FR2458286A1 - Diluant pour le plasma, a base de pullulane - Google Patents
Diluant pour le plasma, a base de pullulane Download PDFInfo
- Publication number
- FR2458286A1 FR2458286A1 FR8011531A FR8011531A FR2458286A1 FR 2458286 A1 FR2458286 A1 FR 2458286A1 FR 8011531 A FR8011531 A FR 8011531A FR 8011531 A FR8011531 A FR 8011531A FR 2458286 A1 FR2458286 A1 FR 2458286A1
- Authority
- FR
- France
- Prior art keywords
- pullulan
- plasma
- volume
- refined
- molecular weight
- 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.)
- Granted
Links
- 239000003085 diluting agent Substances 0.000 claims abstract description 27
- 238000009826 distribution Methods 0.000 claims abstract description 12
- 229920001218 Pullulan Polymers 0.000 claims description 88
- 235000019423 pullulan Nutrition 0.000 claims description 88
- 239000004373 Pullulan Substances 0.000 claims description 82
- 239000000203 mixture Substances 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 18
- 239000007864 aqueous solution Substances 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 10
- 239000004615 ingredient Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 abstract description 62
- 238000001990 intravenous administration Methods 0.000 abstract description 3
- 238000002955 isolation Methods 0.000 abstract description 3
- 230000000740 bleeding effect Effects 0.000 abstract description 2
- 230000002265 prevention Effects 0.000 abstract description 2
- 239000007924 injection Substances 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- 238000001802 infusion Methods 0.000 description 40
- 150000004676 glycans Chemical class 0.000 description 26
- 229920001282 polysaccharide Polymers 0.000 description 26
- 239000005017 polysaccharide Substances 0.000 description 26
- 241001465754 Metazoa Species 0.000 description 22
- 238000011534 incubation Methods 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- 241000283973 Oryctolagus cuniculus Species 0.000 description 16
- 210000004369 blood Anatomy 0.000 description 16
- 239000008280 blood Substances 0.000 description 16
- 238000010586 diagram Methods 0.000 description 16
- 230000007423 decrease Effects 0.000 description 15
- 210000003734 kidney Anatomy 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 239000002504 physiological saline solution Substances 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- 238000005534 hematocrit Methods 0.000 description 11
- 210000000056 organ Anatomy 0.000 description 10
- 238000000354 decomposition reaction Methods 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 210000004185 liver Anatomy 0.000 description 8
- 230000004060 metabolic process Effects 0.000 description 8
- 210000002700 urine Anatomy 0.000 description 8
- 229920002307 Dextran Polymers 0.000 description 7
- 210000004072 lung Anatomy 0.000 description 7
- 230000015556 catabolic process Effects 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 239000006228 supernatant Substances 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 239000000470 constituent Substances 0.000 description 5
- 238000006731 degradation reaction Methods 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 230000029142 excretion Effects 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 239000007951 isotonicity adjuster Substances 0.000 description 3
- 230000003204 osmotic effect Effects 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002510 pyrogen Substances 0.000 description 3
- 231100000161 signs of toxicity Toxicity 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 210000005239 tubule Anatomy 0.000 description 3
- 102000009027 Albumins Human genes 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 241000223678 Aureobasidium pullulans Species 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 229920005654 Sephadex Polymers 0.000 description 2
- 239000012507 Sephadex™ Substances 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 102000003929 Transaminases Human genes 0.000 description 2
- 108090000340 Transaminases Proteins 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 238000000265 homogenisation Methods 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 230000002477 vacuolizing effect Effects 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- MYKOKMFESWKQRX-UHFFFAOYSA-N 10h-anthracen-9-one;sulfuric acid Chemical compound OS(O)(=O)=O.C1=CC=C2C(=O)C3=CC=CC=C3CC2=C1 MYKOKMFESWKQRX-UHFFFAOYSA-N 0.000 description 1
- 241000238876 Acari Species 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 241001260012 Bursa Species 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
- 108010044091 Globulins Proteins 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010028594 Myocardial fibrosis Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 235000008935 nutritious Nutrition 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 230000001698 pyrogenic effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- FYGDTMLNYKFZSV-BYLHFPJWSA-N β-1,4-galactotrioside Chemical group 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](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-BYLHFPJWSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP54063976A JPS6049164B2 (ja) | 1979-05-25 | 1979-05-25 | 血漿増量剤 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| FR2458286A1 true FR2458286A1 (fr) | 1981-01-02 |
| FR2458286B1 FR2458286B1 (en, 2012) | 1983-11-04 |
Family
ID=13244813
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FR8011531A Granted FR2458286A1 (fr) | 1979-05-25 | 1980-05-23 | Diluant pour le plasma, a base de pullulane |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US4370472A (en, 2012) |
| JP (1) | JPS6049164B2 (en, 2012) |
| DE (1) | DE3019895A1 (en, 2012) |
| FR (1) | FR2458286A1 (en, 2012) |
| GB (1) | GB2052975B (en, 2012) |
| IT (1) | IT1130734B (en, 2012) |
| SE (1) | SE456316B (en, 2012) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2517326B1 (fr) * | 1981-12-01 | 1989-09-01 | Hayashibara Biochem Lab | Production d'une preparation de pullulane a repartition etroite de masses moleculaires |
| US4913925A (en) * | 1982-10-25 | 1990-04-03 | Yasutake Hiji | Foodstuff containing a hyperglycemia controlling agent |
| JPS5974976A (ja) * | 1982-10-25 | 1984-04-27 | Yasutake Hichi | 血糖値上昇抑制剤を添加した飲食物 |
| JPS62236469A (ja) * | 1986-04-04 | 1987-10-16 | Yasutake Hichi | 低カロリ−飲食物 |
| US6746836B1 (en) * | 2000-12-08 | 2004-06-08 | Abe Widra | Alpha-keratose as a blood plasma expander and use thereof |
| US10130587B2 (en) | 2011-01-11 | 2018-11-20 | Capsugel Belgium Nv | Hard capsules |
| US11319566B2 (en) | 2017-04-14 | 2022-05-03 | Capsugel Belgium Nv | Process for making pullulan |
| ES3033915T3 (en) | 2017-04-14 | 2025-08-11 | Capsugel Belgium Nv | Pullulan capsules |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1096850B (de) * | 1959-07-24 | 1961-01-12 | Hoechst Ag | Verfahren zur Gewinnung eines dextranaehnlichen Polysaccharids aus Pullularia pullulans |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5142199B2 (en, 2012) * | 1972-09-04 | 1976-11-13 |
-
1979
- 1979-05-25 JP JP54063976A patent/JPS6049164B2/ja not_active Expired
-
1980
- 1980-05-21 US US06/152,151 patent/US4370472A/en not_active Expired - Lifetime
- 1980-05-22 SE SE8003850A patent/SE456316B/sv not_active IP Right Cessation
- 1980-05-23 IT IT22285/80A patent/IT1130734B/it active
- 1980-05-23 FR FR8011531A patent/FR2458286A1/fr active Granted
- 1980-05-23 DE DE19803019895 patent/DE3019895A1/de active Granted
- 1980-05-27 GB GB8017288A patent/GB2052975B/en not_active Expired
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1096850B (de) * | 1959-07-24 | 1961-01-12 | Hoechst Ag | Verfahren zur Gewinnung eines dextranaehnlichen Polysaccharids aus Pullularia pullulans |
Also Published As
| Publication number | Publication date |
|---|---|
| SE8003850L (sv) | 1980-11-26 |
| US4370472A (en) | 1983-01-25 |
| JPS55157513A (en) | 1980-12-08 |
| GB2052975A (en) | 1981-02-04 |
| IT8022285A0 (it) | 1980-05-23 |
| JPS6049164B2 (ja) | 1985-10-31 |
| SE456316B (sv) | 1988-09-26 |
| DE3019895C2 (en, 2012) | 1987-10-29 |
| DE3019895A1 (de) | 1980-11-27 |
| FR2458286B1 (en, 2012) | 1983-11-04 |
| GB2052975B (en) | 1983-09-07 |
| IT1130734B (it) | 1986-06-18 |
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| JPS58162524A (ja) | 抗潰瘍剤 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| TP | Transmission of property | ||
| ST | Notification of lapse |