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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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A new take on efficient delivery in regenerative medicine
http://www.newsfix.ca/2013/11/13/new-take-efficient-delivery-regenerative-medicine/
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MACITENTAN, Actelions, pulmonary arterial hypertension investigational drug
MACITENTAN
N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N’-propylsulfamide,
N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl] -N’-propylsulfamide
CAS NO 441798-33-0
ACT-064992, Opsumit,UNII-Z9K9Y9WMVL
Mechanism of Action: Endothelin receptor antagonist (ERA)
Date of Approval: October 18, 2013(US)
Indication: Pulmonary Hypertension (PAH)
Company: Actelion Pharmaceuticals Ltd
PCT patent application: WO2002053557
FDA N204410, MACITENTANTABLET; ORAL10MG, OPSUMIT, ACTELION PHARMS LTD
Macitentan is achiral
Macitentan is a crystalline powder that is insoluble in water. In the solid state macitentan is very stable, is not hygroscopic, and is not light sensitive.
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Malaria Drug (Furamidine) to Treat Cancer
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Pramlintide
Pramlintide (Symlin), a synthetic version of amylin, is a 37-amino acid peptide that is co-secreted with insulin by pancreatic β-cells. It was developed and approved in 2005 by the FDA for use in US patients with type I and II diabetes in conjunction with the administration of prandial insulin to improve postprandial glycemic control
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Pramlintide (Symlin) is a relatively new adjunct for diabetes (both type 1 and 2), developed by Amylin Pharmaceuticals (now a wholly owned subsidiary of Bristol Myers-Squibb). Pramlintide is delivered as an acetate salt.
Pramlintide is an analogue of amylin, a small peptide hormone that is released into the bloodstream by the β-cells of the pancreas along with insulin, after a meal.[1] Like insulin, amylin is completely absent in individuals with Type I diabetes.[2]
Reduction in glycated hemoglobin and weight loss have been shown in insulin-treated patients with type 2 diabetes taking pramlintide as an adjunctive therapy.[3]
By augmenting endogenous amylin, pramlintide aids in the absorption of glucose by slowing gastric emptying, promoting satiety via hypothalamic receptors (different receptors than for GLP-1), and inhibiting inappropriate secretion of glucagon, a catabolic hormone that opposes the effects of insulin and amylin. Pramlintide also has effects in raising the acute first-phase insulin response threshold following a meal.
Pramlintide has been approved by the FDA, for use by Type 1 and Type 2 Diabetics who use insulin.[4]Pramlintide allows patients to use less insulin, lowers average blood sugar levels, and substantially reduces what otherwise would be a large unhealthy rise in blood sugar that occurs in diabetics right after eating. Apart from insulin analogs, pramlintide is the only drug approved by the FDA to lower blood sugar in type 1 diabetics since insulin in the early 1920s.
Design and structure
Since native human amylin is highly amyloidogenic and potentially toxic, the strategy for designing pramlintide was to substitute residues from rat amylin, which is not amyloidogenic (but would presumably retain clinical activity). Proline residues are known to be structure-breaking residues, so these were directly grafted into the human sequence.
Amino acid sequences:
Pramlintide: KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY-(NH2)
Amylin: KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY-(NH2)
Rat amylin: KCNTATCATQRLANFLVRSSNNLGPVLPPTNVGSNTY-(NH2)
Pramlintide as protein is (positively charged).
- Jones MC (2007). “Therapies for diabetes: pramlintide and exenatide” (pdf). American Family Physician 75 (12): 1831–5. PMID 17619527.
- Edelman, Steve; Maier, Holly; Wilhelm, Ken (2008). “Pramlintide in the Treatment of Diabetes Mellitus”.BioDrugs 22 (6): 375–386. doi:10.2165/0063030-200822060-00004. ISSN 1173-8804.
- Hollander, Priscilla; Maggs, David G.; Ruggles, James A.; Fineman, Mark; Shen, Larry; Kolterman, Orville G.; Weyer, Christian (2004). “Effect of Pramlintide on Weight in Overweight and Obese Insulin-Treated Type 2 Diabetes Patients” (pdf). Obesity 12 (4): 661–668. doi:10.1038/oby.2004.76.ISSN 1930-7381.
- Ryan GJ, Jobe LJ, Martin R (2005). “Pramlintide in the treatment of type 1 and type 2 diabetes mellitus”. Clinical therapeutics 27 (10): 1500–12. doi:10.1016/j.clinthera.2005.10.009. PMID 16330288.
- www.symlin.com – product website
- www.amylin.com – Symlin page on the Amylin Pharmaceuticals website
| Pramlintide Acetate | |
| Pramlintide acetate is a relatively new adjunct treatment for diabetes (both type 1 and 2). |
Pramlintide Acetate, 196078-30-5,
| Synonym | Pramlintide Acetate,Pramlintide acetate hydrate |
| Molecular Formula | C171H267N51O53S2.X(C2H4O2).X(H2O) |
| Molecular Weight | 3949.39 |
FDA Approves Implanted Brain Stimulator for Epilepsy
epilepsy
THURSDAY Nov. 14, 2013 — The U.S. Food and Drug Administration on Thursday gave its approval to a new implanted device that lowers the rate of seizures among people with epilepsy
http://www.drugs.com/news/fda-approves-implanted-brain-stimulator-epilepsy-48978.html
EPROSARTAN MESYLATE
TEVETEN® (eprosartan mesylate) is a non-biphenyl non-tetrazole angiotensin II receptor (AT1) antagonist. A selective non-peptide molecule, TEVETEN® is chemically described as the monomethanesulfonate of (E)-2-butyl-1 -(p-carboxybenzyl)-α-2-thienylmethylimid-azole-5 -acrylic acid.
Its empirical formula is C23H24N2O4S•CH4O3S and molecular weight is 520.625. Its structural formula is:
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EPROSARTAN MESYLATE
tevetenEprosartan mesilate, SK&F-108566-J(?, SK&F-108566, Teveten SB, Navixen, Regulaten, Tevetenz, Teveten
| US 5656650 | exp Aug 12, 2014 |
CAS EPROSARTAN
144143-96-4
133040-01-4
| Chemical Name: | Eprosartan mesylate |
| Synonyms: | EPROSARTAN MESYLATE;Eprosartan Methanesulfonate;4-[[2-butyl-5-(2-carboxy-3-thiophen-2-yl-prop-1-enyl)-imidazol-1-yl]methyl]benzoic acid mesylate;4-({2-butyl-5-[(1E)-2-carboxy-2-(thiophen-2-ylMethyl)eth-1-en-1-yl]-1H-iMidazol-1-yl}Methyl)benzoic acid;(E)-α-[[2-Butyl-1-[(4-carboxyphenyl)Methyl]-1H-iMidazol-5-yl]Methylene]-2-thiophenepropanoic Acid Methanesulfonate;(αE)-α-[[2-Butyl-1-[(4-carboxyphenyl)Methyl]-1H-iMidazol-5-yl]Methylene]-2-thiophenepropanoic Acid MonoMethanesulfonate |
| CBNumber: | CB4842192 |
| Molecular Formula: | C24H28N2O7S2 |
| Formula Weight: | 520.61832 |
Eprosartan is an angiotensin II receptor antagonist used for the treatment of high blood pressure. It is marketed as Teveten byAbbott Laboratories in the United States.It is marketed as Eprozar by INTAS Pharmaceuticals in India and by Abbott Laboratorieselsewhere. It is sometimes paired with hydrochlorothiazide, marketed in the US as Teveten HCT and elsewhere as TevetenPlus.
The drug acts on the renin-angiotensin system in two ways to decrease total peripheral resistance. First, it blocks the binding ofangiotensin II to AT1 receptors in vascular smooth muscle, causing vascular dilatation. Second, it inhibits sympatheticnorepinephrine production, further reducing blood pressure.
As with other angiotensin II receptor antagonists, eprosartan is generally better tolerated than enalapril (an ACE inhibitor), especially among the elderly.[1]
- Ruilope L, Jäger B, Prichard B (2001). “Eprosartan versus enalapril in elderly patients with hypertension: a double-blind, randomized trial”. Blood Press. 10 (4): 223–9. doi:10.1080/08037050152669747. PMID 11800061.
PAT APR EXP
| Canada | 2250395 | 2005-09-06 | 2017-03-26 |
| Canada | 2115170 | 2004-05-25 | 2012-08-12 |
| United States | 5656650 | 1994-08-12 | 2014-08-12 |
| United States | 5185351 | 1993-02-09 | 2010-02-09 |
| Canada | 2115170 | 2004-05-25 | 2012-08-12 |
| United States | 5656650 | 1994-08-12 | 2014-08-12 |
| Canada | 2250395 | 2005-09-06 | 2017-03-26 |
J Med Chem1991,34,(4):1514-7
J Med Chem1993,36,(13):1880-92
Synth Commun1993,23,(22):3231-48
AU 9056901, EP 403159, JP 91115278, US 5185351.
Drugs Fut1997,22,(10):1079
Eprosartan mesylate was developed successfully by SmithKline Beecham Corporation in 1997, and marketed in Germany in 1998 under the trade-name Teveten and in the United States later in 1999. Eprosartan mesylate, as an angiotensin II receptor blocker, is an antihypertensive drug of the latest generation. Eprosartan mesylate is potent to lower systolic and diastolic pressures in mild, moderate and severe hypertensive patients, and is safe and tolerable. Eprosartan mesylate is rapidly absorbed when administrated orally, with a bioavailability of 13% and a protein binding rate of 98%. The blood peak concentration and AUC (Area Under Curve) can be elevated by about 50% in patients with liver and kidney dysfunction, or fullness after administration, and can be elevated by 2 to 3 folds in elderly patients. Eprosartan mesylate has a structure shown as follows:
U.S. Pat. No. 5,185,351 discloses a method for preparing eprosartan mesylate using Eprosartan and methanesulfonic acid in isopropanol (U.S. Pat. No. 5,185,351, Example 41 (ii)). However, it is found when following this method for preparing eprosartan mesylate in industry, an esterification reaction can occur between eprosartan and isopropanol and the following two impurities can be generated:
In addition to the above two esterification impurities, the salifying method provided by the above patent is prone to produce isopropyl mesylate. Considering currently known potential risk of gene toxicity of methylsulfonic acid ester on human as well as the stringent requirements of methylsulfonic acid ester from the Europe and the America authorities, it is important to produce eprosartan mesylate in a non-alcohol solvent during the process of producing eprosartan mesylate, since it avoids the formation of methylsulfonic acid ester and the residue thereof in the final product. Since the dosage of eprosartan mesylate is high, it is particularly important to strictly control methylsulfonic acid ester in eprosartan mesylate.
In addition, for the above salifying method, solid eprosartan is suspended in propanol at a low temperature, then methanesulfonic acid is added, about ten seconds later a great deal of eprosartan mesylate precipitate is obtained. Therefore, solid eprosartan may be embedded by the precipitated eprosartan mesylate. Since isopropyl alcohol has a high viscosity at low temperature, a heavy filtering operation burden is needed to obtain solid from isopropanol, and the obtained solid contains quite an amount of isopropanol.
Eprosartan has been obtained by several different ways: 1) The iodination of 2-butylimidazole (I) with I2 and Na2CO3 in dioxane/water gives 2-butyl-4,5-diiodoimidazole (II), which is treated with benzyl chloromethyl ether (III) and K2CO3 in DMF yielding the imidazole derivative (IV). The condensation of (IV) with N-methyl-N-(2-pyridyl)formamide (V) by means of butyllithium in THF affords 1-(benzyloxymethyl)-2-butyl-4-iodoimidazole-5-carbaldehyde (VI), which is deprotected with concentrated HCl ethanol to give 2-butyl-4-iodoimidazole-5-carbaldehyde (VII). The acylation of (VII) with methyl 4-(bromomethyl)benzoate (VIII) by means of K2CO3 in hot DMF yields 4-(2-butyl-5-formyl-4-iodoimidazol-1 ylmethyl)benzoic acid methyl ester (IX), which is deiodinated by hydrogenation with H2 over Pd/C in methanol affording compound (X). The condensation of (X) with methyl 3-(2-thienyl)propionate (XI) by means of lithium diisopropylamide (LDA) in THF gives (XII), which is acylated with acetic anhydride and dimethylaminopyridine (DMAP) in dichloromethane yielding the corresponding acetate (XIII). Elimination of acetic acid from (XIII) with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in hot toluene affords the expected propenoic ester (XIV), which is finally saponified with NaOH or KOH in ethanol/water.
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WO 1998035962 A1
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Big boost for Incyte as Jakafi shines in PhII
ruxolitinib
Top-line results from a Phase II trial showed that its JAK inhibitor Jakafi (ruxolitinib), in combination with Roche’s Xeloda (capecitabine), improved survival in some patients with recurrent or treatment refractory advanced pancreatic cancer
http://www.pharmatimes.com/Article/13-08-
22/Big_boost_for_Incyte_as_Jakafi_shines_in_PhII.aspx
Ruxolitinib (trade names Jakafi and Jakavi, by Incyte Pharmaceuticals and Novartis) is a drug for the treatment of intermediate or high-risk myelofibrosis, a type of bone marrow cancer.It is also being investigated for the treatment of other types of cancer (such as lymphomas and pancreatic cancer), for polycythemia vera, and for plaque psoriasis.
The phase III Controlled Myelofibrosis Study with Oral JAK Inhibitor-I (COMFORT-I) and COMFORT-II trials showed significant benefits by reducing spleen size, relieving debilitating symptoms, and improving overall survival.
Mechanism of action
Ruxolitinib is a Janus kinase inhibitor with selectivity for subtypes 1 and 2 of this enzyme.
Side effects
Immunologic side effects have included herpes zoster (1.9%) and case reports of…
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QbD: new Guidance from EMA and FDA
QbD: new Guidance from EMA and FDA
The European Medicine Agency (EMA) and the U.S. Food and Drug Agency (FDA) have published a joint question-and-answer document that provides further guidance on the quality-by-design concept. Read more.
http://www.gmp-compliance.org/ecanl_654_0_news_4015_8280,8356,Z-PDM_n.html
The Quality by Design (QbD) concept has been introduced by the International Conference on Harmonisation (ICH) document Q8, supported by Q9, Q10 and also Q11. In the meantime it is well-known within the pharmaceutical industry. However many companies still struggle with the implementation. Both the European Medicine Agency (EMA) and the U.S. Food and Drug Agency (FDA) are supporting the pharmaceutical industry in the employment of the paradigm. Now, EMA and FDA have published a second joint question-and-answer document that provides further guidance on the quality-by-design concept.
The new document focuses on ‘design space verification’ and reflects conclusions reached in the on-going parallel assessment, which was launched in 2011. The objective of the parallel…
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Chugai Pharma to commercialize Helsinn’s Anamorelin for anorexia-cachexia syndrome in Germany, France, Benelux, UK and Ireland
LUGANO, Switzerland, November 12, 2013 /PRNewswire/ —
Swiss Pharma Group Helsinn seals an alliance with Japanese company Chugai by granting exclusive distribution & licensing rights to commercialize its innovative phase III ghrelin receptor agonist in Germany, France, Benelux, UK andIreland
Swiss-based Helsinn group has granted Chugai Pharma Marketing Ltd., a wholly-owned subsidiary of Chugai Pharmaceutical Co., Ltd., exclusive commercialization rights to their innovative ghrelin receptor agonist, anamorelin, for the three major European pharma markets.
Anamorelin is a new first-in-class, oral, once daily drug, currently in phase III for the treatment of anorexia-cachexia in NSCLC, a detrimental multifactorial disorder that affects over 50% of people with cancer and in which systemic inflammation, reduced food intake and altered metabolism contribute to loss of muscle mass and reduction of body weight leading to reduced quality of life, functional impairment and decreased survival.
- Anamorelin is a synthetic orally active ghrelin receptor agonist which is under development for the management of non-small lung cancer associated cachexia/anorexia.
- Development status: Phase 3
- Appetite loss; Aging; Bone injury; Cachexia
Anamorelin HCl
| M. Wt | 583.16 |
|---|---|
| Formula | C31H43ClN6O3 |
| CAS No. | 861998-00-7 |
| Synonyms | RC 1291; RC1291; RC 1291-HCl; ONO-7643; ONO7643; ONO 7643. |
| Chemical Name | 2-amino-N-((R)-1-((R)-3-benzyl-3-(1,2,2-trimethylhydrazinecarbonyl)piperidin-1-yl)-3-(1H-indol-3-yl)-1-oxopropan-2-yl)-2-methylpropanamide hydrochloride |
DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 