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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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IIBR-100


Coronavirus: Israel to start COVID-19 vaccine human trials on November 1 | Al Arabiya English

IIBR-100

Brilife

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.

https://clinicaltrials.gov/ct2/show/NCT04608305

IIBR-100 also known as Brilife is a COVID-19 vaccine candidate developed by The Israel Institute for Biological Research.[1][2]

References

  1. ^ 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
  2. ^ 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.

candidate developed by The Israel Institute for Biological Research.[1][2]

https://www.timesofisrael.com/israeli-institutes-vaccine-candidate-said-highly-effective-in-animal-trials/

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 description
TargetSARS-CoV-2
Vaccine typeViral vector
Clinical data
Other namesBrilife
Routes of
administration
Intramuscular
Part of a series on the
COVID-19 pandemic
COVID-19 (disease)SARS-CoV-2 virus (variants)
showTimeline
showLocations
showInternational response
showMedical response
showImpact
 COVID-19 portal

//////IIBR-100, Brilife,  COVID-19,  vaccine,  israel, corona virus, covid 19, SARS-CoV-2

wdt-21

NEW DRUG APPROVALS

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Israeli scientists turn Nano science fiction into fact


 

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/

INNI

http://www.nanoisrael.org/

NanoIsrael 2016

About the INNI mission

President Shimon Peres holding nanotechnology priz

The INNI Board of Directors is appointed by The Chief Scientist in the Ministry of Economy.  The INNI BoD operates out of The MAGNET Program at the Office of the Chief Scientist.

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.

A primary task for INNI is to promote fruitful collaboration between Israeli and global nanotechnology stakeholders, particularly for projects that lead to continuing success in academia and industry.
To achieve this task, INNI activities include:
  • 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.
Key to development of nanotechnology-based industry in Israel is promotion of academia–industry collaboration. INNI in collaboration with d&a Visual Insights has created a unique graphic mapping engine of Israel’s nanotechnology academia and industry. It is an extensive database of companies and researchers which is accessed with an integrated text and graphical mapping search engine. It is the ideal starting point to locate researchers and companies with the unique knowledge and skill sets for cooperation in research projects and the transfer of technology for innovative products and establishing new nanotechnology enterprises.

Sivan Uri .

Room 611, Lidow Building

Physics

Russell Berrie Nanotechnology InstituteTechnion - Israel Institute of Technology

Nano Area: Nano Electronics, Nano Materials & Nano Particles, Nanobiotechnology & Nanomedicine

Phone: +972-4-8293452

Fax: +972-4-8292418

Email: phsivan@tx.technion.ac.il

Personal website

Main

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

……………………………..
Uriel Levy
Prof. Uriel Levy named outstanding young researcher at the Hebrew University

 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:

Uriel Levy at ulevy@cc.huji.ac.il

Research highlights:

Silicon Photonics
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)

Plasmonics
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)

Metamaterials
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)

Plasmonics
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)

Silicon Photonics
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)

Plasmonics
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)
Hebrew University of Jerusalem
Map of hebrew university of jerusalem
////////

Pixantrone


Chemical structure for CTK0H5262

 

 

Pixantrone.svg

Pixantrone

BBR-2778 , CTK0H5262

 

  • Pixolti
  • Pixuvri
  • UNII-P0R64C4CR9

 

An immunosuppressant.

144510-96-3 [RN]

5,8-Bis((2-aminoethyl)amino)-2-aza-anthracene-9,10-dione

6,9-Bis((2-aminoethyl)amino)benz(g)isoquinoline-5,10-dione

5,8-Bis((2-aminoethyl)amino)-2-aza-anthracene-9,10-dione

6,9-Bis((2-aminoethyl)amino)benz(g)isoquinoline-5,10-dione

CTI BioPharma receives Israeli approval for aggressive B-cell non-Hodgkin’s lymphoma therapy

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.

 

read at

http://www.pharmaceutical-technology.com/news/newscti-biopharma-receives-israeli-approval-aggressive-b-cell-non-hodgkins-lymphoma-therapy-4321986?WT.mc_id=DN_News

 

Pixantrone
Pixantrone.svg
Identifiers
CAS number  144510-96-3
PubChem 134019
ChemSpider 118174 Yes
KEGG D05522 Yes
ChEMBL CHEMBL167731 Yes
ATC code L01DB11
Jmol-3D images Image 1
Properties
Molecular formula C17H19N5O2
Molar mass 325.365 g/mol
Appearance Blue solid
Pharmacology
Routes of
administration
Intravenous
Elimination
half-life
9.5–17.5 hours
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]

CAS  144675-97-8

Molecular Formula

  • C17-H19-N5-O2.2C4-H4-O4

Molecular Weight

  • 441.4417
  • 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.[1] It acts as a topoisomerase II poison and intercalating agent.[2][3] The code name BBR 2778 refers topixantrone dimaleate, the actual substance commonly used in clinical trials.[4]

 

 

History

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.[5] Pixantrone was developed to reduce heart damage related to treatment while retaining efficacy.[1]

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[5] 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.[5] BBR 2778 was originally synthesized by University of Vermont researchers Miles P. Hacker and Paul A. Krapcho[5] 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 VermontBurlington.[4]Other studies have been completed at the University of Texas M. D. Anderson Cancer CenterHouston, the Istituto Nazionale Tumori,Milan, and the University of Padua.[2][6][4] 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.[5]

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.[7] A patent application for the injectable preparation was filed in May 2003.[8]

In 2003, Cell Therapeutics, a Seattle biotechnology company, acquired pixantrone through a merger with Novuspharma.[9]

Clinical trials

Pixantrone is a substance that is being studied in the treatment of cancer. It belongs to the family of drugs called antitumor antibiotics.[10] phase III clinical trials of pixantrone have been completed.[11][12] 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.[1]

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.[13]Previous treatment options for multiply relapsed aggressive non-Hodgkin lymphoma had disappointing response rates.[14]

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.[15]

Pixantrone was shown to have potentially reduced cardiotoxicity and demonstrated promising clinical activity in these phase II studies in heavily pretreated non-Hodgkin lymphomapatients.[14]

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.[16] 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.[14]

Administration

It can be administered through a peripheral vein rather than a central implanted catheter as required for other similar drugs.[8][14]

Regulatory approval

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, 2010[17]show 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.[18]

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.[19] 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.

Research

Pixantrone is as potent as mitoxantrone in animal models of multiple sclerosis.[20] 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.[21] Clinical trials are currently ongoing in Europe.

Pixantrone also reduces the severity of experimental autoimmune myasthenia gravis in Lewis rats,[22] 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.[23]

 

http://www.chemdrug.com/databases/8_0_mhpyqlxgrykqdwig.html

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

SEE MORE

http://www.chemdrug.com/databases/8_0_mhpyqlxgrykqdwig.html

References

  1.  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/s10637-007-9037-8PMID 17285358.
  2. 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.
  3.  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/gkm285PMC 1920253.PMID 17483512.
  4.  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/jm00032a018PMID 8145234.
  5.  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
  6.  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-QPMID 8394077.
  7.  Borchmann P, Reiser M (May 2003). “Pixantrone (Novuspharma)”. IDrugs 6 (5): 486–90. PMID 12789604.
  8.  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.
  9.  Pollack, Andrew (2003-06-17). “Company News; Cell Therapeutics Announces Plan To Buy Novuspharma”The New York Times. Retrieved 2010-05-22.
  10. Jump up^ Mosby’s Medical Dictionary, 8th edition. © 2009, Elsevier. “definition of antineoplastic antibiotic”. Free Online Medical Dictionary, Thesaurus and Encyclopedia. Retrieved 2012-01-31.
  11. Jump up^ “NCT00088530”BBR 2778 for Relapsed, Aggressive Non-Hodgkin’s Lymphoma (NHL). ClinicalTrials.gov. Retrieved 2012-01-31.
  12.  “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.
  13. “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.
  14. Jump up to:a b c d 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.055PMID 17026830.
  15. Jump up^ “NCT00268853”A Trial in Patients With Diffuse Large-B-cell Lymphoma Comparing Pixantrone Against Doxorubicin. ClinicalTrials.gov. Retrieved 2012-01-31.
  16. Jump up^ “NCT00101049”BBR 2778 for Relapsed, Aggressive Non-Hodgkin’s Lymphoma (NHL). ClinicalTrials.gov. Retrieved 2012-01-31.
  17. Jump up^ Vesely N, Eckhardt SG (2010-03-22). “NDA 022-481 PIXUVRI (pixantrone dimaleate) injection” (pdf). Summary Minutes of the Oncologic Drugs Advisory Committee. United States Food and Drug Administration. Retrieved 2012-01-31.
  18. Jump up^ “Cell Therapeutics Formally Appeals FDA’s Nonapprovable Ruling for Pixantrone”. GEN News. 2010-12-03.
  19. Jump up^ “Pixantrone Now Available in Europe on a Named-Patient Basis”. Retrieved 2012-01-31.
  20. Jump up^ 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.2004.04.024PMID 15261566.
  21. Jump up^ Mazzanti B, Biagioli T, Aldinucci A, Cavaletti G, Cavalletti E, Oggioni N, Frigo M, Rota S, Tagliabue E, Ballerini C, Massacesi L, Riccio P, Lolli F (November 2005). “Effects of pixantrone on immune-cell function in the course of acute rat experimental allergic encephalomyelitis”. J. Neuroimmunol. 168 (1-2): 111–7.doi:10.1016/j.jneuroim.2005.07.010PMID 16120465.
  22. Jump up^ Ubiali F, Nava S, Nessi V, Longhi R, Pezzoni G, Capobianco R, Mantegazza R, Antozzi C, Baggi F (February 2008). “Pixantrone (BBR2778) reduces the severity of experimental autoimmune myasthenia gravis in Lewis rats”. J. Immunol. 180 (4): 2696–703. PMID 18250482.
  23. Jump up^ Colombo R, Carotti A, Catto M, Racchi M, Lanni C, Verga L, Caccialanza G, De Lorenzi E (April 2009). “CE can identify small molecules that selectively target soluble oligomers of amyloid beta protein and display antifibrillogenic activity”. Electrophoresis 30(8): 1418–29. doi:10.1002/elps.200800377PMID 19306269.

 

 

FDA approves Alcobra’s protocol for Phase IIb study of metadoxine drug candidate


The salt pyridoxine-pyrrolidone carboxylate.png

 

Metadoxine

Alcobra Ltd.

http://regulatoryaffairs.pharmaceutical-business-review.com/news/fda-approves-alcobras-protocol-for-phase-iib-study-of-metadoxine-drug-candidate-090514-4262995

 

Israel-based Alcobra has received approval from the US Food and Drug Administration (FDA) for its protocol for planned Phase IIb clinical study of Metadoxine Extended Release (MDX) drug candidate for the treatment of Fragile X Syndrome.

 

Image

The multi-center, randomized, placebo-controlled, Phase IIb study, will be conducted primarily in the US and patient enrollment is expected to begin in the near future.

The study is supported by data collected from multiple earlier pre-clinical studies which demonstrated significant improvement in behavioral and cognitive outcomes based on evaluations of memory, learning, and social interaction.

 

 

Metadoxine, or Pyridoxol L-2-pyrrolidone-5-carboxylate, whose structure formula is reported hereinbelow

 

is known for its effectiveness in acute and chronic alcoholism and for the prevention of alcohol related pathology

 

 

Metadoxine
The salt pyridoxine-pyrrolidone carboxylate.png
Systematic (IUPAC) name
L-Proline, 5-oxo-, compd. with 5-hydroxy-6-methylpyridine-3,4-dimethanol (1:1)
Clinical data
Legal status PHASE 2
Routes Oral, IV
Identifiers
CAS number 0074536-44-0
ATC code N07BB
Chemical data
Formula C13H18N2O6 
Mol. mass 298 g/mol

………..

Metadoxine, also known as pyridoxine-pyrrolidone carboxylate, is a drug used to treat chronic and acute alcohol abuse.[1] Metadoxine improved the clinical signs of acute alcohol intoxication and accelerated alcohol clearance from the blood [2]It is presently in human clinical trials as an attention-deficit/hyperactivity disorder predominantly inattentive treatment.[3]

Pyridoxine is one form of vitamin B6 and a precursor to the metabolically active pyridoxal phosphate. Pyridoxal phosphate is a coenzyme to many enzymes: see vitamin B6 metabolic functions.

Pyrrolidone carboxylate is involved in amino acid metabolism through the glutathione pathway.[4] Glutathione is an important antioxidant and combats redox imbalance. It also supports de novo ATP synthesis.[5]

Alcohol-induced liver diseases are a common disorder in modern communities and societies. For example, in Europe there are more than 45 million individuals showing signs of alcohol-related damage such as liver disease and myopathies. Chronic alcohol consumption increases hepatic accumulation of triglycerides and leads to hepatic steatosis, which is the earliest and most common response to severe alcohol intoxication.

Thus, severe alcohol intoxication is a serious disease that should be treated with medication in order to reduce the damage to the human body of the alcohol intoxicated individual. For example, alcohol intoxication can be treated with metadoxine (pyridoxine L-2-pyrrolidone-5-carboxylate). Metadoxine is a salt of the corresponding anion of L-2-pyrrolidone-5-carboxylic acid (L-2-pyroglutamic acid) (1) and the protonated derivative of pyridoxine (vitamin B6) (2), having the following structures:

(1) (2)

WO 2008/066353 discloses the use of Metadoxine in the treatment of alcohol intoxication either alone or in combination with other active agents. WO 2008/066353 mentions that metadoxine does not inhibit the expression and activation of an alcohol-induced cytochrome P450 2El, which is the key enzyme involved in alcohol-induced toxicity. Thus, the use of metadoxine may be limited.

 

Several studies have shown that in order to effectively treat alcohol intoxication, there is a need for a relatively high daily dose (ca. 900 mg) administered intravenously (see, e.g., Lu et al. Chin. Med. J. 2007, 120 (2), 155-168 and Shpilenya et al. Alcohol Clin. Exp. Res. 2002, 26 (3), 340-346). These studies disclose side effects associated with the use of metadoxine, including nausea and vomiting.

Thus, there exists a need in the art for effective and safe drugs for treating alcohol intoxication and other associated diseases.

 

History

Metadoxine is predominantly used in developing nations for acute alcohol intoxication. Alternate names include: Abrixone (Eurodrug, Mexico), Alcotel (Il Yang, South Korea), Ganxin (Qidu Pharmaceutical, China), Metadoxil (Baldacci, Georgia; Baldacci, Italy; Baldacci, Lithuania; CSC, Russian Federation; Eurodrug, Colombia; Eurodrug, Hungary; Eurodrug, Thailand; Micro HC, India), Viboliv (Dr. Reddy’s, India), and Xin Li De (Zhenyuan Pharm, China).[6]

Fatty liver refers to a pathogenic condition where fat comprises more than 5% of the total weight of the liver. Liver diseases including the fatty liver, hepatitis, fibrosis and cirrhosis are known to be the most serious disease next to cancer causing death in people with ages 40 to 50, in the advanced countries. In advanced countries, nearly about 30% of the population is with fatty liver, and about 20% of people with fatty liver progresses to cirrhosis. About half of the cirrhosis patients die of liver diseases within 10 years after the diagnosis. Fatty liver and steatohepatitis are frequently found in people who intake excessive alcohols and who have obesity, diabetes, hyperlipemia, etc. Among them, alcoholic steatohepatitis (ASH), which is caused by excessive alcohol intake, is at high risk of progressing to hepatitis, cirrhosis and hepatoma, along with non-alcoholic steatohepatitis (NASH).

When taken in, alcohol is carried to the liver and oxidized to acetaldehyde by such enzymes as alcohol dehydrogenase, catalase, etc. The acetaldehyde is metabolized and converted into acetate and is used as energy source. Repeated alcohol intake induces the increase of NADH and NADP+ during the metabolism and acetaldehyde which as the metabolite product of alcohol depletes GSH, thereby changing intracellular oxidation-reduction homeostasis and inducing oxidative stress. Oxidative stress may cause mitochondrial dysfunction, lipid peroxidation and protein modification, thereby leading to death of hepatocytes, inflammation, activation of astrocytes, and the like. In addition, the increase of NADH promotes lipid synthesis, thereby inducing fatty liver.

At present, there are few therapeutically effective drugs for treating fatty liver. Exercise and controlled diet are recommended, but these are not so effective in treating fatty liver. The development of an effective treatment drug is in desperate need. As it is known that fatty liver is related with insulin resistance which is found in diabetes and obesity, the therapeutic effect of some anti-diabetic drugs, e.g., metformin, on fatty liver has been reported. But, the drug has the problem that it may induce adverse reactions such as hepatotoxicity or lactic acidosis. Betaine, glucuronate, methionine, choline and lipotrophic agents are often used as alternative supplementary drug therapy, but they are not fully proven on medical or pharmaceutical basis. Accordingly, development of a fatty liver treatment having superior effect and safety with no adverse reactions is in need.

Metadoxine (pyridoxol 1-2-pyrrolidone-5-carboxylate) is a complex compound of pyridoxine and pyrrolidone carboxylate represented by the formula (1) below:

 

 

Metadoxine is a drug used to treat alcoholic liver disease. It is used to treat liver fibrosis and fatty liver through increasing alcohol metabolism and turnover, reducing toxicity of free radicals and restoring the level of ATP and glutathione (Arosio, et al., Pharmacol. Toxicol. 73: 301-304, 1993; Calabrese, et al., Int. J. Tissue React. 17: 101-108, 1995; Calabrese, et al., Drugs Exp. Clin. Res. 24: 85-91, 1998; Caballeria, et al., J. Hepatol. 28: 54-60, 1998; and Muriel, et al., Liver Int. 23: 262-268, 2003).

However, metadoxine is unable to inhibit the expression and activation of alcohol-induced cytochrome P4502E1 (CYP2E1), which is a key enzyme involved in alcohol-induced toxicity, and thus unable to control the augmentation of inflammation mediated by CYP2E1. Therefore, the treatment of alcohol-induced fatty liver using metadoxine is very limited. Further, the expression of CYP2E1 is related with insulin resistance, thus metadoxine cannot not overcome insulin resistance.

Garlic oil is a liquid including about 1% of allicin along with reduced allicin and other sulfur-containing substances. Upon binding to vitamin B1, allicin is turned into allithiamin, which is chemically stable, acts swiftly, and is easily absorbed by the digestive organs. The substance inhibits carcinogenesis induced by chemicals in white rats (Brady, et al., Cancer Res. 48: 5937-5940, 1988; and Reddy, et al., Cancer Res. 53: 3493-3498, 1993), induces phase II enzyme (Hayes, et al., Carcinogenesis 8: 1155-1157, 1987; and Sparnins, et al., Carcinogenesis 9: 131-134, 1988), and inactivates CYP2E1 (Brady, et al., Chem. Res. Toxicol. 4:642-647, 1991). In addition, garlic oil is reported to have antithrombotic, anti-atherosclerotic, antimutagenic, anticancer and antibacterial activities (Agarwal, Med. Res. Rev. 16: 111-124, 1996; and Augusti, Indian J. Exp. Biol. 34: 634-660, 1996).

 

Pharmacology

Treatment for acute alcohol abuse

In an animal model, metadoxine treatment increased the clearance of alcohol and acetaldehyde, reduced the damaging effect of free radicals, and enabled cells to restore cellular ATP and glutathione levels. [7][8] It increases the urinary elimination of ketones, which are formed when the oxidation rate of acetaldehyde into acetate is exceeded on massive alcohol intoxication.[8][4]

As a medical treatment, it is typically given intravenously.

Treatment for AD/HD-PI

Metadoxine is a selective antagonist to the 5-HT2B receptor, a member of the serotonin receptor family.[3] Electrophysiological studies also showed that Metadoxine caused a dose-dependent, reversible reduction in glutamatergic excitatory transmission and enhancement of GABAergic inhibitory transmission, changes that may be associated with cognitive regulation.[3] It is given orally in an extended release pill, which differs from the instant release alcohol treatment.

Treatment for liver disease

Metadoxine may block the differentiation step of preadipocytes by inhibiting CREB phosphorylation and binding to the cAMP response element, thereby repressing CCAAT/enhancer-binding protein b during hormone-induced adipogenesis.[7]

Treatment for Fragile X Syndrome

Metadoxine treatment led to significant improvement in blood and brain biological markers (AKT and ERK), which may have a role in learning and memory.[3] The study also demonstrated a reduction in the amount of immature neurons and abnormally increased protein levels.[3]

…………………..

 

PATENT

http://www.google.com/patents/WO2010013242A1?cl=en

Scheme 1

 

[0054] In another aspect, the invention provides methods of synthetically preparing, e.g., carboxylated lactam ring of formula (II) (e.g. wherein n=2 for a reactant of formula (IVb) in Scheme 2), carboxylated lactam ring of (III) (e.g. wherein n=3 for a reactant of formula (IVb) in Scheme 2) and carboxylated lactam ring of formula (IV) (e.g. wherein n=4 for a reactant of formula (IVb) in Scheme 2), as depicted in Scheme 2.

Scheme 2

pyridoxine

Compound IVb, n=2,3,4

[0055] In another aspect, the invention provides methods of preparing a salt adduct including a positively charged pyridoxine moiety, or a derivative thereof, and a carboxylated 5- to 7-membered lactam ring, including the steps of:

(a) suspending an optionally substituted amino dioic acid in water and heating for a sufficient period of time to allow completing lactamization reaction;

(b) optionally decolorizing the reaction mixture to eliminate impurities;

(c) isolating the lactam carboxylate;

(d) optionally purifying the obtained lactam carboxylate by crystallization;

(e) admixing the obtained lactam carboxylate and a pyridoxine base or a derivative thereof in a solvent mixture optionally under heating; and

(f) isolating the product.

In certain embodiments, a solvent mixture of step (e) includes a mixture of an alcohol such as methanol, ethanol, isopropanol and the like, and water. [0059] According to yet another embodiment, there is provided methods of preparing N-substituted L-pyroglutamic acid and the carboxylate thereof, such as, for example, N-methyl-L-pyroglutamic acid (1-methyl-L-pyroglutamic acid), starting from L-pyroglutamic acid ethyl ester, as depicted in Scheme 3 below. Scheme 3

 

 

1-methyl-L-pyroglutamic acid

[0060] The invention further provides methods of preparing a salt adduct of the invention, wherein said positively charged moiety is a substituted pyridoxine, as depicted in Scheme 4 below. The starting reagent is 2-methyl-3-hydroxy-4- methoxymethyl-5-hydroxymethyl-pyridine hydrochloride (Compound (V)). The preparation of the corresponding salt is described in Example 1. Scheme 4

HCI NH 3 / MeOH 2 L-pyroglutamic acid

Compound V Compound Vl

 

Salt lid

[0061] The invention further provides methods of preparing a salt adduct of the invention, wherein said positively charged moiety is a substituted pyridoxine, as depicted in Scheme 5 below. The starting reagent in scheme 5 is 2-methyl-3-hydroxy- 4-methoxymethyl-5-hydroxymethyl-pyridine hydrochloride (Compound V). The preparation of the corresponding salt is described in Example 2. Scheme 5

 

Compound V

HCI

Compound VIII IX Compound L-pyroglutamic acid

, SaIt IIe

WO2010150261A1 * June 24, 2010 Dec 29, 2010 Alcobra Ltd. A method for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition
WO2011061743A1 * Nov 18, 2010 May 26, 2011 Alcobra Ltd. Metadoxine and derivatives thereof for use in the treatment of inflammation and immune-related disorders
US8476304 Jul 3, 2012 Jul 2, 2013 Alcobra Ltd. Method for decreasing symptoms of alcohol consumption
US8710067 Jul 3, 2012 Apr 29, 2014 Alcobra Ltd. Method for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition
WO2008066353A1 * Nov 30, 2007 June 5, 2008 Jae Hoon Choi Pharmaceutical composition comprising metadoxine and garlic oil for preventing and treating alcohol-induced fatty liver and steatohepatitis
WO2009004629A2 * Jul 3, 2008 Jan 8, 2009 Alcobra Ltd A method for decreasing symptoms of alcohol consumption
FR2172906A1 * Title not available
US4313952 * Dec 8, 1980 Feb 2, 1982 Maximum Baldacci Method of treating acute alcoholic intoxication with pyridoxine P.C.A.

References

  1. Addolorato, G; Ancona C, Capristo E, Gasbarrini G (2003). “Metadoxine in the treatment of acute and chronic alcoholism: a review”. International Journal of Immunopathology and Pharmacology.
  2. Martinez, Diaz; Villamil Salcedo; Cruz Fuentes (2001). “Efficacy of Metadoxine in the Management of Acute Alcohol Intoxication”. Journal of International Medical Research.
  3. “Metadoxine extended release (MDX) for adult ADHD” (in English). Alcobra Ltd. 2014. Retrieved 2014-05-07.
  4. Shpilenya, Leonid S.; Alexander P. Muzychenko; Giovanni Gasbarrini; Giovanni Addolorato (2002). “Metadoxine in Acute Alcohol Intoxication: A Double-Blind, Randomized, Placebo-Controlled Study”. Alcoholism:Clinical and Experimental Research.
  5. Shull, Kenneth H.; Robert Kisilevsky (1996). “Effects of Metadoxine on cellular status of glutathione and on enzymetric defence system following acute ethanol intoxication in rats”. Drugs Exp Clin Res.
  6. “Metadoxine – Drugs.com” (in English). Drugs.com. 2014. Retrieved 2014-05-08.
  7. Yang, YM; HE Kim; SH Ki; SG Kim (2009). “Metadoxine, an ion-pair of pyridoxine and L-2-pyrrolidone-5-carboxylate, blocks adipocyte differentiation in association with inhibition of the PKA-CREB pathway.”. Archives of Biochemistry and Biophysics.
  8. Calabrese, V; A Calderone; N Ragusa; V Rizza (1971). “Effects of l-2-pyrrolidone-5-carboxylate on hepatic adenosine triphosphate levels in the ethionine-treated rat”. Biochemical Pharmacology.
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