US20140005256A1 - Formulations with anti-tumour action - Google Patents
Formulations with anti-tumour action Download PDFInfo
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- US20140005256A1 US20140005256A1 US14/019,674 US201314019674A US2014005256A1 US 20140005256 A1 US20140005256 A1 US 20140005256A1 US 201314019674 A US201314019674 A US 201314019674A US 2014005256 A1 US2014005256 A1 US 2014005256A1
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- defibrotide
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- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
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- 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
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/711—Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
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- 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
-
- 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
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- 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
- A61K31/66—Phosphorus compounds
- A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
-
- 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
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the subject of the present invention is a formulation for treating a tumor-affected mammal by administering to said mammal an effective amount of defibrotide.
- defibrotide normally identifies a polydeoxyribonucleotide that is obtained by extraction from animal and/or vegetable tissues (1, 2) but which might also be obtained synthetically; the polydeoxyribonucleotide is normally used in the form of an alkali-metal salt, generally a sodium salt, and generally has a molecular weight of about 15-30 kDa (CAS Registry Number: 83712-60-1).
- DF is used mainly on account of its antithrombotic activity (3), although it can be used in other applications such as, for example, the treatment of acute renal insufficiency (4) and the treatment of acute myocardial ischaemia (5).
- DF is also used in the treatment of emergency clinical conditions, for example, for suppressing the toxicity correlated with high doses of chemotherapy regimens, in particular, the hepatic veno-occlusive syndrome (10, 11); DF has been shown to have protective action towards apoptosis induced by fludarabine and towards the alloactivation of endothelial and epithelial cells, without also altering the antileukaemic effects of fludarabine (12); pre-clinical data also exists on the protective effects of DF that have been achieved in a model of endothelial damage mediated by lipopolysaccharide (13).
- DF is either of extractive or of synthetic origin.
- FIG. 1 is a graph of the cytotoxicity of cultured mouse EMT-6 mammary carcinoma cells exposed to 4HC, with and without DF;
- FIG. 2 a is a chart of in vivo tumor growth delay in mouse mammary carcinoma 13762 exposed to DF and other agents;
- FIG. 2 b is a graph of tumor volume in mouse mammary carcinoma 13762 exposed to DF and other agents.
- DF was examined in combination with antiblastic cytotoxic agents in a model of mouse EMT-6 mammary carcinoma cells and in bovine endothelial cells, in cell cultures and in an experimental model in which rats carrying tumours subjected to high doses of chemotherapy were used.
- EMT-6 cells to DF before and during exposure to thiotepa increases cytotoxicity towards the tumour cells by two logarithmic units for thiotepa concentrations of between 100 and 250 ⁇ mol.
- An interesting datum which emerges is that the exposure of EMT-6 cells to DF during and after exposure to thiotepa leads to an increase in cytotoxicity, although to a lesser extent, showing an increase of between 0.5 and 1 logarithmic unit in the cytotoxicity of thiotepa.
- a similar result has been observed with carboplatin; however, exposure to DF before and during or during and after exposure to melphalan did not show any significant effect on the cytotoxicity of melphalan towards mouse EMT-6 mammary carcinoma cells in culture.
- hepatotoxin monocrotaline and the AA carmustine (BCNU), alone or in association with DF were tested in vivo in an experimental model which used rats carrying mammary carcinoma 13762.
- BCNU AA carmustine
- no additional toxicity was shown in the animals when they were exposed to these agents together with DF, but a significant tumour growth delay (TGD) was observed (see Table 1 and FIGS. 2 a and 2 b ).
- mice Sixty male SCID/NOD mice (6-8 weeks old) were irradiated (450 rads) and, 24 hrs later, injected s.c. with 5 ⁇ 10 6 MM-1S human MM cells. Upon formation of palpable tumors, mice were randomly assigned to 6 cohorts (10 mice each) receiving a) vehicle; b) DF (i.v. 450 mg/kg b.i.d); c) melphalan (MEL) 2.5 mg/kg i.p.
- MEL melphalan
- cyclophosphamide 50 mg/kg i.p., on days 8, 10, 12, 20, 22 and 24; e) and f) combinations of DF (300 mg/kg i.v.) with MEL or CTX, respectively. Mice were monitored q3 days for body weight, potential toxicity, and electronic caliper-based tumor volumes.
- DF either as single agent or in combination with MEL or CTX, was well tolerated without hemorrhagic complications or body weight loss (P>0.05) in all groups.
- the major endpoints for efficacy were a) tumor volume changes and b) overall survival (time-to-sacrifice, performed when tumor diameters>2 cm).
- DF treatment resulted in significantly lower tumor volumes than in control mice (P ⁇ 0.05 for all comparisons by analysis of variance and post-hoc tests); in combination with MEL or CTX it induced significantly lower tumor volumes than the respective single-agent cytotoxic chemotherapy (P ⁇ 0.05 for all comparisons).
- a method for treating a tumor-affected mammal, preferably a human, by administration of an effective amount of DF is therefore an object of the present invention.
- DF may be administered in combination with at least another active ingredient with anti-tumour action.
- the other active ingredient with anti-tumour action may be selected from paclitaxel, monocrotaline, BCNU, melphalan and/or cyclophosphamide.
- formulations containing DF and at least one other active ingredient with anti-tumour action will preferably be in the form of aqueous solutions and, even more preferably, suitable for intravenous administration, and may contain the excipients and coadjuvants known in the art.
- DF defibrotide
- oligonucleotide and/or polynucleotide produced by extraction from animal and/or vegetable tissues, in particular, from mammalian organs.
- the DF will be produced in accordance with the method described in United States patents (6, 7) which are incorporated herein by reference.
Abstract
Formulations with anti-tumour action containing defibrotide and at least another active ingredient as active agents.
Description
- This application is a divisional of and claims priority to U.S. patent application Ser. No. 11/366,243, filed Mar. 2, 2006, which is a continuation-in-part of and claims priority to prior International Application No. PCT/EP2004/009723, filed Aug. 27, 2004, which claims priority to Italian Application No. MI2003A001714, filed Sep. 5, 2003, and U.S. Provisional Application No. 60/539,344, filed Jan. 28, 2004, the disclosures of all of which are incorporated herein by reference.
- The subject of the present invention is a formulation for treating a tumor-affected mammal by administering to said mammal an effective amount of defibrotide.
- The term defibrotide (hereinafter DF) normally identifies a polydeoxyribonucleotide that is obtained by extraction from animal and/or vegetable tissues (1, 2) but which might also be obtained synthetically; the polydeoxyribonucleotide is normally used in the form of an alkali-metal salt, generally a sodium salt, and generally has a molecular weight of about 15-30 kDa (CAS Registry Number: 83712-60-1).
- DF is used mainly on account of its antithrombotic activity (3), although it can be used in other applications such as, for example, the treatment of acute renal insufficiency (4) and the treatment of acute myocardial ischaemia (5). DF is also used in the treatment of emergency clinical conditions, for example, for suppressing the toxicity correlated with high doses of chemotherapy regimens, in particular, the hepatic veno-occlusive syndrome (10, 11); DF has been shown to have protective action towards apoptosis induced by fludarabine and towards the alloactivation of endothelial and epithelial cells, without also altering the antileukaemic effects of fludarabine (12); pre-clinical data also exists on the protective effects of DF that have been achieved in a model of endothelial damage mediated by lipopolysaccharide (13).
- A method of producing DF that can produce a product which has uniform and well-defined physical/chemical characteristics and which is also free of possible undesirable side effects is described in United States patents (6, 7).
- Within the purposes of the present invention DF is either of extractive or of synthetic origin.
-
FIG. 1 is a graph of the cytotoxicity of cultured mouse EMT-6 mammary carcinoma cells exposed to 4HC, with and without DF; -
FIG. 2 a is a chart of in vivo tumor growth delay in mouse mammary carcinoma 13762 exposed to DF and other agents; -
FIG. 2 b is a graph of tumor volume in mouse mammary carcinoma 13762 exposed to DF and other agents. - In the following study, DF was examined in combination with antiblastic cytotoxic agents in a model of mouse EMT-6 mammary carcinoma cells and in bovine endothelial cells, in cell cultures and in an experimental model in which rats carrying tumours subjected to high doses of chemotherapy were used.
- Exposure to DF at a concentration of 50 μg/ml, either before and during, or during and after the exposure of mouse EMT-6 mammary carcinoma cells in culture with 4-hydroperoxycyclo-phosphamide (4HC) considerably increases the cytotoxicity of 4HC to the extent of bringing about an increment of 2 logarithmic units in the killing of the tumour cells at 4HC concentrations of between 50 and 250 μmol (see
FIG. 1 ). Exposure to DF at concentrations of 50 μg/ml also leads to an increase in the cytotoxicity of thiotepa with a clear difference based on the method of exposure. In particular, exposure of EMT-6 cells to DF before and during exposure to thiotepa increases cytotoxicity towards the tumour cells by two logarithmic units for thiotepa concentrations of between 100 and 250 μmol. An interesting datum which emerges is that the exposure of EMT-6 cells to DF during and after exposure to thiotepa leads to an increase in cytotoxicity, although to a lesser extent, showing an increase of between 0.5 and 1 logarithmic unit in the cytotoxicity of thiotepa. A similar result has been observed with carboplatin; however, exposure to DF before and during or during and after exposure to melphalan did not show any significant effect on the cytotoxicity of melphalan towards mouse EMT-6 mammary carcinoma cells in culture. - On the other hand, although it was demonstrated that the cytotoxicity of these antiblastic alkylating agents (AA) alone towards bovine endothelial cells in culture was similar to that observed in EMT-6 mammary carcinoma cells, no increase in cytotoxicity was shown when this type of cell culture model was exposed to AAs in association with DF at a concentration of 50 μg/ml.
- The hepatotoxin monocrotaline and the AA carmustine (BCNU), alone or in association with DF, were tested in vivo in an experimental model which used rats carrying mammary carcinoma 13762. In this experimental model, no additional toxicity was shown in the animals when they were exposed to these agents together with DF, but a significant tumour growth delay (TGD) was observed (see Table 1 and
FIGS. 2 a and 2 b). -
TABLE 1 Tumour growth delay in rats carrying mammary carcinoma 13762 after treatment with monocrotaline or BCNU, alone or in association with defibrotide (DF). The tumour was implanted on day 0and the chemotherapy was administered on day 8 andday 18.Days to reach Treatment Group 500 mm3 TGD (days) p Value Controls 14.6 ± 0.8 — — Monocrotaline (350 mg/kg) 15.6 ± 1.0 1.0 0.435 ip days 8 & 18DF (200 mg/kg) iv 16.1 ± 0.6 1.5 0.134 twice per day, days 8-26 + Monocrotaline DF (200 mg/kg) iv 18.2 ± 1.5 3.6 0.034 twice per day, days 10-26 + Monocrotaline BCNU (150 mg/kg) ip 18.0 ± 2.5 3.4 0.195 days 8 & 18DF (200 mg/kg) iv 19.7 ± 1.5 5.1 0.003 twice per day, days 8-26 + BCNU DF (200 mg/kg) iv 21.3 ± 1.6 6.7 0.0002 twice per day, days 10-26 + BCNU - These studies have been reproduced with the use of monocrotaline, BCNU, and cyclophosphamide (CTX), alone or in combination with DF, in the same experimental model. In comparison with the control, a significant tumour growth delay (TGD) was observed with the use of DF alone (p<0.05); this delay was particularly significant when DF was associated with CTX and BCNU (p<0.04) and was notably greater than that obtained by the individual use of each agent. Unexpectedly, when DF was used alone, at first it delayed the growth of the tumour but afterwards tumour growth became normal again. Moreover, when DF was used in combination with an AA, the tumour regrowth became rapid as soon as the co-administration of DF ceased. This data suggests not only an additional anti-tumour effect of DF but also a direct antiblastic activity of DF itself.
- A reduction in tumour growth (TGD) and in the number of pulmonary metastases was also observed in mice carrying Lewis pulmonary carcinoma when DF was added to treatment with paclitaxel, whether or not it was associated with carboplatin and in comparison with cytotoxic therapy alone, but without showing an obvious increase in toxicity (data not presented). The mechanism underlying these effects remains to be explained, but it is possible that the anti-adhesive properties of DF are involved, given the role of cell adhesion in the mechanisms implicated in drug resistance (8, 9).
- It was also tested whether DF has in vivo activity in a murine model of human multiple myeloma (MM). Sixty male SCID/NOD mice (6-8 weeks old) were irradiated (450 rads) and, 24 hrs later, injected s.c. with 5×10 6 MM-1S human MM cells. Upon formation of palpable tumors, mice were randomly assigned to 6 cohorts (10 mice each) receiving a) vehicle; b) DF (i.v. 450 mg/kg b.i.d); c) melphalan (MEL) 2.5 mg/kg i.p. once weekly; d) cyclophosphamide (CTX) 50 mg/kg i.p., on
days - DF, either as single agent or in combination with MEL or CTX, was well tolerated without hemorrhagic complications or body weight loss (P>0.05) in all groups. The major endpoints for efficacy were a) tumor volume changes and b) overall survival (time-to-sacrifice, performed when tumor diameters>2 cm). DF treatment resulted in significantly lower tumor volumes than in control mice (P<0.05 for all comparisons by analysis of variance and post-hoc tests); in combination with MEL or CTX it induced significantly lower tumor volumes than the respective single-agent cytotoxic chemotherapy (P<0.05 for all comparisons). Kaplan-Meier survival analyses showed that DF administration, either as single agent or in combination with cytotoxic chemotherapy (MEL or CTX), was associated with statistically significant prolongation of overall survival, in comparison to vehicle-treated control group or MEL- or CTX-treated groups, respectively (P<0.001 for all comparisons, log-rank test). Interestingly, the in vitro studies have not shown a significant direct in vitro cytotoxic effect of DF against MM cells, suggesting that the observed in vivo activity may be due to effect(s) on interactions of MM cells with their local microenvironment.
- These promising results demonstrate that DF does confer tumor protection in this MM chemotherapy model and constitutes the first proof-of-principle that DF not only has in vivo anti-tumor activity against MM but also enhances responses to cytotoxic treatment. This study suggests that the anti-MM activity of DF is possibly due to its effects on MM cell interactions with their microenvironment and provides a framework for future clinical trials of DF in combination with other agents for the treatment of MM and other neoplasias.
- A method for treating a tumor-affected mammal, preferably a human, by administration of an effective amount of DF is therefore an object of the present invention. DF may be administered in combination with at least another active ingredient with anti-tumour action. The other active ingredient with anti-tumour action may be selected from paclitaxel, monocrotaline, BCNU, melphalan and/or cyclophosphamide.
- Further objects of the invention are represented by the formulations containing DF and at least one other active ingredient with anti-tumour action; the formulations will preferably be in the form of aqueous solutions and, even more preferably, suitable for intravenous administration, and may contain the excipients and coadjuvants known in the art.
- For the purposes of the present invention, the term defibrotide (DF) should thus be understood as any oligonucleotide and/or polynucleotide produced by extraction from animal and/or vegetable tissues, in particular, from mammalian organs. Preferably, the DF will be produced in accordance with the method described in United States patents (6, 7) which are incorporated herein by reference.
-
- 1. U.S. Pat. No. 3,770,720
- 2. U.S. Pat. No. 3,899,481
- 3. U.S. Pat. No. 3,829,567
- 4. U.S. Pat. No. 4,694,134
- 5. U.S. Pat. No. 4,693,995
- 6. U.S. Pat. No. 4,985,552
- 7. U.S. Pat. No. 5,223,609
- 8. Carlo-Stella, C., Di Nicola, M., Magni M., et al., Defibrotide in Combination with Granulocyte Colony-stimulating Factor Significantly Enhances the Mobilization of Primitive and Committed Peripheral Blood Progenitor Cells in Mice. Cancer Research, 2002, 62:6152-6157 (Nov. 1, 2002).
- 9. Hazlehurst, L., Damiano, J., Buyuksal, I., Pledger, W. J., Dalton, W. S., Adhesion to fibronectin via b1 integrins regulates p27 kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR). Oncogene, 2000; 19:4319-4327.
- 10. Richardson, P. G., Elias, A. D., Krishnan, A., et al. Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population. Blood, 1998; 92: 737-44.
- 11. Richardson, P., Murakami, C., Jin, Z., et al., Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multi-system organ failure: response without significant toxicity in a high risk population and factors predictive of outcome. Blood, 2002; 100(13):4337-4343.
- 12. Eissner, G., Multhoff, G., Gerbitz, A., et al., Fludarabine induces apoptosis, activation, and allogenicity in human endothelial and epithelial cells: protective effect of defibrotide. Blood, 2002; 100:334-340.
- 13. Falanga, A., Vignoli, A., Marchetti, M., Barbui, T., Defibrotide reduces procoagulant activity and increases fibrinolytic properties of endothelial cells. Leukemia, 2003; in press.
Claims (8)
1. A formulation containing, as active agents, defibrotide and at least another active ingredient with anti-tumour action.
2. A formulation according to claim 1 , which is an aqueous solution.
3. A formulation according to claim 1 , which contains customary excipients and/or adjuvants.
4. A formulation according to claim 1 , wherein the other active ingredient with anti-tumour action is selected from paclitaxel, monocrotaline, BCNU, and/or cyclophosphamide.
5. A formulation according to claim 1 , constituted by two distinct formulations that can be administered separately, one containing defibrotide and the other containing the other active ingredient with anti-tumour action.
6. A formulation according to claim 1 , as a combined preparation for simultaneous, separate, or sequential administration.
7. A formulation according to claim 1 , wherein defibrotide is obtained by extraction from animal and/or vegetable tissues.
8. A formulation according to claim 1 , wherein defibrotide is obtained synthetically.
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US14/019,674 US20140005256A1 (en) | 2003-09-05 | 2013-09-06 | Formulations with anti-tumour action |
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ITMI2003A001714 | 2003-09-05 | ||
IT001714A ITMI20031714A1 (en) | 2003-09-05 | 2003-09-05 | FORMATIONS FOR ANTITUMORAL ACTION. |
EPPCT/EP04/09723 | 2004-08-27 | ||
PCT/EP2004/009723 WO2005023273A1 (en) | 2003-09-05 | 2004-08-27 | Anti-tumor formulations comprising defibrotide alone or in combination with other anti-tumor agents |
US11/366,243 US8551967B2 (en) | 2003-09-05 | 2006-03-02 | Formulations with anti-tumour action |
US14/019,674 US20140005256A1 (en) | 2003-09-05 | 2013-09-06 | Formulations with anti-tumour action |
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JP (1) | JP4671962B2 (en) |
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WO2019028340A1 (en) | 2017-08-03 | 2019-02-07 | Jazz Pharmaceuticals Ireland Limited | Formulations comprising a nucleic acid in a high concentration |
WO2019200251A1 (en) | 2018-04-12 | 2019-10-17 | Jazz Pharmaceuticals, Inc. | Defibrotide for the prevention and treatment of cytokine release syndrome and neurotoxicity associated with immunodepletion |
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EP1853277A1 (en) * | 2005-03-03 | 2007-11-14 | Gentium S.p.A. | Defibrotide and/or oligodeoxyribonucleotides for treating angiogenesis-dependent tumors |
EP1872787A1 (en) * | 2006-06-27 | 2008-01-02 | Gentium S.p.A. | Use of defibrotide for the inhibition of heparanase |
EP2103689A1 (en) * | 2008-03-19 | 2009-09-23 | Gentium S.p.A. | Synthetic phosphodiester oligonucleotides and therapeutical uses thereof |
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EP3026122A1 (en) | 2014-11-27 | 2016-06-01 | Gentium S.p.A. | Cellular-based method for determining the potency of defibrotide |
EP3748358A1 (en) | 2014-11-27 | 2020-12-09 | Gentium S.r.l. | Cellular-based method for determining the potency of defibrotide |
US20180247399A1 (en) * | 2017-02-27 | 2018-08-30 | Aniket Bharat Parikh | System, Method and Computer Program Product for Security Analysis of Jewellery Items |
WO2019028340A1 (en) | 2017-08-03 | 2019-02-07 | Jazz Pharmaceuticals Ireland Limited | Formulations comprising a nucleic acid in a high concentration |
WO2019200251A1 (en) | 2018-04-12 | 2019-10-17 | Jazz Pharmaceuticals, Inc. | Defibrotide for the prevention and treatment of cytokine release syndrome and neurotoxicity associated with immunodepletion |
WO2020118165A1 (en) | 2018-12-07 | 2020-06-11 | Jazz Pharmaceuticals Ireland Limited | Subcutaneous delivery of high concentration formulations |
WO2021174039A1 (en) | 2020-02-28 | 2021-09-02 | Jazz Pharmaceuticals Ireland Limited | Delivery of low viscosity formulations |
WO2022234101A1 (en) | 2021-05-06 | 2022-11-10 | Jazz Pharmaceuticals Ireland Limited | Defibrotide for the treatment and prevention of acute respiratory distress syndrome |
Also Published As
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RS20060154A (en) | 2008-08-07 |
DE602004014787D1 (en) | 2008-08-14 |
EP1660100B1 (en) | 2008-07-02 |
AU2004269896A1 (en) | 2005-03-17 |
IS8334A (en) | 2006-02-28 |
ATE399558T1 (en) | 2008-07-15 |
ES2308223T3 (en) | 2008-12-01 |
NO20061402L (en) | 2006-03-28 |
JP2007504194A (en) | 2007-03-01 |
US8551967B2 (en) | 2013-10-08 |
CN100490820C (en) | 2009-05-27 |
US20060211646A1 (en) | 2006-09-21 |
IL173785A0 (en) | 2006-07-05 |
CA2537226C (en) | 2016-05-03 |
RU2348413C2 (en) | 2009-03-10 |
PT1660100E (en) | 2008-10-14 |
UA83500C2 (en) | 2008-07-25 |
ITMI20031714A1 (en) | 2005-03-06 |
EP1660100A1 (en) | 2006-05-31 |
CA2537226A1 (en) | 2005-03-17 |
CN1845746A (en) | 2006-10-11 |
RU2006109210A (en) | 2007-10-10 |
KR20060061367A (en) | 2006-06-07 |
ZA200601852B (en) | 2007-06-27 |
BRPI0414114A (en) | 2006-10-31 |
WO2005023273A1 (en) | 2005-03-17 |
AU2004269896B2 (en) | 2009-11-19 |
MXPA06002489A (en) | 2006-06-20 |
JP4671962B2 (en) | 2011-04-20 |
DK1660100T3 (en) | 2008-11-10 |
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