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Recombinant vesicular stomatitis virus (rVSV) vaccine
Israel Institute for Biological Research
Hadassah Medical Center; Sheba Medical Center Hospital
The SARS-CoV-2 virus is responsible for the COVID-19 pandemic. The pandemic emerged from Wuhan Province in China in December 2019 and was declared by the WHO Director-General a Public Health Emergency of International Concern on 30 January 2020.
In this study, a vaccine developed by IIBR for SARS-CoV-2 virus will be assessed for its safety and potential efficacy in volunteers. The study is comprised of two phases, a dose-escalation phase (phase I) during which subjects (18-55 years old) will be randomly allocated to receive a single administration of IIBR-100 100 at low, mid or high dose or saline or two administrations of IIBR-100 at low dose, or saline, 28 days apart.
Based on results obtained during phase I, and cumulative phase I data review, the expansion phase (phase II) has begun, during which larger cohorts as well as elderly age subjects will be randomly allocated to receive a single administration of IIBR-100 at low, mid or high dose or saline, or two administrations of IIBR-100 at low, mid or high dose (prime-boost) or saline, 28 days apart. Additional top-dose (prime-boost) may be implemented when immunogenicity of any prime-boost arm is considered insufficient.
Based on immunogenicity preliminary data and DSMB recommendations, the two administrations of mid, high and top dose (prime-boost) or saline will continue.
The subjects will be followed for a period of up to 12 months post last vaccine administration to assess the safety and efficacy of the vaccine.
- ^ Clinical trial number NCT04608305 for “Phase I/II Randomized, Multi-Center, Placebo-Controlled, Dose-Escalation Study to Evaluate the Safety, Immunogenicity and Potential Efficacy of an rVSV-SARS-CoV-2-S Vaccine (IIBR-100) in Adults” at ClinicalTrials.gov
- ^ Jeffay N (29 December 2020). “As Israel goes vaccine-wild, will the homegrown version lose its shot?”. The Times of Israel. Retrieved 1 January 2021.
Israeli institute’s COVID vaccine candidate said very effective in animal trials
Secretive Israeli research center’s shot shows near 100% efficacy in non-human trials, is on par with US company Moderna’s candidate, TV report says
Israeli researchers at a top secret research center have made progress on a coronavirus vaccine that shows a high level of effectiveness in animals, according to a Friday TV report.
However, there is no guarantee that the vaccine under development will be effective in humans, or will be available soon.
The Israel Institute for Biological Research (IIBR), a secretive unit that works under the Prime Minister’s Office, developed a vaccine that shows close to 100 percent protection against the virus in lab animals, the Channel 12 report said, citing “a security source.”
The vaccine under development is on par in effectiveness with a vaccine being developed by US biotechnology company Moderna, the report said.
Unlike vaccines developed abroad, the domestic vaccine will first be delivered to Israeli citizens, it added. If successful, it was expected to provide protection against the disease with a single dose.
The institute has not started human trials but was preparing to manufacture 10 to 15 million doses, report said.
Hebrew media have reported on potential breakthroughs at the shadowy institute several times before, starting in mid-March, with the Defense Ministry pushing back on some of the claims to tamper expectations.
Magen David Adom medical workers test Israelis for the coronavirus at a drive-through site in Lod, on July 10, 2020. (Yossi Aloni/Flash90)
IIBR said last month that it had completed successful coronavirus vaccine trials on rodents, paving the way for further testing on other animals and then possibly human trials.
In a paper published on the website of bioRxiv, an online repository for papers that haven’t yet been peer-reviewed, the institute, which is based in Ness Ziona, said it hopes to have a finished vaccine in a year, or possibly even earlier.
In the abstract of the report, the researchers say their vaccine, which they tested on hamsters, “results in rapid and potent induction of neutralizing antibodies against SARS-CoV-2,” the virus that causes COVID-19.
Earlier this month a vaccine adviser to the government cautioned that there was no guarantee that the shots being developed will prove widely effective.
In May, the institute confirmed that it had isolated an antibody it believed could be used to develop treatments against the virus. The development would not be useful in the creation of a vaccine, but would rather be a move toward a drug treatment for those who have already contracted the disease.
Tal Zaks, Moderna’s Israeli chief medical officer, described to Channel 12 on Friday the company’s push into Phase 3 testing of its vaccine candidate, which was developed with the National Institutes of Health, and began its first injections Monday.
The trial, the world’s largest vaccine study, plans to test the vaccine on 30,000 volunteers.
There’s still no guarantee that the experimental vaccine, developed by the National Institutes of Health and Moderna Inc., will really offer protection.
“The first time we saw the first model, that the vaccine, even if it’s just in mice, successfully stimulated the immune system to identify the virus and neutralize it, I knew that we hadn’t missed anything, that we had the correct vaccine,” he said.
“And of course the second ‘ah-ha’ moment was when we saw the first clinical results, when it was clear that in humans we weren’t just getting to antibody levels we were seeing in sick people, which is what we aspired to, but we were getting to even higher levels,” Zaks said.
A Nurse gives a volunteer an injection, as the world’s biggest study of a possible COVID-19 vaccine, developed by the US National Institutes of Health and Moderna Inc., gets underway on July 27, 2020, in Binghamton, NY. (AP Photo/Hans Pennink)
Last month Israel signed a deal with Moderna for the potential purchase of its coronavirus vaccine if it ends up proving effective.
Moderna said the vaccination was administered in Savannah, Georgia, the first site to get underway among more than seven dozen trial sites scattered around the country.
Several other vaccines made by China and by Britain’s Oxford University earlier this month began smaller final-stage tests in Brazil and other hard-hit countries.
The massive studies aren’t just to test if the shots work — they’re needed to check each potential vaccine’s safety. And following the same study rules will let scientists eventually compare all the shots.
It normally takes years to create a new vaccine from scratch, but scientists are setting speed records this time around, spurred by knowledge that vaccination is the world’s best hope against the pandemic.
If everything goes right with the final studies, it still will take months for the first data to trickle in from the Moderna test, followed by the Oxford one.
Governments around the world are trying to stockpile millions of doses of those leading candidates so if and when regulators approve one or more vaccines, immunizations can begin immediately. But the first available doses will be rationed, presumably reserved for people at highest risk from the virus.
Coronavirus cases in Israel rose by 1,791 in 24 hours on Friday and the national death toll hit 512, according to the latest Health Ministry figures.
The total case count stood at 70,970, with 320 patients in serious condition, including 98 on ventilators. The number of recovered patients reached 43,850.
Israel has the fifth-highest number of new coronavirus infections per capita in the world, overtaking the United States, according to data compiled by a scientific publication based at Oxford University.
And while Israel has seen the number of new coronavirus cases rocket to more than 2,000 a day in recent weeks, a new Hebrew University report published on Thursday asserted that Israel has managed to gain control of the second wave of the coronavirus, thanks to a recent stabilization in the number of seriously and moderately ill patients.
The curve for seriously and moderately ill patients began to spike in late June before stabilizing in recent days, the researchers reported. They credited the restrictions imposed by the government in recent weeks to limit crowding for helping to flatten the curve.
According to the report, the death toll will climb by roughly 200 in the coming three weeks as a result of the high infection rate over the past month.
Experts have blamed a too-speedy reopening and the lack of an effective contact-tracing program as main factors in the virus resurgence, which has come as new daily coronavirus cases around the world have also reached record highs.
|Vaccine type||Viral vector|
|Part of a series on the|
|COVID-19 (disease)SARS-CoV-2 virus (variants)|
//////IIBR-100, Brilife, COVID-19, vaccine, israel, corona virus, covid 19, SARS-CoV-2
NEW DRUG APPROVALS
Find out how Israeli scientists are manipulating the tiniest parts of matter to make life better for millions.
Think of a tiny robot transporting drugs to a cancer cell in your body. An artificial retina to restore lost sight. Self-cleaning windows and bullet-proof fabrics.
It’s all possible today with nanotechnology from Israel.
Tune into ISRAEL21c’s TLV1 radio show for a fascinating discussion of how Israeli scientists are turning science fiction into fact. Guests include Nava Swersky Sofer, founder and co-chair of NanoIsrael; Prof. Uriel Levy, head of the Nanotechnology Institute at the Hebrew University of Jerusalem; and Prof. Uri Sivan, one of the Technion’s leading nanotechnology experts……….http://www.israel21c.org/israeli-scientists-turn-science-fiction-into-fact-audio/
About the INNI mission
The mission of INNI — the Israel National Nanotechnology Initiative is to make nanotechnology the next wave of successful industry in Israel by creating an engine for global leadership.
- Establishing a national policy of resources for nanotechnology, with the aim of faster commercialization.
- Long-range nanotechnology programs for scientific research and technology development in academia and industry, and promoting development of world-class infrastructure in Israel to support them.
- Leading in the creation of projects that promote agreed national priorities; allocate their budgets and review development progress.
- Actively seeking funding resources from public and private sources in order to implement the selected projects.
- Promoting development of innovative local nanotechnology industries which will strongly impact Israeli economic growth and benefit investors.
- Encouraging Academia and Industry cooperation with public access to a national database of Israel’s nanotechnology researchers and industry. Effective access to information about Israel’s researchers and companies accelerates cooperation on R&D projects and on innovative new products. Israel’s nanotechnology National Database may be accessed here or from the link in the INNI website upper navigation menu.
Sivan Uri .
Room 611, Lidow Building
Nano Area: Nano Electronics, Nano Materials & Nano Particles, Nanobiotechnology & Nanomedicine
Ph.D.: Tel Aviv University 1988
M.Sc.: Physics, Tel Aviv University 1984
B.Sc.: Physics and Mathematics, Tel Aviv University 1982
Main Nano Field:
Selection of antibodies and peptides against electronic materials, electrical control over bioreactions, bioassembly of electronic devices.
Bertoldo Badler Chair in Physics
Former director of the Russell Berrie Nanotechnology Institute
Head of Ben and Esther Rosenbloom Center of Excellence in Nanoelectronics by Biotechnology
Prof. Uriel Levy of the Hebrew University of Jerusalem has received the Hebrew University President’s Prize as the Outstanding Young Researcher for 2010-11. The prize is awarded in memory of Prof. Yoram Ben-Porath, former president and rector of the Hebrew University.Hebrew University President Prof. Menahem Ben-Sasson said that the prize was being awarded to Prof. Levy “for his impressive list of scientific articles, for his creativity, and for his groundbreaking innovations.”
Prof. Levy is a member of the applied physics department at the Benin School of Computer Science and Engineering and is a renowned researcher in nanophotonics He is a member of the Harvey M. Kruger Family Center for Nanoscience and Nanotechnology at the Hebrew University.
A graduate of the Technion in physics and materials engineering, he subsequently earned a Ph.D. in electro-optics at Tel Aviv University in 2002. He then was awarded a Rothschild Fellowship for post-doctoral work at the University of California, San Diego, which he completed in 2006.
Prof. Levy has published until now 55 scientific articles and has had a number of his research discoveries patented.
Downloadable File: PresidentsPrize2010.doc
The NanoOpto group is affiliated with the Applied Physics Department at the Hebrew University of Jerusalem, Israel. Our research is mainly focused on Silicon Photonics, Polarization Optics, Plasmonics and Opto-Fluidics.
Our group host SPP7 in Jerusalem from 31 of may till the 5 of June 2015:
|In this work we study the optimization of interleaved Mach-Zehnder silicon carrier depletion electro-optic modulator. Following the simulation results we demonstrate a phase shifter with the lowest figure of merit (modulation efficiency multiplied by the loss per unit length) 6.7V-dB. This result was achieved by reducing the junction width to 200 nm along the phase-shifter and optimizing the doping levels of the PN junction for operation in nearly fully depleted mode. The demonstrated low FOM is the result of both low VπL of ~0.78 Vcm (at reverse bias of 1V), and low free carrier loss (~6.6 dB/cm for zero bias). Our simulation results indicate that additional improvement in performance may be achieved by further reducing the junction width followed by increasing the doping levels. (read more)|
Light vapor interactions on a chip
|Alkali vapours, such as rubidium, are being used extensively in many important fields of research. Recently, there is a growing effort towards miniaturizing traditional centimetre-size vapour cells. Owing to the significant reduction in device dimensions, light– matter interactions are greatly enhanced, enabling new functionalities due to the low power threshold needed for nonlinear interactions. Here, we construct an efficient and flexible platform for tailored light–vapour interactions on a chip, and demonstrate efficient interaction of the electromagnetic guided mode with absorption saturation at powers in the nanowatt regime. (read more)|
Active Silicon Plasmonics
|In this work, we experimentally demonstrate an on-chip nanoscale silicon surface-plasmon Schottky photodetector based on internal photoemission process and operating at telecom wavelengths. The responsivity of the nanodetector to be 0.25 and 13.3mA/W for incident optical wavelengths of 1.55 and 1.31 μm, respectively. The presented device can be integrated with other nanophotonic and nanoplasmonic structures for the realization of monolithic opto-electronic circuitry on-chip. (read more)|
|Planar plasmonic devices are becoming attractive for myriad applications. Mitigating the challenges of using plasmonics in on-chip configurations requires precise control over the properties of plasmonic modes, in particular their shape and size. Here we achieve this goal by demonstrating a planar plasmonic graded index lens focusing surface plasmons propagating along the device. Focusing and divergence of surface plasmons is demonstrated experimentally. The demonstrated approach can be used for manipulating the propagation of surface plasmons, e.g. for beam steering, splitting, cloaking, mode matching and beam shaping applications (read more)|
|The interaction of an incident plane wave with a metamaterial periodic structure consisting of alternating layers of positive and negative refractive index with average zero refractive index is studied. We show that the existence of very narrow resonance peaks for which giant absorption – 50% at layer thickness of 1% of the incident wavelength – is exhibited. Maximum absorption is obtained at a speciﬁc layer thickness satisfying the critical coupling condition. This phenomenon is explained by the Rayleigh anomaly and excitation of Fabry Perot modes. (read more)|
|Great hopes rest on surface plasmon polaritons’ (SPPs) potential to bring new functionalities and applications into various branches of optics. In this work, we demonstrate a pin cushion structure capable of coupling light from free space into SPPs, split them based on the polarization content of the illuminating beam of light, and focus them into small spots. We also show that for a circularly or randomly polarized light, four focal spots will be generated at the center of each quarter circle comprising the pin cushion device. Furthermore, following the relation between the relative intensity of the obtained four focal spots and the relative position of the illuminating beam with respect to the structure, we propose and demonstrate the potential use of our structure as a miniaturized plasmonic version of the well-known four quadrant detector. (read more)|
|We demonstrate a nanoscale mode selector supporting the propagation of the first antisymmetric mode of a silicon waveguide. The mode selector is based on embedding a short section of PhC into the waveguide. On the basis of the difference in k-vector distribution between orthogonal waveguide modes, the PhC can be designed to have a band gap for the fundamental mode, while allowing the transmission of the first antisymmetric mode. The device was tested by directly measuring the modal content before and after the PhC section using a near field scanning optical microscope. Extinction ratio was estimated to be ~23 dB. Finally, we provide numerical simulations demonstrating strong coupling of the antisymmetric mode to metallic nanotips. On the basis of the results, we believe that the mode selector may become an important building block in the realization of on chip nanofocusing devices. (read more)|
|We experimentally demonstrate the focusing of surface plasmon polaritons by a plasmonic lens illuminated with radially polarized light . The field distribution is characterized by near-field scanning optical microscope. A sharp focal spot corresponding to a zero-order Bessel function is observed. For comparison, the plasmonic lens is also measured with linearly polarized light illumination, resulting in two separated lobes. Finally, we verify that the focal spot maintains its width along the optical axis of the plasmonic lens. The results demonstrate the advantage of using radially polarized light for nanofocusing applications involving surface plasmon polaritons. (read more)|
BBR-2778 , CTK0H5262
CTI BioPharma has obtained Israeli Ministry of Health’s approval for Pixuvri (pixantrone), as a monotherapy to treat adult patients with multiply relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma who have received up to three previous courses of treatment.
The company also announced that the Dutch Healthcare Authority and the College voor zorgverzekeringen of the Netherlands have approved funding for Pixuvri as an add-on drug for patients who need a third or fourth-line treatment option for aggressive B-cell lymphoma.
Tel Aviv University faculty of medicine Dr Abraham Avigdor said: “The approval of PIXUVRI in Israel provides patients with aggressive B-cell NHL who have failed second or third-line therapy a new approved option, where none existed before, that can effectively treat their disease with manageable side-effects.
|Jmol-3D images||Image 1|
|Molar mass||325.365 g/mol|
|Excretion||Fecal (main route of excretion) and renal (4–9%)|
|Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)|
Pixantrone dimaleate [USAN]
Benz(g)isoquinoline-5,10-dione, 6,9-bis((2-aminoethyl)amino)-, (2Z)-2-butenedioate (1:2)
On May 10, 2012, the European Commission issued a conditional marketing authorization valid throughout the European Union for pixantrone for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin’s B-cell lymphoma (NHL). Pixantrone is a cytotoxic aza-anthracenedione that directly alkylates DNA-forming stable DNA adducts and cross-strand breaks. The recommended dose of pixantrone is 50 mg/m2 administered on days 1, 8, and 15 of each 28-day cycle for up to 6 cycles. In the main study submitted for this application, a significant difference in response rate (proportion of complete responses and unconfirmed complete responses) was observed in favor of pixantrone (20.0% vs. 5.7% for pixantrone and physician’s best choice, respectively), supported by the results of secondary endpoints of median progression-free and overall survival times (increase of 2.7 and 2.6 months, respectively). The most common side effects with pixantrone were bone marrow suppression (particularly of the neutrophil lineage) nausea, vomiting, and asthenia. This article summarizes the scientific review of the application leading to approval in the European Union. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the European Medicines Agency website (http://www.ema.europa.eu).
Pixantrone (rINN; trade name Pixuvri) is an experimental antineoplastic (anti-cancer) drug, an analogue of mitoxantrone with fewertoxic effects on cardiac tissue. It acts as a topoisomerase II poison and intercalating agent. The code name BBR 2778 refers topixantrone dimaleate, the actual substance commonly used in clinical trials.
Anthracyclines are important chemotherapy agents. However, their use is associated with irreversible and cumulative heart damage. Investigators have attempted to design related drugs that maintain the biological activity, but do not possess the cardiotoxicity of the anthracyclines. Pixantrone was developed to reduce heart damage related to treatment while retaining efficacy.
Random screening at the US National Cancer Institute of a vast number of compounds provided by the Allied Chemical Company led to the discovery of ametantrone as having significant anti-tumor activity. Further investigation regarding the rational development of analogs of ametantrone led to the synthesis of mitoxantrone, which also exhibited marked anti-tumor activity Mitoxantrone was considered as an analog of doxorubicin with less structural complexity but with a similar mode of action. In clinical studies, mitoxantrone was shown to be effective against numerous types of tumors with less toxic side effects than those resulting from doxorubicin therapy. However, mitoxantrone was not totally free of cardiotoxicity. A number of structurally modified analogs of mitoxantrone were synthesized and structure-activity relationship studies made. BBR 2778 was originally synthesized by University of Vermont researchers Miles P. Hacker and Paul A. Krapcho and initially characterized in vitro for tumor cell cytotoxicity and mechanism of action by studies at the Boehringer Mannheim Italia Research Center, Monza, and University of Vermont, Burlington.Other studies have been completed at the University of Texas M. D. Anderson Cancer Center, Houston, the Istituto Nazionale Tumori,Milan, and the University of Padua. In the search for novel heteroanalogs of anthracenediones, it was selected as the most promising compound. Toxicological studies indicated that BBR 2778 was not cardiotoxic, and US patents are held by the University of Vermont. An additional US patent application was completed in June 1995 by Boehringer Mannheim, Italy.
Novuspharma, an Italian company, was established in 1998 following the merger of Boehringer Mannheim and Hoffmann-La Roche, and BBR 2778 was developed as Novuspharma’s leading anti-cancer drug, pixantrone. A patent application for the injectable preparation was filed in May 2003.
Pixantrone is a substance that is being studied in the treatment of cancer. It belongs to the family of drugs called antitumor antibiotics. phase III clinical trials of pixantrone have been completed. Pixantrone is being studied as an antineoplastic for different kinds of cancer, including solid tumors and hematological malignancies such as non-Hodgkin lymphomas.
Animal studies demonstrated that pixantrone does not worsen pre-existing heart muscle damage, suggesting that pixantrone may be useful in patients pretreated with anthracyclines. While only minimal cardiac changes are observed in mice given repeated cycles of pixantrone, 2 cycles of traditional anthracyclines doxorubicin or mitoxantrone result in marked or severe heart muscle degeneragion.
Clinical trials substituting pixantrone for doxorubicin in standard first-line treatment of patients with aggressive non-Hodgkin’s lymphoma, had a reduction in severe side effects when compared to patients treated with standard doxorubicin-based therapy. Despite pixantrone patients receiving more treatment cycles, a three-fold reduction in the incidence of severe heart damage was seen as well as clinically significant reductions in infections and thrombocytopenia, and a significant reduction in febrile neutropenia. These findings could have major implications for treating patients with breast cancer, lymphoma, and leukemia, where debilitating cardiac damage from doxorubicin might be prevented.Previous treatment options for multiply relapsed aggressive non-Hodgkin lymphoma had disappointing response rates.
The completed phase II RAPID trial compared the CHOP-R regimen of Cyclophosphamide, Doxorubicin, Vincristine, Prednisone, and Rituximab to the same regimen, but substituting Doxorubicin with Pixantrone. The objective was to show that Pixantrone was not inferior to Doxorubicin and less toxic to the heart.
The pivotal phase III EXTEND (PIX301) randomized clinical trial studied pixantrone to see how well it works compared to other chemotherapy drugs in treating patients with relapsed non-Hodgkin’s lymphoma. The complete response rate in patients treated with pixantrone has been significantly higher than in those receiving other chemotherapeutic agents for treatment of relapsed/refractory aggressive non-Hodgkin lymphoma.
U.S. Food and Drug Administration
The FDA granted fast track designation for pixantrone in patients who had previously been treated two or more times for relapsed or refractory aggressive NHL. Study sponsor Cell Therapeutics announced that Pixantrone achieved the primary efficacy endpoint. The minutes of the Oncologic Drugs Advisory Committee meeting of March 22, 2010show that this had not in fact been achieved with statistical significance and this combined with major safety concerns lead to the conclusion that the trial was not sufficient to support approval. In April 2010 the FDA asked for an additional trial.
European Medicines Agency
On May 5, 2009, Pixantrone became available in Europe on a Named-Patient Basis. A named-patient program is a compassionate use drug supply program under which physicians can legally supply investigational drugs to qualifying patients. Under a named-patient program, investigational drugs can be administered to patients who are suffering from serious illnesses prior to the drug being approved by the European Medicines Evaluation Agency. “Named-patient” distribution refers to the distribution or sale of a product to a specific healthcare professional for the treatment of an individual patient. In Europe, under the named-patient program the drug is most often purchased through the national health system. In 2012 pixantrone received conditional marketing authorization in the European Union as Monotherapy to Treat Adult Patients with Multiply Relapsed or Refractory Aggressive Non-Hodgkin B-Cell Lymphomas.
Pixantrone is as potent as mitoxantrone in animal models of multiple sclerosis. Pixantrone has a similar mechanism of action as mitoxantrone on the effector function of lymphomonocyte B and T cells in experimental allergic encephalomyelitis but with lower cardiotoxicity. Pixantrone inhibits antigen specific and mitogen induced lymphomononuclear cell proliferation, as well as IFN-gamma production. Clinical trials are currently ongoing in Europe.
Pixantrone also reduces the severity of experimental autoimmune myasthenia gravis in Lewis rats, and in vitro cell viability experiments indicated that Pixantrone significantly reduces amyloid beta (A beta(1-42)) neurotoxicity, a mechanism implicated in Alzheimer’s disease.
3,4-Pyridinedicarboxylic acid (I) was converted to the cyclic anhydride (II) upon heating with acetic anhydride. Friedel-Crafts condensation of anhydride (II) with p-difluorobenzene (III) in the presence of AlCl3 gave rise to a mixture of two regioisomeric keto acids, (IV) and (V). Cyclization of this mixture in fuming sulfuric acid at 140 C generated the benzoisoquinoline (VI) (1,2). Subsequent displacement of the fluorine atoms of (VI) with ethylenediamine ( VII) in pyridine provided the target bis (2-aminoethylamino) derivative, which was finally converted to the stable dimaleate salt. Alternatively, ethylenediamine (VII) was protected as the mono-N-Boc derivative (VIII) by treatment with Boc2O. Condensation of the difluoro compound (VI) with the protected ethylenediamine (VIII) furnished (IX). The Boc groups of (IX) were then removed by treatment with trifluoroacetic acid. After adjustment of the pH to 4.2 with KOH, treatment with maleic acid provided BBR-2778.
J Med Chem1994,37, (6): 828
- Cavalletti E, Crippa L, Mainardi P, Oggioni N, Cavagnoli R, Bellini O, Sala F. (2007). “Pixantrone (BBR 2778) has reduced cardiotoxic potential in mice pretreated with doxorubicin: comparative studies against doxorubicin and mitoxantrone”. Invest New Drugs. 25 (3): 187–95. doi:10.1007/s10637-007-9037-8. PMID 17285358.
- De Isabella P, Palumbo M, Sissi C, Capranico G, Carenini N, Menta E, Oliva A, Spinelli S, Krapcho AP, Giuliani FC, Zunino F. (1995). “Topoisomerase II DNA cleavage stimulation, DNA binding activity, cytotoxicity, and physico-chemical properties of 2-aza- and 2-aza-oxide-anthracenedione derivatives”. Mol Pharmacol. 48 (1): 30–8.PMID 7623772.
- Evison BJ, Mansour OC, Menta E, Phillips DR, Cutts SM (2007). “Pixantrone can be activated by formaldehyde to generate a potent DNA adduct forming agent”. Nucleic Acids Res. 35 (11): 3581–9. doi:10.1093/nar/gkm285. PMC 1920253.PMID 17483512.
- Krapcho AP, Petry ME, Getahun Z, Landi JJ Jr, Stallman J, Polsenberg JF, Gallagher CE, Maresch MJ, Hacker MP, Giuliani FC, Beggiolin G, Pezzoni G, Menta E, Manzotti C, Oliva A, Spinelli S, Tognella S (1994). “6,9-Bis[(aminoalkyl)amino]benzo[g]isoquinoline-5,10-diones. A novel class of chromophore-modified antitumor anthracene-9,10-diones: synthesis and antitumor evaluations”. J Med Chem. 37 (6): 828–37. doi:10.1021/jm00032a018. PMID 8145234.
- US patent 5587382, Krapcho AP, Hacker MP, Cavalletti E, Giuliani FC, “6,9-bis[(2-aminoethyl) amino]benzo [g]isoquinoline-5,10- dione dimaleate; an aza-anthracenedione with reduced cardiotoxicity”, issued 1996-12-24, assigned to Boehringer Mannheim Italia, SpA
- Zwelling LA, Mayes J, Altschuler E, Satitpunwaycha P, Tritton TR, Hacker MP. (1993). “Activity of two novel anthracene-9,10-diones against human leukemia cells containing intercalator-sensitive or -resistant forms of topoisomerase II”. Biochem Pharmacol. 46 (2): 265–71. doi:10.1016/0006-2952(93)90413-Q. PMID 8394077.
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- EP patent 1503797, Bernareggi A, Livi V, “Injectable Pharmaceutical Compositions of an Anthracenedione Derivative with Anti-Tumoral Activity”, published 2003-11-27, issued 2008-09-29, assigned to Cell Therapeutics Europe S.R.L.
- Pollack, Andrew (2003-06-17). “Company News; Cell Therapeutics Announces Plan To Buy Novuspharma”. The New York Times. Retrieved 2010-05-22.
- Mosby’s Medical Dictionary, 8th edition. © 2009, Elsevier. “definition of antineoplastic antibiotic”. Free Online Medical Dictionary, Thesaurus and Encyclopedia. Retrieved 2012-01-31.
- “NCT00088530”. BBR 2778 for Relapsed, Aggressive Non-Hodgkin’s Lymphoma (NHL). ClinicalTrials.gov. Retrieved 2012-01-31.
- “NCT00551239”. Fludarabine and Rituximab With or Without Pixantrone in Treating Patients With Relapsed or Refractory Indolent Non-Hodgkin Lymphoma. ClinicalTrials.gov. 2012-01-31. Retrieved 2012-01-31.
- “Pixantrone Combination Therapy for First-line Treatment of Aggressive Non-Hodgkin’s Lymphoma Results in Reduction in Severe Toxicities Including Heart Damage When Compared to Doxorubicin-based Therapy”. Press Release. Retrieved 2012-01-31.
- Engert A, Herbrecht R, Santoro A, Zinzani PL, Gorbatchevsky I (September 2006). “EXTEND PIX301: a phase III randomized trial of pixantrone versus other chemotherapeutic agents as third-line monotherapy in patients with relapsed, aggressive non-Hodgkin’s lymphoma”. Clin Lymphoma Myeloma 7 (2): 152–4.doi:10.3816/CLM.2006.n.055. PMID 17026830.
- “NCT00268853”. A Trial in Patients With Diffuse Large-B-cell Lymphoma Comparing Pixantrone Against Doxorubicin. ClinicalTrials.gov. Retrieved 2012-01-31.
- “NCT00101049”. BBR 2778 for Relapsed, Aggressive Non-Hodgkin’s Lymphoma (NHL). ClinicalTrials.gov. Retrieved 2012-01-31.
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- “Cell Therapeutics Formally Appeals FDA’s Nonapprovable Ruling for Pixantrone”. GEN News. 2010-12-03.
- “Pixantrone Now Available in Europe on a Named-Patient Basis”. Retrieved 2012-01-31.
- Gonsette RE, Dubois B (August 2004). “Pixantrone (BBR2778): a new immunosuppressant in multiple sclerosis with a low cardiotoxicity”. J. Neurol. Sci. 223(1): 81–6. doi:10.1016/j.jns.2004.04.024. PMID 15261566.
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