CN107635554B - 用于正经受放疗和/或化疗的肿瘤患者的粘膜炎治疗的包含氨基酸的组合物 - Google Patents
用于正经受放疗和/或化疗的肿瘤患者的粘膜炎治疗的包含氨基酸的组合物 Download PDFInfo
- Publication number
- CN107635554B CN107635554B CN201680026570.5A CN201680026570A CN107635554B CN 107635554 B CN107635554 B CN 107635554B CN 201680026570 A CN201680026570 A CN 201680026570A CN 107635554 B CN107635554 B CN 107635554B
- Authority
- CN
- China
- Prior art keywords
- leucine
- composition
- composition according
- weight ratio
- glutamine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 79
- 201000010927 Mucositis Diseases 0.000 title claims abstract description 36
- 206010028116 Mucosal inflammation Diseases 0.000 title claims abstract description 35
- 150000001413 amino acids Chemical class 0.000 title claims abstract description 32
- 238000001959 radiotherapy Methods 0.000 title claims abstract description 19
- 238000011282 treatment Methods 0.000 title claims abstract description 19
- 238000002512 chemotherapy Methods 0.000 title claims abstract description 16
- 206010028980 Neoplasm Diseases 0.000 title description 19
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims abstract description 41
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims abstract description 37
- 229960002743 glutamine Drugs 0.000 claims abstract description 37
- 229940024606 amino acid Drugs 0.000 claims abstract description 31
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims abstract description 29
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims abstract description 29
- 229960003136 leucine Drugs 0.000 claims abstract description 29
- 239000013543 active substance Substances 0.000 claims abstract description 16
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims abstract description 14
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims abstract description 14
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims abstract description 14
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims abstract description 14
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims abstract description 14
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229960000310 isoleucine Drugs 0.000 claims abstract description 14
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229960004295 valine Drugs 0.000 claims abstract description 14
- 239000004474 valine Substances 0.000 claims abstract description 14
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims abstract description 13
- 239000004472 Lysine Substances 0.000 claims abstract description 13
- 229960003646 lysine Drugs 0.000 claims abstract description 13
- 229960004452 methionine Drugs 0.000 claims abstract description 13
- 229960005190 phenylalanine Drugs 0.000 claims abstract description 13
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims abstract description 12
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims abstract description 12
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims abstract description 12
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000004473 Threonine Substances 0.000 claims abstract description 12
- 229930182817 methionine Natural products 0.000 claims abstract description 12
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229960002898 threonine Drugs 0.000 claims abstract description 12
- 229960004441 tyrosine Drugs 0.000 claims abstract description 12
- 229960004799 tryptophan Drugs 0.000 claims abstract description 11
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims abstract description 10
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229960003067 cystine Drugs 0.000 claims abstract description 10
- 229960002885 histidine Drugs 0.000 claims abstract description 10
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims abstract description 10
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims abstract description 10
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 claims abstract 2
- 235000001014 amino acid Nutrition 0.000 claims description 29
- 239000002562 thickening agent Substances 0.000 claims description 8
- 235000014633 carbohydrates Nutrition 0.000 claims description 5
- 150000001720 carbohydrates Chemical class 0.000 claims description 5
- 229930003231 vitamin Natural products 0.000 claims description 5
- 235000013343 vitamin Nutrition 0.000 claims description 5
- 239000011782 vitamin Substances 0.000 claims description 5
- 229940088594 vitamin Drugs 0.000 claims description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- 229920002752 Konjac Polymers 0.000 claims description 4
- 239000000252 konjac Substances 0.000 claims description 4
- 239000011691 vitamin B1 Substances 0.000 claims description 4
- 239000011726 vitamin B6 Substances 0.000 claims description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 3
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 2
- LUEWUZLMQUOBSB-FSKGGBMCSA-N (2s,3s,4s,5s,6r)-2-[(2r,3s,4r,5r,6s)-6-[(2r,3s,4r,5s,6s)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2r,4r,5s,6r)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-4,5-dihydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@@H](O[C@@H]2[C@H](O[C@@H](OC3[C@H](O[C@@H](O)[C@@H](O)[C@H]3O)CO)[C@@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O LUEWUZLMQUOBSB-FSKGGBMCSA-N 0.000 claims description 2
- 244000247812 Amorphophallus rivieri Species 0.000 claims description 2
- 235000001206 Amorphophallus rivieri Nutrition 0.000 claims description 2
- 239000004475 Arginine Substances 0.000 claims description 2
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 2
- 229920002581 Glucomannan Polymers 0.000 claims description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- 229920000084 Gum arabic Polymers 0.000 claims description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 2
- 229930003268 Vitamin C Natural products 0.000 claims description 2
- 235000004279 alanine Nutrition 0.000 claims description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 2
- 229940046240 glucomannan Drugs 0.000 claims description 2
- 235000013922 glutamic acid Nutrition 0.000 claims description 2
- 239000004220 glutamic acid Substances 0.000 claims description 2
- 235000010485 konjac Nutrition 0.000 claims description 2
- 235000019823 konjac gum Nutrition 0.000 claims description 2
- 235000019426 modified starch Nutrition 0.000 claims description 2
- 208000025440 neoplasm of neck Diseases 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 235000019154 vitamin C Nutrition 0.000 claims description 2
- 239000011718 vitamin C Substances 0.000 claims description 2
- 239000000230 xanthan gum Substances 0.000 claims description 2
- 229920001285 xanthan gum Polymers 0.000 claims description 2
- 235000010493 xanthan gum Nutrition 0.000 claims description 2
- 229940082509 xanthan gum Drugs 0.000 claims description 2
- 244000215068 Acacia senegal Species 0.000 claims 1
- 239000000205 acacia gum Substances 0.000 claims 1
- 235000010489 acacia gum Nutrition 0.000 claims 1
- 239000001913 cellulose Substances 0.000 claims 1
- 229920002678 cellulose Polymers 0.000 claims 1
- 201000010536 head and neck cancer Diseases 0.000 abstract description 5
- 208000014829 head and neck neoplasm Diseases 0.000 abstract description 5
- 208000019505 Deglutition disease Diseases 0.000 description 20
- 210000003205 muscle Anatomy 0.000 description 13
- 238000002560 therapeutic procedure Methods 0.000 description 12
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 8
- 230000000259 anti-tumor effect Effects 0.000 description 8
- 235000018977 lysine Nutrition 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- 230000005855 radiation Effects 0.000 description 7
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 6
- 238000012423 maintenance Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 6
- 102000009027 Albumins Human genes 0.000 description 5
- 108010088751 Albumins Proteins 0.000 description 5
- 206010049645 Hypercatabolism Diseases 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 210000000987 immune system Anatomy 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 210000000440 neutrophil Anatomy 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 208000001076 sarcopenia Diseases 0.000 description 5
- 230000009747 swallowing Effects 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 102000004420 Creatine Kinase Human genes 0.000 description 4
- 108010042126 Creatine kinase Proteins 0.000 description 4
- 102000001554 Hemoglobins Human genes 0.000 description 4
- 108010054147 Hemoglobins Proteins 0.000 description 4
- 230000003110 anti-inflammatory effect Effects 0.000 description 4
- 230000003078 antioxidant effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 235000020776 essential amino acid Nutrition 0.000 description 4
- 239000003797 essential amino acid Substances 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
- 235000013355 food flavoring agent Nutrition 0.000 description 4
- 210000000265 leukocyte Anatomy 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 208000015380 nutritional deficiency disease Diseases 0.000 description 4
- 230000009885 systemic effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 108090000695 Cytokines Proteins 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 208000002720 Malnutrition Diseases 0.000 description 3
- 229930003451 Vitamin B1 Natural products 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 208000022531 anorexia Diseases 0.000 description 3
- 230000000118 anti-neoplastic effect Effects 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 230000019522 cellular metabolic process Effects 0.000 description 3
- 206010061428 decreased appetite Diseases 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 229960003180 glutathione Drugs 0.000 description 3
- 230000004968 inflammatory condition Effects 0.000 description 3
- 235000000824 malnutrition Nutrition 0.000 description 3
- 230000001071 malnutrition Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 230000036542 oxidative stress Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000000770 proinflammatory effect Effects 0.000 description 3
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 229960003495 thiamine Drugs 0.000 description 3
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 3
- 235000010374 vitamin B1 Nutrition 0.000 description 3
- 235000019158 vitamin B6 Nutrition 0.000 description 3
- 229940011671 vitamin b6 Drugs 0.000 description 3
- 230000003442 weekly effect Effects 0.000 description 3
- 208000035143 Bacterial infection Diseases 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 108010024636 Glutathione Proteins 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 206010025282 Lymphoedema Diseases 0.000 description 2
- 229920002774 Maltodextrin Polymers 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000002612 cardiopulmonary effect Effects 0.000 description 2
- 230000003920 cognitive function Effects 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 206010013781 dry mouth Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000004761 fibrosis Effects 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 208000002502 lymphedema Diseases 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 229910044991 metal oxide Inorganic materials 0.000 description 2
- 150000004706 metal oxides Chemical class 0.000 description 2
- 230000037023 motor activity Effects 0.000 description 2
- 210000002200 mouth mucosa Anatomy 0.000 description 2
- 235000003715 nutritional status Nutrition 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000001243 protein synthesis Methods 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000003642 reactive oxygen metabolite Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000014616 translation Effects 0.000 description 2
- OCUSNPIJIZCRSZ-ZTZWCFDHSA-N (2s)-2-amino-3-methylbutanoic acid;(2s)-2-amino-4-methylpentanoic acid;(2s,3s)-2-amino-3-methylpentanoic acid Chemical compound CC(C)[C@H](N)C(O)=O.CC[C@H](C)[C@H](N)C(O)=O.CC(C)C[C@H](N)C(O)=O OCUSNPIJIZCRSZ-ZTZWCFDHSA-N 0.000 description 1
- QDGAVODICPCDMU-UHFFFAOYSA-N 2-amino-3-[3-[bis(2-chloroethyl)amino]phenyl]propanoic acid Chemical compound OC(=O)C(N)CC1=CC=CC(N(CCCl)CCCl)=C1 QDGAVODICPCDMU-UHFFFAOYSA-N 0.000 description 1
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 1
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 description 1
- 208000036119 Frailty Diseases 0.000 description 1
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 1
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 1
- 235000019766 L-Lysine Nutrition 0.000 description 1
- FFEARJCKVFRZRR-UHFFFAOYSA-N L-Methionine Natural products CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 description 1
- 229930195722 L-methionine Natural products 0.000 description 1
- 239000005913 Maltodextrin Substances 0.000 description 1
- 240000008790 Musa x paradisiaca Species 0.000 description 1
- 235000018290 Musa x paradisiaca Nutrition 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 239000004376 Sucralose Substances 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 208000005946 Xerostomia Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 235000010358 acesulfame potassium Nutrition 0.000 description 1
- 229960004998 acesulfame potassium Drugs 0.000 description 1
- 239000000619 acesulfame-K Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 206010003549 asthenia Diseases 0.000 description 1
- 230000000386 athletic effect Effects 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 210000000746 body region Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000006790 cellular biosynthetic process Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 238000009223 counseling Methods 0.000 description 1
- 230000001120 cytoprotective effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000446 fuel Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 238000012812 general test Methods 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 210000002490 intestinal epithelial cell Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 210000000867 larynx Anatomy 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 230000006742 locomotor activity Effects 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 230000003843 mucus production Effects 0.000 description 1
- 230000036225 muscular coordination Effects 0.000 description 1
- 208000018066 neoplasm of oropharynx Diseases 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- 230000036314 physical performance Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000650 radiochemotherapeutic effect Effects 0.000 description 1
- 238000011127 radiochemotherapy Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- IFGCUJZIWBUILZ-UHFFFAOYSA-N sodium 2-[[2-[[hydroxy-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyphosphoryl]amino]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid Chemical compound [Na+].C=1NC2=CC=CC=C2C=1CC(C(O)=O)NC(=O)C(CC(C)C)NP(O)(=O)OC1OC(C)C(O)C(O)C1O IFGCUJZIWBUILZ-UHFFFAOYSA-N 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 208000003265 stomatitis Diseases 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4415—Pyridoxine, i.e. Vitamin B6
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
- A61K31/51—Thiamines, e.g. vitamin B1
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
用于正经受放疗和/或化疗的患有头颈癌的患者的粘膜炎治疗的氨基酸组合物,所述组合物包含活性剂,所述活性剂包括氨基酸:谷氨酰胺、亮氨酸、异亮氨酸、缬氨酸、赖氨酸、苏氨酸、组氨酸、苯丙氨酸、甲硫氨酸、色氨酸、酪氨酸和胱氨酸,其中谷氨酰胺:亮氨酸重量比包括在4.3至5.3的范围内。
Description
技术领域
本发明公开内容涉及用于正经受放疗和/或化疗的患有肿瘤,特别是颈部-头部区域的肿瘤,的患者的粘膜炎(mucositides)治疗的包含氨基酸的组合物。
背景技术
在患有颈部-头部区域肿瘤(也称为头颈癌)的患者中,化疗和放疗导致了良好的肿瘤生长控制和提高的存活率。然而,这样的患者常常经历口腔、咽和喉的大区域中严重的粘膜炎的产生,这就是放疗和/或化疗诱发的。由于这样的粘膜炎,患者常常变得不能服用口服药物,这在一些情况中涉及到降低化疗的剂量或停止放疗的需要,其对于患者具有明显负面的结果。
为了克服这种由抗肿瘤治疗诱发的粘膜炎引起的问题,已经努力进行了各种尝试来控制和减少所述问题的发生和/或严重程度,如,例如,更加关注口腔护理,以及使用局部麻醉药和抗微生物药。然而,迄今为止,尚未确认具体地允许抵抗或至少降低这类患者中此类粘膜炎的发生和/或严重程度的治疗。
谷氨酰胺是我们身体中最丰富的氨基酸。其是主要的燃料,并且是用于快速增殖细胞(如肠上皮细胞、成纤维细胞、淋巴细胞和巨噬细胞)中核苷酸生物合成的必需前体,其对于这些细胞代表了必需氨基酸。此外,谷氨酰胺用作谷胱甘肽合成的底物并且具有抗氧化剂特性。
如果暴露于严重应激,身体不能合成足够量的这种氨基酸,导致降低的谷氨酰胺的血浆水平。在这些情况中,粘膜免疫系统受到抑制并且降低了肌肉组织的谷氨酰胺释放。
此外,已经显示出正经受细胞毒性治疗的患有晚期头颈癌的患者产生了谷氨酰胺缺陷(1)。在过去二十年中,几项研究已经检验了是否谷氨酰胺降低了由放疗和/或化疗诱发的粘膜炎的发病率和严重程度(2-7),然而,没有获得关于谷氨酰胺在此类粘膜炎的预防或治疗中的实际作用的结论(4-6)。在出版物Jebb 1994(6)中,作者实际上证明了通过每天施用16克谷氨酰胺,没有观察到粘膜炎的治疗/预防中的显著结果。
最近公布了关于将谷氨酰胺施用于患有头颈癌的患者的功效的临床、双盲、随机化、安慰剂对照的研究的结果(8)并且得出谷氨酰胺-以每日30g剂量给予时-显著降低了由抗肿瘤治疗诱发的粘膜炎的严重程度的结论。在这个出版物中,还陈述了10至26克/天的谷氨酰胺浓度对于粘膜炎的治疗是无效的。然而,该研究的患者受试者的血液化学数据证明与对照组相比几个参数的恶化。特别地,存在恶化的总嗜中性粒细胞计数和总白细胞计数、血红蛋白、肌酸磷酸激酶,以及铁和锌,在这些患者中,这意味着更大的局部和全身性细菌感染出现的发生,静止时的虚弱和运动活动过程中的疲劳(其导致提高的心脏-呼吸工作),降低的产生肌肉能量的能力,降低的多区域抗氧化能力。最后,这些情况引起受损的认知功能(尤其是在老年人中)。总之,这些参数的负面状态使得患者“脆弱”得多。
发明内容
本发明的公开内容具有提供用于治疗正经受放疗和/或化疗的患有颈部-头部区域肿瘤的患者的粘膜炎的基于氨基酸的组合物的目的,其允许降低粘膜炎的发生和/或严重程度,并且同时,对抗由抗肿瘤治疗引起的氧化应激和粘膜免疫系统的抑制。
根据本发明的公开内容,通过在以下权利要求中特意表明的事项来实现以上目的,其打算作为本发明公开内容的整体部分。
本发明的一个实施方式涉及用于正经受放疗和/或化疗的患有颈部-头部区域肿瘤的患者的粘膜炎治疗的氨基酸组合物,其包含活性剂,其中所述活性剂包括氨基酸:谷氨酰胺、亮氨酸、异亮氨酸、缬氨酸、赖氨酸、苏氨酸、组氨酸、苯丙氨酸、甲硫氨酸、色氨酸、酪氨酸和胱氨酸,其中谷氨酰胺:亮氨酸重量比包括在4.3至5.3的范围中。
发明人已经发现了本文中所述的组合物能够确定i)由抗肿瘤治疗诱发的粘膜炎的发生和/或严重程度的降低,ii)与对照相比,免疫血液学框架的改善和iii)由肿瘤自身或由抗肿瘤治疗引起的吞咽困难的发生和/或严重程度的降低,这归功于组合物的抗炎作用(其允许对抗厌食、“疲劳”和/或肌肉减少症的发作),和进一步地iv)通过预防ipercatabolic病症患病率,提高细胞代谢。
关于使用本文中所述的组合物的优势在于可以施用于这些患者的组合物的高耐受性,即使在患有吞咽困难时。
另一个与使用本文中所述的组合物相关的优势在于使用活性剂中包含的游离形式的氨基酸允许以相对于合成的蛋白质和生长因子相对非常低的成本生产此类组合物(通过本身已知的生产方法和制备基于游离氨基酸的组合物的领域中广泛使用)的事实。然而,本发明的应用领域还可以延伸至通过遗传工程或任何其他人工方法获得的氨基酸。
具体实施方式
在以下说明书中,给出多种特定的细节以提供对所述实施方式的全面理解。可以在没有一个或多个特定的细节的情况下,或使用其他方法、组分、材料等,来实施所述实施方式。在其他情况中,没有详细显示或描述公知的特征、材料或操作以避免模糊所述实施方式的方面。
整个说明书中提及“一个(one)实施方式”或“一(an)实施方式”表示结合所述实施方式描述的特定特点、结构或特征包括在至少一个实施方式中。因此,整个说明书中各处出现的短语表述“在一个(one)实施方式中”或“在一(an)实施方式中”不必定是全部指相同的实施方式。另外,特定的特点、结构和特征可以在一个或多个实施方式中以任何合适的方式组合。本文中提供的标题只是为了方便并且不是解释所述实施方式的范围或目的。
在本发明公开内容的一个实施方式中,用于治疗正经受放疗和/或化疗的患有颈部-头部区域肿瘤的患者的粘膜炎的氨基酸组合物包含活性剂,其中所述活性剂包括氨基酸:谷氨酰胺、亮氨酸、异亮氨酸、缬氨酸、赖氨酸、苏氨酸、组氨酸、苯丙氨酸、甲硫氨酸、色氨酸、酪氨酸和胱氨酸,其中谷氨酰胺:亮氨酸重量比包括在4.3至5.3的范围中,优选4.5至5.0,更优选为4.5。
常常,患有颈部-头部区域肿瘤的患者,在放疗开始的4-5周内,产生粘膜炎、皮炎和软组织肿胀。这些副作用是由于反应性氧物质(ROS)和促炎性细胞因子(IL-1、IL-6、TNF-α)的产生,该促炎性细胞因子的合成受到转录因子激活的刺激,特别是核因子-κB(NF-κB)。
在临床上,患者经历疼痛、产生稠的粘液、口干(口腔干燥)、组织肿胀,常常伴随急性吞咽困难。接着是营养不良或甚至是该状况的恶化,这在诊断时已经存在于约30-50%病例中。在预治疗的原因中,营养不良可以是公认的由于肿瘤浸润引起的吞咽痛、机械性梗阻、吞咽困难,并且最后但不是最少,如厌食和“疲劳”这样的因素,其继发于促炎性细胞因子(IL-1、IL-6、TNF)的直接和间接肿瘤产生。
此外,合理推断作为营养不良患者特征的肌肉减少症也可能影响涉及吞咽过程的肌肉并且因此导致吞咽困难的发作或甚至恶化(如果预先存在)。因此其形成营养不良和吞咽困难的恶性循环。
在开始抗肿瘤治疗后3个月的大部分患者中,急性效应消退并且吞咽开始改善。
然而,在一些患者中,急性炎症可能延长或极度严重,使得在由抗肿瘤治疗诱发的组织修复过程中,纤维化期胜过再生期。接着是组织纤维化、淋巴水肿和因此晚期吞咽困难(甚至数年后)
实验和临床研究已经表明谷氨酰胺(9)i)是胞内谷胱甘肽(GSH)(具有对抗氧化应激的细胞保护性作用的三肽)合成的必需前体(经由谷氨酸),和ii)能够直接或间接地保护(通过热休克蛋白的表达)细胞免受由促炎性细胞因子诱发的损伤(抗炎作用)。
通过将本发明公开内容的组合物施用于患有颈部-头部区域的肿瘤并正经受放疗和/或化疗的患者进行的临床研究已经通过测定i)由抗肿瘤治疗诱发的粘膜炎的发生和/或严重程度的降低,ii)与未治疗患者相比免疫血液学框架中出乎预料的改善,和iii)由于组合物的抗炎作用(其允许对抗厌食、“疲劳”和/或肌肉减少症的发作),由肿瘤自身或抗肿瘤治疗引起的吞咽困难的发生和/或严重程度的降低,和进一步v)通过防止ipercatabolic状况的盛行导致这些患者中细胞代谢的提高,证明该组合物能够改善患者的身体状况。
使用本文中描述的组合物进行的临床研究中获得的实验数据表明施用组合物-在患有头颈癌并且正经受抗肿瘤治疗的患者中-6周(21g谷氨酰胺和15g必需氨基酸/天)与现有技术(8)中已经显示的相比降低了粘膜炎,并且同时,允许对抗氧化应激(由于组合物发挥的抗炎作用)以及由抗肿瘤治疗引起的粘膜免疫系统的抑制,并通过测定血液白蛋白的生理水平的维持和免疫血液学框架的几个重要参数,改善了细胞代谢(通过预防分解代谢过度的发作)。
在对照组的患者中,事实上观察到明显更频繁的粘膜炎以及静止时的虚弱和运动活动过程中的疲劳,导致提高的心肺工作,降低的产生肌肉能量的能力,降低的多区域抗氧化能力,通过淋巴水肿和晚期吞咽困难以及通过较少补偿的血液学框架揭示的慢性炎症状况的恶化。
实验数据表明,在用本文中公开的组合物治疗的患者中,获得了白蛋白水平、肌肉强度的维持以及粘膜炎和吞咽困难频率的降低。
完全出乎预料地,本发明组合物的发明人事实上已经证明了施用20-25g/天的谷氨酰胺,补充15-20g/天的必需氨基酸(即,亮氨酸、异亮氨酸、缬氨酸、赖氨酸、苏氨酸、组氨酸、苯丙氨酸、甲硫氨酸、色氨酸、酪氨酸和胱氨酸)使得在各种身体区域中使用谷氨酰胺,尤其是在免疫活性细胞和组织中,超过可以仅通过外源性谷氨酰胺衍生的。此外,组合物允许维持未改变的血红蛋白、白蛋白、总嗜中性粒细胞和淋巴细胞水平(在现有技术中未显示,例如,如出版物(8)和(10)中所示的)。
本发明公开内容的组合物客体事实上允许在存在分解代谢过度的情况下,在全身性和区域性炎症状况的存在下增强多区域蛋白质合成,这随后形成对比并恢复到细胞生理代谢状态。对抗分解代谢过度事实上允许保持组织的完整性,刺激修复过程和保持免疫系统的适当功能,主要是到口腔粘膜水平。
在优选实施方式中,本发明公开内容的组合物具有以下表1中所示的组成(作为单剂量来表示,12mg的总氨基酸小袋)。
表1
在优选实施方式中,本发明组合物还可以包括增稠剂,其(形成凝胶形式的组合物)允许组合物被患有由肿瘤自身引起的吞咽困难或由于非生理代谢状况引起的吞咽困难的晚期发作的患者摄入。
可以加入本文中所述的氨基酸组合物中的增稠剂可以在由黄原胶、甲基羟丙基纤维素、魔芋胶、魔芋葡甘露聚糖、阿拉伯(arabic)胶(阿拉伯(acacia)树胶)、改性淀粉组成的组中选择。优选地,相对于活性剂重量,一种或多种增稠剂以2%至30%重量的量存在,优选4%至15%重量。
一种或多种此类增稠剂的存在允许使液体(优选水)增稠,其中组合物在服用前分散,从而产生具有用于患有吞咽困难的患者摄食的理想粘度的组合物。
已知患有吞咽困难的人通常缺乏适当的肌肉协调和正确地闭合气管的控制或不具有正确地将整个食团和/或饮料推向胃的能力。因此非常重要的是吞咽困难患者食用的食物具有合适的粘度和稠度。
加入本文中所述的组合物中的液体量将取决于例如待获得的稠度。将由本领域技术人员来评价和确定这个参数,也考虑患者吞咽困难的程度。
在一些实施方式中,本文中所述的组合物进一步包含维生素,优选选自维生素B1、维生素B6和维生素C。
在进一步的实施方式中,组合物还包括碳水化合物、添加剂和/或调味剂。
优选的碳水化合物可以选自各种类型的麦芽糊精。添加剂可以选自脱水柠檬酸三钠、阿斯巴甜粉末、安赛蜜钾、三氯蔗糖。优选的调味剂是香蕉香精。
根据本发明公开内容的一些实施方式,优选的异亮氨酸:亮氨酸重量比范围为0.20至0.70,优选0.40至0.60和/或缬氨酸:亮氨酸重量比范围为0.20至0.80,优选0.40至0.70。
在进一步的实施方式中,苏氨酸:亮氨酸重量比范围为0.15至0.50,优选0.20至0.45和/或赖氨酸:亮氨酸重量比范围为0.15至0.60,优选0.30至0.55。
在另一个实施方式中,亮氨酸:异亮氨酸:缬氨酸重量比等于2:1:1。
在进一步的实施方式中,假定亮氨酸、异亮氨酸、缬氨酸、苏氨酸和赖氨酸的总和是1,另外的必需氨基酸的总体量可以进一步在0.02至0.25(即,1:0.02-0.25),优选0.05至0.15(即,1:0.05-0.15)的范围,仍然打算为重量比。
在进一步的实施方式中,胱氨酸以构成甲硫氨酸的150%至350%的重量量存在。
在一些实施方式中,酪氨酸以构成苯丙氨酸重量量的15至50%,优选20至35%的量存在于组合物中。
在进一步的实施方式中,活性剂由以下氨基酸组成:谷氨酰胺、亮氨酸、异亮氨酸、缬氨酸、赖氨酸、苏氨酸、组氨酸、苯丙氨酸、甲硫氨酸、色氨酸、酪氨酸和胱氨酸,其中谷氨酰胺:亮氨酸比率为4.3至5.3,优选4.5至5.0,更优选4.5。
在一个或多个实施方式中,如表1和以下表2中所示,组合物中包括的氨基酸仅由活性剂的氨基酸组成,即谷氨酰胺、亮氨酸、异亮氨酸、缬氨酸、赖氨酸、苏氨酸、组氨酸、苯丙氨酸、甲硫氨酸、色氨酸、酪氨酸和胱氨酸,组合物不含任何其他另外的不同氨基酸。
在一个或多个实施方式中,谷氨酰胺以相对于活性剂总重量的50至65%重量,优选55至60%重量的量存在。
此外,特别地,在制备根据本发明公开内容的组合物并且特别是活性剂时,优选避免氨基酸丝氨酸、脯氨酸、甘氨酸、丙氨酸、谷氨酸以及尤其是精氨酸,已知它们在一定浓度或化学计算比率下对于所述制剂可能是产生相反结果的或甚至是有害的。
上述氨基酸可以用其相应的药物学上可接受的衍生物(即盐)来替代。
优选地,组合物是干粉的形式,并且为了施用于患者,将其分散在液体,优选水中。
就本文中公开的用于治疗中的组合物提供的各种氨基酸之间的量和比率的更多说明包含在所附权利要求中,其形成本文中提供的关于本发明的技术教导的整体部分。
本文中提供的结果表明,由于本文中公开的组合物,有可能获得:
-3级粘膜炎的显著降低(25%vs 55%)(p<0.05);
-3级粘膜炎的延迟发作(23.3±3.6天vs 38.5±4.9天)(p<0.001);
-更好的血液框架,其中白蛋白、总嗜中性粒细胞计数、总白细胞计数和血红蛋白的水平保持未改变;
-在治疗结束时肌肉强度(用握力测量的)维持(+0.4kg vs-7kg)(p<0.05)。这个发现对于预防广义的肌肉减少症是重要的,并且对于肌肉强度和吞咽之间的关系,其表明可能的较少吞咽困难;
-朝向较少感知的疲劳的趋势(p 0.056),通过FACT-HNSI量表评估的。
材料和方法
患者
患有口咽肿瘤的患者,放疗(RT)或放化疗(RCT)的候选者。排除标准:严重体重减轻(1个月内>5%或6个月内>10%)、饮食不足(inadequate ingesta)(<需求的60%)、严重的吞咽困难、肾衰竭、肝衰竭、姑息性放疗。
研究设计
使用自动产生的数字序列的盲法初步研究(在2组中随机化):研究组(G,20名患者)和对照组(C,20名患者)。在研究组中,口服施用凝胶形式的本文中公开的组合物,以3小袋/天的量,从治疗开始(T-1)前7天并直至治疗完成(6周),不进食。
患者接受以下强调束放疗(IMRT)的方案:总放射剂量66-70Gy(1期/天,5天/周)。相关的化疗(研究组中15名患者和对照组中15名患者)包括:i.v.40mg/m2(每周)或100mg/m2(每三周)顺铂。
评价以下主要终点:粘膜炎的发病率、严重程度和发作时间。作为将要终点,考虑了:粘膜炎相关的症状、生活质量、营养状况、肌肉强度、对口腔整合/人工营养的需求、治疗的中断。
在两个组中,结合RT或RCT,使用了相同的粘膜炎预防/治疗的方案(按照需要)。
所有患者在T-1天并且随后每周(T0-T6)接受医学检查和饮食咨询。在每次会见时,进行了以下评价:粘膜炎相关症状的存在(PROMS量表)、生活质量(FACT/HNSI NCCN量表)、营养状态(体重、采血测试、通过过去3天的食物日志的经口摄入)、使用握力的肌肉强度(使用Jamar测力器,三次测定的平均)。
能量需求设定为30kcal/kg/天,蛋白质需求设定为1.5g/kg/天。
在摄入不足的患者中,已经使用了口服补充剂(摄入≥需求的60%)或NA(摄入<需求的60%)。
使用WHO量表,通过放射治疗医生每周进行粘膜炎的严重程度和发作时间的评价。
统计学分析
Student’s t检验,卡方,Fischer检验,Kaplan-Meier曲线。
组合物
研究组(组G)接受了本文中公开的组合物,其提供36g氨基酸/天(一天12g三次,稀释于半杯水中,直至患者排出)。
施用于患者的单剂量组合物中含有的每种氨基酸的量提供于表2中。
表2
*根据“Amino Acid,Nucleic Acids&Related Compounds–Specification/General Tests”,第8版,Kyowa Hakko Kogyo Co.,Ltd.的分子量
如从表2可以看出的,谷氨酰胺:亮氨酸重量比优选为4.5:1;亮氨酸、异亮氨酸和缬氨酸之间的重量比优选等于2:1:1。表1还显示了组氨酸、苯丙氨酸、甲硫氨酸和色氨酸的单独量优选递减(即,组氨酸的量高于苯丙氨酸的量,该苯丙氨酸的量高于甲硫氨酸的量,该甲硫氨酸的量高于色氨酸的量)并且胱氨酸的量(以克或摩尔计的量)优选高于酪氨酸的量。除了谷氨酰胺、亮氨酸、异亮氨酸、缬氨酸、赖氨酸、苏氨酸、组氨酸、苯丙氨酸、甲硫氨酸、色氨酸、酪氨酸和胱氨酸外,组合物不含任何其他氨基酸。
所述氨基酸组合物还优选包含碳水化合物、维生素、调味剂和其他药物学上可接受的赋形剂,以及在一些情况中,包含增稠剂,以允许组合物施用于吞咽困难的患者。
在表3中,提供了本发明公开内容的组合物客体的不同变体(A、B和C)的更多实例。指定为A、B和C的组合物实际上含有-除了表1中所示的氨基酸外-其他各种性质和量组合的添加剂,如碳水化合物、维生素、调味剂和增稠剂。
表3
首先,通过在四通混合器中加载L-苯丙氨酸、L-酪氨酸、L-色氨酸、维生素B1和维生素B6以及L-赖氨酸以获得预混物,来制备表3中所示的组合物。以预混物的%计的组成显示于以下表4中。
表4
成分 | % |
麦芽糊精 | 83.296 |
L-苯丙氨酸 | 8.333 |
L-甲硫氨酸 | 4.167 |
L-酪氨酸 | 2.500 |
L-色氨酸 | 1.667 |
维生素B1 | 0.019 |
维生素B6 | 0.018 |
将所述成分混合10分钟的时间段以获得均匀的预混物。
将表3中所列成分的其余部分加载于四通混合器中并混合20分钟的时间段以获得均匀的最终组合物。
将本发明公开内容的组合物客体添加并分散于液体,优选水中。加入本文中所述的组合物中的液体的量取决于例如待获得的稠度。由本领域技术人员来评价和确定这个参数(也考虑患者吞咽困难的程度)。
结果
将本文中所述的组合物施用于研究组患者使得获得3级粘膜炎的显著减轻(25%vs对照的55%)和3级粘膜炎的延迟发作(23.3±3.6天vs对照组的38.5±4.9天),如通过表5中记载的数据所示的。
表5
此外,观察到了治疗结束时肌肉强度(通过握力测量的)的保持(+0.4kg vs对照组中的-0.7kg)。这个发现对于预防广义的肌肉减少症以及对于肌肉强度和吞咽能力之间的相关性是重要的,研究组中的患者具有随之发生的吞咽困难减轻。
与对照组中的患者相比,研究组中的患者朝向虚弱的趋势(通过FACT-HNSI量表评价的-p=0.056)也明显减轻。
本发明公开内容的组合物客体事实上允许在分解代谢过度发生中存在全身性和区域性炎性状况的情况下增强多区域蛋白质合成,其随后被对抗并返回细胞生理代谢状况,考虑到研究组患者接受的重度放化疗干预。组合物能够对抗分解代谢过度并随后维持组织完整性,刺激修复过程并保持免疫系统的正确功能,主要到口腔粘膜水平。
以下的临床数据表明与分解代谢相关的最重要的血液参数的总体维持,如从表6中显示的数据明显看出的。
表6
*p<0.05
特别地,总嗜中性粒细胞、总白细胞、血红蛋白和白蛋白,与Tsujimoto等中记载的使用30克剂量单独的谷氨酰胺(8)相反,维持在差不多生理水平上,并且随着时间没有降低,如在对照组的患者中观察到的。
特别地,显然本发明的组合物与(8)中提供的数据(其中在研究期中,治疗组与安慰剂相比显示出恶化的免疫血液学分析数据)相比允许获得出乎预料的结果。在(8)中,在治疗的患者中,存在总嗜中性粒细胞计数、总白细胞计数、血红蛋白水平的降低,同时存在肌酸磷酸激酶(CPK)水平的提高,其中随着时间提高的CPK水平与细胞合成损伤和降低的能量-ATP的使用相关。
本文中提供的实验数据证明接受本发明公开内容的组合物的患者将不再经历频繁的局部和全身性的细菌感染,并且在运动活动过程中存在较低频率的虚弱和休息时疲劳。研究组中的患者事实上保持了产生肌肉能量的能力。
总之,以上参数的生理水平的维持允许患者具有更高体能并且在运动活动过程中较少经历疲劳,具有良好的心肺工作的控制,保持产生肌肉能量的能力,以及多区域抗氧化能力。最后,尤其是在老年人中,没有观察到认知功能的损害。
参考文献
1.Savarese等:Prevention of chemotherapy and radiation toxicity withglutamine.Cancer Treat Rev 29:501-513,2003.
2.Huang等:Oral glutamine to alleviate radiation-induced oralmucositis:a pilot randomized trial.Int J Radiat Oncol Biol Phys 46:535-539,2000.
3.Skubitz KM和Anderson PM:Oral glutamine to prevent chemotherapyinduced stomatitis:a pilot study.J Lab Clin Med 127:223-228,1996.
4.Jebb等:A pilot study of oral glutamine supplementation in patientsreceiving bone marrow transplants.Clin Nutr 14:162-165,1995.
5.van Zaanen等:Parenteral glutamine dipeptide supplementation doesnot ameliorate chemotherapy-induced toxicity.Cancer 74:2879-2884,1994.
6.Jebb等:5-fluorouracil and folinic acid-induced mucositis:no effectof oral glutamine supplementation.Br J Cancer 70:732-735,1994.
7.Anderson等:Oral glutamine reduces the duration and severity ofstomatitis after cytotoxic cancer chemotherapy.Cancer 83:1433-1439,1998.
8.Tsujimoto等:L-glutamine decreases the severity of mucositis inducedby chemoradiation therapy in patients with locally advanced head and neckcancer:a double-blind,randomized,placebo-controlled trial.Oncology Reports33:33-39,2015.
9.Kuhn KS等:Glutamine as indispensable nutrient in oncology:experimental and clinical evidence.Eur.J.Nutr.;49(4):197-210,2009
10.Samocha-Bonet等:Glycemic effects and safety of L-Glutaminesupplementation with or without sitagliptin in type 2diabetes patients-arandomized study.PLoS One 9(11):1-7,2014
Claims (13)
1.一种用于治疗患有颈部-头部区域的肿瘤且正经受放疗和/或化疗的患者的粘膜炎的氨基酸组合物,所述组合物包含活性剂,所述活性剂包括氨基酸谷氨酰胺、亮氨酸、异亮氨酸、缬氨酸、赖氨酸、苏氨酸、组氨酸、苯丙氨酸、甲硫氨酸、色氨酸、酪氨酸和胱氨酸,其中谷氨酰胺:亮氨酸重量比在4.3至5.3的范围内,且其中所述活性剂不含精氨酸。
2.根据权利要求1的组合物,其中亮氨酸:异亮氨酸:缬氨酸重量比等于2:1:1。
3.根据权利要求1或权利要求2的组合物,其中
异亮氨酸:亮氨酸重量比在0.2-0.7的范围内,和/或
缬氨酸:亮氨酸重量比在0.2-0.8的范围内。
4.根据权利要求3的组合物,其中
异亮氨酸:亮氨酸重量比在0.4-0.6的范围内,和/或
缬氨酸:亮氨酸重量比在0.4-0.7的范围内。
5.根据权利要求1或权利要求2的组合物,其中
苏氨酸:亮氨酸重量比在0.15至0.50的范围内,和/或
赖氨酸:亮氨酸重量比在0.15至0.60的范围内。
6.根据权利要求5的组合物,其中
苏氨酸:亮氨酸重量比在0.20至0.45的范围内,和/或
赖氨酸:亮氨酸重量比在0.30至0.55的范围内。
7.根据权利要求1或权利要求2的组合物,其中谷氨酰胺以相对于活性剂总重量的50至65%重量的量存在。
8.根据权利要求7的组合物,其中谷氨酰胺以相对于活性剂总重量的55至60%重量的量存在。
9.根据权利要求1或权利要求2的组合物,其中所述组合物进一步包含以下的至少一种:碳水化合物、至少一种增稠剂、至少一种维生素和调味物质。
10.根据权利要求1或权利要求2的组合物,其中所述组合物进一步包含药物学上可接受的赋形剂。
11.根据权利要求9的组合物,其中所述至少一种增稠剂选自黄原胶、纤维素及其衍生物、魔芋胶、魔芋葡甘露聚糖、阿拉伯树胶、改性淀粉。
12.根据权利要求9的组合物,其中所述至少一种维生素选自维生素B1、维生素B6、维生素C。
13.根据权利要求1或权利要求2的组合物,其中所述活性剂不含丝氨酸、脯氨酸、甘氨酸、丙氨酸、谷氨酸。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITUB20150354 | 2015-05-14 | ||
IT102015000015060 | 2015-05-14 | ||
PCT/IB2016/052724 WO2016181335A1 (en) | 2015-05-14 | 2016-05-12 | Compositions comprising amino acids for use in the treatment of mucositides in neoplasia patients undergoing radiation therapy and/or chemotherapy |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107635554A CN107635554A (zh) | 2018-01-26 |
CN107635554B true CN107635554B (zh) | 2020-11-24 |
Family
ID=53765405
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201680026570.5A Active CN107635554B (zh) | 2015-05-14 | 2016-05-12 | 用于正经受放疗和/或化疗的肿瘤患者的粘膜炎治疗的包含氨基酸的组合物 |
Country Status (11)
Country | Link |
---|---|
US (2) | US11234949B2 (zh) |
EP (1) | EP3294279B1 (zh) |
JP (1) | JP6773269B2 (zh) |
KR (1) | KR102553890B1 (zh) |
CN (1) | CN107635554B (zh) |
BR (1) | BR112017022506A2 (zh) |
CA (1) | CA2981757C (zh) |
ES (1) | ES2779749T3 (zh) |
MY (1) | MY187022A (zh) |
PL (1) | PL3294279T3 (zh) |
WO (1) | WO2016181335A1 (zh) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MY187022A (en) | 2015-05-14 | 2021-08-26 | Professional Dietetics Spa | Compositions comprising amino acids for use in the treatment of mucositides in neoplasia patients undergoing radiation therapy and/or chemotherapy |
IT201700087359A1 (it) | 2017-07-28 | 2019-01-28 | Professional Dietetics Spa | Composizioni comprendenti amino acidi per l'uso nel trattamento di malattie associate a disfunzione mitocondriale |
IT201700087376A1 (it) | 2017-07-28 | 2019-01-28 | Professional Dietetics Spa | Composizioni comprendenti amino acidi per l'uso nel trattamento di malattie associate a disfunzione mitocondriale |
RU2671512C1 (ru) * | 2018-04-18 | 2018-11-01 | федеральное государственное бюджетное образовательное учреждение высшего образования "Тюменский государственный медицинский университет" Министерства здравоохранения Российской Федерации (ФГБОУ ВО Тюменский ГМУ Минздрава России) | Средство для лечения заболеваний пародонта и слизистой оболочки рта с репаративным эффектом |
IT202000000442A1 (it) * | 2020-01-13 | 2021-07-13 | Professional Dietetics Spa | Composizioni comprendenti amino acidi per l'uso nella prevenzione e nel trattamento di effetti collaterali della chemioterapia |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1422125A (zh) * | 2000-04-12 | 2003-06-04 | 雀巢制品公司 | 含有游离氨基酸的组合物 |
CN1717184A (zh) * | 2002-10-08 | 2006-01-04 | 艾博特公司 | 用于提供谷氨酰胺的方法和组合物 |
CN101528066A (zh) * | 2006-10-19 | 2009-09-09 | 雀巢产品技术援助有限公司 | 癌症患者的长期喂饲 |
CN103330215A (zh) * | 2013-07-11 | 2013-10-02 | 西安力邦临床营养有限公司 | 一种适用于肿瘤患者的营养配方食品 |
CN103347511A (zh) * | 2011-02-17 | 2013-10-09 | 味之素株式会社 | 化学治疗剂的抗肿瘤活性的增强剂 |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5438075A (en) | 1993-03-30 | 1995-08-01 | Skubitz; Keith M. | Oral glutamine to reduce stomatitis |
EP1343492B1 (en) | 2000-11-22 | 2006-02-01 | Rxkinetix, Inc. | Treatment of mucositis |
AU2003265624B2 (en) * | 2003-08-21 | 2011-03-31 | Abeona Therapeutics Inc. | Liquid formulations for the prevention and treatment of mucosal diseases and disorders |
EP1675480B1 (en) | 2003-10-16 | 2018-06-13 | Nestec S.A. | Nutritional composition against side effects of chemotherapy of radiotherapy |
IT1396935B1 (it) * | 2009-11-26 | 2012-12-20 | Solartium Entpr Ltd | Uso di una combinazione per il trattamento delle mucositi indotte da radiazioni o da chemioterapici |
WO2012140118A1 (en) * | 2011-04-12 | 2012-10-18 | Nestec S.A. | Nutritional compositions including branched chain fatty acids for wound healing |
US10582722B2 (en) * | 2011-12-15 | 2020-03-10 | Societe Des Produits Nestle S.A. | Cohesive thin liquids to promote safe swallowing in dysphagic patients |
JPWO2014061808A1 (ja) * | 2012-10-19 | 2016-09-05 | Eaファーマ株式会社 | 胃ろう栄養患者用栄養組成物 |
SG10202006156XA (en) * | 2013-07-31 | 2020-07-29 | Ajinomoto Kk | Agent for alleviating side effects in cancer chemotherapy |
PL3006027T3 (pl) * | 2014-10-08 | 2018-02-28 | Professional Dietetics S.P.A. | Kompozycje zawierające aminokwasy do stosowania w leczeniu ogólnoustrojowego stanu zapalnego związanego z udarem u pacjentów z dysfagią |
MY187022A (en) | 2015-05-14 | 2021-08-26 | Professional Dietetics Spa | Compositions comprising amino acids for use in the treatment of mucositides in neoplasia patients undergoing radiation therapy and/or chemotherapy |
-
2016
- 2016-05-12 MY MYPI2017001528A patent/MY187022A/en unknown
- 2016-05-12 BR BR112017022506-9A patent/BR112017022506A2/pt not_active Application Discontinuation
- 2016-05-12 JP JP2017552437A patent/JP6773269B2/ja active Active
- 2016-05-12 CN CN201680026570.5A patent/CN107635554B/zh active Active
- 2016-05-12 WO PCT/IB2016/052724 patent/WO2016181335A1/en active Application Filing
- 2016-05-12 KR KR1020177035602A patent/KR102553890B1/ko active IP Right Grant
- 2016-05-12 PL PL16726183T patent/PL3294279T3/pl unknown
- 2016-05-12 US US15/571,130 patent/US11234949B2/en active Active
- 2016-05-12 ES ES16726183T patent/ES2779749T3/es active Active
- 2016-05-12 CA CA2981757A patent/CA2981757C/en active Active
- 2016-05-12 EP EP16726183.3A patent/EP3294279B1/en active Active
-
2021
- 2021-10-29 US US17/515,155 patent/US11896569B2/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1422125A (zh) * | 2000-04-12 | 2003-06-04 | 雀巢制品公司 | 含有游离氨基酸的组合物 |
CN1717184A (zh) * | 2002-10-08 | 2006-01-04 | 艾博特公司 | 用于提供谷氨酰胺的方法和组合物 |
CN101528066A (zh) * | 2006-10-19 | 2009-09-09 | 雀巢产品技术援助有限公司 | 癌症患者的长期喂饲 |
CN103347511A (zh) * | 2011-02-17 | 2013-10-09 | 味之素株式会社 | 化学治疗剂的抗肿瘤活性的增强剂 |
CN103330215A (zh) * | 2013-07-11 | 2013-10-02 | 西安力邦临床营养有限公司 | 一种适用于肿瘤患者的营养配方食品 |
Non-Patent Citations (4)
Title |
---|
Beneficial Effect of Low-Fat Elemental Diet Therapy on Pain in Chronic Pancreatitis;Tsukasa Ikeura et al;《International Journal of Chronic Diseases》;20140414;第2014卷;全文 * |
Effects of glutamine on head and neck squamous cell carcinoma;RICK ERICKSON et al;《Otolaryngology-Head and Neck Surgery》;19991001;第121卷(第4期);摘要、第350页表1和表2 * |
Prophylactic Glutamine Protects the Intestinal Mucosa From Radiation Injury;V. Suzanne Klimberg et al;《Cancer》;19900701;第66卷(第1期);全文 * |
RICK ERICKSON et al.Effects of glutamine on head and neck squamous cell carcinoma.《Otolaryngology-Head and Neck Surgery》.1999,第121卷(第4期), * |
Also Published As
Publication number | Publication date |
---|---|
US11234949B2 (en) | 2022-02-01 |
CA2981757C (en) | 2023-06-27 |
JP6773269B2 (ja) | 2020-10-21 |
CA2981757A1 (en) | 2016-11-17 |
WO2016181335A1 (en) | 2016-11-17 |
US20220047539A1 (en) | 2022-02-17 |
EP3294279A1 (en) | 2018-03-21 |
US20180169042A1 (en) | 2018-06-21 |
BR112017022506A2 (pt) | 2018-07-17 |
EP3294279B1 (en) | 2020-01-01 |
CN107635554A (zh) | 2018-01-26 |
US11896569B2 (en) | 2024-02-13 |
MY187022A (en) | 2021-08-26 |
PL3294279T3 (pl) | 2020-06-29 |
JP2018515441A (ja) | 2018-06-14 |
ES2779749T3 (es) | 2020-08-19 |
KR20180004799A (ko) | 2018-01-12 |
KR102553890B1 (ko) | 2023-07-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107635554B (zh) | 用于正经受放疗和/或化疗的肿瘤患者的粘膜炎治疗的包含氨基酸的组合物 | |
US8703725B2 (en) | Nutritional compositions | |
USRE39705E1 (en) | Method of treating glutathione deficient mammals | |
CN108721596B (zh) | 一种复方氨基酸维生素注射液及其应用 | |
JPH01301619A (ja) | 癌用アミノ酸製剤 | |
JPWO2008123298A1 (ja) | 癌患者用輸液製剤 | |
US6479068B1 (en) | Therapeutic nutrient regimen for alleviating mucositis, stomatitis and cachexia in oncology patients | |
JP3914585B2 (ja) | マクロファージ一酸化窒素産生亢進剤 | |
JP5823303B2 (ja) | 経口アミノ酸組成物 | |
EP3006027B1 (en) | Compositions comprising amino acids for use in the treatment of systemic inflammation state associated to stroke in patients with dysphagia | |
CN1810238A (zh) | 精氨酸口服配方预防和治疗恶液质综合症 | |
Ochiai et al. | Effect of a fermented brown rice extract on the gastrointestinal function in methotrexate-treated rats | |
JP5823695B2 (ja) | 肝機能障害予防剤 | |
JP2020050655A (ja) | 消化管障害を改善する組成物 | |
RU2709501C1 (ru) | Фармацевтическая композиция для парентерального капельного введения | |
RU2720134C1 (ru) | Фармацевтическая композиция для парентерального капельного введения | |
EP4295843A1 (en) | Compositions comprising amino acids for use in the prevention and/or treatment of intestinal diseases | |
CN115427417A (zh) | 含有三磷酸腺苷(atp)的组合物和使用方法 | |
Magazine | Cancer induced cachexia (CIC) | |
Kori | L-Glutamine and Oral Mucositis | |
ZA200501922B (en) | Leucine-enriched nutritional compositions. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |