in a subject with PCOS.
11. A pharmaceutical composition comprising N-acetyl-L-cysteine for use according to claims 1-9 for achieving regular menstrual cycle in a subject with PCOS.
12. A pharmaceutical composition comprising N-acetyl-L-cysteine for use according to claims 1-9 for reducing body weight and body mass index in a subject with PCOS.
13. A pharmaceutical composition comprising N-acetyl-L-cysteine for use according to claims 1-9 for treating infertility or promoting a desired pregnancy in a subject with PCOS.
14. A pharmaceutical composition comprising N-acetyl-L-cysteine for use according to claims 1-9 for reducing acne and/or hirsutism in a subject with PCOS.
15. A pharmaceutical composition comprising N-acetyl-L-cysteine for use according to claims 1-9 for treating insulinemia in a subject with PCOS.
16. A pharmaceutical composition comprising N-acetyl-L-cysteine for use according to claims 1-9 for reducing the risk for cardiovascular diseases in a subject with PCOS.
17. A pharmaceutical composition comprising N-acetyl-L-cysteine for use according to claims 1-9 for reducing the risk for endometrial hyperplasia and endometrial cancer in a subject with PCOS.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE1051339 | 2010-12-16 | ||
SE1051339-8 | 2010-12-16 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2012080273A1 true WO2012080273A1 (en) | 2012-06-21 |
Family
ID=45406715
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2011/072643 WO2012080273A1 (en) | 2010-12-16 | 2011-12-13 | N- acetyl - l - cysteine for treatment of polycystic ovary syndrome |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2012080273A1 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20140045937A1 (en) * | 2012-08-08 | 2014-02-13 | Oculus Innovative Sciences, Inc. | Methods of treating polycystic ovarian syndrome using chlorogenic acid |
WO2014078929A1 (en) * | 2012-11-26 | 2014-05-30 | Universidade Federal De Minas Gerais - Ufmg | Topical formulation for the prevention and treatment of alopecia and for inhibiting hair growth |
US20150283107A1 (en) * | 2014-04-08 | 2015-10-08 | Oculus Innovative Sciences, Inc. | Methods of treating polycystic ovarian syndrome using chlorogenic acid and inositol |
JP2015536961A (en) * | 2012-11-09 | 2015-12-24 | イアソマイ エービー | N-acetyl-L-cysteine used for in vitro fertilization |
AT518311A1 (en) * | 2016-03-07 | 2017-09-15 | Gonadosan Gmbh | combination preparation |
WO2022117828A1 (en) | 2020-12-04 | 2022-06-09 | Chemo Research , S.L. | Specialized pro-resolving lipid mediators for treating pcos |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007056851A1 (en) * | 2005-11-17 | 2007-05-24 | Mount Sinai Hospital | Compositions and methods for enhancing ovulation inducing agents |
-
2011
- 2011-12-13 WO PCT/EP2011/072643 patent/WO2012080273A1/en active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007056851A1 (en) * | 2005-11-17 | 2007-05-24 | Mount Sinai Hospital | Compositions and methods for enhancing ovulation inducing agents |
Non-Patent Citations (13)
Title |
---|
A. C. GUSTAFSSON, BMC CANCER, vol. 5, 2005, pages 75 |
BMC CANCER, vol. 5, 2005, pages 75 |
CELL DEATH AND DIFFERENTIATION, vol. 12, no. 10, 2005, pages 1285 - 1296 |
E. K. KRASNOWSKA, FREE RADICALS BIOLOGY AND MEDICINE, vol. 45, no. 11, 2008, pages 1566 - 72 |
FERTILITY AND STERILITY, vol. 77, no. 6, 2002, pages 1128 - 1135 |
FREE RADICALS BIOLOGY AND MEDICINE, vol. 45, no. 11, 2008, pages 1566 - 72 |
FULGHESU A M ET AL: "N-acetyl-cysteine treatment improves insulin sensitivity in women with polycystic ovary syndrome", FERTILITY AND STERILITY, ELSEVIER SCIENCE INC, NEW YORK, NY, USA, vol. 77, no. 6, 1 June 2002 (2002-06-01), pages 1128 - 1135, XP003013234, ISSN: 0015-0282, DOI: 10.1016/S0015-0282(02)03133-3 * |
MASHA A ET AL: "Prolonged treatment with N-acetylcysteine and L-arginine restores gonadal function in patients with polycystic ovary syndrome.", JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION DEC 2009 LNKD- PUBMED:19494711, vol. 32, no. 11, December 2009 (2009-12-01), pages 870 - 872, XP009155985, ISSN: 1720-8386 * |
NASR A.: "Effect of N-acetyl-cysteine after ovarian drilliing in clomiphene citrate-resistent PCOS women: a pilot study", REPRODUCTIVE BIOMEDICINE, vol. 20, 2010, pages 403 - 409 |
NASR ET AL: "Effect of N-acetyl-cysteine after ovarian drilling in clomiphene citrate-resistant PCOS women: a pilot study", REPRODUCTIVE BIOMEDICINE ONLINE, REPRODUCTIVE HEALTHCARE LTD, GB, vol. 20, no. 3, 1 March 2010 (2010-03-01), pages 403 - 409, XP026920139, ISSN: 1472-6483, [retrieved on 20100222], DOI: 10.1016/J.RBMO.2009.12.012 * |
PENDYALA L; CREAVEN PJ., CANCER EPIDEMIOL BIOMARKERS PREV., vol. 4, 1995, pages 245 - 51 |
PITTALUGA E. ET AL.: "More than antioxidant: N-acetyl-cysteine in a murine model of endometriosis", FERTILITY AND STERILITY, vol. 94, no. 7, 2010, pages 2905 - 2908 |
T. PARASASSI, CELL DEATH AND DIFFERENTIATION, vol. 12, no. 10, 2005, pages 1285 - 1296 |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20140045937A1 (en) * | 2012-08-08 | 2014-02-13 | Oculus Innovative Sciences, Inc. | Methods of treating polycystic ovarian syndrome using chlorogenic acid |
JP2015536961A (en) * | 2012-11-09 | 2015-12-24 | イアソマイ エービー | N-acetyl-L-cysteine used for in vitro fertilization |
WO2014078929A1 (en) * | 2012-11-26 | 2014-05-30 | Universidade Federal De Minas Gerais - Ufmg | Topical formulation for the prevention and treatment of alopecia and for inhibiting hair growth |
US20150283107A1 (en) * | 2014-04-08 | 2015-10-08 | Oculus Innovative Sciences, Inc. | Methods of treating polycystic ovarian syndrome using chlorogenic acid and inositol |
US9259410B2 (en) * | 2014-04-08 | 2016-02-16 | Oculus Innovative Sciences, Inc. | Methods of treating polycystic ovarian syndrome using chlorogenic acid and inositol |
AT518311A1 (en) * | 2016-03-07 | 2017-09-15 | Gonadosan Gmbh | combination preparation |
AT18222U1 (en) * | 2016-03-07 | 2024-06-15 | Gonadosan Gmbh | Kit-of-parts preparation |
WO2022117828A1 (en) | 2020-12-04 | 2022-06-09 | Chemo Research , S.L. | Specialized pro-resolving lipid mediators for treating pcos |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2012080273A1 (en) | N- acetyl - l - cysteine for treatment of polycystic ovary syndrome | |
US20060188575A1 (en) | Methods of treating non-painful bladder disorders using alpha2delta subunit calcium channel modulators | |
US20040198775A1 (en) | Methods for treating lower urinary tract disorders and the related disorders vulvodynia and vulvar vestibulitis using Cav2.2 subunit calcium channel modulators | |
US8637573B2 (en) | N-acetyl-L-cysteine for the treatment of endometriosis | |
ES2741146T3 (en) | Pharmaceutical formulations of nitrio and its uses | |
EP2900230B1 (en) | Compounds for the treatment of obesity and methods of use thereof | |
WO2012080151A1 (en) | Combination therapy comprising vemurafenib and an interferon for use in the treatment of cancer | |
MX2012013014A (en) | Therapeutic regimens. | |
BR112019018687A2 (en) | methods of treatment and / or prevention of actinic keratosis | |
US8367730B2 (en) | Composition of amino acids for sublingual applying for enhanced skin integument repigmentation in vitiligo and method of its administration | |
Campbell et al. | Alteration of methyldopa absorption, metabolism, and blood pressure control caused by ferrous sulfate and ferrous gluconate | |
JP5879359B2 (en) | Pharmaceutical compositions comprising citric acid and bicarbonate and their use for treating cystinuria | |
JP2004091473A (en) | Therapeutic agent for improving chromatosis | |
JP7123058B2 (en) | Combination therapy for the treatment of skin diseases | |
WO2012130646A1 (en) | N-acetyl-l-cysteine for the treatment of dysmenorrhea | |
UA51627C2 (en) | Restoration of tonic estrogen secretion by ovaries for long-term treatment regimens | |
Karaus et al. | Effects of CCK‐receptor antagonist on colonic motor activity in dogs | |
US20230414696A1 (en) | Curcumin compositions and methods of use as an nk3 antagonist | |
Jurgiel et al. | The role of berberine in polycystic ovary syndrome—a summary of knowledge | |
Romualdi et al. | Polycystic Ovary Syndrome | |
WO2024020553A2 (en) | Compositions and methods for peripheral targeting of melatonin receptor agonist | |
US20210085711A1 (en) | Use of ferric citrate in prevention and/or treatment of iron-deficiency anemia in hypermenorrhea patient and/or patient suffering from hypermenorrhea-associated gynecologic disease | |
Petry et al. | The influence of arachidonic acid metabolites on cell division in the intestinal epithelium and in colonic tumors | |
Woodhouse et al. | Delayed gastric emptying with dothiepin | |
CN109331022A (en) | Improving female ovary function improves the composition and preparation process of female skin |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 11801682 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 11801682 Country of ref document: EP Kind code of ref document: A1 |