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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Japanese drugmaker Kyowa Hakko Kirin (TYO: 4151) say that it launched its novel Parkinson’s disease drug Nouriast (istradefylline) in Japan on May 30.
Istradefylline (KW-6002), 8-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione, is a selective antagonist at the A2A receptor. It has been found to be useful in the treatment of Parkinson’s disease.[1] Istradefylline reduces dyskinesia resulting from long-term treatment with classical antiparkinson drugs such as levodopa. Istradefylline is an analog of caffeine.
1–
- Peter A. LeWitt, MD, M. Guttman, James W. Tetrud, MD, Paul J. Tuite, MD, Akihisa Mori, PhD, Philip Chaikin, PharmD, MD, Neil M. Sussman, MD (2008). “Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces off time in Parkinson’s disease: A double-blind, randomized, multicenter clinical trial (6002-US-005)”. Annals of Neurology 63 (3): 295–302. doi:10.1002/ana.21315. PMID 18306243.
Nouriast, which is the world’s first anti-parkinsonian agent of a first-in-class adenosine A2A receptor antagonist, was listed on the National Health Insurance Drug Price List on May 24, 2013 after the manufacturing and marketing approval in Japan on March 25, the company noted. In clinical trials in Japan, Nouriast improved wearing-off phenomena and was well tolerated in Parkinson’s disease patients
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Otsuka Pharmaceutical Submits New Drug Application in Japan for Tolvaptan for the Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD)
TOLVAPTAN
may 30 2013
- Tolvaptan was discovered by Otsuka in Japan, and its primary results from a global clinical trial involving 1,400 ADPKD patients from 15 countries, which demonstrated a statistically significant reduction in the rate of total kidney volume, were published in New England Journal of Medicine in 2012. It is also currently under a fast track review in the US, following our announcement of FDA accepting to review the application in April 2013.
- ADPKD is a hereditary and often physically and mentally burdensome disease characterized by the development of multiple cysts in the kidneys. ADPKD is often associated with pain, hypertension, decreased kidney function and ultimately, kidney failure that may result in hemodialysis or kidney transplantation.
- There are estimated to be approximately 31,000 ADPKD patients in Japan, and the diagnosed prevalence is estimated to be between 1:1000 and 1:4000 globally.
(Tokyo, Japan, May 30, 2013) – Otsuka Pharmaceutical Co., Ltd. Today announced it filed an application with the Pharmaceutical and Medical Devices Agency in Japan (PMDA) to market its novel compound tolvaptan for the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD). Phase III clinical trial results that form the basis of the regulatory filing were published in the New England Journal of Medicine in November 2012. The MHLW has designated tolvaptan as an Orphan Drug.http://www.otsuka.co.jp/en/release/2013/0603_02.html
Tolvaptan (INN), also known as OPC-41061, is a selective, competitive vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated withcongestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone(SIADH). Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca and in India is manufactured & sold by MSN laboratories Ltd. under the trade name Tolvat & Tolsama.
Tolvaptan is also in fast-track clinical trials[2] for polycystic kidney disease. In a 2004 trial, tolvaptan, when administered with traditional diuretics, was noted to increase excretion of excess fluids and improve blood sodium levels in patients with heart failure without producing side effects such as hypotension (low blood pressure) or hypokalemia(decreased blood levels of potassium) and without having an adverse effect on kidney function.[3] In a recently published trial (TEMPO 3:4 ClinicalTrials.gov number, NCT00428948) the study met its primary and secondary end points. Tolvaptan, when given at an average dose of 95 mg per day over a 3-year period, slowed the usual increase in kidney volume by 50% compared to placebo (2.80% per year versus 5.51% per year, respectively, p<0.001) and reduced the decline in kidney function when compared with that of placebo-treated patients by approximately 30% (reciprocal serum creatinine, -2.61 versus -3.81 (mg/mL)-1 per year, p <0.001)[4]
Chemical synthesis:[5] 
- Shoaf S, Elizari M, Wang Z, et al. (2005). “Tolvaptan administration does not affect steady state amiodarone concentrations in patients with cardiac arrhythmias”. J Cardiovasc Pharmacol Ther 10 (3): 165–71. doi:10.1177/107424840501000304. PMID 16211205.
- Otsuka Maryland Research Institute, Inc.
- Gheorghiade M, Gattis W, O’Connor C, et al. (2004). “Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial”. JAMA 291 (16): 1963–71. doi:10.1001/jama.291.16.1963. PMID 15113814.
- (2012) Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease
- Kondo, K.; Ogawa, H.; Yamashita, H.; Miyamoto, H.; Tanaka, M.; Nakaya, K.; Kitano, K.; Yamamura, Y.; Nakamura, S.; Onogawa, T.; et al.; Bioor. Med. Chem. 1999, 7, 1743.
- http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm350185.htm?source=govdelivery
- Gheorghiade M, Niazi I, Ouyang J et al. (2003). “Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial”. Circulation 107 (21): 2690–6. doi:10.1161/01.CIR.0000070422.41439.04.PMID 12742979.
New study reveals Iron supplementation may help Velcade work better
bortezomib
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Bortezomib (INN, originally codenamed PS-341; marketed as Velcade by Millennium Pharmaceuticals) is the first therapeutic proteasome inhibitor to be tested in humans. It is approved in the U.S. for treating relapsed multiple myeloma and mantle cell lymphoma. In multiple myeloma, complete clinical responses have been obtained in patients with otherwise refractory or rapidly advancing disease.
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Bortezomib was originally synthesized in 1995 (MG-341) at a company called Myogenics, which soon changed its name to ProScript. After promising preclinical results, the drug (PS-341) was tested in a small Phase I clinical trial on patients with multiple myeloma cancer. ProScript ran out of money and was bought by Leukosite in May 1999. Leukosite in turn was bought by Millennium Pharmaceuticals in October 1999. At this point in time, the project had low priority amongst other projects at the company. This changed significantly when one of the first volunteers to receive the drug in the clinical trial achieved a complete response and were still alive four years later. At the time this was a remarkable result. Later clinical experimentation indicates the possibility of a complete response in 15% of patients in a similar condition, when treated with bortezomib.
In May 2003, seven years after the initial synthesis, bortezomib (Velcade) was approved in the United States by the Food and Drug Administration (FDA) for use in multiple myeloma, based on the results from the SUMMIT Phase II trial.
Another commercially available bortezomib product – Bortenat (Natco Pharma, India), reportedly contains substantially more active entity than declared, potentially and even more resulting in increase toxicity. Moreover, Bortenat has some other chemical and formulation deviations from the registered ethic product Velcade (Millennium Pharmaceuticals and Janssen-Cilag), with unclear clinical impact.
Pharmacology
Bortezomib bound to the core particle in a yeast proteasome. The bortezomib molecule is in the center colored by atom type (boron = pink, carbon = cyan, nitrogen = blue, oxygen = red), surrounded by the local protein surface. The blue patch is catalytic threonine residue whose activity is blocked by the presence of bortezomib.
Structure
The drug is an N-protected dipeptide and can be written as Pyz-Phe-boroLeu, which stands for pyrazinoic acid, phenylalanine and Leucine with a boronic acid instead of a carboxylic acid. Peptides are written N-terminus to C-terminus, and this convention is used here even though the “C-terminus” is a boronic acid instead of a carboxylic acid.
FDA panel urges looser restrictions on diabetes drug Avandia
june 6 2013,
The controversial diabetes drug Avandia will get a second look from federal regulators this week, nearly two years after its use was severely restricted because of a link to heart problems.
The U.S. Food and Drug Administration has convened a panel of experts to consider an independent review by Duke University researchers of Avandia’s original clinical trial. The expert panel will conclude its sessions on Thursday, and could decide to alter or even lift the tight restrictions now in place regarding the medication’s use.
The Duke scientists did uncover some previously unreported cases of heart complications and deaths, but concluded that these cases did not significantly raise the overall risk of heart disease and the conclusions of the original trial still hold.
The FDA’s reconsideration of Avandia’s safety has prompted stinging criticism from the drug’s detractors, who say the agency is trying to save face following a very public embarrassment over the drug.
“This is a drug that has essentially been off the market in almost the entire world for the last three years. It has been banned in most countries, and is available in the United States under such strict requirements that only 3,000 patients now take it,” said Dr. Steven Nissen, the Cleveland Clinic cardiologist who first led the charge against Avandia. “It’s really about the FDA wanting to clean up its image, not about whether the drug is actually safe or unsafe.”
The FDA has defended its decision to review the Duke re-analysis of the original trial, which was conducted by the drug’s maker, GlaxoSmithKline, under the name Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD).
“Given the public interest in Avandia, the extensive history of the product and the continued uncertainty of risk, the FDA is holding the advisory committee meeting to have a transparent, public discussion of the results of the RECORD readjudication,” FDA spokesperson Morgan Liscinsky said.
Avandia quickly became a blockbuster diabetes drug following its release in 1999, with sales topping $3 billion in 2006.
Eisai Announces Availability of BELVIQ® (lorcaserin HCl) CIV Tablets for Chronic Weight Management in Adults who are Overweight with a Comorbidity or Obese BELVIQ Available in U.S. Pharmacies within One Week
LORCASERIN
june 7, 2013 –Eisai Inc. announced today that BELVIQ (pronounced BEL-VEEK) will be available to eligible patients by prescription in the United States beginning June 11.
BELVIQ was approved by the U.S. Food and Drug Administration on June 27, 2012 to be used along with a reduced-calorie diet and increased physical activity for chronic weight management in adults who have a body mass index (BMI) of 30 kg/m2 or greater (obese), or BMI of 27 kg/m2 or greater (overweight) with at least one weight-related medical condition such as high blood pressure, high cholesterol, or type 2 diabetes. It is not known if BELVIQ is safe and effective when taken with other prescription, over-the-counter, or herbal weight loss products, nor is it known if BELVIQ changes your risk of heart problems or stroke, or of death due to heart problems or stroke.
“BELVIQ is a new treatment option for the medical management of patients who are obese and who have not been able to sustain long-term weight loss by altering their diets or increasing exercise alone,” said Lonnel Coats, President and Chief Executive Officer, Eisai Inc. “Eisai is committed to making BELVIQ available to appropriate patients as part of our human health care corporate mission of keeping patients’ medical needs at the forefront of all that we do.”
BELVIQ will be available in U.S. pharmacies only with a prescription. Patients are cautioned not to buy BELVIQ from parties offering BELVIQ without a valid prescription from their doctor. Eisai will market and distribute BELVIQ in the United States and Arena Pharmaceuticals will manufacture and supply the finished commercial product from its facility in Switzerland.
“BELVIQ provides appropriate patients with a new treatment option that along with diet and exercise can help them lose weight and keep the weight off,” said Ken Fujioka, M.D., Director of the Center for Weight Management at the Scripps Clinic. “Obesity needs to be recognized and treated as a chronic disease. The availability of BELVIQ is a significant milestone in the medical management of overweight and obesity as we work to slow this epidemic in the United States.”
Lorcaserin (APD-356, trade name upon approval Belviq,expected trade name during development, Lorqess) is a weight-loss drug developed by Arena Pharmaceuticals. It has serotonergic properties and acts as an anorectic. On 22 December 2009 a New Drug Application (NDA) was submitted to the Food and Drug Administration (FDA) in the United States.On 16 September 2010, an FDA advisory panel voted to recommend against approval of the drug based on concerns over both safety and efficacy. In October 2010, the FDA stated that it could not approve the application for lorcaserin in its present form.
On 10 May 2012, after a new round of studies submitted by Arena, an FDA panel voted to recommend lorcaserin with certain restrictions and patient monitoring. The restrictions include patients with a BMI of over 30, or with a BMI over 27 and a comorbidity like high blood pressure or type 2 diabetes.
On 27 June 2012, the FDA officially approved lorcaserin for use in the treatment of obesity for adults with a BMI equal to or greater than 30 or adults with a BMI of 27 or greater who “have at least one weight-related health condition, such as high blood pressure, type 2 diabetes, or high cholesterol”.
On 07 May 2013, the US Drug Enforcement Administration has classified lorcaserin as a Schedule IV drug[10] under the Controlled Substances Act.
About BELVIQ (lorcaserin HCl) CIV Tablets
BELVIQ is believed to decrease food consumption and promote satiety by selectively activating serotonin 2C receptors in the brain. The exact mechanism of action of BELVIQ is not known. BELVIQ is a federally controlled substance (CIV) because it may be abused or lead to drug dependence. For more information about BELVIQ,
Idenix Pharmaceuticals Announces Samatasvir (IDX719) Poster Presentations at the Asian Pacific Association for the Study of the Liver (APASL) Conference
New Hepititis C Virus Therapy
Idenix Pharmaceuticals Announces Samatasvir (IDX719) Poster Presentations at …
Wall Street Journal JUNE 6, 2013
… Inc. (Nasdaq:IDIX), a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases, today announced three poster presentations featuring clinical and preclinical data for samatasvir (IDX719), …
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http://online.wsj.com/article/PR-CO-20130606-905746.html
Idenix Pharmaceuticals, the Cambridge-based biotechnology company, announced that their drug, IDX719, was granted a Fast Track designation by the FDA. IDX719, an NS5A inhibitor, is designed to treat chronic hepatitis C virus (HCV) infection in patients. The Fast Track designation will enable Idenix Pharmaceuticals to shave precious time off their predicted timeline for a new drug application (NDA), and even increase interaction with the FDA to guarantee a quicker review and a shorter time to market.
Biocon Seeks Partner to Sell Rival Drug to J J’s Stelara
Managing Director Kiran Mazumdar-Shaw, BIOCON
Photographer-Namas Bhojani/Bloomberg
Rapid commercialization of Alzumab “will be transformational for us,” said Kiran Mazumdar-Shaw, chairman and managing director of Biocon Ltd.
Managing Director Kiran Mazumdar-Shaw, is seeking a partner to help with expertise and funding for the tests needed for approval in the U.S., she said in an interview. Biocon plans to file for permission in the year ending March to sell in the North American nation, and aims to start marketing Alzumab in that country two to three years later, she said.
Alzumab would provide a novel therapy for a plaque-causing form of the immune disorder that would compete with best-selling products from Johnson & Johnson, AbbVie Inc. and Pfizer Inc. (PFE) The biologic psoriasis treatment, made from living cells, will help Biocon enter a market that it estimates will be valued at $8 billion by 2016.
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http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=5630
Itolizumab (Alzumab) is a ‘first in class’ humanized IgG1 monoclonal antibody developed by Biocon. It selectively targets CD6, a pan T cell marker involved in co-stimulation, adhesion and maturation of T cells. Itolizumab, by binding to CD6, down regulates T cell activation, causes reduction in synthesis of pro-inflammatory cytokines and possibly plays an important role by reducing T cell infiltration at sites of inflammation.[1] A double blind, placebo controlled, phase III treat –Plaq study of Itolizumab, successfully met the pre-specified primary end-point of significant improvement in PASI-75 (Psoriasis Area and Severity Index) score after 12 weeks of treatment in patients with moderate to severe psoriasis compared to placebo.[2] Biocon has received marketing authorization for the drug from the Drugs Controller General of India (DCGI).[3]
- http://www.biocon.com/docs/PR_080113.pdf?subLink=news
- http://www.thehindubusinessline.com/companies/article2789996.ece
- http://www.pharmabiz.com/NewsDetails.aspx?aid=73075&sid=2
OXYTOCIN , THE LOVE MOLECULE
OXYTOCIN
1-({(4R,7S,10S,13S,16S,19R)-19-amino-7-(2-amino-2-oxoethyl)-10-(3-amino-3-oxopropyl)-16-(4-hydroxybenzoyl)-13-[(1S)-1-methylpropyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentaazacycloicosan-4-yl}carbonyl)-L-prolyl-L-leucylglycinamide
Oxytocin is a mammalian neurohypophysial hormone that acts primarily as a neuromodulator in the brain.
Oxytocin plays roles in sexual reproduction, in particular during and after childbirth. It is released in large amounts after distension of the cervix and uterus during labor, facilitating birth, maternal bonding, and, after stimulation of the nipples, breastfeeding. Both childbirth and milk ejection result from positive feedback mechanisms.
Recent studies have begun to investigate oxytocin’s role in various behaviors, including orgasm, social recognition, pair bonding, anxiety, and maternal behaviors. For this reason, it is sometimes referred to as the “love hormone”. There is some evidence that oxytocin promotes ethnocentric behavior, incorporating the trust and empathy of in-groups with their suspicion and rejection of outsiders. Furthermore, genetic differences in the oxytocin receptor gene (OXTR) have been associated with maladaptive social traits such as aggressive behaviour.
Oxytocin , sometimes known as the “love molecule” or the “trust molecule” plays an important role in many processes. These include uterine contractions during childbirth, sexual arousal, lactation, puberty, orgasm, facial recognition, trust, memory formation and pair bonding.
Oxytocin is a cyclic peptide hormone with just nine amino acids in sequence (CYIQNCPLG) that also acts as a neurotransmitter in the brain where it is produced in the hypothalamus. It was the first ever polypeptide hormone to be sequenced and synthesized biochemically, work for which the American biochemist Vincent du Vigneaud was awarded the 1955 Nobel Prize in Chemistry.
Together with the neuropeptide argipressin (arginine vasopressin), it is believed to influence social cognition and behaviour. First shown in mice, recent studies have shown that also in humans simply sniffing a spray containing oxytocin increases a person’s level of trust in others.
References
- Lee, H.J., Macbeth, A.H., Pagani, J.H. and Young, W.S. (2009) Oxytocin: the great facilitator of life. Prog. Neurobiol. (Amsterdam, Neth.) 88, 127–151.
- du Vigneaud, V., Ressler, C., Swan, J.M., Roberts, C.W., Katsoyannis, P.G. and Gordon, S. (1953) The synthesis of an octapeptide amide with the hormonal activity of oxytocin. J. Am. Chem. Soc. 75, 4879–4880..
- Kosfeld, M., Heinrichs, M., Zak, P.J., Fischbacher, U. and Fehr, E. (2005) Oxytocin increases trust in humans. Nature 435, 673–676.
Oxytocin (ball-and-stick) bound to its carrier protein neurophysin (ribbons) based on: “Crystal structure of the neurophysin-oxytocin complex” Rose, J.P., Wu, C.K., Hsiao, C.D., Breslow, E., Wang, B.C. (1996) Nat.Struct.Biol. 3: 163-169
OPRD PAPER-An Improved Manufacturing Process for the Antimalaria Drug artemether
OPRD PAPER-Streamlined Process for the Conversion of Artemisinin to Artemether
Correction to A Streamlined Process for the Conversion of Artemisinin to Artemether
The structure for β-artemether is shown above, with the correct stereochemistry shown at the anomeric (8a) position. … Assignments are correct for the α- and β-anomers of artemether and dihydroartemisinin as discussed in the text; only the structure drawings are in error. …The total synthesis of artemisinin from the Isopulegol ((-)-Isopulegol) began [JACS, 1983, 624].Contrast extracted from plants, is not an economical total synthesis method, but activity was found in the total synthesis of analogues are better practical significance of a thing. In this type of terpene total synthesis of natural products stereochemical conformation analysis is also very interesting. Hu menthol with MOMCl protected hydroxy, and get a double borohydride alcohol 1. Hydroboration Addition of anti-Markovnikov rule, which is replaced by hydrogen atoms added to the side of Quito, and the boron atoms added to the less substituted side. As the front side of the double bond MOM large steric hindrance, from the double rear borane adduct, resulting product1 . Compound 1 with a benzyl group protecting the primary alcohol, HCl removal of MOM protecting, PCC oxidation of the secondary alcohol to the ketone 3 . 3 with the hydrogen generating pull enolates LDA 4 , because of steric hindrance than hydrogen methyl, the nucleophilic reaction occurs in the torus , the form compound 5 . Ketone 5 and lithium reagent 6 an addition reaction, if one equivalent of lithium reagent, the resulting product was a 1:1 8 and 9 , if the 10-fold excess of lithium reagent, the resulting product was 8:1 8 and 9 . Lithium reagent 6 as a nucleophile large volume, its addition of cyclohexanone from the equatorial position to attack (such as an intermediate state 7 as shown), so that the generated key in an upright position hydroxyl group. Equivalent of lithium reagent no stereoselectivity of the reaction, but when a large excess of lithium, when chiral ketone 5 lithium reagent of the racemic 6 kinetic resolution becomes possible. Intermediate state 7 in, R configuration of the lithium reagent to Ketones speed is faster than its enantiomer S configuration lithium reagent. So generate eight faster than 9 , and finally get 8 and 9 of the ratio of 8:1. Lithium reagent 6, TMS air resistance maximum (A-value = 2.5 kcal / mol), OMe second air resistance (A-value = 0.75 kcal / mol), so that when the attack is downward TMS, OMe and H is determined by the relative position of cyclohexanone 2,6 substituent to the size and conformation of the decision, and should also be considered in the attack Burgi-Dunitz angle, so that the stereochemistry of the product unpredictable. Compound 8after removal of the benzyl protecting the primary alcohol with excess oxidized to carboxyl groups PCC automatically generate a macrolide 10 . 10 of the vinyl silane with m -CPBA and TFA into one11 , and then generate the enol methyl desilication TBAF ethers 12 , 12 and singlet oxygen reacts13 directly after treatment with acid artemisinin.
New Drug Approvals 