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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.

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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 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

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Recent Posts

loxoprofen

May 3, 2014 4:16 am / Leave a comment


Loxoprofen.svg

loxoprofen

 

cas 68767-14-6, 80382-23-6  Koloxo, Loxoprofene, Loxoprofeno, Loxoprofenum, Loxoprofen [INN], Loxoprofene [French], Loxoprofenum [Latin]
Molecular Formula: C15H18O3
Molecular Weight: 246.30162

(RS)-2-{4-[(2-oxocyclopentyl)methyl]phenyl}propanoic acid

Cyclooxygenase inhibitor; Prostanoid receptor antagonist

Inflammatory disease; Pain

Loxoprofen (INN) is a non-steroidal anti-inflammatory drug in the propionic acid derivatives group, which also includes ibuprofen and naproxen among others. It is marketed in Brazil, Mexico and Japan by Sankyo as its sodium salt, loxoprofen sodium, under the trade name Loxonin, Argentina as Oxeno and in India as Loxomac. It is available in these countries for oral administration, and a transdermal preparation was approved for sale in Japan on January 2006.[1]

Pharmacokinetics

Loxoprofen is a prodrug. It is quickly converted to its active trans-alcohol metabolite following oral administration, and reaches its peak plasma concentration within 30 to 50 minutes.

Mechanism of action

As most NSAIDs, loxoprofen is a non-selective cyclooxygenase inhibitor, and works by reducing the synthesis of prostaglandins from arachidonic acid.

Interactions

Loxoprofen should not be administered at the same time as second-generation quinolone antibiotics such as ciprofloxacin and norfloxacin, as it increases their inhibition of GABA and this may cause seizures.[2] It may also increase the plasma concentration of warfarin, methotrexate, sulfonylurea derivatives and lithium salts, so care should be taken when loxoprofen is administered to patients taking any of these drugs.[2]

synthesis

Ethyl 2-oxocyclopentanecarboxylate (I) reacts with ethyl 2-(4-chloromethylphenyl)propionate (II) in the presence of KOH in hot DMF to afford ethyl 2-[4-(1-ethoxycarbonyl-2-oxocyclopentan-1-ylmethyl)phenyl]propionate (III), which is then hydrolyzed and decarboxylated by treatment with 47% HBr in refluxing dioxane.

Loxoprofen 3D.png

http://zhou.nankai.edu.cn/index.php/highlights

…………….

WO-2014065577

Method for the preparation of loxoprofen (2S,1’R,2’S) trans-alcohol. Appears to be the first filing from the assignee. Sankyo (now Daiichi Sankyo) has developed and launched oral loxoprofen (Loxonin), an NSAID, is indicated for the symptom relief of inflammation and pain associated with eg rheumatoid arthritis, osteoarthritis and low back pain. Regional and national filings based on the product patent, WO03059880 start expiring from Jan 2023.

 

References

  1. Daiichi Sankyo Co. (January 24, 2006). “Percutaneous Absorption-Type Analgesic and Anti-inflammatory Drug Loxonin Poultice 100mg Receives Approval for Manufacture” (Press release). Doctor’s Guide Global Edition. Retrieved 2007-04-19.
  2. (Portuguese) “LOXONIN – Bula do Medicamento [Label Information]”. Centralx. 2007. Retrieved 2007-04-19.

 

US4683325
7-29-1987
Leukotriene antagonists
US4666907
5-20-1987
Phenothiazine and derivatives and analogs and use as leukotriene biosynthesis inhibitors
US4666928
5-20-1987
Propylphenoxy pyridine carboxylates as leukotriene antagonists
US4667032
5-20-1987
Phenothiazone derivatives and analogs
US4667055
5-20-1987
Leukotriene antagonists
US4663347
5-6-1987
Benzofuran 2-carboxylic acid esters useful as inhibitors of leukotriene biosynthesis
US4634766
1-7-1987
1,4-diaza-phenothiazines
US4617407
10-15-1986
Leukotriene antagonists
US4611056
9-10-1986
Benzo[A]phenothiazines and hydro-derivatives
US4609744
9-3-1986
4-oxo-benzopyran carboxylic acids

 

US4599360
7-9-1986
Ophthalmic anti-inflammatory agents
EP0055588
10-27-1983
ANALGESIC AND ANTI-INFLAMMATORY AGENTS
US4400534
8-24-1983
Analgesic and anti-inflammatory agents
US4161538
7-18-1979
Substituted phenylacetic acid derivatives and process for the preparation thereof

 

Fulvestrant… For the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy.

May 3, 2014 3:40 am / Leave a comment


Fulvestrant.svg

 

fulvestrant

Fibrosis; Breast tumor; Female genital tract tumor; Uterus tumor

Estrogen receptor antagonist

(7α,17β)-7-{9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl}estra-1,3,5(10)-triene-3,17-diol

129453-61-8   CAS

C32H47F5O3S

606.771

Fulvestrant is a drug treatment of hormone receptor-positive metastatic breast cancer in post-menopausal women with disease progression following anti-estrogen therapy. It is an estrogen receptor antagonist with no agonist effects, which works both by down-regulating and by degrading the estrogen receptor.

 

Canada 2351004 2003-02-18 EXPIRY 2021-01-08
United States 6774122 2001-01-09 EXPIRY 2021-01-09

Fulvestrant (Faslodex, AstraZeneca) is a drug treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy. It is an estrogen receptor antagonist with no agonist effects, which works by down-regulating the estrogen receptor.[1] It is administered as a once-monthly injection.

Image result for fulvestrant

 

Clinical uses

Fulvestrant is a selective estrogen receptor down-regulator (SERD). Fulvestrant is indicated for the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy. The dosing schedule for fulvestrant remains under investigation in an attempt to optimize its effectiveness.[2]

Clinical trials

Metastatic or locally advanced breast cancer

Fulvestrant provided effective second-line therapy in this setting for postmenopausal women who had relapsed or progressed after previous endocrine therapy.[3]

In particular 4 clinical trials in this setting did show similar efficacy to the other hormonal agents (aromatase inhibitors and tamoxifen) with good tolerability profile. Fulvestrant had a lower incidence of joint disorders.[4][5]

NICE evaluation

The U.K. National Institute for Health and Clinical Excellence (NICE) said in 2011 that it found no evidence Faslodex was significantly better than existing treatments, so its widespread use would not be a good use of resources for the country’s National Health Service

The first month’s treatment of Faslodex, which starts with a loading dose, costs £1,044.82 ($1,666), and subsequent treatments cost £522.41 a month.

A month’s supply of anastrozole (Arimidex), which is off patent, costs £5.99, and letrozole (Femara) costs £84.86.[6][7][8]

Patent extension

The original patent for Faslodex expired in October 2004. Drugs subject to pre-marketing regulatory review are eligible for patent extension, and for this reason AstraZeneca got an extension of the patent to December 2011.[9][10]

AstraZeneca has filed later patents. There is no generic Faslodex available.[11] A later patent for Faslodex expires in January 2021.[12]

FASLODEX® (fulvestrant) injection for intramuscular administration is an estrogen receptor antagonist. The chemical name is 7-alpha-[9-(4,4,5,5,5-penta fluoropentylsulphinyl) nonyl]estra-1,3,5-(10)- triene-3,17beta-diol. The molecular formula is C32H47F5O3S and its structural formula is:

FASLODEX® (fulvestrant) Structural Formula Illustration

 

Fulvestrant is a white powder with a molecular weight of 606.77. The solution for injection is a clear, colorless to yellow, viscous liquid.

Each injection contains as inactive ingredients: 10% w/v Alcohol, USP, 10% w/v Benzyl Alcohol, NF, and 15% w/v Benzyl Benzoate, USP, as co-solvents, and made up to 100% w/v with Castor Oil, USP as a co-solvent and release rate modifier.

 

  • Fulvestrant is a pure antiestrogen that represent a significant breakthrough in the treatment of breast cancer. Despite its pure antagonist activity, studies on ovariectomized rats have confirmed that fulvestrant, in contrast to Tamoxifen which acts like estrogen to reduce periosteal bone formation, does not alter estrogen-like or antiestrogenic effects. Fulvestrant also has some distinct advantages on target organs other than breast tissue.
  • Fulvestrant is a steroidal pure antiestrogen with a chemical structure similar to estradiol. Studies of etrogen receptor (ER) function have demonstrated that estradiol binding to the ER initiate a sequence of events. Fulvestrant antagonizes estrogen action by occupying the ER and preventing estrogen-stimulated gene activation, thus interfering with the estrogen related processes essential for cell-cycle competion.

  • Fulvestrant, 7-alpha- [9-(4,4,5,5,5pentafluoropentylsulphinyl) nonyl]-estra-1,3,5 (10)-triene-3,17β-diol, has the following formula:

    Figure imgb0001
  • WO Patent application No. 02/32922 describes a process for preparing an intermediate compound useful for preparing, e.g. fulvestrant, which process comprises aromatization of a compoud, and thereafter if necessary or desired, carrying out one or more of the following steps: (i) removing any hydroxy protecting group; (ii) converting a precursor group to a different such group.
  • EP Patent No. 0138504 relates to certain 7α-substituted derivatives of oestradiol and related steroids which possess antioestrogenic activity. US Patent No. 4659516 , EP Patent No. 0138504 and Bowler, Steroids 1989, 54, 71 describe a process for making steroids such as fulvestrant, by which 1,6-conjugate addition of an alkyl group to an estra-4,6-diene-3-one gave a ratio of 7α- to 7β-epimer of 1.2 : 1 (isolated). In WO 02/32922 it is stated that the ratio of epimers obtained using this process on an industrial scale is 1.9: 1.
  • US patent No 6288051 describes 7α-(5 -methylaminopentyl)-estratrienes.
  • There remains a need in the art for improved methods of preparing fluvestrant and other 7α-alkylated 19-norsteroids.

PATENT

http://www.google.com/patents/EP1771462B1?cl=en

 

 

 

 

Preparative Example 16: Preparation of fulvestrant (Cp 9305) from Cp 9363 – indirect process (depicted in Figure 12)

  • A solution of 40.5 grams of Cp 9363 in 320 grams tetrahydrofuran and 81 grams methanol was cooled to 5°C and treated with a warm solution of 27 grams sodium (meta) periodate in 183 grams water. The mixture was allowed to stand at room temperature overnight, concentrated under vacuum and then dissolved in dichloromethane, extracted with water and evaporated to give 40 grams of Cp 9368 (fulvestrant 17-acetate).
  • The oily residue of Cp 9368 (40 grams) was dissolved in 320 grams of methanol under nitrogen and treated for 3 hours at room temperature with a solution of 20 grams of potassium hydroxide in 128 grams methanol. After neutralisation with 30 grams of acetic acid, the reaction mixture was concentrated under vacuum and then dissolved in dichloromethane, extracted with water and evaporated. The oily residue was crystallised from 400 grams of toluene, then dried under vacuum to constant weight. 26.6 grams of fulvestrant were obtained.

Example 17: Preparation of fulvestrant (Cp 9305) from Cp 9304 – direct process (depicted in Figure 9)

  • A solution of 41 grams of Cp 9304 in 328 grams tetrahydrofuran and 82 grams methanol was cooled to 5°C and treated with a warm solution of 27 grams sodium (meta)periodate in 185 grams water. The mixture was allowed to stand at room temperature overnight, concentrated under vacuum and then dissolved in dichloromethane, extracted with water, evaporated, and crystallised from toluene to give 28 grams of Cp 9305 (fulvestrant). Further purification can be effected by recrystallisation from ethyl acetate.

PAPER

Org. Process Res. Dev., 2010, 14 (3), pp 544–552

DOI: 10.1021/op900315j

http://pubs.acs.org/doi/abs/10.1021/op900315j

Org. Process Res. Dev., 2010, 14 (3), pp 544–552
DOI: 10.1021/op900315j
Abstract Image
The development of a commercial manufacturing process for fulvestrant (the active ingredient in ‘Faslodex’) is described. Key steps in the synthesis are stereoselective 1,6-addition of an organocuprate to a steroidal dienone followed by copper-mediated aromatisation of the A-ring. The strategy for dealing with noncrystalline intermediates is outlined. The production of drug substance of acceptable quality is critically dependent on limiting the formation of key impurities. The origin of these impurities is discussed, and measures to prevent or control their formation are described.

7α-[9-(4,4,5,5,5-Pentafluoropentylsulfinyl)nonyl]estra-1,3,5-(10)-triene-3,17β-diol (Fulvestrant) (6)

An approximately 50% w/w solution of 26 (assumed content 308 kg, 521 mol as a mixture of 7α- and 7β-isomers) in EtOAc was diluted with more EtOAc (695 kg) and glacial acetic acid (188 kg, 3131 mol). Aqueous hydrogen peroxide (17.5% w/v, 203 kg, 1045 mol) was added, ………………….DELETED………….. to another crystallisation cycle. In total, four crystallisations were carried out to achieve the required purity (<0.1% 7β-isomer). With each successive crystallisation, the EtOAc solution was concentrated to a predetermined volume that decreased in proportion to the estimated weight of product present (based on laboratory experiments and HPLC analysis). After the final crystallisation the product was dried in a stream of nitrogen at 60 °C. The yield of pure fulvestrant at 100% w/w strength was 88.4 kg (mean of five batches) which represents 28% overall yield from dienone 2. Ratio of sulfoxide A to sulfoxide B = 46:54 by HPLC analysis (the retention times of sulfoxide A and sulfoxide B are approximately 20.0 and 23.5 min); mp 104−112 °C by DSC analysis (sulfoxide A and sulfoxide B have mp 102 and 117 °C).
1H NMR (400 MHz, 300 K, CDCl3) δ 0.78 (3H, s), 0.95−1.82 (23H, m), 1.91 (1H, ddd, J = 12.2, 2.9, 2.7 Hz), 2.03−2.40 (8H, m), 2.56−2.90 (6H, m), 3.75 (1H, m), 6.56 (1H, d, J = 2.37 Hz), 6.60−6.66 (1H, m), 6.61 (1H, s), 6.76 (1H, s), 7.12 (1H, d, J = 8.62 Hz); 13C NMR (100 MHz, CDCl3) δ 11.1, 14.7, 22.6, 22.7, 25.1, 27.3, 27.4, 28.6, 28.8, 29.0, 29.3, 29.4, 29.6 (t, JCF = 21.9 Hz), 30.6, 33.3, 34.7, 37.0, 38.3, 42.1, 43.4, 46.5, 50.9, 52.5, 82.0, 113.1, 115.4 (tq, JCF = 253 Hz, 38 Hz), 116.2, 118.9 (qt, JCF = 285 Hz, 36 Hz), 127.0, 131.2, 136.9, 154.1.

str2 str1

Image result for Fulvestrant

7α-[9-(4,4,5,5,5-Pentafluoropentylsulfinyl)nonyl]estra-1,3,5-(10)-triene-3,17β-diol (Fulvestrant)

References

  1. S. Kansra, S. Yamagata, L. Sneade, L. Foster & N. Ben-Jonathan (2005). “Differential effects of estrogen receptor antagonists on pituitary lactotroph proliferation and prolactin release”. Mol Cell Endocrinol 239 (1-2): 27–36. doi:10.1016/j.mce.2005.04.008. PMID 15950373.
  2. Angela Mae Obermiller, PharmD; and Mehmet Sitki Copur, MD (2011). “The Longstanding Quest for a Better Endocrine Therapy Continues High-Dose Fulvestrant: Have We Found Its Effective Dose, Combination, Setting, or Sequence?”. Contemporary Oncology 3 (1).
  3. Croxtall, J. D.; McKeage, K. (2011). “Fulvestrant”. Drugs 71 (3): 363–380. doi:10.2165/11204810-000000000-00000. PMID 21319872. edit
  4. Fulvestrant in the treatment of advanced breast cancer: a systematic review and meta-analysis of randomized controlled trials. Valachis A, Mauri D, Polyzos NP, Mavroudis D, Georgoulias V, Casazza G. Crit Rev Oncol Hematol. 2010 Mar;73(3):220-7. Epub 2009 Apr 14. Review. PMID:19369092
  5. Fulvestrant for systemic therapy of locally advanced or metastatic breast cancer in postmenopausal women: a systematic review. Flemming J, Madarnas Y, Franek JA. Breast Cancer Res Treat. 2009 May;115(2):255-68. Epub 2008 Aug 6. Review. PMID:18683044
  6. UK cost body rules against AstraZeneca cancer drug, Reuters, Nov 9, 2011
  7. UK’s NICE says no to AstraZeneca breast cancer drug Faslodex, The Pharma Letter, 10 November 2011
  8. National Institute for Health and Clinical Excellence Guidance Breast cancer (metastatic) – fulvestrant
  9. Patent Term Extensions The United States Patent and Trademark Office.
  10. Determination of Regulatory Review Period for Purposes of Patent Extension; FASLODEX A Notice by the Food and Drug Administration on 04/17/2003
  11. Generic Faslodex Availability, Drugs.COM
  12. Pink Ribbon Blues: How Breast Cancer Culture Undermines Women’s Health By Gayle A. Sulik, Oxford University Press (Oct. 2010)

 

VERY New patent

WO-2014064712

Process for the preparation of fulvestrant and its intermediates. Appears to be the first filing from Intas Pharmaceuticals on this API. Family members of the product patent, WO0151056 (assigned to AstraZeneca), expire in the EU states and in the US in 2021

Fulvestrant
Fulvestrant.svg
Clinical data
Trade names Faslodex
AHFS/Drugs.com Monograph
Pregnancy
category
  • D
Routes of
administration		 Intramuscular injection
ATC code L02BA03 (WHO)
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Protein binding 99%
Biological half-life 40 days
Identifiers
Synonyms ICI-182,780
CAS Number 129453-61-8 Yes
PubChem (CID) 104741
IUPHAR/BPS 1015
DrugBank DB00947 
ChemSpider 94553 
UNII 22X328QOC4 Yes
KEGG D01161 
ChEBI CHEBI:31638 
ChEMBL CHEMBL1358 
ECHA InfoCard 100.170.955
Chemical and physical data
Formula C32H47F5O3S
Molar mass 606.772 g/mol
3D model (Jmol) Interactive image

//////////

 

Researchers create protein with potential for weight loss, diabetes treatment

May 3, 2014 1:15 am / Leave a comment


Lyranara.me's avatarLyra Nara Blog

It sounds like a magic bullet: Administer a protein, watch the subject lose weight. But that’s exactly what University of Florida scientists found when they discovered a new way to deliver a protein that helps develop cells that convert fat into energy.

The study builds upon on a discovery by Bruce Spiegelman, a cell biologist at the Boston-based Dana-Farber Cancer Institute, who found that human muscles release a hormone he called irisin during exercise. Spiegelman also found that mice lost a small amount of weight when given the irisin gene using a virus to ferry it into cells.

Now the UF team—including researcher Dr. Li-Jun Yang, Shi-Wu Li, and postdoctoral researcher William Donelan—has for the first time created a stable protein form of irisin, opening the door to human studies that weren’t previously possible because the virus has not been approved for use in people.

“We found that if you…

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Cancer: Health Care In India In A Nutshell

May 2, 2014 10:38 am / Leave a comment


DR. Karra's avatarTGI: Thrive Health

Cancerimages

Since independence several measures have been undertaken by the National Government to improve the health of the people. Several National Health Programs have been launched by the Government including programs on Non-communicable diseases (NCD) along with the communicable diseases which are prevalent in India. Now India is experiencing a rapid health transition with rising burden of chronic NCDs especially CVD, Diabetes, Cancer, Stroke and lung diseases. In 2005 NCDs accounted for 53 % of deaths and NCDs are surpassing the burden of communicable diseases in India.

In 2010 the Cancer program was integrated with the then existing program and the new program is NPCDCS (National Program for Prevention and Control of Cancer, Diabetes, Cardiovascular Diseases and Stroke). There are two programs under NPCDCS:

  1. DCS – Diabetes, Cardiovascular Disease and Stroke – under NPCDCS
  2. Cancer component under NPCDCS

The objectives of the new cancer program under NPCDCS are:

  1. Primary prevention: Health education
  2. Secondary…

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Pharmaceutical Packaging – New USP Proposal for Optimised Method of Measuring Moisture Vapour Permeation

May 2, 2014 3:38 am / Leave a comment


DR ANTHONY MELVIN CRASTO Ph.D's avatarDRUG REGULATORY AFFAIRS INTERNATIONAL

Pharmaceutical Packaging – New USP Proposal for Optimised Method of Measuring Moisture Vapour Permeation
An improved method of measuring water vapour permeation for solid oral dosage forms like tablets or capsules has been discussed during a USP – PQRI Workshop and presented in the Pharmacopeial Forum. See the detailed information.

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Revision of the USP Chapter on Spectroscopic Methods

May 2, 2014 3:38 am / Leave a comment


DR ANTHONY MELVIN CRASTO Ph.D's avatarDRUG REGULATORY AFFAIRS INTERNATIONAL

Revision of the USP Chapter on Spectroscopic Methods
A new concept for the representation of different analytical and spectroscopic methods (AAS, IR, UV, etc.) has been presented as general chapter in the USP. In the future, there should be two general chapters for each method. The concrete implementation is planned in the USP38/NF33. Read more here in the News.

GMP News: Revision of the USP Chapter on Spectroscopic Methods

In the USP Pharmacopeial Forum 40(1), a “Stimuli to the Revision Process” article states that the responsible working group of the USP has conducted a review of the existing general chapters on spectroscopic methods.

The goal of this review was to establish a uniform concept for all the spectroscopic methods and generate a common format. As a result, consistency in the overall approach and ease of use in the future should also be enabled for the user. The general chapters smaller…

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Resveratrol remains effective against cancer after the body converts it

May 2, 2014 1:12 am / Leave a comment


Lyranara.me's avatarLyra Nara Blog

A chemical found in red wine remains effective at fighting cancer even after the body’s metabolism has converted it into other compounds. This is an important finding in a new paper published in the journal Science Translational Medicine by Cancer Research UK-funded researchers at the University of Leicester’s Department of Cancer Studies and Molecular Medicine.

The paper reveals that resveratrol – a compound extracted from the skins of red grapes – is not rendered ineffective once it is metabolised by the body.

This is an important development, as resveratrol is metabolised very quickly – and it had previously been thought that levels of the extracted chemical drop too quickly to make it usable in clinical trials.

The new research shows that the chemical can still be taken into cells after it has been metabolised into resveratrol sulfates.

Enzymes within cells are then able to break it down into resveratrol…

View original post 504 more words

Stem cell therapy regenerates heart muscle damaged from heart attacks in primates

May 2, 2014 1:11 am / Leave a comment


Lyranara.me's avatarLyra Nara Blog

Heart cells created from human embryonic stem cells successfully restored damaged heart muscles in monkeys. The results of the experiment appear in the April 30 advanced online edition of the journal Nature in a paper titled, “Human embryonic-stem cell derived cardiomyocytes regenerate non-human primate hearts.”

The findings suggest that the approach should be feasible in humans, the researchers said.

“Before this study, it was not known if it is possible to produce sufficient numbers of these cells and successfully use them to remuscularize damaged hearts in a large animal whose heart size and physiology is similar to that of the human heart,” said Dr. Charles Murry, UW professor of pathology and bioengineering, who led the research team that conducted the experiment.

A physician/scientist, Murry directs the UW Center for Cardiovascular Biology and is a UW Medicine pathologist.

Murry said he expected the approach could be ready for clinical trials in…

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Sanfilippo Syndrome: FDA Orphan Designations For Gene Therapy

May 1, 2014 6:57 am / Leave a comment


Orphan Druganaut Blog's avatarOrphan Druganaut Blog

Abeona Therapeutics , a Cleveland-based biotechnology start-up, is created in March 2013 as a spinoff of Nationwide Children’s Hospital , with the goal of developing therapies for patients with the rare Lysosomal Storage Disorder (LSD), Sanfilippo (SF) Syndrome or Mucopolysaccharidosis III (MPS III). Abeona in Roman Mythology is the Goddess of Departures. She protects children as they step away from home for the first time, keeping them safe as they venture into the world. Her name comes from the Latin verb abeo, “to depart, go away, or go forth”.

SF is a genetic metabolism disorder that prohibits the proper breakdown of the body’s sugar molecules. There are 4 types of MPS III (MPS III A, MPS III B, MPS III C, and MPS III D), each with a deficiency in one of four lysosomal enzymes. The disease first affects the central nervous system, causing severe brain damage, and typically results in hearing loss, vision loss…

View original post 226 more words

Bulaquine a CDRI India Antimalarial

May 1, 2014 6:50 am / 1 Comment on Bulaquine a CDRI India Antimalarial


Figure imgf000005_0001

 

Bulaquine

CAS NO.: 79781-00-3

2(3H)-Furanone, dihydro-3-(1-((4-((6-methoxy-8-quinolinyl)amino)pentyl)amino)ethylidene)-,

 3-[l-[[4-[(6-methoxy-8-quinolinyl)amino]pentyl]amino]- ethyMene]-dihydro-2(3H)furanone

N1– (3-ethylidinotetrahydrofuran-2-one)-N4– (6-methoxy-8-quinolinyl)-1,4-pentanediamine

Aablaquine, Elubaquine, Bulaquine [INN], Compound 80/53, UNII-TSQ6U39Q3G, AC1MI1V2, CHEMBL2106578, CDRI 80/53
Molecular Formula: C21H27N3O3   Molecular Weight: 369.45738

 

BULAQUINE

https://www.ncbi.nlm.nih.gov/pubmed?cmd=search&term=%22bulaquine%22%5BNM%5D

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http://www.cdriindia.org/Bulaquin.htm

The Central Drug Research Institute has developed an antimalarial Drug – given in house number “Compound 80/53” and allotted International Nonproprietary Name (INN) as Bulaquin – which is a primaquine derivative.

Primaquine is the only drug available for use as anti-relapse, antimalarial for prophylactic in P.vivax malaria. However, this drug causes many side effects and the most commonly cited effect is methaemoglobinaemia in patients with G6PD deficiency. Higher doses of primaquine cause methaemoglobinaemia in most subjects and leukopenia in some. However, there is a small fraction of black population with G6PD deficiency who develop anaemia due to intravascular haemolysis at daily dose levels of 15 mg (base) and above.

It is being increasingly felt that the eroding efficacy of commonly used antimalarials has contributed substantially to the resurgence of malaria during last three decades. Although new antimalarials have appeared in the market during this time, none has yet supplemented chloroquine. There are no drugs in the market or in advanced stages of development that appear to be as well tolerated as chloroquine.

Combinations of existing antimalarials especially those now available in rural clinics and market hold great potential for effective, self-administered therapies for uncomplicated malaria, particularly where relapses are frequently encountered. Applying combined therapies to the problem should demand a high standard of proof of safety and efficacy in randomised double blind, placebo controlled trials.

Bulaquin is without any side effects that have been observed with primaquine. A comparative data analysis on initial (0 day pre-drug) and final (+7 day post-drug) values of haemoglobin, methaemoglobin, prothrombin time, partial thromboplastin time and fibrinogen in healthy human subjects treated with primaquine (15 mg OD x7 days) and Bulaquin (25 mg OD x7 days) have been carried out. The study has shown that one week primaquine treatment leads to rise in methaemoglobin levels from 3.97% to 16.32%, which is highly significant in comparison to the 2.29% and 3.02% levels of methaemoglobin before and after 7 days treatment with Bulaquin respectively. Thus, it is evident that primaquine treatment produces rise in methaemoglobin contrary to Bulaquine does not produce rise in methaemoglobin levels. This result manifests a clear superiority of Bulaquin over Primaquine.

Bulaquin has been licenced to Nicholas Piramal India Ltd., Mumbai for marketing. Nicholas Piramal has introduced Bulaquin alongwith chloroquine into the market as a combination pack under the trade name Aablaquine. The objective of the combined therapy is to control P.vivax malaria more effectively by providing initial cure and thereafter preventing relapses by use of this combination pack. It is hoped that the introduction of this combination pack of Bulaquin should contribute substantially to the ongoing National Malaria action programme advocated by Government of India.

http://www.google.com/patents/EP1292306A2?cl=en

Malaria, caused by a parasitic protozoan called Plasmodium, is one of the most serious and complex tropical parasitic diseases. Generally human malaria is caused by four species of malarial parasites which are Plasmodium falciparwn, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae. Of these P. falciparum and P. vivαx are most widespread and cause most of the mortality and morbidity associated with these types of infections.

It is known that the malarial parasites undergo complex life cycle in humans, which is initiated through the bite of an infected female Anopheles mosquito. When the mosquito bites a host, some of the sporozoites are injected into the bloodstream of the host and through the circulation they reach the liver where they multiply and liberate merozoites into the bloodstream which then invade the erythrocytes. In case of infections caused by P. vivαx, most of the time the parasites remain dormant in the liver which stage is termed hypnozoites. Hypnozoites are reactivated and reinitiate blood stage parasitemias causing relapse. It has often been observed that people infected with P. vivax do not experience any symptoms for a very long period after their initial illness but become symptomatic after certain period (Korean J. Intern Med, 1999 Juk 14(2): 86-9).

A number of drugs ranging from those of natural origin to synthetic ones have been developed for the treatment of malaria. Quinine and artemisinin are the commonly known drugs of natural origin, which are mostly used for the treatment of malaria. A number of synthetic anti- malarial drugs such as chloroquine, mefloquine, primaquine, halofantrine, ainodiaquine, proguanil, maloprim are known in the literature. Of all the synthetic anti-malarial agents chloroquine has been the most widely prescribed drug for the treatment of malaria of all the types, for more than last 60 years.

Chloroquine has been the effective treatment so far for the P. vivax malarial infections, however, some strains of P. vivax have shown resistance to this well known drug {Ann. Trop. Med. ParasitoL, 1999 Apr; 93(3): 225-230). In recent years drug resistant malaria has become one of the most serious problems in malaria control. Drug resistance necessitates the use of drugs which are more expensive and may have dangerous side effects. To overcome the problems associated with drug resistance, treatments comprising combinations of anti-malarial agents are on the rise. A number of anti-malarial combinations are already known in the malarial chemotherapy. For example, a combination of amodiaquine and tetracycline, a combination of sulfadoxine and pyrimethamine known as fansidar, are known therapies for the treatment of P. falάparum. Also fansimef, a combination of mefloquine with sulfadoxine and pyrimetha min e is used against multidrug resistant strains of P. faldparum.

United States Patent No. 5 998 449 describes a method for the treatment of malaria wherein combination of atovaquone and proguanil is used for the treatment of malaria. In US Patent No. 5 834 505, combination of fenozan with another anti-malarial agent selected from artemisinin, sodium artesunate, chloroquine, mefloquine is described for the prophylactic and curative treatment of malaria.

All the aforementioned anti-malarial combinations reported heretofore are generally used for the treatment of P. faldparum. None of the standard anti-malarial combination treatment regimens have been found to be favourable for the treatment of P. vivax malaria which is the most relapsing type of malaria. For a very long time chloroquine was used for the treatment of infections caused by P. vivax, however, chloroquine eradicates only the asexual erythrocytic stages of P. vivax and does not eliminate the hypnozoites. Until recently primaquine has been the drug of choice for the treatment of malarial relapse. Generally the standard therapy for the P. vivax malarial infection comprises of a sequential chloroquine-primaquine combination treatment regimen wherein primaquine is administered for 14 days following the 3 days course of chloroquine. WHO (World Health Organisation) also recommends a 14 days primaquine treatment for P. vivax malarial infection. A shorter duration of cMoroquine-primaquine treatment regimen was also tried out wherein primaquine was administered only for 5 days following the chloroquine course. However, the outcome of the treatment was not encouraging, since the percentage relapse was more than the standard 14 days primaquine treatment regimen (Trans. R. Soc. Trop. Med. Hyg., 93(6), 641-643). Also primaquine is known to cause hemolytic anemia in persons deficient in the enzyme glucose-6-phosphate dehydrogenase (G6PD) (Pharmacol Rev. 21: 73-103 (1969); Rev. Cubana Med trop, 1997; 49 (2): 136-8 ). Moreover, methemoglobin toxicity is another predictable dose-related adverse effect associated with primaquine. Needless to say that in the case of sequential combination therapy the patient may not complete the course once the symptoms of malaria are diminished, hence this may increase the chances of relapse. Thus, the chloroquine- primaquine treatment regimen is not safe with respect to toxicity of primaquine and has a further limitation from the standpoint of patient compliance due to longer duration of treatment.

Another anti-relapse agent namely tafenoquine is disclosed in United States Patent 4 617 394. Though more effective than primaquine, the drug was found to cause methemoglobin toxicity almost three times more than that of primaqu ie (Fundam. Appl. Toxicol. 1988, 10(2), 270-275), hence has drawbacks in terms of safety.

The compound, 3-[l-[[4-[(6-nιethoxy-8-quinolinyl)aιnino]pentyl)am.ino]- ethylidene]-dihydro-2(3H)furanone is a derivative of primaquine. It was described in Indian Patent Specification No. 158111 as 6-methoxy-8-(4-

N-(3′-aceto-4^5′-dihydro-2-furanylamino)- l-methylbutylamino)quinoline , the structure of which was revised to that represented by the following formula I. As per the revised structure, the compound is named 3-[l-[[4-

[(6-metJhoxy-8-quinolmyl)amino]pentyl]amino]ethylidene]-dihydro-2(3H)- furanone (hereinafter referred to as compound I). The revised structure is described in WHO Drug Information Vol. 13, No. 4, pg. 268 (1999).

Figure imgf000005_0001

The compound of formula (I) has been found to be safer and less toxic than the parent compound primaquine (Am. J. Trop. Med. Hyg, 1989 Dec; 41(6): 635-637). Its anti-relapse activity has been found to be comparable to primaquine.

Over the years primaquine was the only drug used for the radical cure of malaria caused by P. vivax. Primaquine is associated with a number of severe adverse effects, therefore there is a need to develop agents which are more effective and/ or less toxic than primaquine. The compound I has been found to exhibit anti-relapse activity comparable to Primaquine (Am. J. Trop. Med. Hyg., 41(6): 633-637 (1989)). However, this compound has been shown to cause less methemoglobin formation (Am. J. Trop Hyg., 41(6): 638-642 (1989) ) and also has less effect on anti-oxidant defence enzymes than primaquine (Biochem Pharmacol. 46(10): 1859- 1860 (1993) ). Thus, this primaquine derivative (I) is found to be less toxic as compared to the parent drug, primaquine.

Therefore, there is a longfelt need for a more practical, effective, patient compliant and safe remedy for the radical cure of P. vivax malarial infection.

The inventors have found that the longfelt need may be fulfilled by providing a treatment regimen consisting of regulated use of chloroquine and 3-[l-[[4-[(6-methoxy-8-quinolinyl)aιnino]pentyl]amino]ethylidene]- dihydro-2(3H)furanone of formula I over a period of between 5 to 8 days.

It has also been found that the treatment regimen may be executed most effectively and in a user friendly manner by providing a combination kit which comprises two anti-malarial agents, namely chloroquine and 3-[l- [[4-[(6-meth.oxy-8-qumolmyl)am^

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The title enamine derivative is prepared by condensation of primaquine (I) with acetyl butyrolactone (II) by means of piperidine.

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http://www.google.com/patents/EP1055427B1?cl=en

  • manufacture fo a medicament for the treatment of malaria of primaquine derivative N1-(3-ethylidinotetrahydrofuran-2-one)-N4-(6-methoxy-8-quinolinyl)-1,4-pentanediamine as a gametocytocidal agent. More particularly, this invention relates to the use of primaquine derivative N1– (3-ethylidinotetrahydrofuran-2-one)-N4– (6-methoxy-8-quinolinyl)-1,4-pentanediamine of formula 1 shown below useful for controlling the spread of malaria by virtue of its high therapeutic value as a gametocytocidal agent.
Figure 00010001
    • The primaquine derivative of the present invention does not damage either normal or G-6PD deficient erythrocytes to the extent it is observed with the use of primaquine.
      • scheme:

        Figure 00150001

The following example illustrates the details of the process of this invention:

N1– (3-ethylidinotetrahydrofuran-2-one)-N4– (6-methoxy-8-quinolinyl)-1,4-pentanediamine

  • A mixture of primaquine base (0.97g, 3.7 mmole) freshly distilled 3-acetyl-r-butyrolactone (1.0g, 7.8 mmole) and a base like piperidine (2-3 drops) were stirred under magnetic stirrer at room temperature. In an hour or so the reaction mixture solidified. The product was titrated in ether and filtered to get the product. It was crystallised from alcoholic solvent like propanol. Yield 0.89g, m.p. 118-120°C.

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BELL A.: “Recent developments in the chemotherapy of malaria.” CURRENT OPINION IN ANTI-INFECTIVE INVESTIGATIONAL DRUGS, (2000) 2/1 (63-70). , XP001038054
2 * DUTTA, G. P. ET AL: “Radical curative activity of a new 8-aminoquinoline derivative ( CDRI 80/53) against Plasmodium cynomolgi B in monkeys” AM. J. TROP. MED. HYG. (1989), 41(6), 635-7 , 1989, XP001037488 cited in the application
3 * KAR, K. ET AL: “Pharmacology of compound CDRI 80/53;a potential new antirelapse antimalarial agent” INDIAN J. PARASITOL. (1988), 12, 259-62 , 1988, XP001034143
4 * NEWTON P. ET AL: “Malaria: New developments in treatment and prevention.” ANNUAL REVIEW OF MEDICINE, (1999) 50/- (179-192). , XP001036946
5 * PALIWAL, JYOTI KUMAR ET AL: “Simultaneous determination of a new antimalarial agent, CDRI compound 80/53, and its metabolite primaquine in serum by high-performance liquid chromatography” J. CHROMATOGR., BIOMED. APPL. (1993), 616(1), 155-60 , 1993, XP000955186
6 * PURI, S. K. ET AL: “Methemoglobin toxicity and hematological studies on malaria anti-relapse compound CDRI 80/53 in dogs” AM. J. TROP. MED. HYG. (1989), 41(6), 638-42 , 1989, XP001037486 cited in the application
7 * SETHI, N. ET AL: “Long term toxicity studies with a synthetic anti-relapse antimalarial compound 80/53 in rats and monkeys” INDIAN J. PARASITOL. (1993), 17(1), 15-26 , 1993, XP001034142
8 * VALECHA, NEENA ET AL: “Comparative antirelapse efficacy of CDRI compound 80/53 (Bulaquine) vs. primaquine in double blind clinical trial” CURR. SCI. (2001), 80(4), 561-563 , 2001, XP001037095

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