New Drug Approvals
Follow New Drug Approvals on WordPress.com

FLAGS AND HITS

Flag Counter
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO

Archives

Categories

Join me on Linkedin

View Anthony Melvin Crasto Ph.D's profile on LinkedIn

Join me on Researchgate

Anthony Melvin Crasto Dr.

  Join me on Facebook FACEBOOK   ...................................................................Join me on twitter Follow amcrasto on Twitter     ..................................................................Join me on google plus Googleplus

MYSELF

DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 36Yrs Exp. in the feld of Organic Chemistry,Working for AFRICURE PHARMA as ADVISOR earlier with GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution, ........amcrasto@gmail.com..........+91 9323115463, Skype amcrasto64 View Anthony Melvin Crasto Ph.D's profile on LinkedIn Anthony Melvin Crasto Dr.

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 37.9K other subscribers
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 AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 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, 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 32 PLUS year tenure till date Feb 2023, 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 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 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 38 lakh plus views on New Drug Approvals Blog in 227 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 He has total of 32 International and Indian awards

Verified Services

View Full Profile →

Recent Posts

Solanezumab, Eli Lilly’s anti-beta-amyloid monoclonal antibody for Alzheimer’s disease

November 3, 2013 3:02 am / 3 Comments on Solanezumab, Eli Lilly’s anti-beta-amyloid monoclonal antibody for Alzheimer’s disease


  1. immunoglobulin G1-kappa, anti-[Homo sapiens amyloid-beta (Abeta)

peptide soluble monomer], humanized monoclonal antibody;
gamma1 heavy chain [humanized VH (Homo sapiens IGHV3-23*04
(87.60%) -(IGHD)-IGHJ4*01) [8.8.5] (1-112) -Homo sapiens
IGHG1*01, CH3 K130>del (113-441)], (215-219′)-disulfide with
kappa light chain (1’-219’) [humanized V-KAPPA (Homo sapiens
IGKV2-30*01 (90.00%) -IGKJ1*01) [11.3.9] (1′-112′) -Homo sapiens
IGKC*01 (113′-219′)]; (221-221″:224-224″)-bisdisulfide dimer
neuroprotective agent
C6396H9922N1712O1996S42 955085-14-0

Heavy chain / Chaîne lourde / Cadena pesada
EVQLVESGGG LVQPGGSLRL SCAASGFTFS RYSMSWVRQA PGKGLELVAQ 50
INSVGNSTYY PDTVKGRFTI SRDNAKNTLY LQMNSLRAED TAVYYCASGD 100
YWGQGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT 150
VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT QTYICNVNHK 200
PSNTKVDKKV EPKSCDKTHT CPPCPAPELL GGPSVFLFPP KPKDTLMISR 250
TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ YNSTYRVVSV 300
LTVLHQDWLN GKEYKCKVSN KALPAPIEKT ISKAKGQPRE PQVYTLPPSR 350
DELTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP PVLDSDGSFF 400
LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP G 441
Light chain / Chaîne légère / Cadena ligera
DVVMTQSPLS LPVTLGQPAS ISCRSSQSLI YSDGNAYLHW FLQKPGQSPR 50
LLIYKVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCSQSTHVP 100
WTFGQGTKVE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150
VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200
VTHQGLSSPV TKSFNRGEC 219
Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro
Intra-H 22-96 139-195 256-316 362-420
22”-96” 139”-195” 256”-316” 362”-420”
Intra-L 23′-93′ 139′-199′
23”’-93”’ 139”’-199”’
Inter-H-L 215-219′ 215”-219”’
Inter-H-H 221-221” 224-224”
N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación
292, 292

Solanezumab, Eli Lilly’s anti-beta-amyloid monoclonal antibody for Alzheimer’s disease

The market for Alzheimer’s disease therapies is set to nearly triple between 2012 and 2022, despite increasing genericisation and the fact that few new product launches are expected during this time, according to new forecasts.

The key driver of growth in the AD market will be Eli Lilly’s anti-beta-amyloid monoclonal antibody solanezumab, the first potentially disease-modifying therapy (DMT) to launch for AD, according to the study, from Decision Resources. It reports that solanezumab is expected to launch in the seven major pharmaceutical markets – the US, France, Germany, Italy, Spain, the UK and Japan – starting in 2018 and that, by 2022, the drug is forecast to attain sales in excess of $5 billion in these markets.

More than 85% of solanezumab’s projected total use in 2022 will be in the mild AD market – the population in which the drug is currently being tested – followed by the pre-AD 1-2 years market segment, says the firm, which defines this latter population as those patients who will go on to develop overt AD within the next one to two years.

Solanezumab (proposed INN) is a monoclonal antibody being investigated by Eli Lilly as a neuroprotector[1] for patients withAlzheimer’s disease.[2][3]

It binds to the amyloid-β peptides that make up the protein plaques seen in the brains of people with the disease.

2012 results of the EXPEDITION 1 & 2 phase 3 clinical trials were only mildly encouraging.[4][5][6] but were said to be the “first evidence that targeting the amyloid cascade can slow the progression of disease.”[7]

  1.  International Nonproprietary Names for Pharmaceutical Substances (INN, prepublication copy), World Health Organization.
  2.  ClinicalTrials.gov NCT00749216 Solanezumab Safety Study in Japanese Patients With Alzheimer’s Disease
  3.  ClinicalTrials.gov NCT00905372 Effect of LY2062430 on the Progression of Alzheimer’s Disease (EXPEDITION)
  4.  “Lilly’s Solanezumab Slows Down Alzheimer’s Progression”. 9 Oct 2012.
  5.  Solanezumab Did it actually work
  6.  “Eli Lilly’s solanezumab faces grim prospects of attaining conditional FDA approval in mild Alzheimer’s”. 4 Sep 2012.
  7. “ALZHEIMER’S DRUG SLOWS MEMORY LOSS BY ONE THIRD”. 10 Oct 2012.

yellow coloured SOLANEZUMAB blocks beta amyloid from aa 16 to aa 25

Amyloid precursor protein (APP)

Mitochondria-targeting Cisplatin

November 3, 2013 1:37 am / Leave a comment


DR. Karra's avatarTGI: Thrive Health

Cisplatin is a chemotherapy drug given to more than half of all cancer patients. The drug kills cells very effectively by damaging nuclear DNA, but if tumors become resistant to cisplatin they often grow back.

A new study from the Massachusetts Institute of Technology (MIT) and the University of Toronto offers a possible way to overcome that resistance. The researchers found that when cisplatin was delivered to cellular structures called mitochondria, DNA in this organelle was damaged, leading to cancer cell death. Moreover, the mitochondrial-targeted drug could overcome cisplatin resistance.

“These results suggest that the mitochondria can be an important target for platinum-based drugs,” said Robert Radford, an MIT postdoc and an author of a paper describing the findings in the Oct. 31 online edition of the journal Chemistry & Biology.

Mitochondria-targeting cisplatin might also be effective at lower doses than regular cisplatin, helping to avoid…

View original post 21 more words

EPROSATAN MESYLATE » All About Drugs

November 2, 2013 7:08 am / 2 Comments on EPROSATAN MESYLATE » All About Drugs


http://www.allfordrugs.com/2013/11/02/eprosatan-mesylate/

OTC Drug (Meclizine) to Treat Infectious Diseases and Cancer

November 2, 2013 4:14 am / 1 Comment on OTC Drug (Meclizine) to Treat Infectious Diseases and Cancer


DR. Karra's avatarTGI: Thrive Health

Meclizine, an over-the-counter drug used for decades to treat nausea and motion sickness, has the potential for new uses to treat certain infectious diseases and some forms of cancer, according to Vishal M. Gohil, Texas A&M AgriLife Research biochemist.

 The research on meclizine appears in the current online version of the Journal of Biological Chemistry.

 “We found a particular enzyme which is inhibited by meclizine has been proposed (in other research) to be a drug target for the treatment of many diseases, including infectious diseases like malaria and African sleeping sickness,” Gohil said. “And this pathway has also been proposed to be a critical pathway for the proliferation of cancer cells.”
Read more:

View original post

EGA’S VISION OF FUTURE OF GENERIC AND BIOSIMILAR INDUSTRIES IN EUROPE

November 2, 2013 4:11 am / 3 Comments on EGA’S VISION OF FUTURE OF GENERIC AND BIOSIMILAR INDUSTRIES IN EUROPE


READ ALL AT

http://www.biosimilarnews.com/egas-vision-of-the-future-of-generic-and-biosimilar-industries-in-europe?utm_source=Biosimilar%20News%20%7C%20Newsletter&utm_campaign=77a8d4448a-01_11_2013_Biosimilar_News&utm_medium=email&utm_term=0_9887459b7e-77a8d4448a-335885197

FDA approves Gazyva for chronic lymphocytic leukemia

November 2, 2013 3:41 am / 2 Comments on FDA approves Gazyva for chronic lymphocytic leukemia


Drug is first with breakthrough therapy designation to receive FDA approval

The U.S. Food and Drug Administration today approved Gazyva (obinutuzumab) for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL).

read all at

http://www.pharmalive.com/fda-approves-roche-s-gazyva

 

my old article cut paste

Roche’s new leukaemia drug, Obinutuzumab, superior to Rituxan in clinical trial

JULY 25, 2013 12:52 AM / 6 COMMENTS / EDIT

 Reblogged from :

Click to visit the original postJuly 24 2013 | By Márcio Barra

Roche has announced that its experimental leukemia drug GA101, or obinutuzumab, used in combination with chemotherapy, was better than Rituxan at helping people with chronic lymphocytic leukemia live longer without their disease worsening, according to the results from the second phase of the clinical trial. Both drugs were tested and compared in combination with chlorambucil.

Read more… 329 more words

Roche’s Phase III leukemia drug Obinutuzumab (GA101) yields positive results

FEBRUARY 4, 2013 3:48 AM /

    1. GA101 is the first glycoengineered, type II anti-CD20 mAb.

b-cell-ga101-1

Roche’s Phase III leukemia drug Obinutuzumab (GA101) yields positive results

Obinutuzumab (GA101)

FORMULA C6512H10060N1712O2020S44

GA101 is the first glycoengineered, type II anti-CD20 monoclonal antibody (mAb) that has been designed for increased antibody-dependent cellular cytotoxicity (ADCC) and Direct CellDeath.1 This agent is being investigated in collaboration with Biogen Idec.

Swiss pharmaceutical company Roche has announced that its early Phase III trial of Leukemia drug obinutuzumab (GA101) demonstrated significantly improved progression-free survival in people with chronic lymphocytic leukemia (CLL).

The positive results yield from stage 1 of a three-arm study called CLL11, designed to investigate the efficacy and safety profile of obinutuzumab (GA101) plus chlorambucil, a chemotherapy, compared with chlorambucil alone in people with previously untreated chronic lymphocytic leukemia (CLL).

This phase of the study met its primary endpoint and an improvement in progression-free survival was achieved; obinutuzumab plus chlorambucil significantly reduced the risk of disease worsening or death compared to chlorambucil alone.

Roche chief medical officer and global product development head Hal Barron said; “the improvement in progression-free survival seen with GA101 is encouraging for people with CLL, a chronic illness of older people for which new treatment options are needed.”

“GA101 demonstrates our ongoing commitment to the research and development of new medicines for this disease.”

Obinutuzumab is Roche’s most advanced drug in development for the treatment of hematological malignancies.

It has been specifically designed as the first glycoengineered, type 2 anti-CD20 monoclonal antibody in development for B cell malignancies.

Afutuzumab is a monoclonal antibody being developed by Hoffmann-La Roche Inc. for the treatment of lymphoma.[1] It acts as an immunomodulator.[2][3] It was renamed obinutuzumab in 2009.[4]

References

  1. Robak, T (2009). “GA-101, a third-generation, humanized and glyco-engineered anti-CD20 mAb for the treatment of B-cell lymphoid malignancies”. Current opinion in investigational drugs (London, England : 2000) 10 (6): 588–96. PMID 19513948.
  2. Statement On A Nonproprietary Name Adopted By The Usan Council – Afutuzumab,American Medical Association.
  3. International Nonproprietary Names for Pharmaceutical Substances (INN), World Health Organization.
  4. International Nonproprietary Names for Pharmaceutical Substances (INN), World Health Organization.
  5. OBINUTUZUMAB ISMONOCLONAL ANTIBODY
    TYPE Whole antibody
    SOURCE Humanized (from mouse)
    TARGET CD20

Biosimilar drugs in Portugal

November 2, 2013 12:57 am / Leave a comment


marciocbarra's avatar

November 1 ,2013 | By Márcio Barra

What follows is a list of Biosimilar drugs available in Portugal. This data has been compiled from the INFOMED database, managed by the Portuguese National Competent Authrority on Medicines, INFARMED.  The Portuguese Marketing approval date was also provided. In the Market Status, you may find “no data” on some drugs. This means that the drug in question has no information displayed on the INFOMED database, save for its name.

View original post 486 more words

Cempra’s Taksta secures FDA orphan drug status for prosthetic joint infections treatment

November 1, 2013 4:10 am / 14 Comments on Cempra’s Taksta secures FDA orphan drug status for prosthetic joint infections treatment


FUSIDIC ACID, 6990-06-3

2-[(1S,2S,5R,6S,7S,10S,11S,13S,14Z,15R,17R)-13-(acetyloxy)-5,17-dihydroxy-2,6,10,11-tetramethyltetracyclo[8.7.0.02,7.011,15]heptadecan-14-ylidene]-6-methylhept-5-enoic acid

Taksta (CEM-102)
Clinical-stage pharmaceutical firm Cempra has secured orphan drug status from the US Food and Drug Administration (FDA) for its drug candidate Taksta (CEM-102) to treat patients with prosthetic joint infections (PJI).

Cempra’s Taksta secures FDA orphan drug status for prosthetic joint infections treatment

http://www.pharmaceutical-technology.com/news/newscempras-taksta-secures-fda-orphan-drug-status-prosthetic-joint-infections-treatment?WT.mc_id=DN_News

TAKSTATM (CEM-102)

Fusidic acid is a bacteriostatic antibiotic that is often used topically in creams and eyedrops, but may also be given systemically as tablets or injections. The global problem of advancing antimicrobial resistance has led to a renewed interest in its use recently.

Fusidic acid acts as a bacterial protein synthesis inhibitor by preventing the turnover ofelongation factor G (EF-G) from the ribosome. Fusidic acid is effective primarily ongram-positive bacteria such as Staphylococcus species, Streptococcus species, and Corynebacterium species. Fusidic acid inhibits bacterial replication and does not kill the bacteria, and is therefore termed bacteriostatic.

Fusidic acid is a true antibiotic, derived from the fungus Fusidium coccineum and was developed by Leo Laboratories in Ballerup, Denmark and released for clinical use in the 1960s. It has also been isolated from Mucor ramannianus and Isaria kogana. The drug is licensed for use as its sodium salt sodium fusidate, and it is approved for use under prescription in South Korea, Japan, UK, Canada, Europe, Australia, New Zealand, Thailand, India and Taiwan. A different oral dosing regimen, based on the compound’s Pharmacokinetic/pharmacodynamic (PK-PD) profile is in clinical development in the U.S. as Taksta.

Fusidic acid (TAKSTATM, CEM-102) is an antibiotic with a long history of safety and efficacy outside the United States. Cempra has exclusive rights to the supply of the compound for the U.S. market. Fusidic acid is orally active against gram-positive bacteria, including all S. aureus strains such as HA-MRSA and CA-MRSA. A novel dosing regimen has been successfully evaluated in a Phase II trial in patients with acute bacterial skin and skin structure infections (aBSSSI). Cempra is conducting a Phase II trial of TAKSTA for patients with prosthetic joint infections.


Profile of TAKSTA (CEM-102)
Prosthetic joint infections (PJI) occur in about 1% of hip replacements and 2% of knee replacements, translating to an incidence rate of about 10,000 per year in the U.S. at current hip and knee arthroplasty rates.  There are few good options to treat these serious staphylococcal, often MRSA infections, which require long-term antibiotic treatment.  Current therapy in the U.S. is with intravenous antibiotics such as vancomycin.  An oral drug that can be safely administered for a long period of time could improve care and quality of life for these patients.

TAKSTA has shown potent activity against a large number of S. aureus strains, including CA-MRSA, HA-MRSA and linezolid-resistant strains, isolated in the U.S over a 10 year period. Its broad S. aureus coverage makes it useful for a broad range of clinical applications. Because of its safety and tolerability profile, TAKSTA could be ideal for patients suffering from staphylococcal infections that require long-term therapy such as patients with PJIs.

Cempra has developed a unique oral loading dose regimen to optimize key pathogen coverage and minimize drug resistance development. This regimen is incorporated in our Phase II trial to treat PJIs with TAKSTA in combination with rifampin, which is commonly used with injectible antibiotics such as vancomycin to treat PJIs.

Research on TAKSTA

Publications

The links for the articles go to subscription-based sites and may require a fee to view the article.

In Vitro Activity of CEM-102 (Fusidic Acid) Against Prevalent Clones and Resistant Phenotypes of Staphylococcus aureus 
DF Sahm, J Deane, CM Pillar, P Fernandes
Antimicrobial Agents and Chemotherapy. June 2013  57: 4535-4346
http://aac.asm.org/content/57/9/4535

Efforts to Support the Development of Fusidic Acid in the United States
P Fernandes, D Pereira
Clinical Infectious Disease. June 2011 52:S542-6
http://www.ncbi.nlm.nih.gov/pubmed/21546632

Case report: Treatment of Chronic Osteomyelitis 
CR Wolfe
Clinical Infectious Disease. June 2011 52:S538-41
http://cid.oxfordjournals.org/content/52/suppl_7/S538.long

The Safety Record of Fusidic Acid in Non-US markets: A Focus on Skin Infections
CN Kraus, BW Burnstead
Clinical Infectious Disease. June 2011 52:S527-37
http://cid.oxfordjournals.org/content/52/suppl_7/S527.long

A Randomized, Double-Blind Phase 2 Study Comparing the Efficacy and Safety of an Oral Fusidic Acid Loading-Dose Regimen to Oral Linezolid in the Treatment of Acute Bacterial Skin and Skin Structure Infections 
JC Craft, SR Moriarty, K Clark, D Scott, TP Degenhardt, JG Still, GR Corey, A Das,  P Fernandes
Clinical Infectious Disease. June 2011 52:S520-26
http://cid.oxfordjournals.org/content/52/suppl_7/S520.long

Application of Pharmacokinetic-Pharmacodynamic Modeling and the Justification of a Novel Fusidic Acid Dosing Regimen: Raising Lazarus from the Dead 
BT Tsuji, OO Okusanya, JB Bulitta, A Forrest, SM Bhavnani, P Fernandes, PG Ambrose
Clinical Infectious Disease. June 2011 52:S513-19
http://cid.oxfordjournals.org/content/52/suppl_7/S513.long

Pharmacokinetics and Safety of Single, Multiple, and Loading Doses of Fusidic Acid in Healthy Subjects 
JG Still,  K Clark, TP Degenhardt, D. Scott, P. Fernandes,  M. J. Gutierrez
Clinical Infectious Disease. June 2011 52:S504-12
http://cid.oxfordjournals.org/content/52/suppl_7/S504.long

Activity of Fusidic Acid Against Extracellular and Intracellular Staphylococcus aureus: Influence of pH and Comparison with Linezolid and Clindamycin
S Lemaire,  F Van Bambeke, D Pierard, PC Appelbaum,  PM Tulkens
Clinical Infectious Disease. June 2011 52:S493-503
http://cid.oxfordjournals.org/content/52/suppl_7/S493.long

Characterization of Global Patterns and the Genetics of Fusidic Acid Resistance 
DJ Farrell, M Castanheira, I Chopra
Clinical Infectious Disease. June 2011  52:S487-92
http://cid.oxfordjournals.org/content/52/suppl_7/S493.long

In Vitro Antimicrobial Findings for Fusidic Acid Tested Against Contemporary (2008-2009) Gram-Positive Organisms Collected in the United States
RN Jones, RE Mendes, HS Sader, M Castanheira
Clinical Infectious Disease. June 2011 52:S477-86
http://cid.oxfordjournals.org/content/52/suppl_7/S477.long

New Rules for Clinical Trials in Patients with Acute Bacterial Skin and Skin Structure Iinfections: Do not Let the Perfect be the Enemy of the Good 
GR Corey, ME Stryjewski
Clinical Infectious Disease. June 2011 52:S469-76
http://cid.oxfordjournals.org/content/52/suppl_7/S469.long

Introduction: Fusidic Acid Enters the United States
RC Moellering,  GR Corey, ML Grayson
Clinical Infectious Disease. June 2011 52:S467-8
http://cid.oxfordjournals.org/content/52/suppl_7/S467.long

Evaluation of the Pharmacokinetics-Pharmacodynamics of Fusidic Acid Against Staphylococcus aureus and Streptococcus pyogenes Using In Vitro Infection Models: Implications for Dose Selection 
OO Okusanya, BT Tsuji, JB Bulitta, A Forrest, CC Bulik, SM Bhavnani, P Fernandes, PG Ambrose
Diagnostic Microbiology & Infectious Disease. June 2011 70:101-11
http://www.ncbi.nlm.nih.gov/pubmed/21513848

In Vitro Activity of Fusidic Acid (CEM-102, Sodium Fusidate) Against Staphylococcus aureus Isolated from Cystic Fibrosis Patients and its Effect on the Activities of Tobramycin and Amikacin against Pseudomonas aeruginosa and Burkholderia cepacia 
P McGhee, K Credito, L Beachel, PC Appelbaum,  K Kosowaska-Shick
Antimicrobial Agents and Chemotherapy. June 2011 55:2417-19
http://www.ncbi.nlm.nih.gov/pubmed/21513848

Occurrence and Molecular Characterization of Fusidic Acid Resistance Mechanisms Among Staphylococcus spp. From European Countries (2008)
Castanheira, M., AA Watters, RE Mendes, DJ Farrell, RN Jones
Antimicrobial Agents and Chemotherapy. April 2010 65:1353-8
http://jac.oxfordjournals.org/content/65/7/1353.long

Update on Fusidic Acid (CEM-102) Tested Against Neisseria gonorrhoeae and Chlamydia trachomatis
R Jones, D Biedenbach, P Roblin, S Kohlhoff, M Hammerschlag
Antimicrobial Agents and Chemotherapy. October 2010 54: 4518-4519
http://aac.asm.org/cgi/content/citation/54/10/4518

Fusidic Acid Resistance Rates and Prevalence of Resistance Mechanisms Among Staphylococcus spp. Isolated in North America and Australia, 2007-2008
M Castanheira, AA Watters, JM Bell, JD Turnidge, RN Jones
Antimicrobial Agents and Chemotherapy. September 2010 54: 3614-3617
http://www.ncbi.nlm.nih.gov/pubmed/20566766

Spectrum of Activity, Mutation Rates, Synergistic Interactions, and the Effects of pH and Serum Proteins for Fusidic Acid (CEM-102)
D Biedenbach, P Rhomberg, R Mendes, R Jones
Diagnostic Microbiology & Infectious Disease. March 2010 66: 301-307
http://www.dmidjournal.com/article/S0732-8893(09)00424-6/abstract

Performance of Fusidic Acid (CEM-102) Susceptibility Testing Reagents: Broth Microdilution, Disk Diffusion, and Etest Methods as Applied to Staphylococcus aureus
R Jones, M Castanheira, P Rhomberg, L Woosley, M Pfaller
Journal of Clinical Microbiology. March 2010 48: 972-976
http://jcm.asm.org/cgi/content/abstract/48/3/972

Evaluation of the Activity of Fusidic Acid Tested Against Contemporary Gram-Positive Clinical Isolates From the USA and Canada
M Pfaller, M Castaneira, H Sader, R Jones
International Journal of Antimicrobial Agents. March 2010 35: 282-287
http://www.ijaaonline.com/article/S0924-8579(09)00510-X/abstract

6th ASM Conference on Biofilms 2012 (Sept 29-Oct 4) – Miami, FL 2012

Quantitative and qualitative assessment of antibiotic activity against Staphylococcus aureus biofilm.
Siala, W., M. P. Mingeot-Leclercq, P. M. Tulkens, and F. Van Bambeke.
Abstr. 6th Am. Soc. Microbiol. Conf. Biofilms, abstr A-179.
Download Poster 

NACFC 2011

Activity of Fusidic Acid Against Methicillin-resistant Staphylococcus Aureus (MRSA) Isolated from CF Patients
Prabhavathi Fernandes, Donald Anderson, K. Kosowska-Shick, P. McGhee, L. Beachel and P.C. Appelbaum
Download Abstract  | Download Poster 

ECCMID 2011

Evaluation of L6 Ribosomal Protein Alterations in Fusidic Acid-Resistant Staphylococcus aureus: Fitness Cost and Time Kill Analysis
M Castanheira, RN Jones, LN Woosley, RE Mendes, GJ Moet, DJ Farrell
Download Abstract 

Fusidic Acid Activity and Coverage of Gram-positive Pathogens Associated with Acute Bacterial Skin and Skin Structure Infections (ABSSSI) in the USA (2008-2010)
RN Jones, DJ Farrell, HS Sader, M Castanheira
Download Abstract  | Download Poster 

IDSA 2010
Spectrum of Activity

Activity of Fusidic Acid Tested Against Contemporary Staphylococcus aureus Collected from United States Hospitals
M. Castanheira, R.E. Mendes, P.R. Rhomberg, R.N. Jones
Download Abstract  | Download Poster 

ICAAC 2010
Spectrum of Activity

Pharmacokinetics-Pharmacodynamics (PK-PD) of CEM- 102 (Sodium Fusidate) Against Streptococcus pyogenes Using In Vitro Pharmacodynamic Models (IVPM)
B. T. Tsuji, A. Forrest, P. A. Kelchlin, T. Brown, P. N. Holden, O. O. Okusanya, S. M. Bhavnani, P. Fernandes, P. G. Ambrose
Download Abstract  | Download Poster 

Activity of CEM-102 (sodium fusidate) against 40 MRSA from Cystic Fibrosis Patients
Cynthia Todd, Pamela Mcghee, and Peter Appelbaum
Download Abstract  | Download Poster 

Ability of CEM-102 (Fusidic Acid), Linezolid, Daptomycin to Select Resistant S.aureus Mutants at Steady-state Serum Levels
K. Kosowska-Shick, P. Mcghee, L. Beachel, P. C. Appelbaum;
Download Abstract  | Download Poster 

CEM-102 (Fusidic Acid) Maintains Potency against Resistant MRSA and Prevalent Hospital Acquired, Community Acquired,and Epidemic MRSA Clones
C.M. Pillar, M.K. Torres, D.F. Sahm and P. Fernandes
Download Abstract  | Download Poster 

In Vitro Activity Of Fusicic Acid (CEM-102) Against Resistant Strains Of Staphylococcus aureus
J. dubois, P. Fernandes
Download Abstract  | Download Poster 

Trade names and preparations

  • Fucidin (of Leo in Canada and the US)
  • Fucidin H (topical cream with corticosteroid – Leo)
  • Fucidin (of Leo in UK/ Leo-Ranbaxy-Croslands in India)
  • Fucidine (of Leo in France)
  • Fucidin (of Leo in Norway)
  • Fucidin (of Adcock Ingram, licenced from Leo, in South Africa)
  • Fucithalmic (of Leo in the UK, the Netherlands, Denmark and Portugal)
  • Fucicort (topical mixture with hydrocortisone)
  • Fucibet (topical mixture with betamethasone)
  • Ezaderm (topical mixture with betamethasone)(of United Pharmaceutical “UPM” in Jordan)
  • Fuci (of pharopharm in Egypt)
  • Fucizon (topical mixture with hydrocortisone of pharopharm in Egypt)
  • Foban (topical cream in New Zealand)
  • Betafusin (cream mixture with betamethasone valerate in Greece)
  • Fusimax (of Schwartz in India)
  • Fusiderm (topical cream and ointment by indi pharma in India)
  • Fusid (in Nepal)
  • Fudic (topical cream in India)
  • Fucidin (후시딘, of Dong Wha Pharm in South Korea)
  • Stanicid (in Serbia)
  • Dermy (Topical cream of W.Woodwards in Pakistan)
  • Fugen Cream (膚即淨軟膏 in Taiwan)
  • Phudicin Cream (in China; 夫西地酸[24])
  • Dermofucin cream ,ointment and gel (in Jordan)
  • Optifucin viscous eye drops (of API in Jordan)
  • Verutex (of Roche in Brazil)
  • TAKSTA (of Cempra in U.S.)
  • Futasole (of Julphar in Gulf and north Africa)
  • Stanicid (2% ointment of Hemofarm in Serbia)
  • Fuzidin (tablets of Biosintez in Russia)
  • Fuzimet (ointment with methyluracil of Biosintez in Russia)
  • Axcel Fusidic Acid(2% cream and ointment of Kotra Pharma, Malaysia)

 

MORE INFO

Figure US08450300-20130528-C00002

 

Fusidic acid (FA) is a tetracyclic triterpenoid or fusidane (steroidal) antibiotic derived from the fungus Fusidium coccineum that inhibits bacterial protein synthesis. FA is effective against gram-positive bacteria such as Staphylococcusspecies and Corynebacterium species (L. Verbist, J. Antimicro. Chemo. 25, Suppl. B, 1-5 (1990); A. Bryskier, Fusidic Acid, Chapter 23, in Antimicrobial Agents: Antibacterials and Antifungals (Andre Bryskier, Ed., ASM Press, Washington, USA, 2005)). FA also has moderate activity against Group A beta-hemolytic streptococci, or Streptococcus pyogenes (L. Verbist, J. Antimicro. Chemo. 25, Suppl. B, 1-5 (1990); A. Bryskier, Fusidic Acid, Chapter 23, inAntimicrobial Agents: Antibacterials and Antifungals (Andre Bryskier, Ed., ASM Press, Washington, USA, 2005); Skov et al., Diag. Micro. Infect. Dis. 40:111-116 (2001)).

  • Fusidic acid, chemically (3α, 4α, 8α, 9α, 11α, 13α, 14α, 16α, 17Z)-16-(Acetyloxy)-3,11-dihydroxy-29-nordammara-17(20), 24-dien-21-oic acid, is an antibacterial agent. It is a well-known antibiotic with a unique steroid-like tetracyclic ring system structure, and it is the most potent of a small family of steroidal antibiotics, the fusidanes. It is produced by fermentation under controlled conditions of the fungus Fusidium Coccineum.
  • The excellent distribution in various tissues, low degree of toxicity and allergic reactions and the absence cross-resistance with other clinically used antibiotics has made fusidic acid a highly valuable antibiotic,especially for skin and eye infections. The drug is used clinically both in its acid form, and as the sodium salt (Fusidin®), however Fusidin® is more favored one because of its better solubility in water, enabling a fast absorption from gastro-intestinal tract. As a result, it is more preferable to use sodium salt of fusidin in oral solid forms.
  • Fusidin® has the actions and uses of fusidic acid, and it has been shown that it ameliorates the course of several organ-specific immuno-inflammatory diseases such as chronic uveitis, Behcet’s disease, type I diabetes mellitus, Guillain-Barre syndrome, hepatitis, sepsis, pancreatitis, formalin-induced edema, multiple sclerosis, and scleroderma, whereby fucidin formulations have a great importance in pharmaceutical production.
  • Fusidin® can be presented in various formulations that differ significantly in their pharmacokinetic behaviors such as oral tablets, oral suspensions, intravenous formulations and topical preparation. Considering oral tablets, many of the early clinical studies were performed with capsule containing sodium fusidate. This was also the formulation marketed for many years in several countries. It is currently available as an oral tablet containing the sodium salt. Originally the sodium salt was available as an enteric-coated form but later it was reformulated as a film-coated tablet that appears to be better tolerated and gives higher blood levels.
  • Fusidic acid sodium salt was used in capsules as well as in tablets which were coated enterically. However by this enteric coating, the active fusidic acid sodium salt was not released before the tablets reached the part of the gastrointestinal tract in which the enteric coating would be dissolved. Depending on the time of passage through the stomach together with the food and the pH in the gastrointestinal tract, this led to unpredictable variations in the blood concentration of the patient undergoing treatment. Because of these adverse differences in blood concentration, the tablets without enteric coating were produced. Now, sodium fusidate is available in tablet, oral solution and injection form
  • PCT/WO9603128 A (LEO PHARMACEUTICALS PRODUCTS LTD. ET.AL.) describes the preparation of fusidic acid sodium salt tablets without an enteric coating by using dry granulation method in which a roller compactor was used. The compacted material so produced was size reduced to form a granulate having a bulk density in the range 0.45 to 0.9 g/m3 which was then formed into tablets.

FA was developed for clinical use in the 1960s and it is approved for human use outside of the United States, such as in the UK, Canada, Europe, Israel, Australia and New Zealand. It is typically prescribed at doses of 500 mg TID for treating skin and skin structure infections caused by Staphylococcus aureus (A. Bryskier,Fusidic Acid, Chapter 23, in Antimicrobial Agents: Antibacterials and Antifungals(Andre Bryskier, Ed., ASM Press, Washington, USA, 2005); Collignon et al., Int’l J. Antimicrobial Agents 12:S45-S58 (1999); D. Spelman, Int’l J. Antimicrobial Agents 12:S59-S66 (1999)), although some physicians have routinely prescribed the compound at 500 mg BID for treating skin and skin structure infections due to the long half-life of the compound (Fusidic Acid, in Principles and Practice of Infectious Diseases, 6th ed. (Mandell et al. eds., Elsevier, 2006)).

Treatment using FA has been well studied and it is generally regarded as safe when administered to humans, as evidenced by the fact that the drug has been in continuous use for more than 40 years. There are, however, several characteristics of FA that have prevented use of the drug against a wider spectrum of bacteria and in the treatment in additional types of infection. For example, approved dosing regimens have been shown to select for bacterial resistance, such as in S. aureus. Approved dosing regimens provide low multiples of the MIC and as a result, S. aureus resistant mutants can be selected after the first day of dosing. Once resistance has developed, FA is not effective against the resistant strains. Resistance is reported to occur if FA is used as a single drug as the resistance frequency at 4 and 8 times the MIC is in the range of 10−6 or 10−8 (Evans et al., J. Clin. Path. 19:555-560 (1966); Hansson et al., J. Mol. Biol.348:939-949 (2005), Jensen et al., Acta Pathol Microbiol Scand. 60:271-284 (1964); Besier et al., Antimicrob. Agents Chemo., 49(4):1426-1431 (2005); Gemmell et al., J. Antimicrobial Chemo. 57:589-608 (2006)).

The dosage of the drug cannot be simply increased as a means of avoiding development of resistance. It is difficult to achieve high concentrations of FA in the blood due to the substantial protein binding of the drug (approximately 95-97%) (K. Christiansen, International Journal of Antimicrobial Agents 12:S3-S9 (1999); Coutant et al., Diagn Microbiol Infect Dis 25:9-13 (1996); D. Reeves, J. Antimicrob. Chemo. 20:467-476 (1987); J. Turnidge, Int’l J. Antimicrobial Agents12:S23-S34 (1999); Rieutord et al., Int’l J. Pharmaceutics 119:57-64 (1995)). Moreover, high dosages of FA are not well-tolerated by patients receiving the drug. High doses of FA (e.g., 1 gram TID) are required if the drug is to be used in the treatment of bone and joint infections, less susceptible bacteria and other serious infections. However, treatment regimens using high doses of the drug induce nausea and vomiting and are rejected by patients (Fusidic Acid, inPrinciples and Practice of Infectious Diseases, 6th ed. (Mandell et al. eds., Elsevier, 2006); K. Christiansen, International Journal of Antimicrobial Agents 12:S3-S9 (1999); Nordin et al., Eur. J. Clin. Res. 5:97-106 (1994)).

In view of the tremendous costs associated with the de novo development of new anti-bacterials, expanding the indications for drugs that have already been demonstrated to be safe and effective is strongly needed. Overcoming the limitations on the uses of FA would broaden the population of bacterial infections against which it could be used and thus meet this need.

In a specific commercial pharmaceutical formulation, fusidic acid is presently marketed [see Monographs in the European Pharmacopeia 5.0] as a hemihydrate, which is the only hemihydrate form which has been described.

Patent GB 930,786 discloses salts of fusidic acid with organic and inorganic bases, solvates of fusidic acid, namely a benzene solvate and a methanol solvate. This patent further discloses an unspecified fusidic acid form with IR absorption bands (KBr) at 1265, 1385, 1695, 1730 and 3450 cm“1 and having a specific rotation [α]D 22 of minus 9 degrees (1% solution in CHCI3) obtainable by crystallisation of the methanol solvate of fusidic acid from ether. However, this form is distinct from the form of the present invention evident from the depicted IR spectrum in GB 930,786 which indicates that this form actually corresponds to the presently marketed hemihydrate form.

Solvates and salts of fusidic acid have also been disclosed in British patent GB 999,794. Patent ES 2208110 discloses two solvent free crystalline forms offusidic acid called Form I and Form II, and a crystalline hemihydrate called Form III which is identical to the presently marketed hemihydrate, respectively. The crystalline forms were identified and characterised by IR spectroscopy, differential scanning calorimetry, X-ray diffraction and melting points.

Patent WO 96/03128 discloses tablets containing a sodium salt form of fusidicacid and WO 86/03966 describes an ophthalmic gel composition comprising an undefined form of suspended fusidic acid.

Pimavanserin …New Drug Shows Early Promise in Treating Parkinson’s Psychosis

November 1, 2013 3:50 am / Leave a comment


Pimavanserin, ACP 103

N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N’-(4-(2-methylpropyloxy)phenylmethyl)carbamide, 706779-91-1 cas

 
706782-28-7 (tartrate)

THURSDAY Oct. 31, 2013 — Many people living with Parkinson’s disease suffer from hallucinations and delusions, but an experimental drug might offer some relief without debilitating side effects.

READ ALL AT

http://www.drugs.com/news/new-shows-early-promise-treating-parkinson-s-psychosis-48630.html

The drug — pimavanserin — appears to significantly relieve these troubling symptoms, according to the results of a phase 3 trial to test its effectiveness.

Pimavanserin (ACP-103) is a drug developed by Acadia Pharmaceuticals which acts as an inverse agonist on the serotonin receptor subtype 5-HT2A, with 40x selectivity over 5-HT2C, and no significant affinity or activity at 5-HT2B or dopamine receptors.[1] As of September 3 2009, pimavanserin has not met expectations for Phase III clinical trials for the treatment of Parkinson’s disease psychosis,[2] and is in Phase II trials for adjunctive treatment of schizophrenia alongside an antipsychotic medication.[3] It is expected to improve the effectiveness and side effect profile of antipsychotics.[4][5][6]

3-D MODEL OF DRUG PIMAVANSERIN, THE DEVELOPMENT OF WHICH HAS BEEN EXPEDITED BY THE FDA

  1. Friedman, JH (October 2013). “Pimavanserin for the treatment of Parkinson’s disease psychosis”. Expert Opinion on Pharmacotherapy 14 (14): 1969–1975.doi:10.1517/14656566.2013.819345. PMID 24016069.
  2.  ACADIA Pharmaceuticals. “Treating Parkinson’s Disease – Clinical Trial Pimavanserin – ACADIA”. Retrieved 2009-04-11.[dead link]
  3. “ACADIA Announces Positive Results From ACP-103 Phase II Schizophrenia Co-Therapy Trial” (Press release). ACADIA Pharmaceuticals. 2007-03-19. Retrieved 2009-04-11.
  4. Gardell LR, Vanover KE, Pounds L, Johnson RW, Barido R, Anderson GT, Veinbergs I, Dyssegaard A, Brunmark P, Tabatabaei A, Davis RE, Brann MR, Hacksell U, Bonhaus DW (August 2007). “ACP-103, a 5-hydroxytryptamine 2A receptor inverse agonist, improves the antipsychotic efficacy and side-effect profile of haloperidol and risperidone in experimental models”. J Pharmacol Exp Ther 322 (2): 862–70.doi:10.1124/jpet.107.121715. PMID 17519387.
  5.  Vanover KE, Betz AJ, Weber SM, Bibbiani F, Kielaite A, Weiner DM, Davis RE, Chase TN, Salamone JD (October 2008). “A 5-HT2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model”. Pharmacol Biochem Behav 90 (4): 540–4. doi:10.1016/j.pbb.2008.04.010. PMC 2806670.PMID 18534670.
  6.  Abbas A, Roth BL (December 2008). “Pimavanserin tartrate: a 5-HT2A inverse agonist with potential for treating various neuropsychiatric disorders”. Expert Opin Pharmacother9 (18): 3251–9. doi:10.1517/14656560802532707. PMID 19040345.

Psychiatrist Herb Meltzer sadly watched the agitated woman accuse her son of trying to poison her. Although not her physician, Dr. Meltzer certainly recognized the devastating effects of his mother-in-law’s Parkinson’s disease psychosis (PDP). Occurring in up to half of all patients with Parkinson’s, symptoms of the psychotic disorder may include hallucinations and delusions. The development of PDP often leads to institutionalization and increased mortality.

“I was on the sidelines,” explains Dr. Meltzer, professor of psychiatry and physiology and director of the Translational Neuropharmacology Program at Northwestern University Feinberg School of Medicine. “I told my brother-in-law it was the disease talking, not his mother.”

Ironically, Dr. Meltzer has been far from the sidelines and right on the PDP playing field for quite a while. In fact, he may soon see a drug he helped develop become the first approved treatment for the disorder. In early April, Dr. Meltzer celebrated, along with colleagues at ACADIA Pharmaceuticals in San Diego for which he has been a clinical advisor, the stunning announcement: the Food and Drug Administration (FDA) had expedited the company’s path to filing a new drug application (NDA) for pimavanserin, a selective serotonin 5-HT2Areceptor blocker. Typically, the FDA requires data from two successful pivotal Phase III clinical studies affirming a drug candidate’s safety and efficacy before the agency will even consider an NDA. Just as ACADIA was planning to launch another Phase III study this spring to fulfill this requirement, the FDA decided the company had amassed enough data to support an NDA filing.

HERBERT MELTZER, MD, DESIGNED ACADIA PHARMACEUTICAL’S INITIAL PROOF OF CONCEPT TRIAL OF THE DRUG PIMAVANSERIN TO TREAT PARKINSON’S DISEASE PSYCHOSIS.

“This action on the part of the FDA is extremely unusual,” says Dr. Meltzer, who designed ACADIA’s initial proof-of-concept trial of pimavanserin, a drug he had initially suggested ACADIA develop to treat schizophrenia, with PDP as a secondary indication. “The FDA staff decided that results from my small clinical study and the first successful Phase III study were sufficient to establish efficacy and safety.”

Bringing a safe and effective drug to market is a monumental achievement. Pimavanserin is not yet there but has significantly moved within striking distance with this recent nod from the regulatory agency.

24 YEARS IN THE MAKING

The neuropharmacologist’s collaboration with ACADIA began in 2000. The company wanted to develop a drug targeting the serotonin 5-HT 2A receptor, a neurotransmitter ACADIA believed played a key role in schizophrenia based upon basic research from Meltzer and their own studies. A distinguished schizophrenia investigator, then at Case Western Reserve University, he welcomed ACADIA’s offer to translate his ideas about developing safer and more effective drug treatments for psychosis. Through his provocative and groundbreaking research, Dr. Meltzer originally championed the idea that blocking the 5-HT2A receptor would lead to better antipsychotic drugs with fewer side effects. Existing drugs often impaired motor function because they targeted the dopamine D2 receptor. Of the 14 different types of serotonin receptors in this complex area of study, Dr. Meltzer zeroed in on the 5-HT2A type—the same receptor that leads to hallucinogenic properties of LSD and mescaline. It was an ideal target to complement weak D2 receptor blockade in schizophrenia and as a standalone treatment for PD psychosis.

………………………………………….

Veterinary- Atipamezole

October 31, 2013 7:31 am / Leave a comment


Atipamezole

4-(2-Ethyl-1,3-dihydroinden-2-yl)-3H-imidazole, Atipamezole,  cas 104054-27-5

hydrochloride cas no  104075-48-1

  • MPV 1248 (IS: FarmosGroupLt)
  • UNII-03N9U5JAF6 (IS)
  • UNII-2W4279571X (IS)

Atipamezole is a synthetic alpha2-adrenergic antagonist, indicated for the reversal of the sedative and analgesic effects of dexmedetomidine and medetomidine in dogs. It has also been researched in humans as a potential anti-Parkinsonian drug.Atipamezole is more potent than yohimbine; it is very selective for alpha2-adrenergic vs alpha1sites, but not selelctive for alpha2 – subtypes.

Atipamezole (brand name Antisedan, Pfizer) is a synthetic alpha2–adrenergic antagonist, indicated for the reversal of the sedative and analgesic effects of dexmedetomidine andmedetomidine in dogs.[1] It has also been researched in humans as a potential anti-Parkinsonian drug.[2]

  1.  Pfizer Animal Health ANTISEDAN Product Overview
  2. Pertovaara A, Haapalinna A, Sirviö J, Virtanen R (2005). “Pharmacological properties, central nervous system effects, and potential therapeutic applications of atipamezole, a selective alpha2-adrenoceptor antagonist”. CNS Drug Reviews 11 (3): 273–88.doi:10.1111/j.1527-3458.2005.tb00047.x. PMID 16389294.

Synonyms

1H-imidazole, 4-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-
1H-imidazole, 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-
5-(2-Ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole
Atipamezole
4-(2-Ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole
4-(2-Ethyl-2-indanyl)imidazole
4-(2-Ethyl-indan-2-yl)-1H-imidazole(Atipamezole)
4-(2-ethylindan-2-yl)imidazole
Antisedan
Antisedan
Atipamezol
Atipamezolum
Atipamezole Hydrochloride CAS 104075-48-1

………………………………

Atipamezole is a selective alpha2 – adrenoceptor antagonist which is currently marketed under the trademark Antisedan® for the reversal of sedative- analgesic veterinary drugs. Atipamezole has been disclosed e.g. in the European Patent EP 183492 as useful for the reversal of detomidine. European Patent EP 0589957 discloses the use of atipamezole for the treatment of male sexual impotence. In US 4698692 the use of atipamezole for the attenuation of ethyl alcohol intoxication is disclosed.

US Patent No. US6543389 discloses insecticidal pet collars for dogs comprising amitraz and atipamezole. Atipamezole in the collar provides amelioration of amitraz toxicosis in combination with the amitraz in case the dogs ingests the collar. The pet collar comprises 0.01 to 1%, preferably 0.1 to 1 %, by weight of atipamezole. Safe, effective ways to eliminate ectoparasites are desired for the companion animal’s well-being, for the well-being and comfort of its human associate and for the prevention of losses in livestock

A substantial amount of work has been devoted to identifying the neurotransmitters involved in the facilitation and inhibition of male sexual behaviour (see e.g. Bitran and Hull 1987, Neuroscience and Behavioral reviews 11 , 365-389). Noradrenergic neuro-transmission seems to have an important role.

Atipamezole is a selective and potent a2*-adrenoceptor antagonist which is currently marketed for the reversal of sedative-analgesic veterinary drugs. Atipamezole has been disclosed e.g. in the European Patent EP 183492 as useful for the reversal of detomidine.

We have now found that this compound is also very effective in increasing male sexual capacity in a monkey model. These findings suggest that atipamezole would be an effective therapy in male impotence in humans as well.

Another a2-adrenoreceptor antagonist, yohimbine, is currently used for the treatment of male impotence. Yohimbine increases noradrenergic neurotransmission and has been reported to facilitate the sexual capacity of male animals, although the results of different studies are conflicting.

Atipamezole is, however clearly advantageous over yohimbine for this use because of its excellent selectivity. The a2/a-|selectivity ratio of atipamezole is

200-300 times higher than that of yohimbine.

  • EP 0310745 B (FARMOS OY) 1989.04.12. disclosed preparation of 5-(2-ethyl-2,3-dihydro-1 H-inden-2-yl)-1 H-imidazole salt by two synthetic routes.
  • First synthetic route as starting material was used 2-acetyl-1-indanone, which was alkylated with ethylbromide in acetone in the presence of sodium carbonate to 2-acetyl-2-ethyl-1-indanone. The acetyl group was brominated with bromine in methanol and to imidazole by heating in formamide. Then the intermediate was hydrogenated in 2N hydrochloric acid in the presence of 10% palladium on carbon.
  • Second synthetic route disclosed in the same patent is following, as starting material was used 2,3-dihydro-1H-indene-2-carboxylic acid methyl ester, which was prepared by methylation of 2,3-dihydro-1H-indene-2-carboxylic acid in the presence of sulphuric acid. The 2,3-dihydro-1H-indene-2-carboxylic acid methyl ester was reacted with N-isopropylcyclohexylamide and ethylbromide yielding 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid, then thionyl chloride was added and 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid chloride was obtained. In the next step ethoxymagnesiummalonic acid ethyl ester in dry ether was added to 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid chloride and reaction mixture was treated with sulphuric acid, and 1-(2,3-dihydro-2-ethyl-1H-inden-2-yl)ethanone was obtained, then the intermediate was stirred in methylene chloride and bromine was added by giving a new intermediate 2-bromo-1-(2,3-dihydro-2-methyl-1H-inden-2-yl)ethanone, to which was thereafter added formamide and hydrochloric acid yielding crude product of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole. The last step involved hydrogenation of the crude product of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1 H-imidazole with 10% palladium on carbon.
  • EP 0247764 B (ORION-YHTYMÄ OY) 1987.02.12. disclosed the following process for preparation of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole hydrochloride. The process starts by reaction of alpha, alpha-dibromo-o-xylene with 4-penten-2-one to obtain 1-(2,3-dihydro-2-vinyl-1H-inden-2-yl)ethanone. The obtained intermediate was brominated, e.g. with bromine, methylene chloride was used as solvent and 2-bromo-1-(2,3-dihydro-2-vinyl-1H-inden-2-yl)-ethanone was obtained, which is thereafter reacted with formamide in excess formamide to give a 4(5)-(2,3-dihydro-2-vinyl-1H-inden-2-ylimidazole hydrochloride. As the last step the vinyl group was catalytically hydrogenated to an ethyl group so as to form a product 4(5)-(2,3-dihydro-2-ethyl-1 H-inden-2-yl) imidazole.
  • Another synthetic route for obtaining 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole is disclosed in WAI, Wonf, et al. A Concise Synthesis of Atipamezole. Synthesis. 1995, no.2, p.139-140. The cyclization of alpha, alpha’-dibromo-o-xylene with acetylacetone by means of NaOH and tetrabutylammonium bromide in toluene/water at 80°C under phase-transfer conditions gives the unstable diacetyl derivative, which presumably undergoes cleavage to afford 2-acetylindane. The alkylation of 2-acetylindane with ethyl iodide and potassium tert-butoxide yields 2-acetyl-2-ethylindan, which is brominated with Br2 to give 2-bromoacetyl-2-ethylindan. Finally, this compound is cyclised with formamide at 160°C (some 2-ethyl-2-(4-oxazolyl)indane is also formed but easily eliminated); the cyclization can also be carried out with formamidine in liquid ammonia. Although the substitution of formamide by formamidine acetate eliminates the oxazole formation, it does not increase the yield of Atipamezole (<30%) WAI, Wonf, et al. A Concise Synthesis of Atipamezole. Synthesis. 1995, no.2, p.139-140 in the final step.

    The preparation of atipamezole hydrochloride salt is described in U.S. Patent 4,689,339, wherein atipamezole obtained from the hydrogenation step is first recovered from alkaline solution as free base. After the evaporation of methylene chloride solvent to dryness the isolated crystalline product is converted into its hydrochloride salt by treatment with dry hydrogen chloride in ethyl acetate

Other compounds having alpha-2 adrenoceptor antagonist properties which may be useful in accordance with the present invention include idazoxan related compounds [Reckitt & Colman] Doxey, et al., Br. J. Parmacol., Vol. 78, p.489-505 (1983); imiloxan [Syntex] Michel, et al., Br. J. Pharmacol., Vol. 74, p.255-256 (1981); WY 26703 and related compounds [Wyeth] Latimer, et al., Naunvn Schmiedeberg’s Arch. Pharmacol., Vol. 327, p. 312-318 (1984); CH-38083 [Chinoin] Vizi, et a., J. Pharmacol. Exp. Ther., Vol. 238, p. 701-706 (1986); GR 50360A and related compounds [Glaxo] Halliday, et al., Br. J. Pharmacol., Vol. 95, p. 715 (1988); DG 5128 and related compounds of Daiichi Seiyaku Co., Ltd., Tokyo, Japan; and Yohimbine [Sigma].

………………………………….

WO2009071584A1

    1. 1. an essential process for obtaining 5-(2-ethyl-2,3-1H-inden-2-yl)-1H-imidazole, without bromination in any step of process, thus preventing the possibility of brominated by-products;
    2. 2. This process has given superior yields, compared to patents cited above;
    3. 3. This process is amenable to large scale production which does not require specialized equipment.
  • The condensing of commercially available 1-trityl-1H-imidazole-4-carboxaldehyde (I) with phtalide to form 2-(1-trityl-1H-imidazole-4-yl)indan-1,3-dione (II) is performed under the conditions that are similar to those used for synthesis of 4-(indane-1,3-dionyl) pyridine J. Org. Chem. 1971, vol.36, p.1563. surprisingly, the bulky 1-trityl-1H-imidazole-4-carboxaldehyde (I) reacted as expected and produced 2-(1-trityl-1H-imidazole-4-yl)indan-1,3-dione (II) in over 67% yield. Both ethyl acetate and dioxane can be used as reaction media.
  • The alkylation of (II) by ethyl iodide is performed in boiling acetone with potassium carbonate as basic agent. 2-Ethyl-2-(1-trityl-1H-imidazole-4-yl)indan-1,3-dione (III) is formed in over 67% yield and easily isolated from the acetone solution by concentrating it and diluting with water. A high purity (III) is obtained after crystallization from methanol or ethanol.
  • Removing the trityl group of 2-ethyl-2-(1-trityl-1H-imidazole-4-yl)indan-1,3-dione by acid hydrolysis to yield the deprotected 2-ethyl-2-(1H-imidazol-2-yl)indan-1,3-dione.
  • The reduction of (IV) to 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole hydrochloride (V) is performed in hydrogenation apparatus with Pd/C catalyst under hydrogen pressure in HCI solution. The reaction proceeds under variable pressure and temperature conditions, but a pressure of about 3 bar and the temperature of about 80-85°C is preferable. After removing the catalyst the product crystallizes on chilling in over 77% yield. It can be purified by additional crystallization.
  • EP 0310745 B (FARMOS OY) 1989.04.12. disclosed preparation of 5-(2-ethyl-2,3-dihydro-1 H-inden-2-yl)-1 H-imidazole salt by two synthetic routes.
  • First synthetic route as starting material was used 2-acetyl-1-indanone, which was alkylated with ethylbromide in acetone in the presence of sodium carbonate to 2-acetyl-2-ethyl-1-indanone. The acetyl group was brominated with bromine in methanol and to imidazole by heating in formamide. Then the intermediate was hydrogenated in 2N hydrochloric acid in the presence of 10% palladium on carbon.
  • Second synthetic route disclosed in the same patent is following, as starting material was used 2,3-dihydro-1H-indene-2-carboxylic acid methyl ester, which was prepared by methylation of 2,3-dihydro-1H-indene-2-carboxylic acid in the presence of sulphuric acid. The 2,3-dihydro-1H-indene-2-carboxylic acid methyl ester was reacted with N-isopropylcyclohexylamide and ethylbromide yielding 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid, then thionyl chloride was added and 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid chloride was obtained. In the next step ethoxymagnesiummalonic acid ethyl ester in dry ether was added to 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid chloride and reaction mixture was treated with sulphuric acid, and 1-(2,3-dihydro-2-ethyl-1H-inden-2-yl)ethanone was obtained, then the intermediate was stirred in methylene chloride and bromine was added by giving a new intermediate 2-bromo-1-(2,3-dihydro-2-methyl-1H-inden-2-yl)ethanone, to which was thereafter added formamide and hydrochloric acid yielding crude product of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole. The last step involved hydrogenation of the crude product of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1 H-imidazole with 10% palladium on carbon.
  • EP 0247764 B (ORION-YHTYMÄ OY) 1987.02.12. disclosed the following process for preparation of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole hydrochloride. The process starts by reaction of alpha, alpha-dibromo-o-xylene with 4-penten-2-one to obtain 1-(2,3-dihydro-2-vinyl-1H-inden-2-yl)ethanone. The obtained intermediate was brominated, e.g. with bromine, methylene chloride was used as solvent and 2-bromo-1-(2,3-dihydro-2-vinyl-1H-inden-2-yl)-ethanone was obtained, which is thereafter reacted with formamide in excess formamide to give a 4(5)-(2,3-dihydro-2-vinyl-1H-inden-2-ylimidazole hydrochloride. As the last step the vinyl group was catalytically hydrogenated to an ethyl group so as to form a product 4(5)-(2,3-dihydro-2-ethyl-1 H-inden-2-yl) imidazole.
  • Another synthetic route for obtaining 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole is disclosed in WAI, Wonf, et al. A Concise Synthesis of Atipamezole. Synthesis. 1995, no.2, p.139-140. The cyclization of alpha, alpha’-dibromo-o-xylene with acetylacetone by means of NaOH and tetrabutylammonium bromide in toluene/water at 80°C under phase-transfer conditions gives the unstable diacetyl derivative, which presumably undergoes cleavage to afford 2-acetylindane. The alkylation of 2-acetylindane with ethyl iodide and potassium tert-butoxide yields 2-acetyl-2-ethylindan, which is brominated with Br2 to give 2-bromoacetyl-2-ethylindan. Finally, this compound is cyclised with formamide at 160°C (some 2-ethyl-2-(4-oxazolyl)indane is also formed but easily eliminated); the cyclization can also be carried out with formamidine in liquid ammonia. Although the substitution of formamide by formamidine acetate eliminates the oxazole formation, it does not increase the yield of Atipamezole (<30%) WAI, Wonf, et al. A Concise Synthesis of Atipamezole. Synthesis. 1995, no.2, p.139-140 in the final step.

…………………………….

US Patent 8,431,717

Atipamezole [5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole, 1] is a veterinary drug that has been investigated for treating Parkinson’s disease in humans. V. Lusis and co-inventors summarize several ways to synthesize 1. Some routes give a low yield of 1 and produce large quantities of an oxazole byproduct. Other processes involve a sluggish bromination reaction that leads to many byproducts.

The inventors’ process is intended to overcome these problems. In particular, it does not use the bromination reaction and thus avoids forming brominated byproducts. The process, outlined in the figure, begins with the reaction of imidazole 2 with i-PrMgCl to form iodo Grignard reagent 3, which is treated with DMF to give 4. This intermediate is not isolated but is treated with aq NH4Cl to give aldehyde 5, isolated in 73.2% yield. The aldehyde is condensed with phthalide (6) in the presence of NaOMe to produce imidazolylindane 7, recovered in crude form in 67.2% yield.

Improved synthesis of atipamezole

In the next stage, compound 7 is alkylated with EtI in the presence of K2CO3. Product 8 is isolated in 50.9% yield after being recrystallized from EtOH. Product1 can be produced directly from 8 by making its HCl salt and hydrogenating the salt over Pd/C. Crude atipamezole is isolated as its HCl salt in 26.6% yield.

Alternatively, acid hydrolysis of 8 removes the trityl group to form dione 9, recovered as a white crystalline solid in 76.2% yield. The HCl salt of 9 is then hydrogenated to 1·HCl.

The patent’s claims cover the process to make 1 and new compounds 7 and 8. The overall yield of compound 1 is poor, partly because of the low yield from the hydrogenation step. The inventors claim, however, that the yield is higher than from earlier methods. They point out that the process is amenable to large-scale production without the use of specialized equipment. (JSC Grindeks [Riga, Latvia]. US Patent 8,431,717, April 30, 2013; Keith Turner), View the full-text here.

………………………………

nmr

Atipamezole Hydrochloride CAS 104075-48-1 HNMR

Atipamezole Hydrochloride CAS 104075-48-1 HNMR

……………………………………………………….

Post navigation

← Older posts Newer posts →

DR ANTHONY MELVIN CRASTO

ANTHONY MELVIN CRASTO MY BLOGS......... ALL ABOUT DRUGS, WORLD DRUG TRACKER, MEDICINAL CHEM INTERNATIONAL, DRUG SYN INTERNATIONAL SCALEUP OF DRUGS,   MEDICINAL CHEM INTERNATIONAL, DRUG SYN INTERNATIONAL, SCALEUP OF DRUGS, EUREKAMOMENTS, and my new blog API SYNTHESIS INTERNATIONAL  
Follow New Drug Approvals on WordPress.com

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 37.9K other subscribers

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

feedjit

Feedjit Live Blog Stats

DISCLAIMER

I , Dr A.M.Crasto is writing this blog to share the knowledge/views, after reading Scientific Journals/Articles/News Articles/Wikipedia. My views/comments are based on the results /conclusions by the authors(researchers). I do mention either the link or reference of the article(s) in my blog and hope those interested can read for details. I am briefly summarising the remarks or conclusions of the authors (researchers). If one believe that their intellectual property right /copyright is infringed by any content on this blog, please contact or leave message at below email address amcrasto@gmail.com. It will be removed ASAP