MD1511Z - Method for endoscopic hemostasis of variceal hemorrhages in liver cirrhosis - Google Patents
Method for endoscopic hemostasis of variceal hemorrhages in liver cirrhosis Download PDFInfo
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- MD1511Z MD1511Z MDS20200146A MDS20200146A MD1511Z MD 1511 Z MD1511 Z MD 1511Z MD S20200146 A MDS20200146 A MD S20200146A MD S20200146 A MDS20200146 A MD S20200146A MD 1511 Z MD1511 Z MD 1511Z
- Authority
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- Moldova
- Prior art keywords
- variceal
- liver cirrhosis
- hemorrhages
- chloride
- thrombin
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- 208000032843 Hemorrhage Diseases 0.000 title claims abstract description 19
- 230000023597 hemostasis Effects 0.000 title claims abstract description 14
- 208000019425 cirrhosis of liver Diseases 0.000 title claims abstract description 9
- 238000000034 method Methods 0.000 title claims description 14
- 102000008946 Fibrinogen Human genes 0.000 claims abstract description 14
- 108010049003 Fibrinogen Proteins 0.000 claims abstract description 14
- 229940012952 fibrinogen Drugs 0.000 claims abstract description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims abstract description 13
- 108090000190 Thrombin Proteins 0.000 claims abstract description 13
- 229960004072 thrombin Drugs 0.000 claims abstract description 13
- 108010039627 Aprotinin Proteins 0.000 claims abstract description 12
- 229960004405 aprotinin Drugs 0.000 claims abstract description 12
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 claims abstract description 12
- 108010010803 Gelatin Proteins 0.000 claims abstract description 9
- 229920000159 gelatin Polymers 0.000 claims abstract description 9
- 239000008273 gelatin Substances 0.000 claims abstract description 9
- 235000019322 gelatine Nutrition 0.000 claims abstract description 9
- 235000011852 gelatine desserts Nutrition 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims abstract description 5
- 239000000243 solution Substances 0.000 claims description 13
- 206010046996 Varicose vein Diseases 0.000 claims description 12
- 108010080379 Fibrin Tissue Adhesive Proteins 0.000 claims description 8
- 208000027185 varicose disease Diseases 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 108010073385 Fibrin Proteins 0.000 description 10
- 102000009123 Fibrin Human genes 0.000 description 10
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 10
- 229950003499 fibrin Drugs 0.000 description 10
- 208000034158 bleeding Diseases 0.000 description 9
- 230000000740 bleeding effect Effects 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000002792 vascular Effects 0.000 description 5
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 4
- 238000006116 polymerization reaction Methods 0.000 description 4
- 230000002269 spontaneous effect Effects 0.000 description 4
- 208000000624 Esophageal and Gastric Varices Diseases 0.000 description 3
- 108010071289 Factor XIII Proteins 0.000 description 2
- 108010067306 Fibronectins Proteins 0.000 description 2
- 102000016359 Fibronectins Human genes 0.000 description 2
- 108010051456 Plasminogen Proteins 0.000 description 2
- 102000013566 Plasminogen Human genes 0.000 description 2
- 206010056091 Varices oesophageal Diseases 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 208000024170 esophageal varices Diseases 0.000 description 2
- 201000010120 esophageal varix Diseases 0.000 description 2
- 230000002008 hemorrhagic effect Effects 0.000 description 2
- 208000007232 portal hypertension Diseases 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 206010005144 Bleeding varicose vein Diseases 0.000 description 1
- 208000005489 Esophageal Perforation Diseases 0.000 description 1
- 208000007217 Esophageal Stenosis Diseases 0.000 description 1
- 206010051012 Gastric varices Diseases 0.000 description 1
- 208000032456 Hemorrhagic Shock Diseases 0.000 description 1
- 206010030194 Oesophageal stenosis Diseases 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 206010049771 Shock haemorrhagic Diseases 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229940105784 coagulation factor xiii Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 229940012444 factor xiii Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 201000001231 mediastinitis Diseases 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 229940108461 rennet Drugs 0.000 description 1
- 108010058314 rennet Proteins 0.000 description 1
- 238000007632 sclerotherapy Methods 0.000 description 1
- 229960000776 sodium tetradecyl sulfate Drugs 0.000 description 1
- UPUIQOIQVMNQAP-UHFFFAOYSA-M sodium;tetradecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCOS([O-])(=O)=O UPUIQOIQVMNQAP-UHFFFAOYSA-M 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Materials For Medical Uses (AREA)
Abstract
Invenţia se referă la medicină, în special la hemostaza endoscopică a hemoragiilor variceale esofago-gastrice în ciroza hepatică decompensată.Esenţa invenţiei constă în aceea că endoscopic concomitent se injectează în lumenul varicelui două componente ale unui adeziv fibrinic şi anume, primul component, care include o soluţie de fibrinogen, şi al doilea component, care include un amestec de soluţii de trombină cu gelatină polisuccinilată, aprotinină şi clorură de Ca+2, în următorul raport al componentelor, la 1 ml:fibrinogen (mg)15...45trombină (UI)25...100gelatină polisuccinilată (mg)120...360aprotinină (KIU)250...1000clorură de Ca+2(µmol)15...30.The invention relates to medicine, in particular to the endoscopic hemostasis of esophageal-gastric variceal hemorrhages in decompensated liver cirrhosis. fibrinogen solution, and the second component, which includes a mixture of thrombin solutions with polysuccinylated gelatin, aprotinin and Ca + 2 chloride, in the following ratio of components, to 1 ml: fibrinogen (mg) 15-45 thrombin (IU ) 25 ... 100 polysuccinylated gelatin (mg) 120 ... 360protinin (KIU) 250 ... 1000 Ca + 2 chloride (µmol) 15 ... 30.
Description
Invenţia se referă la medicină, în special la hemostaza endoscopică a hemoragiilor variceale esofago-gastrice în ciroza hepatică decompensată. The invention relates to medicine, in particular to endoscopic hemostasis of esophageal-gastric variceal bleeding in decompensated liver cirrhosis.
Este cunoscută metoda de hemostază endoscopică a hemoragiilor variceale cirogene cu utilizarea soluţiei alcoolice de tetradecil sulfat de sodiu, care provoacă sclerozarea vasului [1]. The method of endoscopic hemostasis of surgical variceal hemorrhages using an alcoholic solution of sodium tetradecyl sulfate, which causes vessel sclerosis, is known [1].
Dezavantajele metodei de sclerozare a varicelor constau în neeficacitatea utilizării ei în cazul varicelor de calibru mare, provocând dureri pronunţate după utilizare şi în unele cazuri necroze locale cu complicaţii severe şi anume perforaţii ale esofagului, mediastinite, recidive frecvente de hemoragii repetate, iar la distanţă se poate complica cu stenoze esofagiene în rezultatul proceselor sclero-atrofice după manipulaţii repetate. The disadvantages of the varicose vein sclerotherapy method are its ineffectiveness in the case of large-caliber varicose veins, causing severe pain after use and in some cases local necrosis with severe complications, namely esophageal perforations, mediastinitis, frequent relapses of repeated bleeding, and at a distance it can be complicated by esophageal stenosis as a result of sclero-atrophic processes after repeated manipulations.
Este cunoscută metoda de hemostază a hemoragiilor variceale prin ligaturarea varicelor cu benzi elastice cu ajutorului unui dispozitiv de aplicare, care este fixat pe endoscop [2]. The method of hemostasis of varicose bleeding is known by ligating the varicose veins with elastic bands using an application device, which is fixed on the endoscope [2].
Dezavantajele metodei menţionate constau în aceea că ligaturile elastice nu pot fi aplicate în cazul sângerărilor din varicele gastrice fundice, din cauza posibilităţilor reduse de manevrare ale aplicatorului endoscopului, iar în cazul varicelor de calibru mare (>1 cm) în timpul aplicării ligaturilor poate fi lezat peretele varicelui cu provocarea unei hemoragii abundente. The disadvantages of the mentioned method are that elastic ligatures cannot be applied in the case of bleeding from fundic gastric varices, due to the limited maneuverability of the endoscope applicator, and in the case of large-caliber varices (>1 cm) during the application of ligatures, the variceal wall may be damaged, causing profuse bleeding.
Este cunoscută metoda de utilizare a adezivului fibrinic pentru hemostaza endoscopică a hemoragiilor variceale în ciroza hepatică, care este compus din fibrinogen, factorul XIII de coagulare, fibronectină, plasminogen şi aprotinină, care se amestecă cu soluţie de trombină şi clorură de Ca+2, în următorul raport al componentelor, la 1 ml: The method of using fibrin glue for endoscopic hemostasis of variceal hemorrhages in liver cirrhosis is known, which is composed of fibrinogen, coagulation factor XIII, fibronectin, plasminogen and aprotinin, which is mixed with thrombin and Ca+2 chloride solution, in the following ratio of components, per 1 ml:
fibrinogen (mg) 70...110 factorul XIII (UI) 10...50 fibronectină (mg) 2...9 plasminogen (mg) 20...120 aprotinină (KIU) 3000 trombină (UI) 500 clorură de Ca+2 (µmol) 40 [3].fibrinogen (mg) 70...110 factor XIII (IU) 10...50 fibronectin (mg) 2...9 plasminogen (mg) 20...120 aprotinin (KIU) 3000 thrombin (IU) 500 Ca+2 chloride (µmol) 40 [3].
Dezavantajele adezivului fibrinic cunoscut constau în aceea că polimerizarea lui are loc imediat după combinarea componentelor, ceea ce nu permite introducerea lui în lumenul varicelui sângerând prin cateterul de injectare al endoscopului lung de 150 cm, datorită polimerizării rapide a compusului cu obturarea lumenului cateterului, aderarea slabă la peretele vascular cu riscul expulzării spontane a cheagului fibrinic. The disadvantages of the known fibrin glue are that its polymerization occurs immediately after combining the components, which does not allow its introduction into the lumen of the bleeding variceal vein through the injection catheter of the 150 cm long endoscope, due to the rapid polymerization of the compound with occlusion of the catheter lumen, poor adhesion to the vascular wall with the risk of spontaneous expulsion of the fibrin clot.
Este cunoscută metoda de hemostază endoscopică a hemoragiilor variceale prin utilizarea adezivului fibrinic, care include soluţie de fibrinogen, care se amestecă cu soluţie de aprotinină, trombină, clorură de Ca+2 şi adrenalină, în următorul raport al componentelor, la 1 ml: The method of endoscopic hemostasis of variceal hemorrhages is known by using fibrin glue, which includes fibrinogen solution, which is mixed with aprotinin solution, thrombin, Ca+2 chloride and adrenaline, in the following ratio of components, per 1 ml:
fibrinogen (mg) 15...30 aprotinină (KIU) 250...1000 trombină (UI) 25...100 clorură de Ca+2 (µmol) 15...30 adrenalină (mg) 0,1...0,3 [4].fibrinogen (mg) 15...30 aprotinin (KIU) 250...1000 thrombin (UI) 25...100 Ca+2 chloride (µmol) 15...30 adrenaline (mg) 0.1...0.3 [4].
Dezavantajele metodei constau în aceea că la injectarea componentelor adezivului în varicele sângerând cu formarea cheagului fibrinic poate surveni expulzarea spontană a cheagului din lumenul vasului din cauza presiunii venoase mari, consistenţei gelatinoase moi a cheagului fibrinic format şi fixării reduse a lui de peretele vascular. The disadvantages of the method are that when injecting the adhesive components into bleeding varicose veins with the formation of a fibrin clot, spontaneous expulsion of the clot from the vessel lumen may occur due to high venous pressure, the soft gelatinous consistency of the formed fibrin clot and its reduced fixation to the vascular wall.
Problema invenţiei constă în elaborarea unei metode de hemostază endoscopică a hemoragiilor variceale în ciroza hepatică decompensată cu utilizarea unui adeziv fibrinic, care permite o hemostază eficientă cu evitarea expulzării spontane a cheagului fibrinic, datorită unei aderări eficiente de peretele vascular cu evitarea recidivelor hemoragice. The problem of the invention consists in developing a method of endoscopic hemostasis of variceal hemorrhages in decompensated liver cirrhosis using a fibrin adhesive, which allows for effective hemostasis while avoiding spontaneous expulsion of the fibrin clot, due to effective adhesion to the vascular wall while avoiding hemorrhagic relapses.
Esenţa invenţiei constă în aceea că endoscopic concomitent se injectează în lumenul varicelui două componente ale unui adeziv fibrinic şi anume, primul component, care include o soluţie de fibrinogen, şi al doilea component, care include un amestec de soluţii de trombină cu gelatină polisuccinilată, aprotinină şi clorură de Ca+2, în următorul raport al componentelor, la 1 ml: The essence of the invention consists in the fact that two components of a fibrin adhesive are simultaneously endoscopically injected into the lumen of the varicose vein, namely, the first component, which includes a fibrinogen solution, and the second component, which includes a mixture of thrombin solutions with polysuccinylated gelatin, aprotinin and Ca+2 chloride, in the following ratio of components, per 1 ml:
fibrinogen (mg) 15...45 trombină (UI) 25...100 gelatină polisuccinilată (mg) 120...360 aprotinină (KIU) 250...1000 clorură de Ca+2(µmol) 15...30.fibrinogen (mg) 15...45 thrombin (IU) 25...100 polysuccinylated gelatin (mg) 120...360 aprotinin (KIU) 250...1000 Ca+2 chloride (µmol) 15...30.
Rezultatul invenţiei constă în aceea că metoda revendicată permite o hemostază eficientă cu evitarea expulzării spontane a cheagului fibrinic, unei aderări eficiente de peretele vascular, datorită obţinerii unui cheag de o consistentă dur-elastică, care ia forma vasului dilatat varicos, formând un dop fibrinic bine fixat de pereţii varicelui, ceea ce permite realizarea unei hemostaze sigure. The result of the invention is that the claimed method allows for efficient hemostasis while avoiding spontaneous expulsion of the fibrin clot, for efficient adhesion to the vascular wall, due to obtaining a clot of a hard-elastic consistency, which takes the shape of the varicose dilated vessel, forming a fibrin plug well fixed to the walls of the varicose vein, which allows for reliable hemostasis.
Avantajele invenţiei: Advantages of the invention:
- obţinerea unui cheag fibrinic de o consistenţă dur-elastică; - obtaining a fibrin clot of a hard-elastic consistency;
- fixare sigură de pereţii interiori ai varicelui; - secure attachment to the inner walls of the varicose vein;
- formarea unui dop fibrinic consistent ce duce la stoparea hemoragiei variceale; - the formation of a consistent fibrin plug that stops varicose bleeding;
- datorită consistenţei dure, perioada de degradare biologică a cheagului este de lungă durată; - due to the hard consistency, the biological degradation period of the rennet is long;
- evitarea recidivelor hemoragice. - avoiding hemorrhagic relapses.
Metoda se efectuează în modul următor. The method is performed in the following way.
Pacientului diagnosticat cu hemoragie din varicele esofagiene în cazul hipertensiunii portale, cauzate de ciroza hepatica, i se efectuează lavajul gastric, apoi examenul endoscopic, după care prin intermediul unui cateter introdus prin canalul de lucru al endoscopului se injectează în lumenul varicelui concomitent două componente ale unui adeziv fibrinic şi anume, primul component, care include soluţie de fibrinogen, şi al doilea component, care include amestecul de soluţii de trombină cu gelatină polisuccinilată, aprotinină şi clorură de Ca+2, în următorul raport al componentelor, la 1 ml: The patient diagnosed with bleeding from esophageal varices in the case of portal hypertension, caused by liver cirrhosis, undergoes gastric lavage, then an endoscopic examination, after which, through a catheter inserted through the working channel of the endoscope, two components of a fibrin adhesive are simultaneously injected into the lumen of the varice, namely, the first component, which includes fibrinogen solution, and the second component, which includes the mixture of thrombin solutions with polysuccinylated gelatin, aprotinin and Ca+2 chloride, in the following ratio of components, per 1 ml:
fibrinogen (mg) 15...45 trombină (UI) 25...100 gelatină polisuccinilată (mg) 120...360 aprotinină (KIU) 250...1000 clorură de Ca+2(µmol) 15...30.fibrinogen (mg) 15...45 thrombin (IU) 25...100 polysuccinylated gelatin (mg) 120...360 aprotinin (KIU) 250...1000 Ca+2 chloride (µmol) 15...30.
Soluţia de fibrinogen se aspiră într-o seringă, celelalte componente în combinaţie - în altă seringă, care se injectează separat printr-un cateter trifurcat la capătul proximal. În interiorul cateterului ambele componente se combină, iniţiind procesul de polimerizare cu formarea unui compus geliform, iar în interiorul varicelui are loc finisarea procesului de polimerizare cu formarea cheagului fibrinic stabil şi bine fixat de peretele vascular, care obturează lumenul vasului cu realizarea unei hemostaze eficiente. The fibrinogen solution is drawn into a syringe, the other components in combination - into another syringe, which is injected separately through a trifurcated catheter at the proximal end. Inside the catheter, both components combine, initiating the polymerization process with the formation of a gel-like compound, and inside the varicose vein, the polymerization process is completed with the formation of a stable fibrin clot well fixed to the vascular wall, which occludes the lumen of the vessel with the achievement of effective hemostasis.
Metoda revendicată a fost utilizată la 98 de pacienţi cu ciroză hepatică şi hipertensiune portală cu hemoragii variceale. The claimed method was used in 98 patients with liver cirrhosis and portal hypertension with variceal bleeding.
Exemplu Example
Pacientul P., 32 de ani, spitalizat în secţia chirurgie cu diagnosticul: Ciroză hepatică decompensată Child C 10) de etiologie virală HVC. Hemoragie variceală profuză. Soc hemoragic gr.II. La fibroesofagogastroscopie s-au determinat prezenţa de varice esofagiene de gr. III-IV în 1/3 inferioară al esofagului. Varicele peretelui antero-medial cu o ruptură de 0,2 cm cu hemoragie în jet, Forrest Ia. S-a efectuat hemostaza endoscopică prin injectarea în lumenul varicelui concomitent a două componente ale adezivului fibrinic şi anume, primul component soluţie de fibrinogen, iar al doilea component amestecul de soluţii de trombină cu gelatină polisuccinilată, aprotinină şi clorură de Ca+2, în raportul cantitativ revendicat. După injectare s-a obţinut formarea unui cheag fibrinic dur-elastic stabil şi bine fixat în lumenul variceal cu stoparea definitivă a hemoragiei. Varicele restante au fost de asemenea ocluzionate cu adeziv. Externat peste 8 zile în stare satisfacătoare. Patient P., 32 years old, hospitalized in the surgery department with the diagnosis: Decompensated liver cirrhosis Child C 10) of HCV viral etiology. Profuse variceal hemorrhage. Hemorrhagic shock grade II. At fibroesophagogastroscopy, the presence of esophageal varices of grade III-IV in the lower 1/3 of the esophagus was determined. Varicose veins of the antero-medial wall with a 0.2 cm rupture with jet hemorrhage, Forrest Ia. Endoscopic hemostasis was performed by injecting into the lumen of the variceal vein simultaneously two components of the fibrin glue, namely, the first component fibrinogen solution, and the second component the mixture of thrombin solutions with polysuccinylated gelatin, aprotinin and Ca+2 chloride, in the claimed quantitative ratio. After injection, the formation of a stable hard-elastic fibrin clot was obtained and well fixed in the variceal lumen with the definitive cessation of hemorrhage. The remaining varicose veins were also occluded with adhesive. Discharged after 8 days in satisfactory condition.
1. Paquet K.J., Kuhn R. Prophylactic Endoscopic sclerotherapy in Patients with Liver Cirrhosis, Portal Hypertension and Esophageal Varices.- Hepato-Gastroenterology, 1997, no44, p. 625-636 1. Paquet K.J., Kuhn R. Prophylactic Endoscopic sclerotherapy in Patients with Liver Cirrhosis, Portal Hypertension and Esophageal Varices.- Hepato-Gastroenterology, 1997, no44, p. 625-636
2. Yoshida H., Mamada Y., Taniai N., Yamamoto K., Kawano Y., Mizuguchi Y, et al. A randomized trial control trial of bimonthly versus biweekly endoscopic variceal ligation of esophageal varices. Am. J. Gastroenterol., 2005, no100, p. 2005-2009 2. Yoshida H., Mamada Y., Taniai N., Yamamoto K., Kawano Y., Mizuguchi Y., et al. A randomized control trial of bimonthly versus biweekly endoscopic variceal ligation of esophageal varices. I have. J. Gastroenterol., 2005, no100, p. 2005-2009
3. AT 359652 1980.04.15 3. AT 359652 1980.04.15
4. MD 2328 F1 2003.12.31 4. MD 2328 F1 2003.12.31
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