MD854Z - Method for treating locally advanced II-III stage cervical canrcinoma - Google Patents
Method for treating locally advanced II-III stage cervical canrcinoma Download PDFInfo
- Publication number
- MD854Z MD854Z MDS20140049A MDS20140049A MD854Z MD 854 Z MD854 Z MD 854Z MD S20140049 A MDS20140049 A MD S20140049A MD S20140049 A MDS20140049 A MD S20140049A MD 854 Z MD854 Z MD 854Z
- Authority
- MD
- Moldova
- Prior art keywords
- treatment
- radiotherapy
- locally advanced
- patients
- cervical cancer
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 13
- 238000011282 treatment Methods 0.000 claims abstract description 40
- 238000001959 radiotherapy Methods 0.000 claims abstract description 25
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims abstract description 10
- 229960004316 cisplatin Drugs 0.000 claims abstract description 10
- 235000016425 Arthrospira platensis Nutrition 0.000 claims abstract description 9
- 240000002900 Arthrospira platensis Species 0.000 claims abstract description 9
- 239000013543 active substance Substances 0.000 claims abstract description 6
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 23
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 23
- 201000010881 cervical cancer Diseases 0.000 claims description 23
- 238000001990 intravenous administration Methods 0.000 claims description 2
- 230000000771 oncological effect Effects 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 2
- 238000002512 chemotherapy Methods 0.000 description 11
- 230000001900 immune effect Effects 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 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 8
- 238000011835 investigation Methods 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- 108010024636 Glutathione Proteins 0.000 description 5
- 210000001744 T-lymphocyte Anatomy 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000009257 reactivity Effects 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 230000002519 immonomodulatory effect Effects 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 206010067484 Adverse reaction Diseases 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 230000006838 adverse reaction Effects 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- 210000003719 b-lymphocyte Anatomy 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 229960003180 glutathione Drugs 0.000 description 3
- 210000004698 lymphocyte Anatomy 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000005855 radiation Effects 0.000 description 3
- 102000006354 HLA-DR Antigens Human genes 0.000 description 2
- 108010058597 HLA-DR Antigens Proteins 0.000 description 2
- 102000001554 Hemoglobins Human genes 0.000 description 2
- 108010054147 Hemoglobins Proteins 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- 206010067482 No adverse event Diseases 0.000 description 2
- 108010038807 Oligopeptides Proteins 0.000 description 2
- 102000015636 Oligopeptides Human genes 0.000 description 2
- 206010037601 Pyelonephritis chronic Diseases 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- 238000004159 blood analysis Methods 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 201000006368 chronic pyelonephritis Diseases 0.000 description 2
- 238000003759 clinical diagnosis Methods 0.000 description 2
- 239000000824 cytostatic agent Substances 0.000 description 2
- 230000001085 cytostatic effect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 238000005534 hematocrit Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 235000003724 spirulina extract Nutrition 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 238000011269 treatment regimen Methods 0.000 description 2
- 230000008673 vomiting Effects 0.000 description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 102000016938 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 108010063907 Glutathione Reductase Proteins 0.000 description 1
- 102000006587 Glutathione peroxidase Human genes 0.000 description 1
- 108700016172 Glutathione peroxidases Proteins 0.000 description 1
- 102100036442 Glutathione reductase, mitochondrial Human genes 0.000 description 1
- 102000005720 Glutathione transferase Human genes 0.000 description 1
- 108010070675 Glutathione transferase Proteins 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 1
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 1
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 102000019197 Superoxide Dismutase Human genes 0.000 description 1
- 108010012715 Superoxide dismutase Proteins 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 230000007503 antigenic stimulation Effects 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 230000007969 cellular immunity Effects 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 230000004727 humoral immunity Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000013394 immunophenotyping Methods 0.000 description 1
- 230000004957 immunoregulator effect Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 230000005741 malignant process Effects 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 210000004197 pelvis Anatomy 0.000 description 1
- 210000005105 peripheral blood lymphocyte Anatomy 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 230000005195 poor health Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 235000004400 serine Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000008521 threonine Nutrition 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 235000014393 valine Nutrition 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Invenţia se referă la medicină, în special la ginecologia oncologică, şi poate fi utilizată pentru tratamentul pacientelor cu cancer de col uterin local avansat de stadiul II…III. The invention relates to medicine, in particular to oncological gynecology, and can be used for the treatment of patients with locally advanced stage II...III cervical cancer.
Este cunoscută metoda de tratament al formelor de cancer cervical local avansat, care include chimioterapia cu 5-fluoruracil timp de 5 zile, concomitent cu administrarea preparatelor cu conţinut de platină se efectuează radioterapia după schema de fracţionare dinamică a dozei de iradiere de câte 4 Gy a bazinului mic timp de 3 zile, ulterior radioterapia cu fracţii mici în regim multifracţionat a câte 1,25 Gy, de 2 ori pe zi, cu un interval de 4…5 ore [1]. The method of treatment of locally advanced cervical cancer is known, which includes chemotherapy with 5-fluorouracil for 5 days, simultaneously with the administration of platinum-containing preparations, radiotherapy is performed according to the dynamic fractionation scheme of the irradiation dose of 4 Gy to the small pelvis for 3 days, subsequently radiotherapy with small fractions in a multifractionated regimen of 1.25 Gy, 2 times a day, with an interval of 4...5 hours [1].
Dezavantajul metodei cunoscute constă în aceea că nu este posibilă efectuarea curei de tratament continuu, deoarece acţiunea toxică dublă din partea chimiopreparatelor şi radioterapiei duce la accelerarea reacţiei din partea ţesuturilor neafectate, de aceea uneori nu este posibil de a efectua tratamentul într-un volum necesar şi deplin, ceea ce duce la diminuarea calităţii vieţii pacientelor şi a eficacităţii tratamentului. The disadvantage of the known method is that it is not possible to carry out a continuous treatment course, because the double toxic action of chemotherapy and radiotherapy leads to an acceleration of the reaction of unaffected tissues, therefore sometimes it is not possible to carry out the treatment in a necessary and full volume, which leads to a decrease in the quality of life of patients and the effectiveness of the treatment.
Problema pe care o rezolvă invenţia constă în elaborarea unei metode de tratament care ar spori indicii reactivităţii imunologice şi rezistenţei naturale, ar micşora toxicitatea şi formarea de radicali liberi în tratamentul complex al pacientelor cu cancer cervical local avansat; îmbunătăţind calitatea vieţii pacientelor şi supravieţuirea până la 5 ani, diminuând ratele de abandonare a tratamentului radiant şi reacţiile adverse. The problem solved by the invention consists in developing a treatment method that would increase the indices of immunological reactivity and natural resistance, reduce toxicity and the formation of free radicals in the complex treatment of patients with locally advanced cervical cancer; improving the quality of life of patients and survival up to 5 years, reducing the rates of abandonment of radiation treatment and adverse reactions.
Conform invenţiei, metoda revendicată constă în aceea că se efectuează radioterapia în doză a câte 2 Gy pentru o şedinţă, cura de tratament constituie 40 Gy, concomitent se introduce intravenos soluţie de cisplatină, câte 100 mg pe zi, timp de 4 zile, iar intramuscular câte 1,0 ml soluţie de 0,5% din extract de Spirulina platensis, timp de 10 zile, apoi câte 1 comprimat ce conţine 5 mg de substanţă activă de Spirulina platensis, de 2 ori pe zi, timp de 5 săptămâni. According to the invention, the claimed method consists in performing radiotherapy at a dose of 2 Gy per session, the treatment course is 40 Gy, simultaneously introducing intravenous cisplatin solution, 100 mg per day, for 4 days, and intramuscularly 1.0 ml of 0.5% solution of Spirulina platensis extract, for 10 days, then 1 tablet containing 5 mg of the active substance of Spirulina platensis, 2 times a day, for 5 weeks.
Rezultatul invenţiei constă în aceea că la aplicarea concomitentă a radioterapiei, chimioterapiei şi a extractului din Spirulina platensis (preparat imunomodulator BioR) sporesc indicii reactivităţii imunologice şi rezistenţei naturale, se micşorează toxicitatea şi formarea de radicali liberi, îmbunătăţind calitatea vieţii pacientelor şi supravieţuirea până la 5 ani, diminuând ratele de abandonare a tratamentului radiant şi reacţiile adverse. The result of the invention is that the simultaneous application of radiotherapy, chemotherapy and Spirulina platensis extract (BioR immunomodulatory preparation) increases the indices of immunological reactivity and natural resistance, reduces toxicity and the formation of free radicals, improving the quality of life of patients and survival up to 5 years, reducing the rates of abandonment of radiation treatment and adverse reactions.
Preparatul BioR reprezintă un complex de principii bioactive constituit din aminoacizi, în stare liberă şi în componenţa oligopeptidelor, dintre care circa 78% revin aminoacizilor consideraţi „imunoactivi” - glicina, valina, alanina, acidul glutamic, acidul asparagic, arginina, serina, treonina, triptofanul, cisteina, acidul gama aminobutiric, care în sinergism cu hidraţii de carbon, macro- şi microelementele devin antioxidanţi şi imunogeni. Preparatul BioR în capsule de 5 mg posedă acţiune antioxidativă şi de stabilizare a membranelor celulare şi lizozomale prin normalizarea metabolismului glutationului (inducerea sintezei glutationului redus, sporirea enzimelor ciclului glutationic - glutationreductazei, glutationperoxidazei, glutation-S-transferazelor şi γ-glutatiotransferazei). Menţine la un nivel optim echilibrul dintre sistemele de oxidare peroxidică a lipidelor şi cel antioxidant (reducerea radicalilor liberi ai oxigenului, conjugatelor dienice şi dialdehidei malonice, creşterea potenţialului antioxidant, inclusiv a verigilor enzimatice şi celor neenzimatice, majorarea nivelului superoxiddismutazei, catalazei, enzimelor glutationice, restabilirea conţinutului glutationului redus, tocoferolului, SH-grupelor etc.). Prezenţa în componenţa lui a aminoacizilor, oligopeptidelor şi a microelementelor Mn, Fe, Zn, Cu, Se, Cr, etc. stimulează procesele de regenerare a ţesuturilor şi influenţează pozitiv asupra imunităţii celulare şi umorale. BioR-ul reprezintă un imunocorector al reactivităţii imunologice şi rezistenţei naturale prin acţiunea sa asupra metabolismului celulelor imunocompetente: normalizează schimbul energetic al limfocitelor şi funcţiile enzimelor oxido-reducătoare ale neutrofilelor (Rudic V., 2004; Ghinda S., 2004). În contextul celor expuse, au prezentat interes investigaţiile ce ţin de acţiunea preparatului imunomodulator de generaţie nouă BioR asupra reactivităţii imunologice şi rezistenţei naturale cu micşorarea toxicităţii şi a formării de radicali liberi în tratamentul complex al pacientelor cu cancer cervical local avansat. The BioR preparation represents a complex of bioactive principles consisting of amino acids, in a free state and in the composition of oligopeptides, of which about 78% belong to amino acids considered "immunoactive" - glycine, valine, alanine, glutamic acid, aspartic acid, arginine, serine, threonine, tryptophan, cysteine, gamma aminobutyric acid, which in synergy with carbohydrates, macro- and microelements become antioxidants and immunogens. The BioR preparation in 5 mg capsules has an antioxidant action and stabilizes cell and lysosomal membranes by normalizing glutathione metabolism (induction of reduced glutathione synthesis, increase of glutathione cycle enzymes - glutathione reductase, glutathione peroxidase, glutathione-S-transferases and γ-glutathiotransferase). It maintains the balance between the lipid peroxidation and antioxidant systems at an optimal level (reduction of free radicals of oxygen, diene conjugates and malonic dialdehyde, increase of antioxidant potential, including enzymatic and non-enzymatic links, increase of the level of superoxide dismutase, catalase, glutathione enzymes, restoration of the content of reduced glutathione, tocopherol, SH-groups, etc.). The presence in its composition of amino acids, oligopeptides and microelements Mn, Fe, Zn, Cu, Se, Cr, etc. stimulates the processes of tissue regeneration and positively influences cellular and humoral immunity. BioR is an immunocorrector of immunological reactivity and natural resistance through its action on the metabolism of immunocompetent cells: it normalizes the energy exchange of lymphocytes and the functions of oxido-reducing enzymes of neutrophils (Rudic V., 2004; Ghinda S., 2004). In the context of the above, investigations related to the action of the new generation immunomodulatory preparation BioR on immunological reactivity and natural resistance with the reduction of toxicity and free radical formation in the complex treatment of patients with locally advanced cervical cancer were of interest.
Cancerul cervical ocupă locul întâi în structura morbidităţii (43,7%) a tumorilor maligne ale sistemului reproductiv la femei. În acelaşi timp, mortalitatea cauzată de cancerul cervical constituie circa 10% din decesele de pe urma cancerului genital, ceea ce e determinat în mare măsură de diagnosticul tardiv. Cervical cancer ranks first in the morbidity structure (43.7%) of malignant tumors of the reproductive system in women. At the same time, mortality caused by cervical cancer constitutes about 10% of deaths from genital cancer, which is largely determined by late diagnosis.
Printre explicaţiile posibile s-ar număra educaţia sanitară precară a unui important segment din populaţia feminină, igiena personală deficitară, neadresarea pentru control profilactic la medicul ginecolog. La 50…54% din pacientele primare se determină st. III…IV al procesului malign, iar tratamentul aplicat asigură supravieţuirea de 5 ani la 63,1% paciente. Among the possible explanations would be the poor health education of a significant segment of the female population, poor personal hygiene, failure to seek prophylactic control from a gynecologist. In 50…54% of primary patients, stage III…IV of the malignant process is determined, and the applied treatment ensures 5-year survival in 63.1% of patients.
Analiza tratamentului cancerului cervical demonstrează că această localizare rămâne o problemă dificilă de rezolvat în rândul tumorilor maligne la femei, în special cancerul cervical local avansat. Ultimul deceniu se caracterizează prin tendinţa optimizării tratamentului cancerului cervical, optând pentru metode combinate, care includ tratamentul chirurgical, chimio- şi radioterapia. Cele mai mari dificultăţi în tratamentul pacientelor de cancer cervical se constată în stadiile local avansate ale procesului, care se manifestă prin agresivitate sporită, o rată înaltă de recidive şi metastaze. Analysis of cervical cancer treatment demonstrates that this location remains a difficult problem to solve among malignant tumors in women, especially locally advanced cervical cancer. The last decade is characterized by the trend of optimizing the treatment of cervical cancer, opting for combined methods, which include surgical treatment, chemo- and radiotherapy. The greatest difficulties in the treatment of cervical cancer patients are observed in the locally advanced stages of the process, which are manifested by increased aggressiveness, a high rate of relapses and metastases.
Ratele înalte ale recidivelor după tratamentul complex al pacientelor cu cancer cervical local avansat, stadiile II…III, şi anume de 30…85%, se datorează în mare parte şi statutului imunologic deprimat. Starea imunologică patologică este generată atât de persistenţa în timp a proceselor oncologice declanşate la nivel de cervix, cât şi de rezistenţa epuizată a organismului afectat. The high rates of relapses after complex treatment of patients with locally advanced cervical cancer, stages II…III, namely 30…85%, are largely due to the depressed immunological status. The pathological immunological state is generated both by the persistence over time of the oncological processes triggered at the level of the cervix, and by the exhausted resistance of the affected organism.
În cadrul studiului au fost efectuate cercetări imunologice la 57 paciente cu cancer cervical, stadiile II şi III, care au urmat numai radioterapie sau concomitent chimioterapia cu platină. Au fost efectuate în total 171 de investigaţii utilizând metoda imunofenotipizării limfocitelor sângelui periferic cu anticorpi monoclonali pe parcursul aplicării tratamentului radioterapic. Panoul MON AT a inclus: The study included immunological investigations in 57 patients with cervical cancer, stages II and III, who underwent radiotherapy alone or concomitant platinum chemotherapy. A total of 171 investigations were performed using the method of immunophenotyping peripheral blood lymphocytes with monoclonal antibodies during radiotherapy treatment. The MON AT panel included:
CD 19 - B limfocite CD 19 - B lymphocytes
CD3 - T limfocite CD3 - T lymphocytes
CD4 - T limfocite helper CD4 - T helper lymphocytes
CD8 - T limfocite citostatice/supresorii CD8 - T cytostatic/suppressor lymphocytes
CD5 - T limfocite mature CD5 - mature T lymphocytes
CD16 - kileri naturali CD16 - natural cellars
CD HELA DR - B limfocite şi limfocite T activate CD HELA DR - B lymphocytes and activated T lymphocytes
Au fost luaţi în consideraţie indicii imunoregulatori: CD4/CD8 (IRI) şi CD4/CD3 (IRI 2), care caracterizează nivelul de tensionare a răspunsului imun. The immunoregulatory indices were taken into account: CD4/CD8 (IRI) and CD4/CD3 (IRI 2), which characterize the level of tension of the immune response.
Investigaţia imunologică a fost efectuată fiecărei paciente de 3 ori: până la începutul tratamentului (1), în mijlocul curei de radioterapie şi chimioterapie (2) şi imediat după finalizarea tratamentului (3). Rezultatele obţinute sunt prezentate în tabelul 1. The immunological investigation was performed on each patient 3 times: before the start of treatment (1), in the middle of the radiotherapy and chemotherapy course (2) and immediately after the completion of treatment (3). The results obtained are presented in Table 1.
Tabelul 1 Table 1
Etapele investigaţiei, valorile medii către etapa radioterapiei Antigenii CD 1 2 3 CD 19 8,3 4,1 3,3 CD 3 50,7 40,1 32,7 CD 8 19,8 17,0 16,5 CD 5 36,0 24,2 21,0 CD 16 15,8 20,0 23,4 CD HLA DR 14,0 16,4 10,7 CD4/CD8 2,05 1,4 1,3 CD4 / CD3 1,1 1,2 1,23Investigation stages, average values towards radiotherapy stage Antigens CD 1 2 3 CD 19 8.3 4.1 3.3 CD 3 50.7 40.1 32.7 CD 8 19.8 17.0 16.5 CD 5 36.0 24.2 21.0 CD 16 15.8 20.0 23.4 CD HLA DR 14.0 16.4 10.7 CD4/CD8 2.05 1.4 1.3 CD4 / CD3 1.1 1.2 1.23
Rezultatele studiului: Study results:
1. Scăderea subpopulaţiilor de bază a limfocitelor B şi T, descreşterea numărului limfocitelor mature funcţionale T CD5 şi IRI CD4/ CD8 care sunt notate chiar în mijlocul curei de tratament. 1. Decrease in the basic subpopulations of B and T lymphocytes, decrease in the number of mature functional T lymphocytes CD5 and IRI CD4/CD8 which are noted right in the middle of the treatment course.
2. Scăderea numărului de celule ce poartă la suprafaţa membranei molecule active CD HLA DR. 2. Decrease in the number of cells carrying active CD HLA DR molecules on their membrane surface.
3. În acelaşi timp, creşte numărul kilerilor naturali CD 16, care, probabil, este cauzat de asocierea pe parcursul tratamentului a proceselor inflamatorii în regiunea tumorii. 3. At the same time, the number of CD 16 natural killers increases, which is probably caused by the association of inflammatory processes in the tumor region during treatment.
4. Creşterea CD4/CD3, ceea ce poate fi asociat stimulării antigenice sporite în urma destrucţiei tumorii şi acutizării patologiei cronice preexistente odată cu administrarea în schema de tratament a chimiopreparatelor citostatice ce posedă un efect imunosupresiv. 4. Increase in CD4/CD3, which may be associated with increased antigenic stimulation following tumor destruction and exacerbation of pre-existing chronic pathology with the administration of cytostatic chemopreparations that have an immunosuppressive effect in the treatment regimen.
Constatare: includerea preparatelor imunomodulatoare în schema propusă de tratament al pacientelor cu cancer cervical st. II…III în cadrul studiului dat este raţională deja la această etapă incipientă de investigaţii, fapt ce ar putea duce la prevenirea mai multor complicaţii, ar favoriza regenerarea ţesuturilor supuse tratamentului oncologic specific şi ar îmbunătăţi calitatea vieţii pacientelor respective şi rezultatele supravieţuirii până la 5 ani. Finding: the inclusion of immunomodulatory preparations in the proposed treatment regimen for patients with stage II…III cervical cancer in this study is rational already at this early stage of investigations, which could lead to the prevention of several complications, would favor the regeneration of tissues undergoing specific oncological treatment and would improve the quality of life of the respective patients and survival results up to 5 years.
Prezintă interes şi investigaţiile cu referire la acţiunea preparatului imunomodulator BioR asupra reactivităţii imunologice şi rezistenţei naturale, cu micşorarea toxicităţii şi a formării de radicali liberi în tratamentul complex al pacientelor cu cancer cervical local avansat. Also of interest are investigations regarding the action of the immunomodulatory preparation BioR on immunological reactivity and natural resistance, with the reduction of toxicity and free radical formation in the complex treatment of patients with locally advanced cervical cancer.
În studiu au fost incluse datele investigaţiilor clinice şi paraclinice efectuate la 220 paciente, apreciindu-se eficacitatea diferitor modalităţi de tratament combinat al cancerului cervical: chirurgical, radioterapic şi chimioterapic în scheme combinate şi complexe. Actualmente, tratamentul cancerului cervical poate include un tratament prin asocierea concomitentă a chimio- şi radioterapiei. The study included data from clinical and paraclinical investigations performed on 220 patients, assessing the effectiveness of different combined treatment modalities for cervical cancer: surgery, radiotherapy and chemotherapy in combined and complex schemes. Currently, the treatment of cervical cancer may include treatment by concomitant association of chemo- and radiotherapy.
Loturile de paciente cu cancer cervical stadiile II şi III sunt prezentate în tabelul 2. The groups of patients with stage II and III cervical cancer are presented in Table 2.
Tabelul 2 Table 2
Lotul I: Radioterapie + soluţie de cisplatină (4 cure) + BioR II:Radioterapie+ soluţie de cisplatină (4 cure) Control: radioterapie Numărul Pacientelor 44 48 112 Total 204 pacienteGroup I: Radiotherapy + cisplatin solution (4 courses) + BioR II: Radiotherapy + cisplatin solution (4 courses) Control: radiotherapy Number of Patients 44 48 112 Total 204 patients
BioR s-a administrat câte 1 ml i/m - 10 zile, apoi câte 1 comprimat de 5 mg de substanţă activă de 2 ori pe zi, timp de 5 săptămâni. BioR was administered 1 ml i/m for 10 days, then 1 tablet of 5 mg of active substance 2 times a day for 5 weeks.
Rezultate: 112 paciente cu cancer cervical local avansat au fost randomizate în loturile de studiu: radioterapie + soluţie de cisplatină 100 mg (4 cure) + BioR, radioterapie + soluţie de cisplatină 100 mg (4 cure). Progresarea a survenit la 29 paciente după 78 luni. Pacientele din ambele loturi, cărora li s-a administrat chimioterapia concomitent cu radioterapia, au prezentat un indice fără boală semnificativ mai lung cu 9 luni şi o supravieţuire la 5 ani mai mare cu 12% comparativ cu pacientele ce au urmat doar radioterapia standard. Totodată în lotul pacientelor cu cancer cervical local avansat: radioterapie + soluţie de cisplatină 100 mg (4 cure) + BioR s-a constat de asemenea o diminuare semnificativă a reacţiilor adverse, îmbunătăţirea calităţii vieţii, micşorarea cazurilor de suspendare a tratamentului, o îmbunătăţire a indicelui fără boală mai lung cu 9 luni şi o supravieţuire la 5 ani mai mare cu 12% comparativ cu pacientele ce au urmat doar radioterapia standard. Results: 112 patients with locally advanced cervical cancer were randomized into the study groups: radiotherapy + cisplatin solution 100 mg (4 courses) + BioR, radiotherapy + cisplatin solution 100 mg (4 courses). Progression occurred in 29 patients after 78 months. Patients in both groups, who received chemotherapy concomitantly with radiotherapy, had a significantly longer disease-free index by 9 months and a 12% higher 5-year survival compared to patients who received standard radiotherapy alone. At the same time, in the group of patients with locally advanced cervical cancer: radiotherapy + cisplatin solution 100 mg (4 courses) + BioR, there was also a significant reduction in adverse reactions, improvement in quality of life, reduction in cases of treatment suspension, an improvement in the disease-free index longer by 9 months and a 5-year survival higher by 12% compared to patients who only followed standard radiotherapy.
Exemple de realizare Examples of implementation
Exemplul 1 Example 1
Pacienta N., 1953, a fost internată în I.M.S.P.I.O., oncoginecologie cu diagnosticul clinic de cancer cervical local avansat st. IIA. Pacienta a fost investigată clinic şi paraclinic. Analiza generală a sangelui: hemoglobina - 137 g/l; eritrocitele - 4,4 mil.; hematocritul - 0,42; leucocitele - 4,5 mii. Patologie concomitentă: cardiopatie ischemică şi dismetabolică, I.C. I N.I.H.A., colecisto-pancreatită cronică, pielonefrită cronică. S-a efectuat următorul tratament: radioterapie în doză a câte 2 Gy la o şedinţă, cura de tratament a fost de 40 Gy, concomitent s-a administrat intravenos soluţie de cisplatină, câte 100 mg pe zi, timp de 4 zile, şi soluţie de 0,5% din extract de Spirulina platensis, câte 1 ml, i/m, timp de 10 zile. În timpul tratamentului nu s-au determinat reacţii adverse ca greţuri, vome, nu a fost abandonată seria de tratament cu preparatul chimioterapic. După externarea pacientei în stare satisfăcătoare a fost prelungit tratamentul cu extract de spirulină, câte 1 comprimat de 5 mg de substanţă activă, de 2 ori pe zi, timp de 5 săptămâni. La control repetat timp de 5 ani nu s-au determinat recidive. Patient N., 1953, was admitted to I.M.S.P.I.O., oncogynecology with the clinical diagnosis of locally advanced cervical cancer st. IIA. The patient was investigated clinically and paraclinically. General blood analysis: hemoglobin - 137 g/l; erythrocytes - 4.4 million; hematocrit - 0.42; leukocytes - 4.5 thousand. Concomitant pathology: ischemic and dysmetabolic cardiopathy, I.C. I N.I.H.A., chronic cholecysto-pancreatitis, chronic pyelonephritis. The following treatment was performed: radiotherapy at a dose of 2 Gy per session, the treatment course was 40 Gy, simultaneously cisplatin solution was administered intravenously, 100 mg per day, for 4 days, and 0.5% solution of Spirulina platensis extract, 1 ml, i/m, for 10 days. During the treatment, no adverse reactions such as nausea, vomiting were determined, the treatment series with the chemotherapy preparation was not abandoned. After the patient was discharged in satisfactory condition, the treatment with spirulina extract was prolonged, 1 tablet of 5 mg of active substance, 2 times a day, for 5 weeks. At repeated control for 5 years, no relapses were determined.
Exemplul 2 Example 2
Pacienta E, 1951, a fost internată în I.M.S.P.I.O., oncoginecologie cu diagnosticul clinic de cancer cervical local avansat de st. IIIA. Pacienta a fost investigată clinic şi paraclinic. Analiza generală a sangelui: hemoglobina - 122 g/l; eritrocitele - 3,0 mil.; hematocritul - 0,4; leucocitele - 5,8 mii. Patologie concomitentă: cardiopatie ischemică, pielonefrită cronică. S-a efectuat următorul tratament: radioterapia în doză a câte 2 Gy la o şedinţă, cura de tratament a fost de 40 Gy, concomitent s-a administrat intravenos soluţie de cisplatină, câte 100 mg pe zi, timp de 4 zile, şi soluţie de 0,5% din extract de Spirulina platensis, câte 1 ml, i/m, timp de 10 zile. În timpul tratamentului nu s-au determinat reacţii adverse ca greţuri, vome, nu a fost abandonată seria de tratament cu preparatul chimioterapic. După externarea pacientei în stare satisfăcătoare a fost prelungit tratamentul cu extract de spirulină, câte 1 comprimat de 5 mg de substanţă activă, de 2 ori pe zi, timp de 5 săptămâni. La control repetat timp de 5 ani nu s-au determinat recidive. Patient E, 1951, was admitted to I.M.S.P.I.O., oncogynecology with the clinical diagnosis of locally advanced cervical cancer of stage IIIA. The patient was investigated clinically and paraclinically. General blood analysis: hemoglobin - 122 g/l; erythrocytes - 3.0 million; hematocrit - 0.4; leukocytes - 5.8 thousand. Concomitant pathology: ischemic cardiopathy, chronic pyelonephritis. The following treatment was performed: radiotherapy in a dose of 2 Gy per session, the treatment course was 40 Gy, concomitantly cisplatin solution was administered intravenously, 100 mg per day, for 4 days, and 0.5% solution of Spirulina platensis extract, 1 ml, i/m, for 10 days. During the treatment, no adverse reactions such as nausea, vomiting were determined, the treatment series with the chemotherapy preparation was not abandoned. After the patient was discharged in satisfactory condition, the treatment with spirulina extract was prolonged, 1 tablet of 5 mg of active substance, 2 times a day, for 5 weeks. At repeated control for 5 years, no relapses were determined.
1. Бойко А.В. и др. Использование радиомодификации для расширения показаний к радикальному лучевому лечению больных с местно-распространенными формами рака шейки матки. Казанский медицинский журнал. Том LXXXI, №4, 2000, p.287-289 1. Бойко А.В. and others The use of radiomodification for the extension of indications for radical radiation treatment of patients with locally widespread forms of cervical cancer. Kazan medical journal. Volume LXXXI, №4, 2000, p.287-289
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MDS20140049A MD854Z (en) | 2014-04-14 | 2014-04-14 | Method for treating locally advanced II-III stage cervical canrcinoma |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MDS20140049A MD854Z (en) | 2014-04-14 | 2014-04-14 | Method for treating locally advanced II-III stage cervical canrcinoma |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MD854Y MD854Y (en) | 2014-12-31 |
| MD854Z true MD854Z (en) | 2015-08-31 |
Family
ID=52211088
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MDS20140049A MD854Z (en) | 2014-04-14 | 2014-04-14 | Method for treating locally advanced II-III stage cervical canrcinoma |
Country Status (1)
| Country | Link |
|---|---|
| MD (1) | MD854Z (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MD2544G2 (en) * | 2004-05-14 | 2005-04-30 | Андрей ДОРУК | Combined method of treatment of locally spread malignant cephalic and neck cancers |
| MD2543G2 (en) * | 2004-05-14 | 2005-04-30 | Андрей ДОРУК | Method of treatment of locally spread malignant tumors |
| MD2601G2 (en) * | 2004-05-14 | 2005-07-31 | Андрей ДОРУК | Combined method of treatment of the locally spread malignant tumors |
| MD3204G2 (en) * | 2005-12-29 | 2007-07-31 | Валентина ДАРИЙ | Method of laryngeal cancer preoperative treatment |
-
2014
- 2014-04-14 MD MDS20140049A patent/MD854Z/en not_active IP Right Cessation
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MD2544G2 (en) * | 2004-05-14 | 2005-04-30 | Андрей ДОРУК | Combined method of treatment of locally spread malignant cephalic and neck cancers |
| MD2543G2 (en) * | 2004-05-14 | 2005-04-30 | Андрей ДОРУК | Method of treatment of locally spread malignant tumors |
| MD2601G2 (en) * | 2004-05-14 | 2005-07-31 | Андрей ДОРУК | Combined method of treatment of the locally spread malignant tumors |
| MD3204G2 (en) * | 2005-12-29 | 2007-07-31 | Валентина ДАРИЙ | Method of laryngeal cancer preoperative treatment |
Non-Patent Citations (1)
| Title |
|---|
| Бойко А.В. и др. Использование радиомодификации для расширения показаний к радикальному лучевому лечению больных с местно-распространенными формами рака шейки матки. Казанский медицинский журнал. Том LXXXI, №4, 2000, p.287-289 * |
Also Published As
| Publication number | Publication date |
|---|---|
| MD854Y (en) | 2014-12-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US12350298B2 (en) | Microbiome related immunotherapies | |
| Xue et al. | Astaxanthin attenuates total body irradiation-induced hematopoietic system injury in mice via inhibition of oxidative stress and apoptosis | |
| Mo et al. | ROS scavenging nanozyme modulates immunosuppression for sensitized cancer immunotherapy | |
| WO2010009735A2 (en) | Combinatorial analysis and repair | |
| JP6488276B2 (en) | Regulation of cancer using natural compounds and / or diet | |
| US20200323820A1 (en) | Materials and methods for inhibiting tumor growth | |
| EP4226930A1 (en) | Composition for preventing or treating cancer comprising bifidobacterium longum rapo (kctc13773bp) | |
| Liu et al. | Low-dose naltrexone inhibits the epithelial-mesenchymal transition of cervical cancer cells in vitro and effects indirectly on tumor-associated macrophages in vivo | |
| Yan et al. | Ligilactobacillus salivarius CCFM 1266 modulates gut microbiota and GPR109a-mediated immune suppression to attenuate immune checkpoint blockade-induced colitis | |
| Haiyan et al. | Growth of breast cancer cells inhibited by bromelains extracted from the different tissues of pineapple | |
| JP2022533723A (en) | Use of metal ions to enhance the therapeutic effect of arsenic | |
| CN116726021A (en) | A combination drug of DRP1 inhibitor and ferroptosis inducer and its anti-tumor use | |
| Jia et al. | An injectable biomimetic hydrogel adapting brain tissue mechanical strength for postoperative treatment of glioblastoma without anti-tumor drugs participation | |
| CN107557333A (en) | A kind of neoantigen for cell therapy is in the preparation method of delivery cell | |
| MD854Z (en) | Method for treating locally advanced II-III stage cervical canrcinoma | |
| Dodge et al. | Effects of donor vitamin A deficiency and pharmacologic modulation of donor T cell retinoic acid pathway on the severity of experimental graft-versus-host disease | |
| JP2019508388A (en) | Use of fullerenes / metalfullerenes in the manufacture of a medicament for treating myelosuppression | |
| CN117298043A (en) | Nanometer hydrogel precursor and preparation method and application thereof | |
| CN105168241B (en) | Application of the hydrogen sulfide in antitumor drug tumour inhibiting rate is improved | |
| CN115554317A (en) | Pharmaceutical composition for treating tumors, kit and application thereof | |
| TWI722492B (en) | Composition containing lotus extract and its use for treating head and neck cancer | |
| Niu et al. | Manganese-based nanozymes as broad-spectrum antioxidants against cisplatin-induced skeletal muscle atrophy | |
| EP1881838B1 (en) | Antitumor agent on the base of bcg vaccine, method for its preparation and its use | |
| TWI690327B (en) | Use of daphnoretin in the prevention of tissue or organ transplant rejection or graft-versus-host-disease | |
| US20150329824A1 (en) | Z cells activated by zinc finger-like protein and uses thereof in cancer treatment |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FG9Y | Short term patent issued | ||
| KA4Y | Short-term patent lapsed due to non-payment of fees (with right of restoration) | ||
| MM4Y | Short-term patent definitely lapsed due to non-payment of fees |