Graphical abstract
Plus the 14 other new drugs marketed in 2010.
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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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FDA Approves Xgeva,denosumab to Treat Giant Cell Tumor of the Bone
June 13, 2013 — The U.S. Food and Drug Administration today expanded the approved use of Xgeva (denosumab) to treat adults and some adolescents with giant cell tumor of the bone (GCTB), a rare and usually non-cancerous tumor.
GCTB generally occurs in adults between the ages of 20 and 40 years. In most cases, GCTB does not spread to other parts of the body but destroys normal bone as it grows, causing pain, limited range of motion and bone fractures. Rarely, GCTB can transform into a cancerous tumor and spread to the lungs.
Xgeva is a monoclonal antibody that binds to RANKL, a protein essential for maintenance of healthy bone. RANKL is also present in GCTB. Xgeva is intended for patients whose GCTB cannot be surgically removed (unresectable) or when surgery is likely to result in severe morbidity, such as loss of limbs or joint removal. It should only be used in adolescents whose bones have matured
http://www.drugs.com/newdrugs/fda-approves-xgeva-giant-cell-tumor-bone-3815.html
Denosumab is a fully human monoclonal antibody for the treatment of osteoporosis, treatment-induced bone loss, bone metastases, rheumatoid arthritis, multiple myeloma, and giant cell tumor of bone. It was developed by the biotechnology companyAmgen.
Denosumab is designed to inhibit RANKL (RANK ligand), a protein that acts as the primary signal for bone removal. In many bone loss conditions, RANKL overwhelms the body’s natural defenses against bone destruction.
In June 2010, denosumab was approved by the U.S. Food and Drug Administration (FDA) for use in postmenopausal women with risk of osteoporosis under the trade nameProlia, and in November 2010, as Xgeva, for the prevention of skeleton-related events in patients with bone metastases from solid tumors.Denosumab is the first RANKL inhibitor to be approved by the FDA. In the summer of 2011 clinical trials were investigating denosumab in giant cell tumors, multiple myeloma with bone metastases, and hypercalcemia of malignancy, and further investigating its dosing and safety.
Synthetic approaches to the 2010 new drugs-Review Article Bioorganic & Medicinal Chemistry, Vol 20, Issue 3,2012, Pg 1155-1174
| Synthetic approaches to the 2010 new drugsReview Article Bioorganic & Medicinal Chemistry, Volume 20, Issue 3, 1 February 2012, Pages 1155-1174 Kevin K.-C. Liu, Subas M. Sakya, Christopher J. O’Donnell, Andrew C. Flick, Hong X. Ding |
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Miglustat- to treat Type 1 Gaucher disease (GD1)
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| Miglustat | |
| (2R,3R,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol |
PATENT-US 5,525,616, US 5,472,969 TO Actelion Pharms Ltd
Miglustat is a drug developed by Actelion and is used primarily to treat Type 1 Gaucher disease (GD1). It is marketed under the trade name Zavesca. Miglustat (OGT 918, N-butyl-deoxynojirimycin) is an imino sugar (molecular weight: 219 daltons), a synthetic analogue of D-glucose and a white to off-white crystalline solid that has a bitter taste The primary pharmacological activity of miglustat is inhibition of the enzyme glucosylceramide synthase, catalyzing the first step in the biosynthesis of glycosphingolipids (GSL), i.e., the formation of glucosylceramide (GlcCer). Reduced formation of GlcCer will lead to decreased biosynthesis of more complex GSL. This therapeutic principle, called substrate reduction therapy (SRT), may be useful in disorders of intracellular (predominantly lysosomal) accumulation of GSL either due to their deficient breakdown or intracellular transport/trafficking. Miglustat exhibits a large volume of distribution and has the capacity to access deep organs such as the brain, bone and lung.
Miglustat is a synthetic derivative of a family of polyhydroxylated alkaloids or amino sugar extracted from plants and microorganisms. Its synthesis starts from D-glucose sugar in plants. The sugar then aminated and oxidized to amino fructose sugar, which then can form a cyclic aminohemiacetal called nojirimycin. Then the dehydration and reduction takes place successively before the formation of deoxynojirimycin, which is a precursor of miglustat. Since it is a synthetic derivative drug, alkylation ofdeoxynojirimycin can be synthesized in the laboratory with 1-butyl halide via amine alkylation.
Miglustat
CAS : 72599-27-0
(2R,3R,4R,5S)-1-Butyl-2-(hydroxymethyl)-3,4,5-piperidinetriol
Additional Names: N-butyldeoxynojirimycin; N-butylmoranoline
Manufacturers’ Codes: OGT-918; SC-48334
Trademarks: Zavesca (Actelion)
Molecular Formula: C10H21NO4
Molecular Weight: 219.28
C 54.77%, H 9.65%, N 6.39%, O 29.19%
Literature Ref: Amino sugar; inhibitor of glucosyltransferase, an enzyme involved in the biosynthesis of glycosphingolipids.
Prepn: B. Junge et al., DE 2758025; see also, eidem, US 4639436 (1979, 1987 both to Bayer).
Improved synthesis: E. W. Baxter, A. B. Reitz, J. Org. Chem. 59, 3175 (1994); C. R. R. Matos et al., Synthesis 1999, 571.
In vitro efficacy vs HIV: A. Karpas et al., Proc. Natl. Acad. Sci. USA 85, 9229 (1988). Inhibition of glycolipid biosynthesis: F. M. Platt et al., J. Biol. Chem. 269, 8362 (1994).
Clinical evaluation in Gaucher’s disease: T. Cox et al., Lancet 355, 1481 (2000). Review of pharmacology and clinical development in Gaucher’s disease: P. L. McCormack, K. L. Goa, Drugs 63, 2427-2434 (2003).
Properties: White to off-white crystalline solid, mp 125-126°. [a]D25 -15.9° (c = 0.77 in water). Highly sol in water (>1000 mg/ml).
Melting point: mp 125-126°
Optical Rotation: [a]D25 -15.9° (c = 0.77 in water)
Therap-Cat: In treatment of inherited glycosphingolipid lysosomal storage disorders.
by
WORLD DRUG TRACKER
Vitaros Approved in 10 Countries
Vitaros, alprostadil
7-[(1R,3R)-3-hydroxy-2-[(1E,3S)-3-hydroxyoct-1-en-1-yl]-5-oxocyclopentyl]heptanoic acid
Apricus Biosciences Inc. said that its impotence drug Vitaros has been approved in 10 European countries. The company said Vitaros is now approved in the Netherlands, Germany, France, Italy, and the U.K., among other countries, for the treatment of erectile dysfunction.
The active ingredient in Vitaros, alprostadil, is an ingredient in other approved impotence treatments and Apricus is also studying it as a treatment for female sexual arousal disorder.
Prostaglandin E1 (PGE1), known pharmaceutically as alprostadil,[1] is a prostaglandin. It is a drug used in the treatment of erectile dysfunction[2] and has vasodilatory properties.
Patent ductus arteriosus
Alprostadil is also used in maintaining a patent ductus arteriosus in newborns. This is primarily useful when there is threat of premature closure of the ductus arteriosus in an infant with ductal-dependent congenital heart disease, including cyanotic lesions (e.g., pulmonary atresia/stenosis, tricuspid atresia/stenosis, transposition of the great arteries) and acyanotic lesions (e.g., coarctation of the aorta, hypoplastic left heart syndrome, critical aortic stenosis, interrupted aortic arch).
Sexual dysfunction
Alprostadil is sold in the United States as urethral suppositories and in injectable form. The suppositories are sold under the brand name MUSE.[3] The injectable forms are Edex[4] and Caverject.[5] Muse delivers alprostadil as a penile suppository, inserted into the urethra, at least ten minutes before the erection will be needed. Caverject and Edex are similarly fast-acting, but instead are injected by syringe directly into the corpus cavernosum of the penis.
Apricus Biosciences is developing proprietary drugs; Vitaros for men with erectile dysfunction, Femprox for female sexual arousal disorder and RayVa for Raynaud’s phenomenon. Two Phase III studies have been completed for Vitaros, and approval has been granted in Canada. Apricus Biosciences is seeking regulatory approval in Europe, South America, and other territories. Apricus Biosciences sold the rights for Vitaros in the US to Warner Chilcott.[6]
Alprostadil is also available as a generic. The major cost is that it must be mixed by a compounding pharmacy and supplies of alprostadil may be difficult to obtain. There are different formulations, including Bimix and Trimix, which may include papaverine and/or phentolamine. A typical mix might be 30 mg of papaverine, 2 mg of phentolamine, and 20 mcg alprostadil. As a generic, it is much less expensive than the pre-packaged injectables. It is premixed and must be kept refrigerated and the user must load a syringe with the quantity needed.
Critical limb ischemia
Alprostadil is also used for critical limb ischemia. It increases blood flow by peripheral vasodilation within 5 minutes and induces angiogenesis. It is most effective when the ankle pressure is at least 30 mmHg and at least one tibial artery is patent.
- Cawello W, Leonhardt A, Schweer H, Seyberth HW, Bonn R, Lomeli AL (September 1995). “Dose proportional pharmacokinetics of alprostadil (prostaglandin E1) in healthy volunteers following intravenous infusion”. British Journal of Clinical Pharmacology 40 (3): 273–6. PMC 1365109. PMID 8527291.
- Harding LM, Adeniyi A, Everson R, Barker S, Ralph DJ, Baranowski AP (December 2002). “Comparison of a needle-free high-pressure injection system with needle-tipped injection of intracavernosal alprostadil for erectile dysfunction”. International Journal of Impotence Research 14 (6): 498–501. doi:10.1038/sj.ijir.3900916. PMID 12494285.
- “Muse Suppository – Facts and Comparisons”. Drugs.com. Retrieved 4 January 2013.
- Edex – Facts and Comparisons Drugs.com
- Caverject – Facts and Comparisons Drugs.com
- Fain Hughes (2007-10-29). “NEXM: Dutton Sees Strong Speculative Buy and 12-Month Price Double”. Retrieved 2007-11-01.
Prostaglandin E1 (alprostadil, PGE1) erectile dysfunction drug, molecular model. PGE1 is a prostaglandin used in the treatment of erectile dysfunction.
Krill oil is being studied as a natural remedy for high cholesterol
Krill Oil
Krill are shrimp-like crustaceans that are approximately 1 to 6 centimeters long. They live is the ocean, where they feed mainly on phytoplankton. They’re near the bottom of the food chain and are eaten by whales, seals, penguins, squid and fish.
Commercial fishing of krill occurs primarily in the Southern Ocean and the northern Pacific Ocean along the coasts of Canada and Japan. Krill that are caught are used for aquaculture and aquarium feeds, sport fishing bait or they are eaten as food. In Japan, krill that’s caught for food is called okiami.
Krill oil, the oil that’s found naturally in krill, is extracted and sold as a nutritional supplement. It’s sold in some health food stores and online in capsule form.
Krill oil contains omega-3 fatty acids, which is the main reason it’s becoming popular as a nutritional supplement.
Another reason krill oil is becoming popular is because it contains an antioxidant called astaxanthin. The algae that krill eat produces the bright red pigment astaxanthin that gives krill and other crustaceans such as lobster and shrimp their reddish-pink color.
Antioxidants protect our body cells from damage from free radicals, unstable substances that are thought to contribute to certain chronic diseases. Unlike many other antioxidants, astaxanthin crosses the blood-brain barrier, where it could theoretically protect the eye, brain and central nervous system from free radical damage.
The recent popularity of krill oil supplements has raised concerns that it could threaten the population of its predators, including penguins, seals and whales. people use krill oil for the same reasons they use fish oil, flax oil or other omega-3 fatty acids. Unlike fish oil, krill oil doesn’t cause fishy burps or an aftertaste, a common side effect of fish oil. Also, krill oil contains higher amounts of astaxanthin than fish oil. Here are some specific conditions for which it’s used.
1) High Cholesterol
Krill oil is being studied as a natural remedy for high cholesterol. In one study, 120 people were given krill oil, fish oil or a placebo. Krill oil reduced LDL (commonly referred to as “bad”) cholesterol by 34% and increased HDL (“good”) cholesterol by 43.5% compared to the placebo. In comparison, fish oil reduced LDL cholesterol by 4.6% and increased HDL cholesterol by 4.2%. Krill also lowered triglycerides.
2) Premenstrual Syndrome
Preliminary research suggests krill oil may help reduce symptoms of premenstrual syndrome (PMS), however, more research is needed.
Arthritis
A study in the Journal of the American College of Nutrition examined krill oil (300 mg daily) compared to a placebo and found that krill oil was effective at reducing arthritis symptoms and inflammation.
People with allergies to seafood shouldn’t use krill oil. People with bleeding disorders shouldn’t use krill oil unless under the supervision of a qualified health professional.
Side effects of krill oil may include loose stools, diarrhea or indigestion.
people taking blood thinners (anticoagulant or anti-platelet medication), such as aspirin, warfarin (Coumadin), heparin, clopidogrel (Plavix), non-steroidal anti-inflammatory medications (NSAIDS) such as ibuprofen (Motrin, Advil), naproxen (Naprosyn, Aleve) should only use krill oil under a physician’s supervision.
Krill oil should also be used with caution by people taking herbs and supplements that are thought to increase the risk of bleeding, such as ginkgo biloba and garlic.
Sources
Bunea R, El Farrah K, Deutsch L.Evaluation of the effects of Neptune Krill Oil on the clinical course of hyperlipidemia. Altern Med Rev. (2004) 9.4: 420-428.
Deutsch L. Evaluation of the effect of Neptune Krill Oil on chronic inflammation and arthritic symptoms. J Am Coll Nutr. (2007) 26.1: 39-48.
MORE INFO
Krill oil is a nutrient from a tiny crustacean (similar to a shrimp) that lives in the icy waters around the Antarctic. It is a rich source of the omega-3 essential fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
The main selling points for krill oil are that its omega-3s are packaged differently from fish oils, in the form of a phospholipid that is easier for the body to absorb. This better absorption rate – up to 60 per cent, according to some manufacturers – means less capsules need to be taken to achieve the desired health benefits.
It is also said to have the added bonus of containing another essential nutrient, choline, as well as an antioxidant, astaxanthin. Astaxanthin is found in sea algae and it’s what gives shrimp, lobster, salmon, krill and other sea-life that feed on algae their rosy color.
Krill oil supplements are also more expensive than fish oils because of the extensive processes undertaken to ensure quality and eco-sustainability. However, many argue that it is better value for money, as you have to take less capsules than if you were taking fish oil.
Rare Undersea Discovery Could Extend Your Life by 10, 20 or 30 Years
Scientists are claiming that they have now isolated unusual ingredients in a rare seaweed discovered by fishermen off the coast of Korea that offer incredible health benefits—including the ability to restore blood pressure to normal levels.
The first is Seanol, an extremely rare seaweed extract from Ecklonia Cava that’s proven to be 100 times more powerful than any land-based antioxidant. That’s because it stays working in your body for 12 hours, compared to land-based antioxidants that work for 30 minutes.
“Its secret is its make-up of special polyphenol antioxidants that are a whopping 40% lipid (fat) soluble,” Dr. Lee explains. “Unlike nearly all land-based antioxidants that are water soluble, Seanol’s protective compounds can get into things like the fatty tissues of your brain and penetrate all three layers of your cells, including the outside, the oil-based cell membranes, and your DNA.”
Indeed, Seanol is so powerful, it’s the only FDA-approved Ecklonia Cava marine-algae extract in existence.
The second ingredient is Calamarine, a deep-sea omega-3 discovery that delivers 85% more DHA omega-3s to your heart, brain, joints, and eyes. It’s known to combat everything from fatigue and poor memory, to vision problems, joint pain, mood swings and depression.
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Ecklonia cava is an edible marine brown alga species found in the ocean off Japan andKorea.
It is used as a herbal remedy in the form of an extract called Seanol, a polyphenolic extract. Another phlorotannin-rich natural agent, Ventol, is also extracted from E. cava.[1]
Phlorotannins, such as fucodiphlorethol G,[2] 7-phloro eckol, 6,6′-bieckol,[3] eckol, 8,8′-bieckol, 8,4″‘-dieckol and phlorofucofuroeckol A can be isolated from Ecklonia cava.[4]
Other components are common sterol derivatives (fucosterol, ergosterol and cholesterol).[3]
A brownish colored seaweed, Ecklonia Cava
- Kang, K.; Hwang, H. J.; Hong, D. H.; Park, Y.; Kim, S. H.; Lee, B. H.; Shin, H. C. (2004). “Antioxidant and antiinflammatory activities of ventol, a phlorotannin-rich natural agent derived from Ecklonia cava, and its effect on proteoglycan degradation in cartilage explant culture”. Research communications in molecular pathology and pharmacology. 115-116: 77–95. PMID 17564307.
- Isolation of a New Phlorotannin, Fucodiphlorethol G, from a Brown Alga Ecklonia cava. Young Min Ham, Jong Seok Baik, Jin Won Hyun and Nam Ho Lee, Bull. Korean Chem. Soc. 2007, Vol. 28, No. 9 1595
- Li, Y.; Qian, Z. J.; Ryu, B.; Lee, S. H.; Kim, M. M.; Kim, S. K. (2009). “Chemical components and its antioxidant properties in vitro: An edible marine brown alga, Ecklonia cava”. Bioorganic & Medicinal Chemistry 17 (5): 1963–1973.doi:10.1016/j.bmc.2009.01.031. PMID 19201199.
- Ahn, M. J.; Yoon, K. D.; Min, S. Y.; Lee, J. S.; Kim, J. H.; Kim, T. G.; Kim, S. H.; Kim, N. G. et al. (2004). “Inhibition of HIV-1 reverse transcriptase and protease by phlorotannins from the brown alga Ecklonia cava”. Biological & pharmaceutical bulletin 27 (4): 544–547.PMID 15056863.
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Calamarine is new super DHA
One of the myths associated with aging is that your body wears out and there is nothing we can do about it. As we get older, we just have to live with chronic disease and the only way to improve the quality of our health and life is to treat the symptoms.
Overwhelmingly, research suggests that this is simply not true. In fact, the American Journal of Clinical Nutrition and Circulation provide documented evidence that consumption of Omega-3 fatty acids from dietary sources and supplements cut the likelihood of an early death.DHA and EPA not only prevent heart disease and sudden death from a sudden heart attack, they lower the risk…
A positive genotoxicity result can throw the fate of a promising drug candidate—in which a firm has invested significant time and money—into doubt
A positive genotoxicity result can throw the fate of a promising drug candidate-in which a firm has invested significant time and money-into doubt. The statistical improbability and challenges of bringing a drug to market become paramount.
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BY WORLD DRUG TRACKER
Automating Lead Optimization
This diagram illustrates the methods used to determine solubility as a compound advances toward further clinical study, and the increasing reach of automation and informatics systems. Initially, screens are run in silico on a library after hits are determined through a high-throughput screen; then various kinetic solubility assays are used to determine the compound’s potency at various concentrations. Two rounds of kinetic solubility assays determine gross and broad solubility (mmol/L) and finite solubility (less than 20 µmol/L) before the compound is advanced into thermodynamic solubility assays. Figure modified from Petereit A, Saal C. What is the Solubility of My Compound? Assessing Solubility for Pharmaceutical Research and Development Compounds. Am Pharm Rev. 2011; 14
The drug discovery business is changing rapidly. More pharmaceutical companies are working with smaller biotech firms to create early-stage compounds, and thus need quicker and standardized solutions to early-stage development problems.
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by
WORLD DRUGTRACKER
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.
Tesaro and the European Network of Gynecological Oncological Trial Groups Forge Partnership to Develop Niraparib for Ovarian Cancer
Niraparib; MK 4827
MOLECULAR FORMULA C19H20N4O
MOLECULAR WEIGHT 320.4
SPONSOR Merck Sharp & Dohme Corp.
CAS REGISTRY NUMBER 1038915-60-4
THERAPEUTIC CLAIM Antineoplastic
CHEMICAL NAMES
1. 2H-Indazole-7-carboxamide, 2-[4-(3S)-3-piperidinylphenyl]-
2. 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
TESARO and the European Network of Gynecological Oncological Trial Groups (ENGOT) Forge Partnership to Develop Niraparib for Ovarian Cancer
June 3, 2013 — TESARO, Inc. an oncology-focused biopharmaceutical company, and the European Network of Gynecological Oncological Trial Groups (ENGOT), a network of national and regional clinical trial organizations, today announced a partnership for the Phase 3 clinical development of niraparib, an orally active, potent poly (ADP-ribose) polymerase (PARP) inhibitor. READ ALL AT http://www.pharmalive.com/tesaro-and-the-european-network-of-gynecological-oncological-trial-groups-forge-partnership-to
http://www.ama-assn.org/resources/doc/usan/niraparib.pdf
http://clinicaltrials.gov/show/NCT01847274
MK-4827:
MK-4827 is a potent, Selective, PARP 1/2 inhibitor with IC50 of 3.8 and 2.1 nM for PARP1 and 2, respectively. MK-4827 possesses potential Antineoplastic Activity. In a Whole Cell assay, MK -4827 prevented PARP activity with an EC50 of 4 nM, enhancing the accumulation of DNA strand breaks and promoting genomic instability and apoptosis. MK-4827 induces selective synthetic lethality in homologous recombination (HR) repair deficient tumors with BRCA1 / 2 loss and tumor cell lines with non-BRCA-related HR defects, supporting clinical utility in sporadic tumors. MK-4827 reveals good pharmacokinetic properties and is currently in phase I clin. trials. The phase I clinical trials for MK-4827 is ongoing in the treatment of solid tumors.
BY WORLD DRUG TRACKER
New Drug Approvals 