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EYLEA® (aflibercept) Injection Approved For The Treatment of Macular Edema Following Central Retinal Vein Occlusion In Japan
TARRYTOWN, N.Y., Nov. 22, 2013 /PRNewswire/ — Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced that EYLEA® (aflibercept) Injection has received approval for the treatment of Macular Edema Following Central Retinal Vein Occlusion (CRVO) from the Japanese Ministry of Health, Labour and Welfare.http://www.pharmalive.com/japan-approves-eylea
In November 2011 the United States Food and Drug Administration approved aflibercept for the treatment of wet macular degeneration.
On August 3, 2012 the United States Food and Drug Administration approved Zaltrap (ziv-aflibercept) for use in combination with 5-fluorouracil, leucovorin and irinotecan to treat adults with metastatic colorectal cancer that is resistant to or has progressed following an oxaliplatin‑containing regimen.
In November 2012 the European Medicines Agency (EMA) approved aflibercept for the treatment of wet macular degeneration.
On February 1, 2013 the European Commission granted a marketing authorisation valid throughout the European Union for treatment of adults with metastatic colorectal cancer for whom treatment based on oxaliplatin has not worked or the cancer got worse.
Tecfidera wins “new active substance” designation in Europe
November 22,2013 | By Márcio Barra
Biogen Idec’s multiple sclerosis drug Tecfidera (dymethil Fumarate ) won today designation as a “new active substance” in Europe by the European Medicines Agency, giving it added protection against generic copies and paving the way its approval in European soil.
The designation, issued by the Committee for Medicinal Products for Human Use and posted today on the EMA’s website, gives an additional 10 years of patent protection for Tecfidera, The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) posted this decision on its website today, updating a previous opinion.
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Zucapsaicin (Zuacta)
Zucapsaicin (Zuacta), cas 25775-90-0
Chemical name: (Z)-8-methyl-N-vanillyl-6-nonenamide
Molecular formula: C18H27NO3
Molecular mass: 305.41
E merck
Civanex (zucapsaicin) cream is a TRPV-1 modulator in development for the treatment of signs and symptoms of osteoarthritis of the knee.
Zucapsaicin, the cis-isomer of the natural product capsaicin, is a
topical analgesic that was initially developed by Winston Pharmaceuticals
and approved in Canada in July 2010 for the treatment of
severe pain in adults with osteoarthritis of the knee.
Bronson, J.; Dhar, M.; Ewing, W.; Lonberg, N. In Annual Reports in MedicinalChemistry; John, E. M., Ed.; Academic Press, 2011; Vol. 46, p 433.
The advantagesof zucapsaicin compared with naturally-occurring capsaicin, are reported to be a lesser degree of local irritation (stinging, burning,
erythema) in patients and a greater degree of efficacy in preclinical
animal models of pain.
Bernstein, J. E. U.S. 5063060, 1991.
Bernstein, J. E. U.S. 20050084520 A1, 2005.
The analgesic action of both
zucapsaicin and capsaicin is mediated through the transient receptor
potential vanilloid type 1 (TRPV1) channel, a ligand-gated ion
channel expressed in the spinal cord, brain, and localized on neurons
in sensory projections to the skin, muscles, joints, and
gut.
Westaway, S. M. J. Med. Chem. 2007, 50, 2589.
The scale preparation of zucapsaicin likely parallels the original
approach described by Gannett and co-workers involving the
coupling of vanillylamine with (Z)-8-methylnon-6-enoyl chloride.
Gannett, P. M.; Nagel, D. L.; Reilly, P. J.; Lawson, T.; Sharpe, J.; Toth, B. J. Org.Chem. 1988, 53, 1064.
Orito and co-workers elaborated this original approach in
an effort to prepare both capsaicin and zucapsaicin on gram-scale,
Kaga, H.; Miura, M.; Orito, K. J. Org. Chem. 1989, 54, 3477.
Zucapsaicin (Civanex) is a medication used to treat osteoarthritis of the knee and otherneuropathic pain. It is applied three times daily for a maximum of three months. It reduces pain, and improves articular functions. It is the cis-isomer of capsaicin. Civamide, manufactured by Winston Pharmaceuticals, is produced in formulations for oral, nasal, and topical use (patch and cream).[1]
Zucapsaicin has been tested for treatment of a variety of conditions associated with ongoing nerve pain. This includes herpes simplex infections; cluster headaches andmigraine; and knee osteoarthritis.[2]
- Winston Pharmaceuticals websitehttp://www.winstonlabs.com/productdevelopment/civamide.asp
- Zucapsaicin information from the National Library of Medicinehttp://druginfo.nlm.nih.gov/drugportal
- http://products.sanofi.ca/en/zuacta.pdf
CHINESE MEDICINE-Xuezhikang , A blood lipid regulator
Xuezhikang
Xuezhikang, the extract of red yeast rice, has been widely used as a Chinese traditional medicine for the therapy of patients with cardiovascular diseases. It contains natural Lovastatin and its homologues, as well as unsaturated fatty acids, flavonoids, plant sterols and other biologically active substances
The product is a world-recognized blood lipid regulator, which is made by extracting from “specially-made red yeast rice”. It combines modern high-tech biotechnology with traditional Chinese medicine, which can safely and effectively regulate blood lipids in a comprehensive way with proven curative effects and reliable safety.
Pharmacological Effects: the product can reduce blood cholesterol, triglycerides, low density lipoprotein cholesterol, improve high density lipoprotein cholesterol, inhibit atherosclerotic plaque formation, and protect vascular endothelial cells; and inhibit lipid deposition in the liver. The large-scale evidence-based research has proven that long-term use of XUEZHIKANG can greatly reduce the risk of CHD occurrence and decrease the mortality. XUEZHIKANG is the only Chinese medicine with blood lipids regulating function which is listed into the National Basic Medicine List.
Beijing Peking University WBL Biotech (WPU) has developed and launched Xuezhikang, a capsule formulation of Monascus purpureus-fermented rice, for the oral treatment of hyperlipidemia and cardiovascular disease
CLINICAL TRIAL, NCT01327014 PHASE 2
The data had shown that Xuezhikang significantly reduced the level of low density lipoprotein cholesterin (LDL-C) in patients in a similar manner to statins and increased the level of the beneficial high density lipoprotein cholesterin (HDL-C). It had a good safety profile with no significant liver enzyme abnormal events observed. Besides regulation of dyslipidemia, the drug also signifcantly reduced cardiovascular events and general mortality rate of patients
NCT01686451 PHASE 4
Both XueZhiKang and Statins are cholesterol-lowering medications that are often prescribed for individuals with high cholesterol and who are at risk for cardiovascular disease (CVD). Several studies, including one randomized, double-blind, placebo-controlled clinical trial, have suggested that the use of statins is more frequently associated with fatigue. And XueZhiKang may be not. The purpose of this study is to compare the effect of these two medications on fatigue in persons who are at moderate to low CVD risk based on the risk estimation system in ESC(European Society of Cardiology)/ESA(European Atherosclerosis Society) guidelines (2011) for the management of dyslipidemias.
Those of you with high cholesterol will be happy to learn that there are some legitimate options to your statin pills. Many people cannot tolerate the extremely popular statin pills, especially from side effects of muscle aches. But there’s now some very strong evidence that herbal medicines, including red yeast rice, can be at least as effective as a statin, and without the side effects. Too good to be true? Maybe not…
Red yeast rice is a bright reddish purple fermented rice, which acquires its colour from being cultivated with the mold Monascus purpureus. Red yeast rice is known as Zhi Tai when in powdered form but is called Xue Zhi Kang in alcohol extract form. This has been used in China for many centuries for many reasons, but researchers have been very interested in its effectiveness in lowering cholesterol and preventing heart disease (similar benefits from statins). It seems that the main active ingredient is indeed the natural form of a common statin, lovastatin — but researchers feel that other ingredients inside may add more protective effects. There is an official patented Chinese TCM formulation, called Xue Zhi Kang (xue2 zhi1 kang2 jiao nang 血脂康 胶囊), which has the equivalent of 10mg of lovastatin. The ScienceDaily website has a nice 2008 review of a well-designed study, printed in American Journal of Cardiology, which followed 5,000 persons after their first heart attack, and divided them into two groups taking either xuezhikang or placebo. After 5 years:
Frequencies of the primary end point were 10.4% in the placebo group and 5.7% in the XZK-treated group, with absolute and relative decreases of 4.7% and 45%, respectively. Treatment with XZK also significantly decreased CV and total mortality by 30% and 33%, the need for coronary revascularization by 1/3, and lowered total and low-density lipoprotein cholesterol and triglycerides, but raised high-density lipoprotein cholesterol levels. In conclusion, long-term therapy with XZK significantly decreased the recurrence of coronary events and the occurrence of new CV events and deaths, improved lipoprotein regulation, and was safe and well tolerated.
This is impressive data, and the study design is very well done, which means the evidence is quite strong. One co-author, Dr Capuzzi, has a nice summary:
“It’s very exciting because this is a natural product and had very few adverse side effects including no abnormal blood changes,” said Capuzzi. “People in the Far East have been taking Chinese red yeast rice as food for thousands of years, but no one has ever studied it clinically in a double-blind manner with a purified product against a placebo group until now and we are pleased with the results. However, people in the United States should know that the commercially available over-the-counter supplement found in your average health food store is not what was studied here. Those over-the-counter supplements are not regulated, so exact amounts of active ingredient are unknown and their efficacy has not been studied yet.”
- XueZhiKang
In another randomized trial study, printed last year in the Annals of Internal Medicine, patients who had previously failed treatment of statins due to side effects were given 1800mg of red yeast rice twice a day versus placebo. The red yeast rice group had a significant improvement in cholesterol numbers — with no major reports of severe muscle aches they previously had on the statins.
There are other studies that also show similar benefits. In fact, the evidence is so strong that it is classified as Grade A evidence: “Strong scientific evidence for use”. This is the highest grade that any therapy can get. There are a number of good reviews of red yeast rice in Western literature, including from Medscape; the Mayo Clinic; WebMD; MedlinePlus; and NCCAM. There’s also more informal information from the TCM blog Qi Spot. You can find more scholarly information in the 2008 review from Chinese Medical Journal.
http://www.hindawi.com/journals/ecam/2012/636547/
(U.S. patent #6,046,022), ethanol extract of red yeast rice, with a total monacolins content of approx. 0.8%.
1 Heber D et al. Cholesterol-lowering effects of a proprietary Chinese red-yeast-rice dietary supplement. American Journal of Clinical Nutrition 1999;69(2): 231-236
2) SoRelle R. Appeals court says Food and Drug Administration can regulate cholestin. Circulation 200;102 (7): E9012?E9013.
3) Li, C et al. Monascus purpureus-fermented rice (red yeast rice): a natural food product that lowers blood cholesterol in animal models of hypercholesterolemia. Nutrition Research 1998;18 (1): 71-81
4) Becker DJ et al. Red yeast rice for dyslipidemia in statin-intolerant patients: a randomized trial.Ann Intern Med. 2009 Jun 16;150(12):830-9, W147-9
5) Lu Z et al.Effect of Xuezhikang, an extract from red yeast Chinese rice, on coronary events in a Chinese population with previous myocardial infarction. Am J Cardiol. 2008 Jun 15;101(12):1689-93.
Hypochol is the same product. Xuezhikang is the brand name marketed in China. Hypochol, is manufactured by a Singapore comapany who have a joint venture agreement with Peking University who perfected the processing and quality control of the Red Yeast Rice Extract Product. You can order directly from: http://www.hypocol.com/wbm.html
or thru their New Zealand distributor (very good service) at: http://www.hypocol.co.nz/
Dried grain red yeast rice
Red yeast rice (simplified Chinese: 红曲米; traditional Chinese: 紅麴米); pinyin: hóng qū mǐ; literally “red yeast rice”), red rice koji (べにこうじ, lit. ‘red koji‘) or akakoji (あかこぎ, also meaning ‘red koji‘), red fermented rice, red kojic rice, red koji rice, anka, or ang-kak, is a bright reddish purple fermented rice, which acquires its colour from being cultivated with the mold Monascus purpureus.
Red yeast rice is what is referred to, in Japanese, as a koji, meaning ‘grain or bean overgrown with a mold culture’, a food preparation tradition going back to ca. 300 BC.[1] In both the scientific and popular literature in English that draws principally on Japanese, it is most often known as “red rice koji“. English works favoring Chinese sources may prefer the translation “red yeast rice”.
In addition to its culinary use, red yeast rice is also used in Chinese herbology and traditional Chinese medicine. Its use has been documented as far back as the Tang Dynasty in China in 800 AD. It is taken internally to invigorate the body, aid in digestion, and revitalize the blood. A more complete description is in the traditional Chinese pharmacopoeia, Ben Cao Gang Mu-Dan Shi Bu Yi, from the Ming Dynasty (1378–1644).
What other names is Red Yeast known by?
Arroz de Levadura Roja, Cholestin, Hong Qu, Koji Rouge, Levure de Riz Rouge, Monascus, Monascus purpureus, Monascus Purpureus Went, Red Rice, Red Rice Yeast, Red Yeast Rice, Red Yeast Rice Extract, Riz Rouge, Xue Zhi Kang, XueZhiKang, XZK, Zhibituo, Zhi Tai.
What is Red Yeast?
Red yeast is the product of rice fermented with Monascus purpureus yeast. Red yeast supplements are different from red yeast rice sold in Chinese grocery stores. People use red yeast as medicine.
Possibly Effective for…
- High cholesterol.
- High cholesterol and triglyceride levels caused by human immunodeficiency virus (HIV) disease (AIDS).
Insufficient Evidence to Rate Effectiveness for…
- Indigestion, diarrhea, improving blood circulation, spleen and stomach problems, and other conditions.
In the late 1970s, researchers in the United States and Japan were isolating lovastatin from Aspergillus and monacolins fromMonascus, respectively, the latter being the same fungus used to make red yeast rice but cultured under carefully controlled conditions. Chemical analysis soon showed that lovastatin and monacolin K are identical. The article “The origin of statins” summarizes how the two isolations, documentations and patent applications were just months apart.[5] Lovastatin became the patented, prescription drug Mevacor for Merck & Co. Red yeast rice went on to become a contentious non-prescription dietary supplement in the United States and other countries.
Lovastatin and other prescription “statin” drugs inhibit cholesterol synthesis by blocking action of the enzyme HMG-CoA reductase. As a consequence, circulating total cholesterol and LDL-cholesterol are lowered. In a meta-analysis of 91 randomized clinical trial of ≥12 weeks duration, totaling 68,485 participants, LDL-cholesterol was lowered by 24-49% depending on the statin. Different strains ofMonascus fungus will produce different amounts of monacolins. The ‘Went’ strain of Monascus purpureus (purpureus = dark red in Latin), when properly fermented and processed, will yield a dried red yeast rice powder that is approximately 0.4% monacolins, of which roughly half will be monacolin K (identical to lovastatin). Monacolin content of a red yeast rice product is described in a 2008 clinical trial report.
- Website about medicinal use of Monascus purpureus
- Medicinal use of Red yeast rice
- Fermentiertes Rotes Reismehl (in German)
Europace Publishes Data Supporting Use Of BRINAVESS™ (Vernakalant) As A First Line Agent For Pharmacological Cardioversion Of Atrial Fibrillation
Vernakalant, MK-6621, RSD 1235
(3R)-1-{(1R,2R)-2-[2-(3,4-dimethoxyphenyl)
ethoxy]cyclohexyl}pyrrolidin-3-ol
C20H31NO4 , 349.47, Brinavess , Kynapid
cas no 794466-70-9
748810-28-8 (HCl)
EMA:Link click here
PATENT WO 2004099137
VANCOUVER, Nov. 21, 2013 /PRNewswire/ – Cardiome Pharma Corp. (NASDAQ: CRME / TSX: COM) today announced that a publication titled, Pharmacological Cardioversion of Atrial Fibrillation with Vernakalant: Evidence in Support of the ESC Guidelines, was published in Europace, the official Journal of the European Heart Rhythm Association, and was made available in the advanced online article access section. The authors conclude that BRINAVESS is an efficacious and rapid acting pharmacological cardioversion agent, for recent-onset atrial fibrillation (AF,) that can be used first line in patients with little or no underlying cardiovascular disease and in patients with moderate disease, such as stable coronary and hypertensive heart disease.
Vernakalant (INN; codenamed RSD1235, proposed tradenames Kynapid and Brinavess) is an investigational drug under regulatory review for the acute conversion of atrial fibrillation. It was initially developed by Cardiome Pharma, and the intravenous formulation has been bought for further development by Merck in April 2009.[1] In September 2012, Merck terminated its agreements with Cardiom and has consequently returned all rights of the drug back to Cardiom.
On 11 December 2007, the Cardiovascular and Renal Drugs Advisory Committee of the USFood and Drug Administration (FDA) voted to recommend the approval of vernakalant,[2]but in August 2008 the FDA judged that additional information was necessary for approval.[1] The drug was approved in Europe on 1 September 2010.[3]
An oral formulation underwent Phase II clinical trials between 2005 and 2008.[4][5]
Like other class III antiarrhythmics, vernakalant blocks atrial potassium channels, thereby prolonging repolarization. It differs from typical class III agents by blocking a certain type of potassium channel, the cardiac transient outward potassium current, with increased potency as the heart rate increases. This means that it is more effective at high heart rates, while other class III agents tend to lose effectiveness under these circumstances. It also slightly blocks the hERG potassium channel, leading to a prolonged QT interval. This may theoretically increase the risk of ventricular tachycardia, though this does not seem to be clinically relevant.[6]
The drug also blocks atrial sodium channels.[6]
- “Merck and Cardiome Pharma Sign License Agreement for Vernakalant, an Investigational Drug for Treatment of Atrial Fibrillation”. FierceBiotech. 9 April 2009. Retrieved 12 October 2010.
- “FDA Advisory Committee Recommends Approval of Kynapid for Acute Atrial Fibrillation”. Drugs.com. Retrieved 2008-03-15.
- “BRINAVESS (vernakalant) for Infusion Approved in the European Union for Rapid Conversion of Recent Onset Atrial Fibrillation” (Press release). Merck & Co., Inc. 1 September 2010. Retrieved 28 September 2010.
- ClinicalTrials.gov NCT00267930 Study of RSD1235-SR for the Prevention of Atrial Fibrillation/Atrial Flutter Recurrence
- ClinicalTrials.gov NCT00526136 Vernakalant (Oral) Prevention of Atrial Fibrillation Recurrence Post-Conversion Study
- Miki Finnin, Vernakalant: A Novel Agent for the Termination of Atrial Fibrillation: Pharmacology, Medscape Today, retrieved 12 October 2010
- Arzneimittel-Fachinformation (EMA)
- Cheng J.W. Vernakalant in the management of atrial fibrillation. Ann Pharmacother, 2008, 42(4), 533-42Pubmed
- Dobrev D., Nattel S. New antiarrhythmic drugs for treatment of atrial fibrillation. Lancet, 2010, 375(9721), 1212-23 Pubmed
- Finnin M. Vernakalant: A novel agent for the termination of atrial fibrillation. Am J Health Syst Pharm, 2010, 67(14), 1157-64 Pubmed
- Mason P.K., DiMarco J.P. New pharmacological agents for arrhythmias. Circ Arrhythm Electrophysiol, 2009, 2(5), 588-97 Pubmed
- Naccarelli G.V., Wolbrette D.L., Samii S., Banchs J.E., Penny-Peterson E., Stevenson R., Gonzalez M.D. Vernakalant – a promising therapy for conversion of recent-onset atrial fibrillation. Expert Opin Investig Drugs, 2008, 17(5), 805-10 Pubmed
- European Patent No. 1,560,812
- WO 2006138673
, WO 200653037 - WO 200597203, WO 200688525
- Vernakalant HydrochlorideDrugs Fut 2007, 32(3): 234
//////////////////////////////////////////////////////
NMR
1H NMR (300 MHz, CDCI3) 5 6.75 (m, 3H), 4.22 (m, 1H), 3.87 (s, 3H), 3.85 (m, 3H), 3.74 (m, 1H), 3.57 (m, 1H), 3.32 (td, J =
7.7, 3.5, 1H), 2.96-2.75 (m, 5H), 2.64 (dd, J= 10.0, 5.0, 1H), 2.49-2.37 (m, 2H), 2.05-1.98 (m, 2H), 1.84 (m, 1H), 1.69-1.62 (m, 3H), 1.35-1.19 (m, 4H).
IN
WO 201240846
Arrhythmias are abnormal rhythms of the heart. The term “arrhythmia” refers to a deviation from the normal sequence of initiation and conduction of electrical impulses that cause the heart to beat. Arrhythmias may occur in the atria or the ventricles. Atrial arrhythmias are widespread and relatively benign, although they place the subject at a higher risk of stroke and heart failure. Ventricular arrhythmias are typically less common, but very often fatal.
Arrhythmia is a variation from the normal rhythm of the heart beat and generally represents the end product of abnormal ion-channel structure, number or function. Both atrial arrhythmias and ventricular arrhythmias are known. The major cause of fatalities due to cardiac arrhythmias is the subtype of ventricular arrhythmias known as ventricular fibrillation (VF). Conservative estimates indicate that, in the U.S. alone, each year over one million Americans will have a new or recurrent coronary attack (defined as myocardial infarction or fatal coronary heart disease). About 650,000 of these will be first heart attacks and 450,000 will be recurrent attacks. About one-third of the people experiencing these attacks will die of them. At least 250,000 people a year die of coronary heart disease within 1 hour of the onset of symptoms and before they reach a hospital. These are sudden deaths caused by cardiac arrest, usually resulting from ventricular fibrillation.
Atrial fibrillation (AF) is the most common arrhythmia seen in clinical practice and is a cause of morbidity in many individuals (Pritchett E.L., N. Engl. J. Med. 327(14):1031 Oct. 1, 1992, discussion 1031-2; Kannel and Wolf, Am. Heart J. 123(l):264-7 Jan. 1992). Its prevalence is likely to increase as the population ages and it is estimated that 3-5% of patients over the age of 60 years have AF (Kannel W.B., Abbot R.D., Savage D.D., McNamara P.M., N. Engl. J. Med. 306(17): 1018-22, 1982; Wolf P.A., Abbot R.D., Kannel W.B. Stroke. 22(8):983-8, 1991). While AF is rarely fatal, it can impair cardiac function and is a major cause of stroke (Hinton R.C., Kistler J.P., Fallon J.T., Friedlich A.L., Fisher CM., American Journal of Cardiology 40(4):509-13, 1977; Wolf P.A., Abbot R.D., Kannel W.B., Archives of Internal Medicine 147(9): 1561 -4, 1987; Wolf P. A., Abbot R.D., Kannel W.B. Stroke. 22(8):983-8, 1991; Cabin H.S., Clubb K.S., Hall C, Perlmutter R.A., Feinstein A.R., American Journal of Cardiology 65(16): 1112-6, 1990).
WO95/08544 discloses a class of aminocyclohexylester compounds as useful in the treatment of arrhythmias.
WO93/ 19056 discloses a class of aminocyclohexylamides as useful in the treatment of arrhythmia and in the inducement of local anaesthesia.
WO99/50225 discloses a class of aminocyclohexylether compounds as useful in the treatment of arrhythmias.
Antiarrhythmic agents have been developed to prevent or alleviate cardiac arrhythmia. For example, Class I antiarrhythmic compounds have been used to treat supraventricular arrhythmias and ventricular arrhythmias. Treatment of ventricular arrhythmia is very important since such an arrhythmia can be fatal. Serious ventricular arrhythmias (ventricular tachycardia and ventricular fibrillation) occur most often in the presence of myocardial ischemia and/or infarction. Ventricular fibrillation often occurs in the setting of acute myocardial ischemia, before infarction fully develops. At present, there is no satisfactory pharmacotherapy for the treatment and/or prevention of ventricular fibrillation during acute ischemia. In fact, many Class I antiarrhythmic compounds may actually increase mortality in patients who have had a myocardial infarction.
Class la, Ic and HI antiarrhythmic drugs have been used to convert recent onset AF to sinus rhythm and prevent recurrence of the arrhythmia (Fuch and Podrid, 1992; Nattel S., Hadjis T., Talajic M., Drugs 48(3):345-7l, 1994). However, drug therapy is often limited by adverse effects, including the possibility of increased mortality, and inadequate efficacy (Feld G.K., Circulation. <°3(<5):2248-50, 1990; Coplen S.E., Antman E.M., Berlin J.A., Hewitt P., Chalmers T.C., Circulation 1991; S3(2):714 and Circulation 82(4):1106-16, 1990; Flaker G.C., Blackshear J.L., McBride R., Kronmal R.A., Halperin J.L., Hart R.G., Journal of the American College of Cardiology 20(3):527-32, 1992; CAST, N. Engl. J. Med. 321:406, 1989; Nattel S., Cardiovascular Research. 37(3):567 -77, 1998). Conversion rates for Class I antiarrhythmics range between 50-90% (Nattel S., Hadjis T., Talajic M., Drugs 48(3)345-71, 1994; Steinbeck G., Remp T., Hoffmann E., Journal of Cardiovascular Electrophysiology. 9(8 Suppl):S 104-8, 1998). Class ILT antiarrhythmics appear to be more effective for terminating atrial flutter than for AF and are generally regarded as less effective than Class I drugs for terminating of AF (Nattel S., Hadjis T., Talajic M., Drugs. 48(3):345-71, 1994; Capucci A., Aschieri D., Villani G.Q., Drugs & Aging 13(l):5l- 70, 1998). Examples of such drugs include ibutilide, dofetilide and sotalol. Conversion rates for these drugs range between 30-50% for recent onset AF (Capucci A., Aschieri D., Nillani G.Q., Drugs & Aging J3(l):5l-70, 1998), and they are also associated with a risk of the induction of Torsades de Pointes ventricular tachyarrhythmias. For ibutilide, the risk of ventricular proarrhythmia is estimated at ~4.4%, with ~1.7% of patients requiring cardioversion for refractory ventricular arrhythmias (Kowey P.R., NanderLugt J.T., Luderer J.R., American Journal of Cardiology 78(8A):46-52, 1996). Such events are particularly tragic in the case of AF as this arrhythmia is rarely a fatal in and of itself.
Atrial fibrillation is the most common arrhythmia encountered in clinical practice. It has been estimated that 2.2 million individuals in the United States have paroxysmal or persistent atrial fibrillation. The prevalence of atrial fibrillation is estimated at 0.4% of the general population, and increases with age. Atrial fibrillation is usually associated with age and general physical condition, rather than with a specific cardiac event, as is often the case with ventricular arrhythmia. While not directly life threatening, atrial arrhythmias can cause discomfort and can lead to stroke or congestive heart failure, and increase overall morbidity.
There are two general therapeutic strategies used in treating subjects with atrial fibrillation. One strategy is to allow the atrial fibrillation to continue and to control the ventricular response rate by slowing the conduction through the atrioventricular (AV) node with digoxin, calcium channel blockers or beta-blockers; this is referred to as rate control. The other strategy, known as rhythm control, seeks to convert the atrial fibrillation and then maintain normal sinus rhythm, thus attempting to avoid the morbidity associated with chronic atrial fibrillation. The main disadvantage of the rhythm control strategy is related to the toxicities and proarrhythmic potential of the anti-arrhythmic drugs used in this strategy. Most drugs currently used to prevent atrial or ventricular arrhythmias have effects on the entire heart muscle, including both healthy and damaged tissue. These drugs, which globally block ion channels in the heart, have long been associated with life-threatening ventricular arrhythmia, leading to increased, rather than decreased, mortality in broad subject populations. There is therefore a long recognized need for antiarrhythmic drugs that are more selective for the tissue responsible for the arrhythmia, leaving the rest of the heart to function normally, less likely to cause ventricular arrhythmias.
One specific class of ion channel modulating compounds selective for the tissue responsible for arrhythmia has been described in U.S. Pat. No. 7,057,053, including the ion channel modulating compound known as vernakalant hydrochloride. Vernakalant hydrochloride is the non-proprietary name adopted by the United States Adopted Name (USAN) council for the ion channel modulating compound (1R,2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane monohydrochloride, which compound has the following formula:
Vernakalant hydrochloride may also be referred to as “vernakalant” herein.
Vernakalant hydrochloride modifies atrial electrical activity through a combination of concentration-, voltage- and frequency-dependent blockade of sodium channels and blockade of potassium channels, including, e.g., the ultra-rapidly activating (lKur) and transient outward (lto) channels. These combined effects prolong atrial refractoriness and rate-dependently slow atrial conduction. This unique profile provides an effective anti-fibrillatory approach suitable for conversion of atrial fibrillation and the prevention of atrial fibrillation.
C20H32ClNO4, Mr = 385.9 g/mol
Pfizer’s Xalkori Granted Regular FDA Approval
Pfizer’s XALKORI® Granted Regular FDA Approval
Standard of Care for Patients With Metastatic ALK-Positive Non-Small Cell Lung Cancer
NEW YORK, November 21, 2013–(BUSINESS WIRE)–Pfizer Inc. announced today that the U.S. Food and Drug Administration (FDA) has granted Pfizer’s XALKORI® (crizotinib) regular approval for the treatment of patients with metastatic ALK-positive non-small cell lung cancer (NSCLC) as detected by an FDA-approved test. XALKORI was previously granted accelerated approval in August 2011 due to the critical need for new agents for people living with ALK-positive NSCLC
read all at
http://www.pharmalive.com/pfizer%E2%80%99s-xalkori-granted-regular-fda-approval
Daiichi Sankyo anticoagulant edoxaban succeeds in Phase III
Edoxaban, DU-176b
Daiichi Sankyo, APPROVED IN JAPAN as tosylate monohydrate salt in 2011 for the prevention of venous embolism in patients undergoing total hip replacement surgery
for synthesis see….http://www.sciencedirect.com/science/article/pii/S0968089613002642 Bioorganic & Medicinal Chemistry 21 (2013) 2795–2825, see s[pecific page 2808 for description ie 14/31 of pdf
WO 2010071121, http://www.google.com/patents/WO2010071121A1
WO 2007032498
N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide
NOV20, 2013
Daiichi Sankyo will file edoxaban on both sides of the Atlantic shortly after the bloodthinner proved as effective and safer than warfarin in a Phase III trial of patients with atrial fibrillation.
The company has presented data on edoxaban, a once-daily oral factor Xa inhibitor, at the American Heart Association meeting in Dallas, from a study involving 21,105 patients across 46 countries. The drug, evaluated in 60mg and 30mg doses, met its primary endpoint of non-inferiority compared to warfarin for the prevention of stroke or systemic embolic events in patients with non-valvular AF.http://www.pharmatimes.com/Article/13-11-20/Daiichi_Sankyo_anticoagulant_edoxaban_succeeds_in_Phase_III.aspx
Edoxaban (INN, codenamed DU-176b, trade name Lixiana) is an anticoagulant drug which acts as a direct factor Xa inhibitor. It is being developed by Daiichi Sankyo. It was approved in July 2011 in Japan for prevention of venous thromboembolisms (VTE) following lower-limb orthopedic surgery.[1]
In animal studies, edoxaban is potent, selective for factor Xa and has good oral bioavailability.[2]
Daichi Sankyo’s edoxaban tosilate is an orally administered
coagulation factor Xa inhibitor that was approved and launched
in Japan for the preventive treatment of venous thromboembolic
events (VTE) in patients undergoing total knee arthroplasty, total
hip arthroplasty, or hip fracture surgery. Edoxaban has been
shown to have a rapid onset of anticoagulant effect due to short
Tmax (1–2 h) after dosing and sustained for up to 24 h post-dose.
Marketed under the brand name Lixiana, it is currently in phase
III studies in the US for the prevention of stroke and systemic embolic
events in patients with atrial fibrillation (AF) and venous
thromboembolism (VTE).
Several Phase II clinical trials have been conducted, for example for thromboprophylaxis after total hip replacement[3] (phase III early results compare well to enoxaparin[4]), and for stroke prevention in patients with atrial fibrillation[5][6].Those papers follow similar recent major trials showing similar results for the other new factor Xa inhibitors, rivaroxaban and apixaban.
A large phase III trial showed that edoxaban was non inferior to warfarin in preventing recurrent venous thromboembolic events with fewer episodes of major bleeding.[7]
- “First market approval in Japan for LIXIANA (Edoxaban)”. Press Release. Daiichi Sankyo Europe GmbH. 2011-04-22.
- Furugohri T, Isobe K, Honda Y, Kamisato-Matsumoto C, Sugiyama N, Nagahara T, Morishima Y, Shibano T (September 2008). “DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles”. J. Thromb. Haemost. 6 (9): 1542–9. doi:10.1111/j.1538-7836.2008.03064.x. PMID 18624979.
- Raskob, G.; Cohen, A. T.; Eriksson, B. I.; Puskas, D.; Shi, M.; Bocanegra, T.; Weitz, J. I. (2010). “Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement”. Thrombosis and Haemostasis 104 (3): 642–649. doi:10.1160/TH10-02-0142.PMID 20589317. edit
- “Phase III Trial Finds Edoxaban Outclasses Enoxaparin in Preventing Venous Thromboembolic Events”. 8 Dec 2010.
- Weitz JI, Connolly SJ, Patel I, Salazar D, Rohatagi S, Mendell J, Kastrissios H, Jin J, Kunitada S (September 2010). “Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation”. Thromb. Haemost. 104 (3): 633–41. doi:10.1160/TH10-01-0066.
- Edoxaban versus Warfarin in Patients with Atrial Fibrillation Robert P. Giugliano, M.D., Christian T. Ruff, M.D., M.P.H., Eugene Braunwald, M.D., Sabina A. Murphy, M.P.H., Stephen D. Wiviott, M.D., Jonathan L. Halperin, M.D., Albert L. Waldo, M.D., Michael D. Ezekowitz, M.D., D.Phil., Jeffrey I. Weitz, M.D., Jindřich Špinar, M.D., Witold Ruzyllo, M.D., Mikhail Ruda, M.D., Yukihiro Koretsune, M.D., Joshua Betcher, Ph.D., Minggao Shi, Ph.D., Laura T. Grip, A.B., Shirali P. Patel, B.S., Indravadan Patel, M.D., James J. Hanyok, Pharm.D., Michele Mercuri, M.D., and Elliott M. Antman, M.D. for the ENGAGE AF-TIMI 48 InvestigatorsDOI: 10.1056/NEJMoa1310907
- “Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism”. N. Engl. J. Med. August 2013. doi:10.1056/NEJMoa1306638. PMID 23991658.
- WO 03/000657 pamphlet WO 03/000680 pamphlet WO 03/016302 pamphlet WO 04/058715 pamphlet WO 05/047296 pamphlet WO 07/032498 pamphlet WO 08/129846 pamphlet WO 08/156159 pamphlet
- J Am Chem Soc 1978, 100(16): 5199
Drug formulation , lixiana, edoxaban tosylate monohydrate, CAS 912273-65-5, C24 H30 Cl N7 O4 S . C7 H8 O3 S . H2 O, 738.274
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N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide p-toluenesulfonic acid monohydrate represented by the following formula (A) (hereinafter, also referred to as compound A) :
-
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is known as a compound that exhibits an inhibitory effect on activated blood coagulation factor X (FXa), and is useful as a preventive and/or therapeutic drug for thrombotic diseases (Patent Literature 1 to 8).
-
For example, a method comprising mixing the free form of compound A represented by the following formula (B) (hereinafter, also referred to as compound B):
-
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with p-toluenesulfonic acid or p-toluenesulfonic acid monohydrate, followed by crystallization from aqueous ethanol, is known as a method for obtaining compound A (Patent Literature 1 to 8). These literature documents do not make any mention about adding p-toluenesulfonic acid or p-toluenesulfonic acid monohydrate in a stepwise manner in the step of obtaining compound A from compound B.
Citation ListPatent Literature
-
- Patent Literature 1: International Publication No. WO 03/000657
- Patent Literature 2: International Publication No. WO 03/000680
- Patent Literature 3: International Publication No. WO 03/016302
- Patent Literature 4: International Publication No. WO 04/058715
- Patent Literature 5: International Publication No. WO 05/047296
- Patent Literature 6: International Publication No. WO 07/032498
- Patent Literature 7: International Publication No. WO 08/129846
- Patent Literature 8: International Publication No. WO 08/156159
SIMILAR
OTHER SALTS
Edoxaban hydrochloride
CAS Number: 480448-29-1
Molecular Formula: C24H30ClN7O4S · HCl
Molecular Weight: 584.52 g.mol-1
Edoxaban is reported to be a member of the so-called “Xaban-group” and as such to be a low molecular inhibitor of the enzyme factor Xa, participating in the blood coagulation system. Therefore, edoxaban is classified as an antithrombotic drug and its possible medical indications are reported to be treatment of thrombosis and thrombosis prophylaxis after orthopaedic operations, such as total hip replacement, as well as for stroke prevention in patients with atrial fibrillation, the prophylaxis of the acute coronary syndrome and the prophylaxis after thrombosis and pulmonary embolism.
The IUPAC name for edoxaban is N’-(5-chloropyridin-2-yl)-N-[(15,2^,4S)-4- (dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[l ,3]thiazolo[5,4-c]pyridine-2- carbonyl)amino]cyclohexyl]oxamide. The chemical structure of edoxaban is shown in the formula (1) below:
formula ( 1 ) While Edoxaban is reported to be soluble in strongly acidic aqueous solutions, its solubility is considered to be very low in neutral or alkaline aqueous media. EP 2 140 867 A 1 claims an edoxaban-containing pharmaceutical composition comprising a water-swelling additive and/or a sugar alcohol. Further, it is alleged that compositions comprising lactose or cornstarch do not have good dissolution properties. The claimed pharmaceutical compositions in EP 2 140 867 Al are considered to show good dissolution properties in a neutral aqueous medium as well. Tablets comprising said composition were produced by wet granulation. However, it turned out that prior art pharmaceutical formulations comprising edoxaban being suitable for oral administration are still improvable with regards to dissolution rate and bioavailability. Further, stability and content uniformity of the known formulations could be improved. Further, due to the intolerance of many people to sugar alcohol(s), such as sorbitol, the use of sugar alcohol(s) should be avoided.
New anticoagulant Edoxaban is non inferior to Warfarin, and cuts bleeding risks
November 21,2013 | By Márcio Barra
Daiichi Sankyo’s edoxaban proved as effective and safer than warfarin in a Phase III trial of patients with atrial fibrillation, according to the results presented at the American Heart Association Scientific Sessions yesterday and published simultaneously online in The New England Journal of Medicine.
The trial, entitled ENGAGE AF-TIMI 48, compared two daily dosages of Edoxaban, 60 mg and 30 mg, against warfarin, dose-adjusted to achieve an international normalized ratio (INR) of 2.0 to 3.0, in the largest – 21,105 patients across 46 countries – and longest – 2.8 years average follow-up – clinical trial in the company’s history.
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DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 