AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Antimicrobial resistance

 Uncategorized  Comments Off on Antimicrobial resistance
Aug 182014
 

 

Antimicrobials are medicines that kill or inactivate microbes, small disease-causing organisms. They include antibiotics, which are used against bacteria. After being exposed to an antimicrobial repeatedly, microbes can undergo changes that stop them being killed or inactivated by the treatments. This is known as antimicrobial resistance.

The European Medicines Agency is concerned about the development of antimicrobial resistance, particularly resistance to antibiotics. A well-known example of a bacterium that is resistant to a number of antibiotics is meticillin-resistant Staphylococcus aureus(MRSA), which has caused infections that are difficult to treat across the European Union (EU).

 

This problem is being made worse by the fact that few new antimicrobials have been authorised over the past few years. This may lead to infections becoming more difficult to treat in the future.

Antimicrobial resistance is a growing problem in humans and in animals. Resistance can also spread from animals to humans through the food chain or direct contact.

The role of the Agency

The Agency works in collaboration with its EU and international partners in a number of initiatives aiming to limit the development of resistance. It is also monitoring and evaluating the risks to human and animal health.

A major such initiative is the Transatlantic Task Force on Antimicrobial ResistanceExternal link icon(TATFAR), which was established following the EU-United States summit in November 2009. The Task Force aims to increase levels of communication, coordination and co-operation between the EU and the United States on human and veterinary antimicrobials.

 

Human health

In human medicine, the availability of medicines to treat infections with resistant organisms has become a major problem in recent years.

In September 2009, the Agency published a joint report together with the European Centre for Disease Prevention and ControlExternal link icon (ECDC) and the international network ReAct – Action on Antibiotic ResistanceExternal link icon. This report highlights the gap between infections due to resistant bacteria and the development of new antibiotics.

The report states that at least 25,000 patients in the EU die each year from infections due to bacteria that are resistant to many medicines, and that infections due to these bacteria in the EU result in extra healthcare costs and productivity losses of at least €1.5 billion each year. Although it identified 15 antibiotics under development, most of these were early in development and were targeted against bacteria for which treatment options were already available.

 

Authorisation of new antibiotics

The Agency plays a key role in the authorisation of new antibiotics, because medicines with a significant therapeutic innovation or that are in the interest of public or animal health are authorised centrally in the EU, on the recommendation of the Agency.

In January 2012, the Agency updated its guidance to companies developing antibiotics, covering how they should carry out studies to test these medicines’ benefits and risks:

This is accompanied by an addendum giving information on how to study medicines for specific indications. The final addendum was published in November 2013 following a public consultation:

 

Animal health

The Agency is focused on promoting the prudent use of antimicrobials in animals, to limit the development of resistance. This goal is addressed in this document:

In line with this strategy, the Agency published a revised version of its guideline onefficacy for public consultation in May 2013. This draft guideline provides detailed recommendations for the design and conduct of pre-clinical and clinical studies to support clinical efficacy for antimicrobial veterinary products:

Since early 2010, the Agency has been leading a project collecting information on the sale of veterinary antimicrobials across the EU:

The CVMP has also published a large number of documents on microbial resistance in animals and its risks for humans.

Reports published by the Agency together with other European bodies, including ECDC, EFSA and the European Commission’s Scientific Committee on Emerging and Newly Identified Health RisksExternal link icon (SCENIHR) have emphasised the need for the prudent use of antibiotics in animals and the role of basic hygiene, and called for strengthened surveillance of resistance, the development of new antimicrobials and new strategies to combat the spread of resistance:

In 2013 and 2014, the Agency carried out a large body of work to provide advice to the European Commission on the use of antibiotics in animals and the impact on public health and animal health.

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Turkish man pleads guilty to importing illegal cancer drugs

 cancer, Uncategorized  Comments Off on Turkish man pleads guilty to importing illegal cancer drugs
Aug 182014
 

 

August 15, 2014

Release

Sabahaddin Akman, owner of the Istanbul, Turkey, firm Ozay Pharmaceuticals, has pleaded guilty to charges of smuggling misbranded and adulterated cancer treatment drugs into the United States.

Akman pleaded guilty in the U.S. District Court for the Eastern District of Missouri, in St. Louis, Missouri, where he initially shipped his illegal drugs. The drugs did not meet the FDA’s standards and had not been approved for distribution in the United States.

The FDA’s Office of Criminal Investigations coordinated a complex, multi-layered international investigation that led to Akman’s arrest in Puerto Rico in January 2014. The investigation identified Akman and his company as a source of Altuzan, the Turkish version of the cancer treatment drug Avastin.

“These criminals exploited our most vulnerable patients when they arranged for their illicit drugs to be brought into the United States and used to treat cancer patients. We will continue to investigate and bring to justice those who prey on our ill, susceptible patients,” said Philip J. Walsky, acting director of the FDA’s Office of Criminal Investigations. “We commend our colleagues – international, national, state, and local – whose contributions helped bring this case to a successful conclusion.”

Akman, along with his employee, Ozkan Semizoglu, obtained the illicit drugs and then used shipping labels to conceal the illegal nature of the shipments, including customs declarations falsely describing the contents as gifts. They also broke large drug shipments into several smaller packages to reduce the likelihood of seizures by U.S. Customs and Border Protection authorities.

Along with the FDA and Europol, the international operation involved several German government offices: the Bonn prosecutor; the Federal Criminal Police, the Dusseldorf police, and the German State Criminal Police.  Special agents of the U.S. Department of State’s Diplomatic Security Service assigned to the U.S. Embassy’s Regional Security Office in Ankara, Turkey, and the U.S. Consulate General’s Overseas Criminal Investigations Branch in Istanbul, Turkey also played key roles in the successful resolution of this case.

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Road map to 2015, The European Medicines Agency’s contribution to science, medicines and health

 EU, regulatory, Uncategorized  Comments Off on Road map to 2015, The European Medicines Agency’s contribution to science, medicines and health
Aug 182014
 

 

One of the European Medicines Agency’s long-term strategic goals is to foster researchand the uptake of innovative methods in the development of medicines.

READ………….Road map to 2015

The European Medicines Agency’s
contribution to science, medicines and health……………..http://www.ema.europa.eu/docs/en_GB/document_library/Report/2011/01/WC500101373.pdf

This helps the Agency to meet its objective of making safe and effective medicines available to patients in a timely manner, following evaluation using state-of-the-art methods.

The Agency also supports the development of new therapies and technologies by working with interested parties in the European Union (EU).

Activities at the Agency

In 2004, the Agency set up the European Medicines Agency/Committee for Medicinal Products for Human Use (CHMP) Think-Tank Group on Innovative Drug Development.

This group included Agency staff and members of the CHMP and its working parties. Its work focused on identifying scientific bottlenecks and emerging science in the development of medicines, both in industry research and development and in academia, and on generating recommendations for future activities at the Agency:

In 2008 the EMA and its Scientific Committees integrated the recommendations made by the Think Tank in its strategy for supporting innovative medicines developments. Key areas of action included the strengthening of the EU scientific network model, emphasis on communication during the lifecycle of medicinal products development and international activities. Overview of measures implemented in the period 2008-2010.

The recently published Road Map to 2015 further expands on the role the Agency plays to promote innovation in pharmaceuticals.

The Agency also contributes to the Innovative Medicines InitiativeExternal link icon (IMI). This is a public-private initiative that aims to speed up the development of better and safer medicines for patients:

Support for business

The Agency provides support for business on issues related to innovative medicines:

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Lupin launches insulin glargine in India

 diabetes, Uncategorized  Comments Off on Lupin launches insulin glargine in India
Aug 182014
 

lupin ltd biosimilarnews Lupin launches insulin glargine in India

Lupin launches insulin glargine in India:

Indian pharma company, Lupin Limited announced a strategic distribution agreement with LG Life Sciences of South Korea to launch Insulin Glargine, a novel insulin analogue under the brand name Basugine™.

According to the agreement, Lupin would be responsible for marketing and sales of Basugine™ in India.

READ MORE

http://www.biosimilarnews.com/lupin-launches-insulin-glargine-in-india?utm_source=Biosimilar%20News%20%7C%20Newsletter&utm_campaign=0b76af10ab-15_08_2014_Biosimilar_News&utm_medium=email&utm_term=0_9887459b7e-0b76af10ab-335885197

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Celltrion files Remsima in the United States

 Uncategorized  Comments Off on Celltrion files Remsima in the United States
Aug 182014
 

 

Celltrion files Remsima in the United States:

Celltrion announced that the company, on August 8, 2014, completed the filing procedure to obtain US FDA approval for its infliximab biosimilar. This marks the first 351(k) biosimilar mAb application to be filed in the U.S.A. and the second application for a biosimilar to be filed through the US BPCIA.

READ MORE

http://www.biosimilarnews.com/celltrion-files-remsima-in-the-us?utm_source=Biosimilar%20News%20%7C%20Newsletter&utm_campaign=0b76af10ab-15_08_2014_Biosimilar_News&utm_medium=email&utm_term=0_9887459b7e-0b76af10ab-335885197

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Zopolrestat

 Uncategorized  Comments Off on Zopolrestat
Aug 182014
 

 

Chemical structure for zopolrestat

 

Zopolrestat

Zopolrestat
CAS : 110703-94-1
110765-49-6 (Na salt)
3,4-Dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-1-phthalazineacetic acid
2- [4-Oxo-3- [5- (trifluoromethyl) benzothiazol-2-ylmethyl] -3,4-dihydrophthalazin-1-yl] acetic acid
3-(5-trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-3H-phthalazin-1-ylacetate
Pfizer Inc. INNOVATOR
2-[4-oxo-3-[5-(trifluoromethyl)benzothiazol-2-ylmethyl]-3,4-dihydrophthalazin-1-yl]acetic acid
Manufacturers’ Codes: CP-73850
MF: C19H12F3N3O3S
MW: 419.38
C 54.41%, H 2.88%, F 13.59%, N 10.02%, O 11.45%, S 7.65%
 Crystals, mp 197-198°. pKa (dioxane/water): 5.46 (1:1); 6.38 (2:1). Log P (n-octanol/water): 3.43.
 mp 197-198°
pKa: pKa (dioxane/water): 5.46 (1:1); 6.38 (2:1)
Log P: Log P (n-octanol/water): 3.43
Therap-Cat: Treatment of diabetic complications.
Keywords: Aldose Reductase Inhibitor.
…………………………..
synthesis
2-(8-oxo-7-((5-trifluromethyl)-1H-benzo[d]imidazol-2-yl)methyl)7,8-dihydropyrazin[2,3-d]pyridazin-5-yl)acetic acid and [4-oxo-(5-trifluoromethyl-benzothaiazol-2-ylmethyl)-3,4-dihydro-phthalazin-1-yl]-acetic acid (also known as zopolrestat), pharmaceutical compositions thereof and methods of treating diabetic complications in mammals comprising administering to mammals these salt and compositions. 2-(8-oxo-7-((5-trifluromethyl)-1H-benzo[d]imidazol-2-yl)methyl)8-dihydropyrazin[2,3-d]pyridazin-5-yl) acetic acid (formula II), is disclosed in WO 2012/009553 A1. Zopolrestat (formula III) is disclosed in U.S. Pat. No. 4,939,140.
Each of the patents, applications, and other references referred to herein are incorporated by reference. The diabetic complications include neuropathy, nephropathy, retinopathy, cataracts and cardiovascular complications, including myocardial infarction and cardiomyopathy. This invention is also directed to combinations of these salts and antihypertensive agents. These combinations are also useful in treating diabetic complications in mammals.
2-(8-oxo-7-((5-trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)8-dihydropyrazin[2,3-d]pyridazin-5-yl)acetic acid is prepared as disclosed in WO 2012/009553 A1, which is incorporated herein by reference. Zopolrestat is prepared as disclosed in U.S. Pat. No. 4,939,140.
…………………………
Zopolrestat can be obtained by several different ways: 1) The reaction of 2- (4-oxo-3,4-dihydrophthalazin-1-yl) acetic acid ethyl ester (I) with 2-chloroacetonitrile by means of potassium tert-butoxide in DMF gives 2- [3- (cyanomethyl) -4-oxo-3,4-dihydrophthalazin-1-yl] acetic acid ethyl ester (II), which is cyclized with 2-amino-4- (trifluoromethyl) thiophenol (III) in refluxing ethanol yielding zopolrestat ethyl ester (IV). Finally, this compound is hydrolyzed with KOH in methanol / water / THF. 2) Compound (IV) can also be obtained by cyclization of (II) with 4-chloro-3-nitrobenzotrifluoride . (V) in hot DMF saturated with H2S 3) Compound (II) can also be obtained as follows: The reaction of phthalazine (I) with aqueous formaldehyde gives 2- [3- (hydroxymethyl) -4-oxo-3,4 -dihydrophthalazin-1-yl] acetic acid ethyl ester (VI), which is treated with PBr3 in ethyl ether yielding the bromomethyl derivative (VII). Finally, this compound is treated with potassium cyanide and KI in acetone / water.
……………………….
5=CF3 IS SUBS
EXAMPLE 7

  • [0051]
    In accordance with Example 6, the following compounds are prepared:

    Figure imgb0011
    Figure imgb0012
    Figure imgb0013
……………………..
EXAMPLE 18 Sodium 3-(5-trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-3H-phthalazin-1-ylacetateSodium methoxide (54 mg) was added to 3-(5-trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-phthalazin-1-ylacetic acid (0.4 g) in methanol 10 ml) at room temperature. After the addition was complete, a clear solution was obtained which was stirred for 15 minutes at room temperature. The excess methanol was evaporated. The residue was triturated with ether (20 ml) and filtered to obtain the product (0.43 g; m.p. 300° C.).EXAMPLE 19 3-(5-Trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-3H-phthalazin-1-ylacetate, dicyclohexylamine saltTo a mixture of 3-(5-trifluromethylbenzothiazol-2ylmethyl)-4-oxo-phthalazin-1-ylacetic acid (0.42 g) in methanol (10 ml) was added dicyclohexylamine (0.2 g) in methanol (5 ml). The resulting clear solution was stirred at room temperature for 15 minutes and then evaporated to dryness. Trituration of the residue with ether (30 ml) gave a white solid (0.38 g; m.p. 207° C.).EXAMPLE 20 3-(5-Trifluoromethylbenzothiazol-2ylmethyl)-4-oxo-3H-phthalazin-1-ylacetic acid, meglumine saltA solution of 3-(5-trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-phthalazin-1-ylacetic acid (419 mg) and meglumine (196 mg) in methanol (50 ml) was stirred at room temperature for an hour and then evaporated to dryness. The residue was triturated with ether (25 ml), filtered and the collected solid was air dried (610 mg; m.p. 157° C.)……………………………

J. Med. Chem., 1991, 34 (1), pp 108–122
DOI: 10.1021/jm00105a018

http://pubs.acs.org/doi/abs/10.1021/jm00105a018

……………………………………

Mylari, Banavara L.; Zembrowski, William J.; Beyer, Thomas A.; Aldinger, Charles E.; Siegel, Todd W.
Journal of Medicinal Chemistry, 1992 ,  vol. 35,   12  p. 2155 – 2162

………………………………..

Mylari; Beyer; Scott; Aldinger; Dee; Siegel; Zembrowski
Journal of Medicinal Chemistry, 1992 ,  vol. 35,   3  p. 457 – 465

…………………………….

Literature References:
Aldose reductase inhibitor. Prepn: B. L. Mylari et al., EP 222576; E. R. Larson, B. L. Mylari, US 4939140(1987, 1990 both to Pfizer);
B. L. Mylari et al. J. Med. Chem. 34, 108 (1991).
Pharmacology: B. Tesfamariam et al., J. Cardiovasc.Pharmacol. 21, 205 (1993); B. Tesfamariam et al., Am. J. Physiol. 265, H1189 (1993).
Clinical pharmacokinetics: P. B. Inskeep et al., J. Clin. Pharmacol. 34, 760 (1994).
Zopolrestat < Rec INN; BAN; USAN >
Drugs Fut 1995, 20(1): 33
Synthesis of aldose reductase inhibitor, 3, 4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2 14C benzothiazolyl]methyl]-1-phthalazineacetic acid
J Label Compd Radiopharm 1991, 29(2): 143
3-19-1992
HETEROCYCLIC OXOPHTHALAZINYL ACETIC ACIDS
3-6-1992
3-(5-TRIFLUOROMETHYLBENZOTHIAZOL-2-YLMETHYL)-4-OXO-3H-PHYTHALAZIN-1-YLACETIC ACID MONOHYDRATE
7-4-1990
Heterocyclic oxophthalazinyl acetic acids
3-24-2006
Medical devices to treat or inhibit restenosis
12-30-2004
N-[(SUBSTITUTED FIVE-MEMBERED DI- OR TRIAZA DIUNSATURATED RING)CARBONYL]GUANIDINE DERIVATIVES FOR THE TREATMENT OF ISCHEMIA
10-7-2004
COMBINATION OF AN ALDOSE REDUCTASE INHIBITOR AND A GLYCOGEN PHOSPHORYLASE INHIBITOR COMBINATION OF AN ALDOSE REDUCTASE INHIBITOR AND A GLYCOGEN PHOSPHORYLASE INHIBITOR
9-30-2004
Aldose reductase inhibition in preventing or reversing diabetic cardiomyopathy
5-27-2004
SUBSTITUTED FUSED HETEROCYCLIC COMPOUNDS
4-15-2004
Compounds for treating and preventing diabetic complications
3-32-2004
IMPROVED MUTANTS OF (2,5-DKG) REDUCTASE A
12-18-2003
Pharmaceutical composition for use in treatment of diabetes
11-14-2003
Salts of zopolrestat
4-18-2002
Use of an aldose reductase inhibitor for reducing non-cardiac tissue damage
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REFLECTION PAPER ON NANOTECHNOLOGY-BASED MEDICINAL PRODUCTS FOR HUMAN USE

 nanotechnology, Uncategorized  Comments Off on REFLECTION PAPER ON NANOTECHNOLOGY-BASED MEDICINAL PRODUCTS FOR HUMAN USE
Aug 182014
 

Nanotechnology

Nanotechnology is the use of tiny structures – less than 1,000 nanometres across – that are designed to have specific properties. Nanotechnology is an emerging field in science that is used in a wide range of applications, from consumer goods to health products.

 

In medicine, nanotechnology has only partially been exploited. It is being investigated as a way to improve the properties of medicines, such as their solubility or stability, and to develop medicines that may provide new ways to:

  • deliver medicines to the body;
  • target medicines in the body more accurately;
  • diagnose and treat diseases;
  • support the regeneration of cells and tissues.

Activities at the European Medicines Agency 

The European Medicines Agency follows the latest developments in nanotechnology that are relevant to the development of medicines. Recommendations from the Agency’sCommittee for Medicinal Products for Human Use (CHMP) have already led to the approval of a number of medicines based on nanotechnology. These include medicines containing:

 

  • liposomes (microscopic fatty structures containing the active substance), such asCaelyx (doxorubicin), Mepact (mifamurtide) and Myocet (doxorubicin);
  • nano-scale particles of the active substance, such as Abraxane (paclitaxel), Emend(aprepitant) and Rapamune (sirolimus).

The development of medicines using newer, innovative nanotechnology techniques may raise new challenges for the Agency in the future. These include discussions on whether the current regulatory framework is appropriate for these medicines and whether existing guidelines and requirements on the way the medicines are assessed and monitored are adequate.

The Agency also needs to consider the acceptability of new testing methods and the availability of experts to guide the Agency’s opinion-making.

 

An overview of the initiatives taken by European Union (EU) regulators in relation to the development and evaluation of nanomedicines and nanosimilars was published in the scientific journal Nanomedicines. The article describes the regulatory challenges and perspectives in this field:

Ad hoc expert group on nanomedicines

In 2009, the CHMP established an ad hoc expert group on nanomedicines.

This group includes selected experts from academia and the European regulatory network, who support the Agency’s activities by providing specialist input on new scientific knowledge and who help with the review of guidelines on nanomedicines. The group also helps the Agency’s discussions with international partners on issues concerning nanomedicines.

The group held the first ad hoc expert group meeting on nanomedicines on 29 April 2009.

 

Reflection papers on nanomedicines

In 2011, the CHMP began to develop in 2011 a series of four reflection papers on nanomedicines to provide guidance to sponsors developing nanomedicines.

These documents cover the development both of new nanomedicines and of nanosimilars (nanomedicines that are claimed to be similar to a reference nanomedicine), since the first generation of nanomedicines, including liposomal formulations, iron-based preparations and nanocrystal-based medicines, have started to come off patent:

The fourth document, a draft reflection paper on the data requirements for intravenous iron-based nanocolloidal products developed with reference to an innovator medicine, will be released for a six-month public consultation in 2013.

International workshops on nanomedicines

The Agency organises workshops on nanomedicines to explore the scientific aspects of nanomedicines and enable the sharing of experience at an international level, in order to assist future developments in the field:

REFLECTION PAPER ON NANOTECHNOLOGY-BASED MEDICINAL PRODUCTS FOR
HUMAN USE

http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2010/01/WC500069728.pdf

Related information

 

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