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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Celgene makes good start to 2013 as Revlimid hits $1 billion
April 26, 2013
Celgene Corp has posted a healthy set of financials for the first quarter despite a 4.1% decline in net income to $410.2 million, as product sales increased 15% to $1.43 billion. read more at————http://www.pharmatimes.com/Article/13-04-26/Celgene_makes_good_start_to_2013_as_Revlimid_hits_1_billion.aspx
(RS)-3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol- 2-yl)piperidine-2,6-dione
Lenalidomide
REVLIMID® is an oral immunomodulatory drug marketed in the United States and many international markets, in combination with dexamethasone, for treatment of patients with multiple myeloma who have received at least one prior therapy. It is also marketed in the United States and certain international markets for the treatment of transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes, or MDS, associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalitie.Revlimid Worldwide annual sales in 2011 was $3.2bLenalidomide (Revlimid) is a derivative of thalidomideintroduced in 2004.It was initially intended as a treatment for multiple myeloma, for which thalidomide is an accepted therapeutic treatment. Lenalidomide has also shown efficacy in the class of hematological disorders known as myelodysplastic syndromes (MDS). Lenalidomide has significantly improved overall survival in myeloma (which generally carries a poor prognosis), although toxicity remains an issue for users. [1]It costs $163,381 per year for the average patient.[2]
Lenalidomide has been used to successfully treat both inflammatory disorders and cancers in the past 10 years. There are multiple mechanisms of action, and they can be simplified by organizing them as mechanisms of action in vitro and in vivo.[3] In vitro, lenalidomide has three main activities: direct anti-tumor effect, inhibition of the microenvironment support for tumor cells, and immunomodulatory role. In vivo, lenalidomide induces tumor cell apoptosis directly and indirectly by inhibition of bone marrow stromal cell support, by anti-angiogenic and anti-osteoclastogenic effects, and by immunomodulatory activity. Lenalidomide has a broad range of activities that can be exploited to treat many hematologic and solid cancers.
- McCarthy; Philip L. McCarthy, Kouros Owzar, Craig C. Hofmeister, et al. (May 10, 2012). “Lenalidomide after Stem-Cell Transplantation for Multiple Myeloma”. N Engl J Med 366 (19): 1770–1781. doi:10.1056/NEJMoa1114083. PMID 22571201.
- Badros, Ashraf Z. Badros (May 10, 2012). “Lenalidomide in Myeloma — A High-Maintenance Friend”. N Engl J Med 366 (19): 1836–1838. doi:10.1056/NEJMe1202819. PMID 22571206.
- Vallet S, Palumbo A, Raje N, Boccadoro M, Anderson KC (July 2008). “Thalidomide and lenalidomide: Mechanism-based potential drug combinations”. Leukemia & Lymphoma 49 (7): 1238–45. doi:10.1080/10428190802005191. PMID 18452080.
Shire move delays Intuniv generic until 2014
Guanfacine (brand name Tenex, and the extended release Intuniv) is a sympatholytic. It is a selective α2A receptor agonist. These receptors are concentrated heavily in the prefrontal cortex and the locus coeruleus, with the potential to improve attention abilities via modulating post-synaptic α2A receptors in the prefrontal cortex. Guanfacine lowers both systolic and diastolic blood pressure by activating the central nervous system α2A norepinephrine autoreceptors, which results in reduced peripheral sympathetic outflow and thus a reduction in peripheral sympathetic tone. Its side-effects are dose dependent, with practically no dryness of the mouth at doses of 2 mg and less
April 26, 2013
Shire has come to an agreement with drugmakers Actavis and Watson that lays to rest all pending litigation over their attempts to launch a generic form of the attention-deficit hyperactivity drug (ADHD) Intuniv (guanfacine hydrochloride) in the US.
Under the settlement, Shire has granted Actavis a license to make and market its version of Intuniv in the US from December 1 next year, in return for a 25% royalty on gross profit during the 180 day period of exclusivity.
read more at—–http://www.pharmatimes.com/Article/13-04-26/Shire_move_delays_Intuniv_generic_until_2014.aspx
TOXINS-Occurrence of ochratoxin A in Korean paprika
ochratoxin A
Occurrence of ochratoxin A in Korean red paprika
http://www.ncbi.nlm.nih.gov/pubmed/23605491
National Agricultural Products Quality Management Service, Seoul, 150-804, Korea, ahnjs@naqs.go.kr.
A large amount-260,000 tons-of red paprika is consumed annually in Korea, where the people prefer hot and pungent to sweet foods.
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Occurrence of ochratoxin A in herbal drugs of Indian origin – a report.
Source
Medicinal Plant Research Laboratory, University Department of Botany, Bhagalpur University, 812 007, Bhagalpur, India.
Abstract
This paper contains a report of occurrence of ochratoxin A in some common herbal medicines collected from different store-houses and shop-keepers of Bihar, India. Of 129 samples of 9 plants, 55 were found to be contaminated with various levels of ochratoxin A. The level of ochratoxin A was found maximal in barks ofHolarrhena antidysenterica (1.14…
View original post 190 more words
TOXINS-Occurrence of ochratoxin A in herbal drugs of Indian origin – a report.
ochratoxin A
Occurrence of ochratoxin A in Korean red paprika
http://www.ncbi.nlm.nih.gov/pubmed/23605491
National Agricultural Products Quality Management Service, Seoul, 150-804, Korea, ahnjs@naqs.go.kr.
A large amount-260,000 tons-of red paprika is consumed annually in Korea, where the people prefer hot and pungent to sweet foods.
,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
Occurrence of ochratoxin A in herbal drugs of Indian origin – a report.
Source
Medicinal Plant Research Laboratory, University Department of Botany, Bhagalpur University, 812 007, Bhagalpur, India.
Abstract
This paper contains a report of occurrence of ochratoxin A in some common herbal medicines collected from different store-houses and shop-keepers of Bihar, India. Of 129 samples of 9 plants, 55 were found to be contaminated with various levels of ochratoxin A. The level of ochratoxin A was found maximal in barks ofHolarrhena antidysenterica (1.14 – 2.34 μg/g) whereas it was minimal in rhizomes ofTacca aspera (0.3 – 0.74 μg/g).Aspergillus ochraceus, A sulphureus and Penicillium viridicatum isolates obtained from drug samples were also examined for their toxigenic potentials. 19 isolates ofA ochraceus, 13 ofA sulphureus and 37 isolates ofP viridicatum were found to be toxigenic out of 67, 33, and 107 isolates, respectively. The ochratoxin A produced by Aochraceus was in the range of 0.09 to 2.44 μg/mL, byA sulphureus 0.1 to 1.76 μg/mL, and byP viridicatum 0.14 to 2.78 μg/mL of the culture filtrate.
Ochratoxin A, a toxin produced by Aspergillus ochraceus, Aspergillus carbonarius and Penicillium verrucosum, is one of the most abundant food-contaminating mycotoxins.It is also a frequent contaminant of water-damaged houses and of heating ducts.Human exposure can occur through consumption of contaminated food products, particularly contaminated grain and pork products, as well as coffee, wine grapes and dried grapes.[4][5][6] The toxin has been found in the tissues and organs of animals, including human blood and breast milk. Ochratoxin A, like most toxic substances, has large species- and sex-specific toxicological differences.
Drug Spotlight: Zioptan, Tafluprost, Merck,
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|---|
isopropyl (5Z)-7-{(1R,2R,3R,5S)-2-[(1E)-3,3-difluoro-4-phenoxybut-1-en-1-yl]-3,5-dihydroxycyclopentyl}hept-5-enoate,
Drug: Zioptan
Generic molecule: tafluprost
Company: Merck
Approval date: Feb. 10, 2012
The scoop: Merck says this is the first (get ready for a mouthful) preservative-free prostaglandin analog ophthalmic solution and is for treating elevated eye pressure in some patients with the most common form of glaucoma. Merck sells the ointment in the U.S. and most of Europe, while it licensed it to Japanese drugmaker Santen in Japan, Germany and northern Europe.
Tafluprost (trade names Taflotan, marketed by Santen Pharmaceutical Co. and Zioptan, by Merck (U.S.)) is a prostaglandin analogue used topically (as eye drops) to control the progression of glaucoma and in the management of ocular hypertension. It reduces http://en.wikipedia.org/wiki/Intraocular_pressure”; rel=”nofollow”>intraocular pressure by increasing the outflow of aqueous fluid from the eyes.[1][2]
Taflotan contains 15 µg/ml Tafluprost. Taflotan sine is a preservative-free, single-dose formulation containing 0.3 ml per dose.[3]
|
|
| Systematic (IUPAC) name | |
|---|---|
| isopropyl (5Z)-7-{(1R,2R,3R,5S)-2-[(1E)-3,3-difluoro-4-phenoxybut-1-en-1-yl]-3,5-dihydroxycyclopentyl}hept-5-enoate | |
| Clinical data | |
| Trade names | Saflutan, Taflotan, Tapros, Zioptan |
| AHFS/Drugs.com | International Drug Names |
| Pregnancy cat. | C (US) |
| Legal status | ℞-only (US) |
| Routes | Topical (eye drops) |
| Identifiers | |
| CAS number | 209860-87-7 |
| ATC code | S01EE05 |
| PubChem | CID 6433101 |
| ChemSpider | 8044182 |
| UNII | 1O6WQ6T7G3  |
| ChEBI | CHEBI:66899 |
| ChEMBL | CHEMBL1963683 |
| Chemical data | |
| Formula | C25H34F2O5 |
| Mol. mass | 452.531266 g/mol |
- Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel 2008/2009
- Santen Home Page
- Gelbe Liste (in German)
European Patent No. 8509621 discloses a process for the preparation of tafluprost. In the first step, (3afl,4fl,5fl,6aS)-4-formyl-2-oxohexahydro-2 — cyclopenta[b]furan-5-ylbenzoate (CTAF 1 (i)) is condensed with dimethyl (2-oxo-3- phenoxypropyl)-phosphonate in the presence of lithium chloride and triethylamine, to provide (3aft,4F?,5F?,6aS)-2-oxo-4-((£)-3-oxo-4-phenoxybut-1 -en-1 -yl)hexahydro-2H- cyclopenta[b]-furan-5-ylbenzoate (CTAF1 ). In the second step, CTAF 1 is reacted with morpholinosulfurtrifluoride to provide (3aH,4H,5H,6aS)-4-((£)-3,3-difluoro-4- phenoxybut-1 -en-1 -yl)-2-oxohexahydro-2 –cyclopenta-[b]furan-5-yl benzoate (CTAF2). CTAF 2 is debenzoylated by potassium carbonate in methanol, to provide (3aH,4H,5H,6aS)-4-((£)-3,3-difluoro-4-phenoxybut-1 -en-1 -yl)-5-hydroxyhexahydro-2H- cyclopenta[b]furan-2-one(CTAF 3), which is further reduced by diisobutyl aluminum hydride (DIBALH) to provide (3af?,4f?,5f?,6aS)-4-((£)-3,3-difluoro-4-phenoxybut-1 -en-1 – yl) hexahydro-2H-cyclopenta[b]furan-2,5-diol (CTAF 4). CTAF 4 is then treated with (4- carboxybutyl)triphenylphosphonium bromide, in the presence of potassium bis(trimethylsilyl)amide in THF, to provide (Z)-7-((1 f?,2f?,3f?,5S)-2-((£)-3,3-difluoro-4- phenoxybut-1 -en-1 -yl)-3,5-dihydroxycyclopentyl)hept-5-enoic acid (“tafluprost free acid,” CTAF5), which is reacted with isopropyl iodide in the presence of DBU to provide (Z)- isopropyl 7-((1 F?,2F?,3F?,5S)-2-((£)-3,3-difluoro-4-phenoxybut-1 -en-1 -yl)-3,5-dihydroxy- cyclopentyl)hept-5-enoate (“tafluprost,” CTAF 6). The reaction sequence is summarized in Scheme 1 .
CTAF 1(i)
CTAF 1 CTAF 2
U.S. Patent Application Publication No. 2010/0105775A1 discloses amino acid salts of prostaglandins. The application also discloses a process for the preparation of prostaglandins, comprising forming an amino acid salt of a prostaglandin and converting the amino acid salt to the prostaglandin.
EXAMPLE 1 : Preparation of CTAF 1
CTAF1(i)
CTAF1
To a stirred suspension of sodium hydride (60% dispersion in mineral oil, 0.217 g, 5.429 mmol) in THF (5 ml_) was added a solution of dimethyl (2-oxo-3- phenoxypropyl)phosphonate(1 .21 g, 4.705 mmol) in THF (2 ml_), over 15 minutes at 0- 5°C under a nitrogen atmosphere. The mixture was warmed to 25-35 , 0.5 M zinc chloride solution in THF (9.4 ml_, 4.705 mmol) was added over 10 minutes, and then the mixture was stirred for 15 minutes at 25-35<€. CTAF1 (i) (3af?,4F?,5F?,6aS)-4-formyl-2- oxohexahydro-2 –cyclopenta[b]furan-5-yl benzoate (1 g) in dichloromethane (10 ml_) was added over 5 minutes at 25-35 °C. The temperature was raised to 35-40 °C and the mixture was stirred for 2hours under a nitrogen atmosphere. The mixture was cooled to 15°C and the reaction was quenched by adding acetic acid (0.2 mL), followed by adding saturated ammonium chloride solution (10 mL), and further stirring for 15 minutes. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (5 mL). The combined organic layers were evaporated under reduced pressure below 50°C. The crude product was purified by column chromatography on silica gel (100-200 mesh) with 30% ethyl acetate in hexane, to afford the title compound (0.9 g, 61 %yield).
EXAMPLE 2: Preparation of CTAF 2
CTAF1 CTAF2
To a stirred solution of CTAF1 (5 g, 0.0123 mol) in dichloromethane (100 mL) was added diethylaminosulfurtrifluoride (13 mL, 0.09841 mol) at 0-5 °C under a nitrogen atmosphere. The temperature was raised to 25-35 °C and maintained for 24 hours under a nitrogen atmosphere at the same temperature. The mass was slowly added into a saturated sodium bicarbonate solution (75 mL) at 0-5 °C. Temperature was raised to 25- 35 °C, the layers were separated, and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layer was washed with water (25mL) and dried over sodium sulfate (5 g). The organic layer was evaporated to dryness under reduced pressure below 40 °C. The crude product was purified by column chromatography on silica gel (100-200 mesh) with 30% ethyl acetate in hexane, to afford the title compound (4.2 g, 79% yield). EXAMPLE 3: Preparation of CTAF 4
CTAF 2 CTAF 4
CTAF 2 (2.30 g, 5.37 mmol) was dissolved in toluene (25 mL) and the solution was cooled to -65 °C under nitrogen. Diisobutyl aluminum hydride (1 .5 M in toluene, 1 1 .8 mL, 17.7mmol) was added over 15 minutes at -61 to -65 . The mixture was stirred for 3hours and then the reaction was quenched by adding methanol (1 .5 mL). Sulfuric acid (1 M, 25 mL) was added and the temperature rose to -20°C during the addition. Methyl t-butyl ether (MTBE) (10 mL) was added and the mixture was allowed to warm to room temperature. The organic phase was separated and the aqueous phase was extracted with MTBE (2x 10 mL). The combined organic phase was washed with water (10 mL), saturated aqueous sodium bicarbonate (10 mL), and then brine (10 mL). The washes were back-extracted with MTBE (10 mL). The combined organic phases were dried with magnesium sulfate, filtered, and evaporated to give a colourless oil (2.20 g). The crude product was chromatographed on silica (60 g), eluting with a mixture of ethyl acetate and heptane (2:1 by volume), and then with ethyl acetate, to give CTAF 4 as a colourless oil (1 .71 g, 97% yield).
EXAMPLE 4: Preparation of CTAF 2
CTAF1 CTAF2
To a stirred solution of CTAF1 (20 g, 0.0492 mol) in dichloromethane(400 mL) was added diethylaminosulfurtrifluoride (52 mL, 0.393 mol) at 0-10°C under a nitrogen atmosphere. The temperature was raised to 25-35 and maintained for 96hours under a nitrogen atmosphere at that temperature. The mass was slowly added to a saturated NaHCOs solution (600 mL) at 0-10°C. The mixture was heated to 25-35 <€ and filtered through aCelite bed. The layers were separated and the aqueous layer was extracted with DCM (2×100 mL). The combined organic layer was washed with 10% NaCI solution (100 mL) and evaporated to dryness under reduced pressure below 40°C. The residue was purified by column chromatography on silica gel (100-200 mesh) with 30% ethyl acetate in hexane.
Column purified material was dissolved in MTBE (80 mL) at 40°C and stirred for 30 minutes at that temperature. Diisopropyl ether (160 mL) was added at 35-40 and stirring continued for 30 minutes at 35-40 . Cooled the mass to 5-15°C and stirred for 30 minutes at that temperature. The solid was filtered, washed with a mixture of MTBE and diisopropyl ether (DIPE) (1 :2 by volume, 60 mL), and dried at 40°C under vacuum, to afford pure CTAF2 (12.0 g, 57% yield).
EXAMPLE 5: Preparation of CTAF 5
(4-Carboxybutyl)triphenylphosphonium bromide (10.32 g, 23.3 mmol, 4 eq) was suspended in THF (20 mL) under a nitrogen atmosphere and cooled to 5°C. NaHMDS solution (1 M in THF, 46.6 mL, 46.6 mmol, 8 eq) was added over 10 minutes. The red/orange mixture was stirred for 30 minutes. A solution of CTAF 4 (1 .90 g, 5.82 mmol) in THF (10 mL) was added over 30 minutes at 0-3 . The mixture was stirred for 1 .5hours and then the reaction was quenched by adding water (30 mL) and the masswas warmed to room temperature. The aqueous phase was separated and the organic phase was washed with water (20 mL). The combined aqueous phases were washed with MTBE (30 mL). The organic phases up to this point were discarded. The aqueous phase was acidified with 2M hydrochloric acid (14 mL, to pH 3-4) and extracted with ethyl acetate (2×30 mL). The combined ethyl acetate layers were washed with brine (20 mL), dried with magnesium sulfate, filtered, and evaporated under reduced pressure to give CTAF 5 asa yellow oil (8.60 g).
A 2.96 g sample was removed and the remainder (5.64 g) was chromatographed on silica (30 g) eluting with ethyl acetate to give purified CTAF 5 (1 .41 g) asa yellow oil. NMR analysis showed approximately 90% purity, remainder triphenyl phosphine oxide.
EXAMPLE 6: Preparation of CTAF 5 DCHA salt
CTAF 5 CTAF 5 DCHA sa t
CTAF5 (1 1 .72 g, 90% purity, 25.7 mmol, containing 1 .4% trans isomer) was dissolved in acetone (60 mL). Dicyclohexylamine (4.66 g, 25.7 mmol) was added and the mixture was stirred at room temperature overnight. The solid was filtered and washed with acetone (6 mL), then dried to give the DCHA salt (12.93 g, 85% yield, 0.29% trans-isomer).
A sample (7.03 g) was further purified by recrystallisation. It was dissolved in hot acetone (30 mL) and cooled to room temperature with stirring. The mixture was stirred for 3 hours, filtered and the solid was washed with acetone (3 mL) and dried to give a white solid (6.41 g, 91 % recovery, 0.1 1 % trans-isomer).
A PXRD pattern of the product is shown as Fig. 1 , obtained using copper Ka radiation. In the drawing, the y-axis is intensity units and the x-axis is the 2-theta angle, in degrees. EXAMPLE 7: Pre aration of CTAF 6
CTAF 5 DCH A sa l ^ I AI- O
CTAF 5 DCHA salt (5.80 g, 9.80 mmol) was suspended in ethyl acetate (20 mL). Sulfuric acid (1 M, 20 mL) was added and the mixture was stirred until a clear solution was obtained. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL), dried with magnesium sulfate, filtered, and evaporated. The residue was dissolved in acetone (40 mL) and charged into a jacketed vessel at 30°C. 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (8.95 g, 58.8 mmol) was added, then 2- iodopropane (10.0 g, 58.8 mmol) was added, and the mixture was stirred for 20hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (30 mL) and aqueous potassium dihydrogen orthophosphate (8 g) in water (50 mL). The organic phase was separated and the aqueous was extracted with ethyl acetate (30 mL). The combined organic phases were washed with brine (20 mL), dried with magnesium sulfate, filtered and evaporated to give a yellow oil (4.83 g). The crude product was chromatographed on silica (130 g), eluting with a mixture of ethyl acetate and heptane (2:1 by volume), to give CTAF 6 (3.98 g, 90% yield) as a colorless oil.
DRUG SPOTLIGHT-Afinitor (everolimus) , Novartis:
Afinitor (everolimus)
40-O-(2-hydroxyethyl)-rapamycin
Company: Novartis
Approval Status: Approved July 2012
Treatment Area: hormone receptor-positive, HER2-negative breast cancer
Everolimus is a derivative of Rapamycin (sirolimus), and works similarly to Rapamycin as an mTOR (mammalian target of rapamycin) inhibitor. It is currently used as an immunosuppressant to prevent rejection of organ transplants. In a similar fashion to other mTOR inhibitors Everolimus’ effect is solely on the mTORC1 protein and not on the mTORC2 protein.
159351-69-6 CAS NO
BRANDS
| Afinitor | Novartis |
| Certican | Novartis |
| VOTUBIA | Novartis |
| Zortress | Novartis |
Afinitor (everolimus), an inhibitor of mTOR (mammalian target of rapamycin), is an antineoplastic agent.
Afinitor is specifically approved for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole.
Afinitor is supplied as a tablet for oral administration. The recommended dose of Afinitor for breast cancer is 10 mg, to be taken once daily, at the same time every day, either consistently with food or consistently without food.
FDA Approval
The FDA approval of Afinitor for the treatment of advanced hormone receptor-positive, HER2-negative breast cancer was based on a randomized, double-blind, multicenter study in 724 postmenopausal women with estrogen receptor-positive, HER 2/neu-negative advanced breast cancer with recurrence or progression following prior therapy with letrozole or anastrozole.
Everolimus is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. Indicated for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease. Indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. Indicated for the treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. Indicated in pediatric and adult patients with tuberous sclerosis complex (TSC) for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected.
Everolimus (RAD-001) is the 40-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an inhibitor of mammalian target of rapamycin (mTOR).
It is currently used as an immunosuppressant to prevent rejection of organ transplants and treatment of renal cell cancer and other tumours. Much research has also been conducted on everolimus and other mTOR inhibitors for use in a number of cancers.
It is marketed by Novartis under the tradenames Zortress (USA) and Certican (Europe and other countries) in transplantation medicine, and Afinitor in oncology.
AFINITOR (everolimus), an inhibitor of mTOR, is an antineoplastic agent.
The chemical name of everolimus is (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18- dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20pentaone.
The molecular formula is C53H83NO14 and the molecular weight is 958.2. The structural formula is:
 |
AFINITOR Tablets are supplied for oral administration and contain 2.5 mg, 5 mg, 7.5 mg, or 10 mg of everolimus. The tablets also contain anhydrous lactose, butylated hydroxytoluene, crospovidone, hypromellose, lactose monohydrate, and magnesium stearate as inactive ingredients.
AFINITOR DISPERZ (everolimus tablets for oral suspension) is supplied for oral administration and contains 2 mg, 3 mg, or 5 mg of everolimus. The tablets for oral suspension also contain butylated hydroxytoluene, colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, mannitol, and microcrystalline cellulose as inactive ingredients.
- R.N Formica Jra, K.M Lorberb, A.L Friedmanb, M.J Biaa, F Lakkisa, J.D Smitha, M.I Lorber (March 2004). “The evolving experience using everolimus in clinical transplantation”. Elsevier 36 (2): S495–S499.
- “Afinitor approved in US as first treatment for patients with advanced kidney cancer after failure of either sunitinib or sorafenib” (Press release). Novartis. 2009-03-30. Retrieved April 6, 2009.
- “Novartis receives US FDA approval for Zortress (everolimus) to prevent organ rejection in adult kidney transplant recipients” (Press release). Novartis. 2010-04-22. Retrieved April 26, 2010.
- “Novartis’ Afinitor Cleared by FDA for Treating SEGA Tumors in Tuberous Sclerosis”. 1 Nov 2010.
- http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm254350.htm
- “US FDA approves Novartis drug Afinitor for breast cancer”. 20 Jul 2012.
PATENTS
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Country
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Patent Number
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Approved
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Expires (estimated)
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|---|---|---|---|
| United States | 6440990 | 1993-09-24 | 2013-09-24 |
| Canada | 2145383 | 2004-11-16 | 2013-09-24 |
| Canada | 2225960 | 2004-05-11 | 2016-07-12 |
| United States | 7297703 | 1999-12-06 | 2019-12-06 |
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10-28-2011
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METHODS OF TREATMENT
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1-21-2011
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ANTI-IGF1R
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1-14-2011
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HISTONE H2AX (HH2AX) BIOMARKER FOR FTI SENSITIVITY
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3-24-2010
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Thermal treatment of a drug eluting implantable medical device
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1-13-2010
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Therapeutic phosphonate compounds
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10-21-2009
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Processes for preparing water-soluble polyethylene glycol conjugates of macrolide immunosuppressants
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10-16-2009
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Heparin Prodrugs and Drug Delivery Stents Formed Therefrom
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9-11-2009
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PHOSPHONATE COMPOUNDS HAVING IMMUNO-MODULATORY ACTIVITY
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12-31-2008
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Phosphonate compounds having immuno-modulatory activity
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10-8-2008
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Anti-inflammatory phosphonate compounds
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6-27-2008
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Genes Involved in Neurodegenerative Conditions
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10-24-2007
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Fluid treatment of a polymeric coating on an implantable medical device
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7-11-2007
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Oxepane isomer of 42-O-(2-hydroxy)ethyl-rapamycin
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2-9-2007
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40-O-(2-hydroxy)ethyl-rapamycin coated stent
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1-5-2007
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Methods for treating neurofibromatosis 1
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9-8-2006
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Anti-inflammatory phosphonate compounds
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| WO1994009010A1 | Sep 24, 1993 | Apr 28, 1994 | Sandoz Ag | O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants |
| WO2007135397A1 * | May 18, 2007 | Nov 29, 2007 | Christoph Beckmann | 36 -des (3 -methoxy-4 -hydroxycyclohexyl) 36 – (3 -hydroxycycloheptyl) derivatives of rapamycin for the treatment of cancer and other disorders |
| EP0663916A1 | Sep 24, 1993 | Jul 26, 1995 | Novartis AG | O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants |
| US5665772 | Sep 24, 1993 | Sep 9, 1997 | Sandoz Ltd. | O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants |
| US20030125800 | Apr 24, 2002 | Jul 3, 2003 | Shulze John E. | Drug-delivery endovascular stent and method for treating restenosis |
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Rapamycin is a known macrolide antibiotic produced by Streptomvces hvgroscopicus. having the structure depicted in Formula A:
See, e.g., McAlpine, J.B., et al., J. Antibiotics (1991) 44: 688; Schreiber, S.L., et al., J. Am. Chem. Soc. (1991) J_13: 7433‘- US Patent No. 3 929 992. Rapamycin is an extremely potent immunosuppressant and has also been shown to have antitumor and antifungal activity. Its utility as a pharmaceutical, however, is restricted by its very low and variable bioavailabiiity as well as its high toxicity. Moreover, rapamycin is highly insoluble, making it difficult to formulate stable galenic compositions.
Everolimus, 40-O-(2-hydroxyethyl)-rapamycin of formula (1) is a synthetic derivative of rapamycin (sirolimus) of formula (2), which is produced by a certain bacteria strain and is also pharmaceutically active.
(1) (2)
Everolimus is marketed under the brand name Certican for the prevention of rejection episodes following heart and kidney transplantation, and under the brand name Afinitor for treatment of advanced kidney cancer.
Due to its complicated macrolide chemical structure, everolimus is, similarly as the parent rapamycin, an extremely unstable compound. It is sensitive, in particular, towards oxidation, including aerial oxidation. It is also unstable at temperatures higher than 25°C and at alkaline pH.
Everolimus and a process of making it have been disclosed in WO 94/09010
Synthesis
Alkylation of rapamycin (I) with 2-(tert-butyldimethylsilyloxy)ethyl triflate (II) by means of 2,6-lutidine in hot toluene gives the silylated target compound (III), which is deprotected by means of 1N HCl in methanol (1). (Scheme 21042401a) Manufacturer Novartis AG (CH). References 1. Cottens, S., Sedrani, R. (Sandoz-Refindungen VmbH; Sandoz-Patent GmbH; Sandoz Ltd.). O-Alkylated rapamycin derivatives and their use, particularly as immunosuppressants. EP 663916, EP 867438, JP 96502266, US 5665772, WO 9409010.EP 0663916; EP 0867438; JP 1996502266; JP 1999240884; US 5665772; WO 9409010
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SYNTHESIS
https://www.google.com/patents/WO2012103960A1
(US 5,665,772, EP 663916). The process principle is shown in the scheme below, wherein the abbreviation RAP-OH has been used as an abbreviation for the rapamycin structure of formula (2) above, L is a leaving group and P is a trisubstituted silyl group serving as a OH- protective group.
RAP-OH + L-CH2-CH2-0-P — –> RAP-O-CH2-CH2-O-P — – > RAP-O-CH2-CH2-OH
(2) (4) (1)
Specifically, the L- group is a trifluoromethanesulfonate (triflate) group and the protective group P- is typically a tert-butyldimethylsilyloxy- group. Accordingly, the known useful reagent within the above general formula (3) for making everolimus from rapamycin is 2-(tert-butyldimethylsilyloxy)ethyl triflate of formula (3 A):
According to a known synthetic procedure disclosed in Example 8 of WO 94/09010 and in Example 1 of US application 2003/0125800, rapamycin (2) reacts in hot toluene and in the presence of 2,6-lutidine with a molar excess of the compound (3 A), which is charged in several portions, to form the t-butyldimethylsilyl-protected everolimus (4A). This compound is isolated and deprotected by means of IN aqueous HC1 in methanol. Crude everolimus is then purified by column chromatography. Yields were not reported.
(2) (3A) (4A) (1)
In an article of Moenius et al. (J. Labelled Cpd. Radiopharm. 43, 113-120 (2000)), which used the above process for making C14-labelled and tritiated everolimus, a diphenyl- tert.butylsilyloxy -protective group was used as the alkylation agent of formula (3B).
Only 8% yield of the corresponding compound (4B)
and 21% yield of the compound (1) have been reported.
Little is known about the compounds of the general formula (3) and methods of their preparation. The synthesis of the compound (3 A) was disclosed in Example 1 of US application 2003/0125800. It should be noted that specification of the reaction solvent in the key step B of this synthesis was omitted in the disclosure; however, the data about isolation of the product allow for estimation that such solvent is dichloromethane. Similarly also a second article of Moenius et al. (J. Labelled Cpd. Radiopharm.42, 29-41 (1999)) teaches that dichloromethane is the solvent in the reaction.
It appears that the compounds of formula (3) are very reactive, and thus also very unstable compounds. This is reflected by the fact that the yields of the reaction with rapamycine are very low and the compound (3) is charged in high molar extent. Methods how to monitor the reactivity and/or improve the stability of compounds of general formula (3), however, do not exist.
Thus, it would be useful to improve both processes of making compounds of formula (3) and, as well, processes of their application in chemical synthesis.
xample 6: 40-O-[2-((2,3-dimethylbut-2-yl)dimethylsilyloxy)ethyl]rapamycin
In a 100 mL flask, Rapamycin (6 g, 6.56 mmol) was dissolved in dimethoxyethane (4.2 ml) and toluene (24 ml) to give a white suspension and the temperature was raised to 70°C. After 20 min, N,N-diisopropylethylamine (4.56 ml, 27.6 mmol) and 2-((2,3-dimethylbutan-2- yl)dimethylsilyloxy)ethyl trifluoromethanesulfonate (8.83 g, 26.3 mmol) were added in 2 portions with a 2 hr interval at 70°C. The mixture was stirred overnight at room temperature, then diluted with EtOAc (40 ml) and washed with sat. NaHC03 (30 ml) and brine (30 ml). The organic layer was dried with Na2S04, filtered and concentrated. The cmde product was chromatographed on a silica gel column (EtOAc/heptane 1/1 ; yield 4.47 g).
Example 7: 40-O-(2-hydroxyethyl)-rapamycin [everolimus]
In a 100 mL flask, 40-O-[2-((2,3-dimethylbut-2-yl)dimethylsilyloxy)ethyl]rapamycin (4.47 g, 4.06 mmol) was dissolved in methanol (20 ml) to give a colorless solution. At 0°C, IN aqueous hydrochloric acid (2.0 ml, 2.0 mmol) was added and the mixture was stirred for 90 min. The reaction was followed by TLC (ethyl acetate/n-heptane 3 :2) and HPLC. Then 20 ml of saturated aqueous NaHC03 were added, followed by 20 ml of brine and 80 ml of ethyl acetate. The phases were separated and the organic layer was washed with saturated aqueous NaCl until pH 6/7. The organic layer was dried by Na2S04, filtered and concentrated to yield 3.3 g of the product.
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SYNTHESIS
https://www.google.co.in/patents/WO1994009010A1
Example 8: 40-O-(2-Hydroxy)ethyl-rapamycin
a) 40-O-[2-(t-Butyldimethylsilyl)oxy]ethyl-rapamycin
A solution of 9.14 g (10 mmol) of rapamycin and 4.70 mL (40 mmol) of 2,6-lutidine in 30 mL of toluene is warmed to 60°C and a solution of 6.17 g (20 mmol) of 2-(t-butyldimethylsilyl)oxyethyl triflate and 2.35 mL (20 mmol) of 2,6-lutidine in 20 mL of toluene is added. This mixture is stirred for 1.5h. Then two batches of a solution of 3.08 g (10 mmol) of triflate and 1.2 mL (10 mmol) of 2,6-lutidine in 10 mL of toluene are added in a 1.5h interval. After addition of the last batch, stirring is continued at 60°C for 2h and the resulting brown suspension is filtered. The filtrate is diluted with ethyl acetate and washed with aq. sodium bicarbonate and brine. The organic solution is dried over anhydrous sodium sulfate, filtered and concentrated. The residue is purified by column chromatography on silica gel (40:60 hexane-ethyl acetate) to afford 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl-rapamycin as a white solid: 1H NMR (CDCl3) δ 0.06 (6H, s), 0.72 (1H, dd), 0.90 (9H, s), 1.65 (3H, s), 1.75 (3H, s), 3.02 (1H, m), 3.63 (3H, m), 3.72 (3H, m); MS (FAB) m/z 1094 ([M+Na]+), 1022 ([M-(OCH3+H2O)]+).
b) 40-O-(2-Hydroxy)ethyl-rapamycin
To a stirred, cooled (0°C) solution of 4.5 g (4.2 mmol) of 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl-rapamycin in 20 mL of methanol is added 2 mL of IN HCl. This solution is stirred for 2h and neutralized with aq. sodium bicarbonate. The mixture is extracted with three portions of ethyl acetate. The organic solution is washed with aq.
sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and
concentrated. Purification by column chromatography on silica gel (ethyl acetate) gave the title compound as a white solid:1H NMR (CDCl3) δ 0.72 (1H, dd), 1.65 (3H, s), 1.75 (3H, s), 3.13 (5H, s and m), 3.52-3.91 (8H, m); MS (FAB) m/z 980 ([M+Na]+), 926 ([M-OCH3]+), 908 ([M-(OCH3+H2O)]+), 890 ([M-(OCH3+2H2O)]+), 876 ([M-(2CH3OH+OH)]+), 858 ([M-(OCH3+CH3OH+2H2O)]+).
MBA (rel. IC50) 2.2
IL-6 dep. prol. (rel. IC50) 2.8
MLR (rel. IC50) 3.4
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synthesis
Everolimus (Everolimus) was synthesized by the Sirolimus (sirolimus, also known as rapamycin Rapamycin) ether from. Sirolimus is from the soil bacterium Streptomyces hygroscopicus isolated metabolites. Activation end sirolimus (triflate, Tf) the other end of the protection (t-butyldimethylsilyl, TBS) of ethylene glycol 1 reaction of 2 , because the hydroxyl group 42 hydroxyl site over the 31-bit resistance is small, so the reaction only occurs in 42. Compound 2under acidic conditions TBS protection is removed everolimus.
Xolair gains final NICE approval
NICE is recommending Novartis’ asthma drug Xolair as a cost effective treatment for young children and adults with a severe form of the condition in England.
Novartis’ Xolair (omalizumab) is now recommended as an option for treating severe, persistent confirmed allergic immunoglobulin E (IgE)-mediated asthma in people aged six years and older.
read more at http://www.pharmatimes.com/Article/13-04-24/Xolair_gains_final_NICE_approval.aspx
Omalizumab (trade name Xolair, Roche/Genentech and Novartis) is a humanized antibody approved for patients 12 years and older with moderate to severe allergic asthmain the United States and with severe, persistent allergic asthma in many other countries. It has also been approved for pediatric patients 6 to 11 years old with severe, persistent allergic asthma in the European Union. Omalizumab’s cost is high, ranging from $6,000 to $24,000 a year and hence omalizumab is mainly prescribed for patients with severe, persistent asthma, which cannot be controlled even with high doses of corticosteroids.
Omalizumab is a recombinant DNA-derived humanized IgG1k monoclonal antibody that selectively binds to free human immunoglobulin E (IgE) in the blood and interstitial fluid and to membrane-bound form of IgE (mIgE) on the surface of mIgE-expressing B lymphocytes. Unlike an ordinary anti-IgE antibody, omalizumab does not bind to IgE that is already bound by the high affinity IgE receptor (FcεRI) on the surface of mast cells,basophils, and antigen-presenting dendritic cells. IgE is commonly involved in type I hypersensitivity, which manifests the most prevalent allergic diseases. It has been estimated that as high as 20 to 40% of the populations who live a western lifestyle in economically advanced countries are affected by allergy and seek medical help.[1] While allergy occurs more frequently in individuals with higher serum IgE levels, such a correlation is only statistical and not absolute. Some allergic individuals have very low serum IgE, and some people with very high IgE have no allergic problems.
Xolair received approval by the U.S. Food and Drug Administration (FDA) in 2003 for treating patients 12 years and older with moderate to severe allergic asthma. It has also received approval in many other countries for treating patients 12 years and older with severe, persistent allergic asthma. Xolair was approved by the European Union in 2009 for treating patients 6 to 12 years old with severe, persistent allergic asthma. Thus, the primary use of Xolair is for patients mostly with severe, persistent allergic asthma, uncontrollable with oral or injectable corticosteroids.[2] The efficacy is more evident among severe asthmatics than among those with moderately severe disease. The response rates among treated severe “allergic” asthma patients are 60-80% or higher, probably depending on the patient screening procedures used by the various clinical groups of different specialties. Because 30-40% of adult asthma cases are not related to allergy and unresponsive to Xolair, a reliable way to identify treatable patients has been a subject of considerable research interest. The primary benefits for the responding patients are reduced numbers of exacerbations, improved lung function, reduced numbers of emergency visits to the doctors, reduced days of hospitalization, and increased quality of life measurements. The other major benefit is that most responding patients can reduce or spare entirely the use of corticosteroids, which cause multiple serious side effects, when used at high doses for extended periods.
Due to the requirement for long-term administration and hence the high cost of a Xolair treatment regimen, and to the concern over long-term safety, Xolair treatment is not yet very common, especially in developing countries where medical funds are relatively scarce. Another barrier to Xolair’s wide use is its injectable dosage form, which requires the patient to visit a physician’s office or clinic every 2 to 4 weeks during treatment. In August 2010, the National Institute for Clinical Excellence (NICE) in the United Kingdom ruled that Xolair should not be prescribed on the National Health Service (NHS) to children under 12, causing widespread condemnation from asthma charities.[3] NICE concluded that the high costs of the compound, over £250 per vial, did not represent a sufficiently high increase in quality of life. Additionally, as IgE could be a natural defense against parasitic diseases, treatment is usually not recommended when living in environments where the presence of parasites is common.
The website clinicaltrials.gov reveals that 102 clinical trials on omalizumab on various clinical indications have been finished or are in progress as of June 23, 2012. Among those more than 70 are multi-center, placebo-controlled phase II or III trials.[4] The tested indications are in the areas of allergic asthma, perennial and seasonal allergic rhinitis, peanut allergy, latex allergy, atopic dermatitis,chronic urticaria, idiopathic anaphylaxis, mastocytosis, eosinophilic gastroenteritis, nasal polyposis, and others. The relatively recent clinical trial results, which indicate that omalizumab has excellent effects on patients with recalcitrant, antihistamine-resistant chronic idiopathic urticaria, including those cases of autoimmune cause,[5][6] have generated much excitement among dermatologists as well as patients affected by chronic urticaria. Omalizumab has also been studied in combination with allergen-based specificimmunotherapy (allergy shots) for the purpose of reducing anaphylactic reactions when receiving allergen immunizations and of accelerating immunization schedule and dosing, so as to achieve therapeutic effects in shorter treatment periods and in broader patient populations.[7][8][9]
While data from additional clinical trials are required for omalizumab to be reviewed by governmental regulatory bodies for approval for any of the new indications, the data from finished trials thus far indicate that omalizumab is efficacious and safe for treating various IgE-mediated allergic or non-allergic diseases
- http://www.aaaai.org/about-the-aaaai/newsroom/allergy-statistics.aspx
- Davydov L (January 2005). “Omalizumab (Xolair) for treatment of asthma”. Am Fam Physician 71 (2): 341–2. PMID 15686303.
- “Asthma drug ruling ‘nonsensical'”. BBC News. August 12, 2010.
- http://clinicaltrials.gov/ct2/results?term=omalizumab
- Saini S, Rosen KE, Hsieh HJ, Wong DA, Conner E, Kaplan A, Spector S, Maurer M (September 2011). “A randomized, placebo-controlled, dose-ranging study of single-dose omalizumab in patients with H1-antihistamine-refractory chronic idiopathic urticaria”. J. Allergy Clin. Immunol. 128 (3): 567–73.e1. doi:10.1016/j.jaci.2011.06.010. PMID 21762974.
- Kaplan AP, Joseph K, Maykut RJ, Geba GP, Zeldin RK (September 2008). “Treatment of chronic autoimmune urticaria with omalizumab”. J. Allergy Clin. Immunol. 122 (3): 569–73. doi:10.1016/j.jaci.2008.07.006. PMID 18774392.
- Casale TB, Busse WW, Kline JN, Ballas ZK, Moss MH, Townley RG, Mokhtarani M, Seyfert-Margolis V, Asare A, Bateman K, Deniz Y (January 2006). “Omalizumab pretreatment decreases acute reactions after rush immunotherapy for ragweed-induced seasonal allergic rhinitis”. J. Allergy Clin. Immunol. 117 (1): 134–40. doi:10.1016/j.jaci.2005.09.036. PMID 16387596.
- Kopp MV, Hamelmann E, Zielen S, Kamin W, Bergmann KC, Sieder C, Stenglein S, Seyfried S, Wahn U; DUAL study group (October 2008). “Combination of omalizumab and specific immunotherapy is superior to immunotherapy in patients with seasonal allergic rhinoconjunctivitis and co-morbid seasonal allergic asthma”. Clin Exp Allergy 39 (2): 271–9. doi:10.1111/j.1365-2222.2008.03121.x.PMID 19016798.
- Massanari M, Nelson H, Casale T, Busse W, Kianifard F, Geba GP, Zeldin RK (February 2010). “Effect of pretreatment with omalizumab on the tolerability of specific immunotherapy in allergic asthma”. J. Allergy Clin. Immunol. 125 (2): 383–9.doi:10.1016/j.jaci.2009.11.022. PMID 20159249.
Merck’s Lambrolizumab Designated As A Breakthrough Therapy By FDA
Lambrolizumab
STRUCTURAL FORMULA of Lambrolizumab
Heavy chain
QVQLVQSGVE VKKPGASVKV SCKASGYTFT NYYMYWVRQA PGQGLEWMGG 50
INPSNGGTNF NEKFKNRVTL TTDSSTTTAY MELKSLQFDD TAVYYCARRD 100
YRFDMGFDYW GQGTTVTVSS ASTKGPSVFP LAPCSRSTSE STAALGCLVK 150
DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTKT 200
YTCNVDHKPS NTKVDKRVES KYGPPCPPCP APEFLGGPSV FLFPPKPKDT 250
LMISRTPEVT CVVVDVSQED PEVQFNWYVD GVEVHNAKTK PREEQFNSTY 300
RVVSVLTVLH QDWLNGKEYK CKVSNKGLPS SIEKTISKAK GQPREPQVYT 350
LPPSQEEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS 400
DGSFFLYSRL TVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSLGK 447
Light chain
EIVLTQSPAT LSLSPGERAT LSCRASKGVS TSGYSYLHWY QQKPGQAPRL 50′
LIYLASYLES GVPARFSGSG SGTDFTLTIS SLEPEDFAVY YCQHSRDLPL 100′
TFGGGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV 150′
QWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV 200′
THQGLSSPVT KSFNRGEC 218′
Disulfide bridges
22-96 22”-96” 23′-92′ 23”’-92”’ 134-218′ 134”-218”’ 138′-198′ 138”’-198”’
147-203 147”-203” 226-226” 229-229” 261-321 261”-321” 367-425 367”-425”
Glycosylation sites (N)
Asn-297 Asn-297”
MOLECULAR FORMULA C6504H10004N1716O2036S46 (peptide)
MOLECULAR WEIGHT 146.3 kDa (peptide)
TRADEMARK None as yet
SPONSOR Merck Sharp & Dohme Corp.
CAS REGISTRY NUMBER 1374853-91-4
THERAPEUTIC CLAIM Antineoplastic, immunomodulatory, immunotherapy
CHEMICAL NAMES
1. Immunoglobulin G4, anti-(human protein PDCD1 (programmed cell death 1))
(human-Mus musculus monoclonal heavy chain), disulfide with human-Mus
musculus monoclonal light chain, dimer
2. Immunoglobulin G4, anti-(human programmed cell death 1); humanized
mouse monoclonal [228-L-proline(H10
-S>P)]γ4 heavy chain (134-218′)-disulfide
with humanized mouse monoclonal κ light chain dimer (226-226”:229-229”)-
bisdisulfide
04/24/2013
Merck announced that the U.S. Food and Drug Administration (FDA) has designated lambrolizumab (MK-3475) as a Breakthrough Therapy for the treatment of patients with advanced melanoma. Lambrolizumab is Merck’s investigational antibody therapy targeting the programmed death receptor (PD-1) that is currently being evaluated for the treatment of patients with advanced melanoma, and other tumor types.
Merck & Co. Inc., also known as MSD outisdeUS and Canada, a provider of health solutions through prescription medicines, vaccines, biologic therapies, animal health, and consumer care products, Wednesday announced that the US Food and Drug Administration or FDA has designated its investigational antibody therapy, Lambrolizumab or MK-3475 as a Breakthrough Therapy for the treatment of patients with advanced melanoma, and other tumor types.
The Food and Drug Administration Safety and Innovation Act includes a provision that allows sponsors to request that an investigational drug be designated as a Breakthrough Therapy.
Lambrolizumab is targeting Programmed Death receptor or PD-1 that is currently being evaluated for the treatment of patients with advanced melanoma, and other tumor types. Advanced melanoma accounts for more than 80 percent of skin cancer-related deaths and one to two percent of all cancer deaths in the United States.
Gary Gilliland, senior vice president and oncology franchise head of Merck Research Laboratories stated, “”The FDA’s decision to place lambrolizumab in a category that may enable expedited development and review is an important milestone for Merck as we advance ongoing programs in multiple cancer indications.”
FDA spokeswoman Sandy Walsh noted that “the concept behind ‘breakthrough’ is that, with increased communication, FDA will work with new drug developers to help design efficient ways to study the safety and effectiveness of their drug.” The agency indicated that it has received 45 requests for breakthrough status designation, with 11 requests approved and 18 requests rejected. Other drugs granted breakthrough status include: Johnson & Johnson and Pharmacyclics’ ibrutinib for mantle cell lymphoma and other cancers; Novartis’ LDK378 for certain patients with non-small-cell lung cancer; and Pfizer’s palbociclib for breast cancer.
The Merck drug is an antibody designed to help the body’s immune system go after cancer cells. Lambrolizumab, also known as MK-3475, specifically targets the “programmed death” 1 receptor, or PD-1, which cancer cells can exploit to escape destruction by the immune system. Bristol-Myers Squibb Co. also is developing an anti-PD-1 drug, nivolumab, that is in Phase 3 testing.
image credit http://anewmerckreviewed.wordpress.com/
DRUG SPOTLIGHT –CUBICIN, DAPTOMYCIN
Daptomycin
N-decanoyl-L-tryptophyl-L-asparaginyl-L-aspartyl-L-threonylglycyl-
L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3-methyl-L-glutamyl-3-anthraniloyl-L-alanine[egr]1-lactone
Daptomycin is a lipopeptide antibiotic used in the treatment of systemic and life-threatening infections caused by Gram-positive organisms. It is a naturally occurring compound found in the soil saprotroph Streptomyces roseosporus. Its distinct mechanism of action makes it useful in treating infections caused by multi-resistant bacteria. It is marketed in the United States under the trade name Cubicin by Cubist Pharmaceuticals.
The compound LY 146032 was discovered by researchers at Eli Lilly and Company in the late 1980s.LY 146032 showed promise in Phase I/II clinical trials for treatment of infection caused by Gram-positive organisms. Lilly ceased development because high-dose therapy was associated with adverse effects on skeletal muscle, including myalgia and potential myositis.
The rights to LY 146032 were acquired by Cubist Pharmaceuticals in 1997, which following U.S. Food and Drug Administration (FDA) approval in September 2003 for use in people older than 18 years began marketing the drug under the trade name CUBICIN. Cubicin is marketed in the EU and in several other countries by Novartis following its purchase of Chiron Corporation, previous licensee.
Daptomycin has a distinct mechanism of action, disrupting multiple aspects of bacterial cell membrane function. It appears to bind to the membrane and cause rapid depolarization, resulting in a loss of membrane potential leading to inhibition of protein, DNA and RNA synthesis, which results in bacterial cell death
US HERBS- FIGHT CANCER WITH BROCCOLI
An example of the superfoods is the broccoli. Broccoli belongs to the cruciferous group of vegetables. Naturally, broccoli is an an excellent source of vitamins, minerals and fiber. These are elements from Nature that have been extensively studied.
Epidemiological studies provideevidence that the consumption of this vegetable protects against cancer. The protection against cancer is mainly derived from altering estrogen metabolism and antioxidant properties, enhancing detoxification, decreasing carcinogen coumpound activation, slowing tumor growth and inducing cancer cell apoptosis (death). Such attributes qualify broccoli as a superfood.
American Institute of Cancer Research estimates that a daily intake of three servings would potentially reduce cancer rates by 20%.
Broccoli contains certain chemicals that may reduce the risk of colorectal or other cancers, although it is not clear which individual compounds may be responsible for the protective effects. While research in this area continues, the best advice at this time to reduce cancer risk is to eat a wide variety of vegetables. It is reasonable to include broccoli as part of a balanced diet.
roccoli has been around for more than 2,000 years but has only been commercially grown in the United States since the 1920s. Today, more than 90% of the broccoli harvested in the United States comes from California, although it is also grown in other parts of the country.
About 2 decades ago, researchers first suggested a possible link between diets high in cruciferous vegetables (a group of plants including cauliflower, cabbage, broccoli, and Brussels sprouts)) and a lower risk of cancer. However, it was not until the 1990s that certain chemicals found in broccoli were identified as possible cancer-preventing compounds. In 1997, a study was published that noted broccoli sprouts had higher levels of one of these compounds than mature broccoli.
Broccoli is a plant in the cabbage family, whose large flower head is used as a vegetable. The word broccoli, from the Italian plural of broccolo, refers to “the flowering top of a cabbage”. Broccoli is usually boiled or steamed but may be eaten raw and has become popular as a raw vegetable in hors d’œuvre trays. The leaves may also be eaten.
Broccoli is classified in the Italica cultivar group of the species Brassica oleracea. Broccoli has large flower heads, usually green in color, arranged in a tree-like structure on branchessprouting from a thick, edible stalk. The mass of flower heads is surrounded by leaves. Broccoli most closely resembles cauliflower, which is a different cultivar group of the same species.
Broccoli was derived from cultivated leafy cole crops in the Northern Mediterranean in about the 6th century BCE. Since the Roman Empire, broccoli has been considered a uniquely valuable food among Italians. Broccoli was brought to England from Antwerp in the mid-18th century by Peter Scheemakers. Broccoli was first introduced to the United States by Italian immigrants but did not become widely known there until the 1920s
Broccoli is high in vitamin C and dietary fiber; it also contains multiple nutrients with potent anti-cancer properties, such as diindolylmethane and small amounts of selenium. A single serving provides more than 30 mg of vitamin C and a half-cup provides 52 mg of vitamin C. The 3,3′-Diindolylmethane found in broccoli is a potent modulator of theinnate immune response system with anti-viral, anti-bacterial and anti-cancer activity. Broccoli also contains the compound glucoraphanin, which can be processed into an anti-cancer compound sulforaphane, though the benefits of broccoli are greatly reduced if the vegetable is boiled. Broccoli is also an excellent source of indole-3-carbinol, a chemical which boosts DNA repair in cells and appears to block the growth of cancer cells.
Boiling broccoli reduces the levels of suspected anti-carcinogenic compounds, such as sulforaphane, with losses of 20–30% after five minutes, 40–50% after ten minutes, and 77% after thirty minutes. However, other preparation methods such as steaming,microwaving, and stir frying had no significant effect on the compounds.
Broccoli has the highest levels of carotenoids in the brassica family.[17] It is particularly rich in lutein and also provides a modest amount of beta-carotene.
A high intake of broccoli has been found to reduce the risk of aggressive prostate cancer. Broccoli consumption may also help prevent heart disease.
Broccoli sprouts are often suggested for their health benefits
| Nutritional value per 100 g (3.5 oz) | |
|---|---|
| Energy | 141 kJ (34 kcal) |
| Carbohydrates | 6.64 g |
| – Sugars | 1.7 g |
| – Dietary fiber | 2.6 g |
| Fat | 0.37 g |
| Protein | 2.82 g |
| Water | 89.3 g |
| Vitamin A equiv. | 31 μg (4%) |
| – beta-carotene | 361 μg (3%) |
| – lutein and zeaxanthin | 1403 μg |
| Thiamine (vit. B1) | 0.071 mg (6%) |
| Riboflavin (vit. B2) | 0.117 mg (10%) |
| Niacin (vit. B3) | 0.639 mg (4%) |
| Pantothenic acid (B5) | 0.573 mg (11%) |
| Vitamin B6 | 0.175 mg (13%) |
| Folate (vit. B9) | 63 μg (16%) |
| Vitamin C | 89.2 mg (107%) |
| Vitamin E | 0.78 mg (5%) |
| Vitamin K | 101.6 μg (97%) |
| Calcium | 47 mg (5%) |
| Iron | 0.73 mg (6%) |
| Magnesium | 21 mg (6%) |
| Manganese | 0.21 mg (10%) |
| Phosphorus | 66 mg (9%) |
| Potassium | 316 mg (7%) |
| Zinc | 0.41 mg (4%) |
| Link to USDA Database entry Percentages are relative to US recommendations for adults. Source: USDA Nutrient Database
Broccoli is considered a good source of nutrients because it is rich in vitamin C, carotenoids (vitamin A-like substances), fiber, calcium, and folate. Broccoli is also a source of many substances called phytochemicals, or plant chemicals, that may have anticancer properties. For example, broccoli contains several compounds called isothiocyanates, including sulforaphane and indole-3-carbinol (I3C), which have been touted as possible anti-cancer agents in recent years. Early studies have shown these substances may act as anti-oxidants and may boost detoxifying enzymes in the body. Some studies have also suggested they may alter the levels of estrogen in the body, which might affect breast cancer risk.The chemical composition of broccoli and other cruciferous vegetables is complex, which makes it hard to determine which compound or combination of compounds may provide protection against cancer. Eating a wide variety of plant-based foods may be the best way to get the necessary components.Some researchers suggest that small amounts of broccoli sprouts may protect against the risk of cancer as effectively as much larger amounts of the mature vegetable. We are not aware of any clinical studies that have been done in humans to verify this claim.Another substance in broccoli, indole-3-carbinol (I3C), seems to alter estrogen levels and may also raise levels of protective enzymes in the body. Several studies of cancer cells growing in laboratory dishes or flasks have shown it may slow or stop the growth of breast, prostate, and other cancer cells. Some early studies in animals have shown similar results. Small studies in humans have found it may prevent the development of pre-cancerous growths in the cervix, as well as growths called papillomas in the throat. Again, larger studies are needed to find out what benefits I3C may have against cancer. THE MOLECULES The active molecules are Indole-3-carbinol (1H-indol-3-ylmethanol IUPAC name) OR I3C and isothiocyanates (mostly sulforaphane: 1-Isothiocyanato-4-methylsulfinylbutane). Indole-3-carbinol has a indole with a hydroxymethyl group that represents the hydrophilic group. Sulfurofane is a isothiocyanate, it means that it has a –N=C=S chemical group, formed by substituting sulfur for oxygen in the isocyanate group, bounded to a big alkyl chain containing a sulfinyl S=O group. Both indole-3-carbinol and sulphoraphane derive from glucosinolates. Glucosinolates are a class of organic compounds that contain sulfur and nitrogen and are derived from glucose and an amino acid. They occur as secondary metabolites of almost all plants of the order Brassicales. GENERAL EFFECTS ON HEALTH I3C has been shown to have a chemopreventive action on several human cancers. The first and greatest effects concern breast and cervical estrogen-dependant cancer. Later, many researches managed to relate I3C with the prevention from colon, lung and prostate cancer too. The micronutrient indole-3-carbinol: implications for disease and chemoprevention, 2000 Sulforaphane, like I3C, is useful against many types of cancer. Moreover, it has antimicrobial properties, as it appears to help eradicate Helicobacter Pylori from the stomach. Molecular targets of dietary phenethyl isothiocyanate and sulforaphane for cancer |
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