AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Health Canada Approves Bayer’s Hypertension Drug

 CANADA  Comments Off on Health Canada Approves Bayer’s Hypertension Drug
Sep 242013
 

 

File:Riociguat structure.svg

riociguat

Bayer Inc. announced today that the Health Canada has approved the drug Adempas (riociguat) for the treatment of inoperable, or persistent and recurrent chronic thromboembolic pulmonary hypertension (CTEPH) after surgery in adult patients. Learn more…http://www.dddmag.com/news/2013/09/health-canada-approves-bayers-hypertension-drug?et_cid=3497158&et_rid=523035093&type=headline

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Synthetic drug Tramadol found in nature,pin cushion tree

 Ayurveda, drugs  Comments Off on Synthetic drug Tramadol found in nature,pin cushion tree
Sep 182013
 

The bark of Nauclea latifolia contains tramadol at medicinal concentrations © imagebroker / Alamy

http://www.rsc.org/chemistryworld/2013/09/african-plant-natural-source-tramadol

In another example of nature beating chemists, the African plant Nauclea latifolia has been found to be a natural source of the synthetic opioid tramadol. First marketed in 1977, tramadol is frequently used to relive moderate to moderately-severe pain. While other synthetic drugs have later been found in nature, this is the first instance where the discovery involves clinically viable concentrations.

Colloquially known as the ‘African peach’ or ‘pin cushion tree’, N. latifolia is a flowering, sub-Saharan evergreen that grows widely across Central and West Africa and is used by local populations to treat a wide variety of ailments – including epilepsy, malaria, general pain and many infectious diseases………………………. READ ALL AT

http://www.rsc.org/chemistryworld/2013/09/african-plant-natural-source-tramadol

 

tramadol

tramadol hydrocloride

The chemical name for tramadol hydrochloride is (±)cis-2-[(dimethylamino)methyl]-1-(3methoxyphenyl) cyclohexanol hydrochloride

Tramadol (marketed as the hydrochloride salt by Janssen Pharmaceutica as Ultram in the United States, Ralivia by Biovail in Canada and many other companies throughout the world) is a centrally acting synthetic opioid analgesic used to treat moderate to moderately severe pain. The drug has a wide range of applications, including treatment of rheumatoid arthritis, restless legs syndrome, motor neurone disease and fibromyalgia.[citation needed] It was launched and marketed as Tramal by the German pharmaceutical company Grünenthal GmbH in 1977.

Tramadol is a weak μ-opioid receptor agonist, a serotonin releaser and a reuptake inhibitor of norepinephrine. Tramadol is metabolized to O-desmethyltramadol, a significantly more potent μ-opioid agonist. Tramadol and its major metabolite(s) are distinguished from other more potent opioid agonists by relative selectivity for μ-opioid receptors.

Chemistry

Characteristics

Structurally, tramadol closely resembles a stripped down version of codeine. Both codeine and tramadol share the 3-methyl ether group, and both compounds are metabolized along the same hepatic pathway and mechanism to the stronger opioid, phenol agonist analogs. For codeine, this is morphine, and for tramadol, it is the O-desmethyltramadol.

When administered through IV, patients notice very little clinical difference in subjective potency compared to morphine.

Comparison with related substances

Structurally, tapentadol is the closest chemical relative of tramadol in clinical use. Tapentadol is also an opioid, but unlike both tramadol and venlafaxine, tapentadol represents only one stereoisomer and is the weaker of the two, in terms of opioid effect. Both tramadol and venlafaxine are racemic mixtures. Structurally, tapentadol also differs from tramadol in being a phenol, and not an ether. Also, both tramadol and venlafaxine incorporate a cyclohexyl moiety, attached directly to the aromatic, while tapentadol lacks this feature.

Synthesis and stereoisomerism

(1R,2R)-Tramadol   (1S,2S)-Tramadol
(1R,2R)-Tramadol     (1S,2S)-Tramadol
(1R,2S)-Tramadol   (1S,2R)-Tramadol
(1R,2S)-Tramadol     (1S,2R)-Tramadol

The chemical synthesis of tramadol is described in the literature.[62] Tramadol [2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol] has two stereogenic centers at the cyclohexane ring. Thus, 2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol may exist in four different configurational forms:

  • (1R,2R)-isomer
  • (1S,2S)-isomer
  • (1R,2S)-isomer
  • (1S,2R)-isomer

The synthetic pathway leads to the racemate (1:1 mixture) of (1R,2R)-isomer and the (1S,2S)-isomer as the main products. Minor amounts of the racemic mixture of the (1R,2S)-isomer and the (1S,2R)-isomer are formed as well. The isolation of the (1R,2R)-isomer and the (1S,2S)-isomer from the diastereomeric minor racemate [(1R,2S)-isomer and (1S,2R)-isomer] is realized by the recrystallization of the hydrochlorides. The drug tramadol is a racemate of the hydrochlorides of the (1R,2R)-(+)- and the (1S,2S)-(–)-enantiomers. The resolution of the racemate [(1R,2R)-(+)-isomer / (1S,2S)-(–)-isomer] was described[63] employing (R)-(–)- or (S)-(+)-mandelic acid. This process does not find industrial application, since tramadol is used as a racemate, despite known different physiological effects[64] of the (1R,2R)- and (1S,2S)-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals[65] and in humans.[66]

  1. 62…..Pharmaceutical Substances, Axel Kleemann, Jürgen Engel, Bernd Kutscher and Dieter Reichert, 4. ed. (2000) 2 volumes, Thieme-Verlag Stuttgart (Germany), p. 2085 bis 2086, ISBN 978-1-58890-031-9; since 2003 online with biannual actualizations.
  2. 63………Zynovy, Zinovy; Meckler, Harold (2000). “A Practical Procedure for the Resolution of (+)- and (−)-Tramadol”. Organic Process Research & Development 4 (4): 291–294. doi:10.1021/op000281v.
  3. 64……..Burke D, Henderson DJ (April 2002). “Chirality: a blueprint for the future”. British Journal of Anaesthesia 88 (4): 563–76. doi:10.1093/bja/88.4.563. PMID 12066734.
  4. 65…Raffa, R. B.; Friderichs, E.; Reimann, W.; Shank, R. P.; Codd, E. E.; Vaught, J. L.; Jacoby, H. I.; Selve, N. (1993). “Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol”. The Journal of Pharmacology and Experimental Therapeutics 267 (1): 331–340. PMID 8229760.  
  5. 66 ..Grond, S.; Meuser, T.; Zech, D.; Hennig, U.; Lehmann, K. A. (1995). “Analgesic efficacy and safety of tramadol enantiomers in comparison with the racemate: a randomised, double-blind study with gynaecological patients using intravenous patient-controlled analgesia”. Pain 62 (3): 313–320. doi:10.1016/0304-3959(94)00274-I. PMID 8657431.  
  • tramadol hydrochloride, which is (RR, SS)-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol hydrochloride (trans), from a mixture of its (RS, SR) (cis) and trans bases, and to an improved process for the preparation of tramadol (base) monohydrate, sometimes used as an intermediate in the preparation of tramadol hydrochloride.
  • Tramadol is a well-established drug disclosed in US patent specification no. 3 652 589, which is used in the form of its hydrochloride salt as a non-narcotic analgesic drug. Tramadol is the pharmacologically active trans isomer of 2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol, as opposed to the corresponding cis isomer, namely, (RS, SR)-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol.
  • Various processes for the synthesis of tramadol hydrochloride have been described in the prior art. For example, US 3 652 589 and British patent specification no. 992 399 describe the preparation of tramadol hydrochloride. In this method, Grignard reaction of 2-dimethylaminomethyl cyclohexanone (Mannich base) with metabromo-anisole gives an oily mixture of tramadol and the corresponding cis isomer, along with Grignard impurities. This oily reaction mixture is subjected to high vacuum distillation at high temperature to give both the geometric isomers of the product base as an oil. This oil, on acidification with hydrogen chloride gas, furnishes insufficiently pure tramadol hydrochloride as a solid. This must then be purified, by using a halogenated solvent and 1,4-dioxane, to give sufficiently pure tramadol hydrochloride. The main drawback of this process is the use of large quantities of 1,4-dioxane and the need for multiple crystallizations to get sufficiently pure trans isomer hydrochloride (Scheme – 1).
  • The use of dioxane for the separation of tramadol hydrochloride from the corresponding cis isomer has many disadvantages, such as safety hazards by potentially forming explosive peroxides, and it is also a category 1 carcinogen (Kirk and Othmer, 3rd edition, 17, 48). Toxicological studies of dioxane show side effects such as CNS depression, and necrosis of the liver and kidneys. Furthermore, the content of dioxane in the final tramadol hydrochloride has been strictly limited; for example, the German Drug Codex (Deutscher Arzneimittel Codex, DAC (1991)) restricts the level of dioxane in tramadol hydrochloride to 0.5 parts per million (ppm).

    Figure 00020001
  • In another process, disclosed in US patent specification no. 5 414 129, the purification and separation of tramadol hydrochloride is undertaken from a reaction mixture containing the trans and cis isomers, and Grignard reaction side products, in which the reaction mixture is diluted in isopropyl alcohol and acidified with gaseous hydrogen chloride to yield (trans) tramadol hydrochloride (97.8%) and its cis isomer (2.2%), which is itself crystallized twice with isopropyl alcohol to give pure (trans) tramadol hydrochloride (Scheme – 2). This process relies on the use of multiple solvents to separate the isomers (ie butylacetate, 1-butanol, 1-pentanol, primary amyl alcohol mixture, 1-hexanol, cyclohexanol, 1-octanol, 2-ethylhexanol and anisole). The main drawback of this process is therefore in using high boiling solvents; furthermore, the yields of tramadol hydrochloride are still relatively low and the yield of the corresponding cis hydrochloride is relatively high in most cases.

    Figure 00030001
  • PCT patent specification no. WO 99/03820 describes a method of preparation of tramadol (base) monohydrate, which involves the reaction of Mannich base with metabromo-anisole (Grignard reaction) to furnish a mixture of tramadol base with its corresponding cis isomer and Grignard impurities. This, on treatment with an equimolar quantity of water and cooling to 0 to -5°C, gives a mixture of tramadol (base) monohydrate with the corresponding cis isomer (crude). It is further purified with ethyl acetate to furnish pure (trans) tramadol (base) monohydrate, which is again treated with hydrochloric acid in the presence of a suitable solvent to give its hydrochloride salt (Scheme – 2). The drawback of this method is that, to get pure (trans) tramadol hydrochloride, first is prepared pure (trans) tramadol (base) monohydrate, involving a two-step process, and this is then converted to its hydrochloride salt. The overall yield is low because of the multiple steps and tedious process involved.
  • More recently, a process for the separation of tramadol hydrochloride from a mixture with its cis isomer, using an electrophilic reagent, has been described in US patent specification no. 5 874 620. The mixture of tramadol hydrochloride with the corresponding cis isomer is reacted with an electrophilic reagent, such as acetic anhydride, thionyl chloride or sodium azide, using an appropriate solvent (dimethylformamide or chlorobenzene) to furnish a mixture of tramadol hydrochloride (93.3 to 98.6%) with the corresponding cis isomer (1.4 to 6.66%), (Scheme – 3). The product thus obtained is further purified in isopropyl alcohol to give pure (trans) tramadol hydrochloride. However, the drawback of this process is that a mixture of tramadol base with its cis isomer is first converted into the hydrochloride salts, and this is further reacted with toxic, hazardous and expensive electrophilic reagents to get semi-pure (trans) tramadol hydrochloride. The content of the cis isomer is sufficiently high to require further purification, and this therefore results in a lower overall yield.

 

 

Synthesis and stereoisomerism
The chemical synthesis of tramadol is described in the literature. Tramadol [2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol] has two stereogenic centers at the cyclohexane ring. Thus, 2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol may exist in four different configurational forms:
  • (1R,2R)-isomer
  • (1S,2S)-isomer
  • (1R,2S)-isomer
  • (1S,2R)-isomer

 

The synthetic pathway leads to the racemate (1:1 mixture) of (1R,2R)-isomer and the (1S,2S)-isomer as the main products. Minor amounts of the racemic mixture of the (1R,2S)-isomer and the (1S,2R)-isomer are formed as well. The isolation of the (1R,2R)-isomer and the (1S,2S)-isomer from the diastereomeric minor racemate [(1R,2S)-isomer and (1S,2R)-isomer] is realized by the recrystallization of the hydrochlorides. The drug tramadol is a racemate of the hydrochlorides of the (1R,2R)-(+)- and the (1S,2S)-(–)-enantiomers. The resolution of the racemate [(1R,2R)-(+)-isomer / (1S,2S)-(–)-isomer] was described[62] employing (R)-(–)- or (S)-(+)-mandelic acid. This process does not find industrial application, since tramadol is used as a racemate, despite known different physiological effects of the (1R,2R)- and (1S,2S)-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals and in humans.
……………………………………………………
EP 1346978 A1
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The first generic version of the oral chemotherapy drug Xeloda (capecitabine) has been approved by the U.S. Food and Drug Administration to treat cancers of the colon/rectum or breast

 cancer  Comments Off on The first generic version of the oral chemotherapy drug Xeloda (capecitabine) has been approved by the U.S. Food and Drug Administration to treat cancers of the colon/rectum or breast
Sep 172013
 

capecitabine

154361-50-9

  • R-340, Ro-09-1978, Xeloda

pentyl [1-(3,4-dihydroxy-5-methyltetrahydrofuran-2-yl)-5-fluoro-2-oxo-1H-pyrimidin-4-yl]carbamate

MONDAY Sept. 16, 2013 — The first generic version of the oral chemotherapy drug Xeloda (capecitabine) has been approved by the U.S. Food and Drug Administration to treat cancers of the colon/rectum or breast, the agency said Monday in a news release.

This year, an estimated 142,820 people will be diagnosed with cancer of the colon/rectum, and 50,830 are predicted to die from the disease, the FDA said, citing the U.S. National Cancer Institute. An estimated 232,340 women will be diagnosed with cancer of the breast this year, and some 39,620 will die from it.

The most common side effects of the drug are diarrhea, vomiting; pain, redness, swelling or sores in the mouth; fever and infection, the FDA said.

The agency stressed that approved generics have the same high quality and strength as their brand-name counterparts.

License to produce the generic drug was given to Israel-based Teva Pharmaceuticals. The brand name drug is produced by the Swiss pharma firm Roche.

Capecitabine (INN/kpˈstəbn/ (Xeloda, Roche) is an orally-administeredchemotherapeutic agent used in the treatment of metastatic breast andcolorectal cancers. Capecitabine is a prodrug, that is enzymatically converted to 5-fluorouracil in the tumor, where it inhibits DNA synthesis and slows growth of tumor tissue. The activation of capecitabine follows a pathway with three enzymatic steps and two intermediary metabolites, 5′-deoxy-5-fluorocytidine (5′-DFCR) and 5′-deoxy-5-fluorouridine (5′-DFUR), to form 5-fluorouracil

Indications

Capecitabine is FDA-approved for:

  • Adjuvant in colorectal cancer Stage III Dukes’ C – used as first-line monotherapy.
  • Metastatic colorectal cancer – used as first-line monotherapy, if appropriate.
  • Metastatic breast cancer – used in combination with docetaxel, after failure of anthracycline-based treatment. Also as monotherapy, if the patient has failed paclitaxel-based treatment, and if anthracycline-based treatment has either failed or cannot be continued for other reasons (i.e., the patient has already received the maximum lifetime dose of an anthracycline).

In the UK, capecitabine is approved by the National Institute for Health and Clinical Excellence (NICE) for colon and colorectal cancer, and locally advanced or metastatic breast cancer.[1] On March 29, 2007, the European Commission approved Capecitabine, in combination with platinum-based therapy (with or without epirubicin), for the first-line treatment of advanced stomach cancer.

Capecitabine is a cancer chemotherapeutic agent that interferes with the growth of cancer cells and slows their distribution in the body. Capecitabine is used to treat breast cancer and colon or rectum cancer that has spread to other parts of the body.

Formulation

Capecitabine (as brand-name Xeloda) is available in light peach 150 mg tablets and peach 500 mg tablets.

 

 

WO2009066892A1

Capecitabine is an orally-administered anticancer agent widely used in the treatment of metastatic breast and colorectal cancers. Capecitabine is a ribofuranose-based nucleoside, and has the sterochemical structure of a ribofuranose having an β-oriented 5-fluorocytosine moiety at C-I position.

US Patent Nos. 5,472,949 and 5,453,497 disclose a method for preparing capecitabine by glycosylating tri-O-acetyl-5-deoxy-β-D-ribofuranose of formula I using 5-fluorocytosine to obtain cytidine of formula II; and carbamoylating and hydrolyzing the resulting compound, as shown in Reaction Scheme 1 :

Reaction Scheme 1

Figure imgf000002_0001

1

The compound of formula I employed as an intermediate in Reaction

Scheme 1 is the isomer having a β-oriented acetyl group at the 1 -position, for the reason that 5-fluorocytosine is more reactive toward the β-isomer than the α-isomer in the glycosylation reaction due to the occurrence of a significant neighboring group participation effect which takes place when the protecting group of the 2-hydroxy group is acyl.

Accordingly, β-oriented tri-O-acetyl-5-deoxy-β-D-ribofuranose (formula

I) has been regarded in the conventional art to the essential intermediate for the preparation of capecitabine. However, such a reaction gives a mixture of β- and α-isomers from which cytidine (formula II) must be isolated by an uneconomical step.

Meanwhile, US Patent No. 4,340,729 teaches a method for obtaining capecitabine by the procedure shown in Reaction Scheme 2, which comprises hydrolyzing 1-methyl-acetonide of formula III to obtain a triol of formula IV; acetylating the compound of formula IV using anhydrous acetic anhydride in pyridine to obtain a β-/α-anomeric mixture of tri-O-acetyl-5-deoxy-D-ribofuranose of formula V; conducting vacuum distillation to purify the β-/α-anomeric mixture; and isolating the β-anomer of formula I therefrom:

Reaction Scheme 2

Figure imgf000003_0001

III IV

However, the above method is also hampered by the requirement to perform an uneconomical and complicated recrystallization steps for isolating the β-anomer from the mixture of β-/α-anomers of formula V, which leads to a low yield of only about 35% to 40% (Guangyi Wang et al., J. Med. Chem., 2000, vol. 43, 2566-2574; Pothukuchi Sairam et al., Carbohydrate Research, 2003, vol. 338, 303-306; Xiangshu Fei et al., Nuclear Medicine and Biology, 2004, vol. 31, 1033-1041; and Henry M. Kissman et al., J. Am. Chem. Soc, 1957, vol. 79, 5534-5540).

Further, US Patent No. 5,476,932 discloses a method for preparing capecitabine by subjecting 5′-deoxy-5-fluorocytidine of formula VI to a reaction with pentylchloroformate to obtain the compound of formula VII having the amino group and the 2-,3-hydroxy groups protected with C5Hi1CO2 groups; and removing the hydroxy-protecting groups from the resulting compound, as shown in Reaction Scheme 3 :

Reaction Scheme 3

Figure imgf000004_0001

Vl VII 1

However, this method suffers from a high manufacturing cost and also requires several complicated steps for preparing the 5′-deoxy-5-fluorocytidine of formula VI: protecting the 2-,3-hydroxy groups; conducting a reaction thereof with 5-fluorocytosine; and deprotecting the 2-,3-hydroxy groups.

Accordingly, the present inventors have endeavored to develop an efficient method for preparing capecitabine, and have unexpectedly found an efficient, novel method for preparing highly pure capecitabine using a trialkyl carbonate intermediate, which does not require the uneconomical β-anomer isolation steps.

synthesis

WO2010065586A2

more info and description

Aspects of the present invention relate to capecitabine and processes for the preparation thereof.

The drug compound having the adopted name “capecitabine” has a chemical name 5′-deoxy-5-fluoro-N-[(pentyloxy) carbonyl] cytidine and has structural formula I.

H

Figure imgf000002_0001

OH OH I

This compound is a fluoropyrimidine carbamate with antineoplastic activity. The commercial product XELODA™ tablets from Roche Pharmaceuticals contains either 150 or 500 mg of capecitabine as the active ingredient.

U.S. Patent No. 4,966,891 describes capecitabine generically and a process for the preparation thereof. It also describes pharmaceutical compositions, and methods of treating of sarcoma and fibrosarcoma. This patent also discloses the use of ethyl acetate for recrystallization of capecitabine. The overall process is summarized in Scheme I.

Figure imgf000002_0002

Scheme I

U.S. Patent No. 5,453,497 discloses a process for producing capecitabine that comprises: coupling of th-O-acetyl-5-deoxy-β-D-hbofuranose with 5- fluorocytosine to obtain 2′,3′-di-O-acetyl-5′-deoxy-5-fluorocytidine; acylating a 2′, 3′- di-O-acetyl-5′-deoxy-5-fluorocytidine with n-pentyl chloroformate to form 5′-deoxy- 2′,3′-di-O-alkylcarbonyl-5-fluoro-N-alkyloxycarbonyl cytidine, and deacylating the 2′ and 3′ positions of the carbohydrate moiety to form capecitabine. The overall process is summarized in Scheme II.

Figure imgf000003_0001

Capecitabine

Scheme Il

The preparation of capecitabine is also disclosed by N. Shimma et al., “The Design and Synthesis of a New Tumor-Selective Fluoropyrimidine Carbamate, Capecitabine,” Bioorganic & Medicinal Chemistry, Vol. 8, pp. 1697-1706 (2000). U.S. Patent No. 7,365,188 discloses a process for the production of capecitabine, comprising reacting 5-fluorocytosine with a first silylating agent in the presence of an acid catalyst under conditions sufficient to produce a first silylated compound; reacting the first silylated compound with 2,3-diprotected-5- deoxy-furanoside to produce a coupled product; reacting the coupled product with a second silylating agent to produce a second silylated product; acylating the second silylated product to produce an acylated product; and selectively removing the silyl moiety and hydroxyl protecting groups to produce capecitabine. The overall process is summarized in Scheme III. te

Figure imgf000004_0001

R: hydrocarbyl

Figure imgf000004_0002

Scheme III

Further, this patent discloses crystallization of capecitabine, using a solvent mixture of ethyl acetate and n-heptane. International Application Publication No. WO 2005/080351 A1 describes a process for the preparation of capecitabine that involves the refluxing N4– pentyloxycarbonyl-5-fluorocytosine with trimethylsiloxane, hexamethyl disilazanyl, or sodium iodide with trimethyl chlorosilane in anhydrous acetonitrile, dichloromethane, or toluene, and 5-deoxy-1 ,2,3-tri-O-acetyl-D-ribofuranose, followed by hydrolysis using ammonia/methanol to give capecitabine. The overall process is summarized in Scheme IV.

Figure imgf000004_0003

Scheme IV

International Application Publication No. WO 2007/009303 A1 discloses a method of synthesis for capecitabine, comprising reacting 5′-deoxy-5- fluorocytidine using double (trichloromethyl) carbonate in an inert organic solvent and organic alkali to introduce a protective lactone ring to the hydroxyl of the saccharide moiety; reacting the obtained compound with chloroformate in organic alkali; followed by selective hydrolysis of the sugar component hydrolytic group using an inorganic base to give capecitabine. The overall process is summarized in Scheme V.

Figure imgf000005_0001

Scheme V

Even though all the above documents collectively disclose various processes for the preparation of capecitabine, removal of process-related impurities in the final product has not been adequately addressed. Impurities in any active pharmaceutical ingredient (API) are undesirable, and, in extreme cases, might even be harmful to a patient. Furthermore, the existence of undesired as well as unknown impurities reduces the bioavailability of the API in pharmaceutical products and often decreases the stability and shelf life of a pharmaceutical dosage form.

nmr

1H NMR(CD3OD) δ 0.91(3H5 t), 1.36~1.40(4H, m), 1.41(3H, d), 1.68~1.73(2H, m), 3.72(1H, dd), 4.08(1H, dd), 4.13~4.21(3H, m), 5.7O(1H, s), 7.96(1H, d)

 

  • The acetylation of 5′-deoxy-5-fluorocytidine (I) with acetic anhydride in dry pyridine gives 2′,3′-di-O-acetyl-5′-deoxy-5-fluorocytidine (II), which is condensed with pentyl chloroformate (III) by means of pyridine in dichromethane yielding 2′,3′-di-O-acetyl-5′-deoxy-5-fluoro-N4-(pentyloxycarbonyl)cytidine (IV). Finally, this compound is deacetylated with NaOH in dichloromethane/water. The diacetylated cytidine (II) can also be obtained by condensation of 5-fluorocytosine (V) with 1,2,3-tri-O-acetyl-5-deoxy-beta-D-ribofuranose (VI) by means of trimethylchlorosilane in acetonitrile or HMDS and SnCl4 in dichloromethane..
    • EP 602454, JP 94211891, US 5472949.
      • Capecitabine. Drugs Fut 1996, 21, 4, 358,
        • Bioorg Med Chem Lett2000,8,(7):1697,
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ESCITALOPRAM

 GENERIC, Uncategorized  Comments Off on ESCITALOPRAM
Sep 152013
 

File:Escitalopram structure.svg

128196-01-0 ESCITALOPRAM

Escitalopram (also known under various trade names) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults and children over 12 years of age with major depressive disorder and generalized anxiety disorder. Escitalopram is the (S)-stereoisomer (enantiomer) of the earlier Lundbeck drug citalopram, hence the name escitalopram. Escitalopram is noted for its high selectivity with serotonin reuptake inhibition. The similarity between escitalopram and citalopram has led to accusations of “evergreening“, an accusation that Lundbeck has rejected.[1]

Escitalopram has FDA approval for the treatment of major depressive disorder and generalized anxiety disorder in adults.[2]

Off-label uses

Escitalopram is sometimes prescribed off-label for the treatment of other conditions: social anxiety disorder,[3] panic disorder[4]and obsessive-compulsive disorder.[5] There is some evidence favouring escitalopram over the antidepressants citalopram andfluoxetine in the first two weeks of major depression.[6] Concerns of sponsorship bias with the studies are however noted.[6] In another review escitalopram and sertraline had the highest rate of efficacy and acceptability among adults receiving treatment for major depression with second-generation antidepressants.[7]

Efficacy

There is some controversy over selective publishing of SSRI clinical trials.[8] A meta-analysis analyzing published as well as unpublished trials found placebos to be similarly effective to SSRIs in treating mild depression, although SSRIs were more effective than placebo in more severe cases, with the magnitude of SSRI superiority increasing with increasing depression severity.[9]

A series of randomized, double-blind trials have found Escitalopram to be more efficacious and have fewer adverse effects than Citalopram.[10][11][12][13] Meta-analysis show a “small” but statistically significant improvement in effect strength [14][15] and some dispute these findings.[16]

Pharmacology

Cipralex brand escitalopram 10mg package and tablet sheet

Escitalopram increases intrasynaptic levels of the neurotransmitter serotonin by blocking the reuptake of the neurotransmitter into the presynaptic neuron. Of the SSRIs currently on the market, escitalopram has the highest affinity for the human serotonin transporter (SERT). The enantiomer of escitalopram ((R)-citalopram) counteracts to a certain degree the serotonin-enhancing action of escitalopram. As a result, escitalopram has been claimed to be a more potent antidepressant than citalopram, which is a mixture of escitalopram and (R)-citalopram. In order to explain this phenomenon, researchers from Lundbeck proposed that escitalopram enhances its own binding via an additional interaction with another allosteric site on the transporter.[42] Further research by the same group showed that (R)-citalopram also enhances binding of escitalopram,[43] and therefore the allosteric interaction cannot explain the observed counteracting effect. In the most recent paper, however, the same authors again reversed their findings and reported that R-citalopram decreases binding of escitalopram to the transporter.[44] Although allosteric binding of escitalopram to the serotonin transporter is of unquestionable research interest, its clinical relevance is unclear since the binding of escitalopram to the allosteric site is at least 1000 times weaker than to the primary binding site.

In vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of escitalopram. The resulting metabolites, desmethylescitalopram and didesmethylescitalopram, are significantly less active and their contribution to the overall action of escitalopram is negligible.

History

Escitalopram was developed in close cooperation between Lundbeck and Forest Laboratories. Its development was initiated in the summer of 1997, and the resulting new drug application was submitted to the U.S. FDA in March 2001. The short time (3.5 years) it took to develop escitalopram can be attributed to the previous extensive experience of Lundbeck and Forest with citalopram, which has similar pharmacology.[45] The FDA issued the approval of escitalopram for major depression in August 2002 and for generalized anxiety disorder in December 2003. Escitalopram can be considered an example of “evergreening[46] (also called “lifecycle management”[47])– the long-term strategy pharmaceutical companies use in order to extend the lifetime of a drug, in this case of the citalopram franchise. Escitalopram is an enantiopure compound of theracemic mixture citalopram, used for the same indication, and for that reason it required less investment and less time to develop. Two years after escitalopram’s launch, when the patent on citalopram expired, the escitalopram sales successfully made up for the loss. On May 23, 2006, the FDA approved a generic version of escitalopram by Teva.[48]On July 14 of that year, however, the U.S. District Court of Delaware decided in favor of Lundbeck regarding the patent infringement dispute and ruled the patent on escitalopram valid.[49]

In 2006 Forest Laboratories was granted an 828 day (2 years and 3 months) extension on its US patent for escitalopram.[50] This pushed the patent expiration date from December 7, 2009 to September 14, 2011. Together with the 6-month pediatric exclusivity, the final expiration date was March 14, 2012.

Brand names

Escitalopram is sold under the following brand names:

  • Animaxen (Colombia)
  • Anxiset-E (India)
  • Cipralex
  • Escital (Nigeria)
  • Citalin
  • Citram (Croatia)
  • Ecytara (Slovenia)
  • Elicea
  • Entact (Greece)
  • Escitalopram Actavis (Finland)
  • Escitil (Czech Republic)
  • Esitalo (Australia)
  • Esopram, by Actavis (Iceland)
  • Esto (Israel)
  • Escitalopram Teva (Israel)
  • Exodus (Brazil)
  • Lexam
  • Lexamil (South Africa)
  • Lexapro
  • Losita (Bangladesh)
  • Nexito
  • Reposil (Chile)
  • Selectra (Russia)
  • Selpram (Pakistan)
  • Seroplex
  • Sipralexa (Belgium)

References

  1. a b c NHS pays millions of pounds more than it needs to for drugsThe Independent. Retrieved 05/10/2011.
  2. ^ “Escitalopram Oxalate”. The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
  3. ^ Kasper, S; Stein, DJ; Loft, H; Nil, R (2005). “Escitalopram in the treatment of social anxiety disorder: Randomised, placebo-controlled, flexible-dosage study”. The British journal of psychiatry : the journal of mental science 186 (3): 222–6.doi:10.1192/bjp.186.3.222PMID 15738503.
  4. ^ Stahl, SM; Gergel, I; Li, D (2003). “Escitalopram in the treatment of panic disorder: A randomized, double-blind, placebo-controlled trial”. The Journal of clinical psychiatry 64(11): 1322–7. PMID 14658946.
  5. ^ Stein, DJ; Andersen, EW; Tonnoir, B; Fineberg, N (2007). “Escitalopram in obsessive-compulsive disorder: A randomized, placebo-controlled, paroxetine-referenced, fixed-dose, 24-week study”. Current medical research and opinion 23 (4): 701–11. doi:10.1185/030079907X178838PMID 17407626.
  6. a b Cipriani, A; Santilli C; Furukawa TA; Signoretti A; Nakagawa A; McGuire H; Churchill R; Barbui C (2009 April 15). “Escitalopram versus other antidepressant agents for depression”. In Cipriani, Andrea. Cochrane database of systematic reviews(2): CD006532. doi:10.1002/14651858.CD006532.pub2PMID 19370639. CD006532.
  7. ^ Cipriani, A; Furukawa TA; Salanti G; Geddes JR; Higgins JP; Churchill R; Watanabe N; Nakagawa A; Omori IM; McGuire H; Tansella M; Barbui C (2009 February 28). “Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis”. Lancet 373 (9665): 746–58. doi:10.1016/S0140-6736(09)60046-5PMID 19185342.
  8. ^ Ioannidis JP (2008). “Effectiveness of antidepressants: an evidence myth constructed from a thousand randomized trials?”Philos Ethics Humanit Med 3: 14.doi:10.1186/1747-5341-3-14PMC 2412901PMID 18505564.
  9. ^ Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD, Shelton RC, Fawcett J (January 2010). “Antidepressant drug effects and depression severity: a patient-level meta-analysis”. JAMA 303 (1): 47–53. doi:10.1001/jama.2009.1943.PMID 20051569.
  10. ^ Ou, JJ; Xun, GL; Wu, RR; Li, LH; Fang, MS; Zhang, HG; Xie, SP; Shi, JG; Du, B; Yuan, XQ; Zhao, JP (2011 Feb). “Efficacy and safety of escitalopram versus citalopram in major depressive disorder: a 6-week, multicenter, randomized, double-blind, flexible-dose study.”. Psychopharmacology 213 (2-3): 639–46. doi:10.1007/s00213-010-1822-yPMID 20340011|accessdate= requires |url= (help)
  11. ^ Yevtushenko, VY; Belous, AI; Yevtushenko, YG; Gusinin, SE; Buzik, OJ; Agibalova, TV (2007 Nov). “Efficacy and tolerability of escitalopram versus citalopram in major depressive disorder: a 6-week, multicenter, prospective, randomized, double-blind, active-controlled study in adult outpatients.”. Clinical therapeutics 29 (11): 2319–32.PMID 18158074.
  12. ^ Colonna, L; Andersen, HF; Reines, EH (2005 Oct). “A randomized, double-blind, 24-week study of escitalopram (10 mg/day) versus citalopram (20 mg/day) in primary care patients with major depressive disorder.”. Current medical research and opinion 21(10): 1659–68. PMID 16238906.
  13. ^ Moore, N; Verdoux, H; Fantino, B (2005 May). “Prospective, multicentre, randomized, double-blind study of the efficacy of escitalopram versus citalopram in outpatient treatment of major depressive disorder.”. International clinical psychopharmacology 20 (3): 131–7. PMID 15812262.
  14. ^ Montgomery, Stuart; Hansen, Thomas; Kasper, Siegfried (28 September 2010). “Efficacy of escitalopram compared to citalopram: a meta-analysis”. The International Journal of Neuropsychopharmacology 14 (02): 261–268.doi:10.1017/S146114571000115XPMID 20875220.
  15. ^ Gorman, JM; Korotzer, A; Su, G (2002 Apr). “Efficacy comparison of escitalopram and citalopram in the treatment of major depressive disorder: pooled analysis of placebo-controlled trials.”. CNS spectrums 7 (4 Suppl 1): 40–4. PMID 15131492.
  16. ^ Trkulja, V (2010 Feb). “Is escitalopram really relevantly superior to citalopram in treatment of major depressive disorder? A meta-analysis of head-to-head randomized trials.”Croatian medical journal 51 (1): 61–73. PMID 20162747.
  17. ^ “Citalopram and escitalopram: QT interval prolongation—new maximum daily dose restrictions (including in elderly patients), contraindications, and warnings”.Medicines and Healthcare products Regulatory Agency. December 2011. Retrieved March 5, 2013.
  18. ^ Van Gorp, Freek; Whyte, Ian M.; Isbister, Geoffrey K. (2009). “Clinical and ECG Effects of Escitalopram Overdose”Annals of Emergency Medicine 54 (3): 404–8.doi:10.1016/j.annemergmed.2009.04.016PMID 19556032.
  19. ^ FDA Center for Drug Evaluation and Research (2001). “Review and evaluation of clinical data for application 21-323”. Retrieved 2009-12-03.
  20. ^ Bolton JM, Sareen J, Reiss JP (2006). “Genital anesthesia persisting six years after sertraline discontinuation”. J Sex Marital Ther 32 (4): 327–30.doi:10.1080/00926230600666410PMID 16709553.
  21. ^ Clayton A, Keller A, McGarvey EL (2006). “Burden of phase-specific sexual dysfunction with SSRIs”. Journal of Affective Disorders 91 (1): 27–32.doi:10.1016/j.jad.2005.12.007PMID 16430968.
  22. ^ Lexapro prescribing information
  23. ^ Csoka AB, Bahrick AS, Mehtonen O-P (2008). “Persistent Sexual Dysfunction after Discontinuation of Selective Serotonin Reuptake Inhibitors (SSRIs)”. J Sex Med. 5 (1): 227–33. doi:10.1111/j.1743-6109.2007.00630.xPMID 18173768.
  24. ^ Baldwin DS, Reines EH, Guiton C, Weiller E (2007). “Escitalopram therapy for major depression and anxiety disorders”. Ann Pharmacother 41 (10): 1583–92.doi:10.1345/aph.1K089PMID 17848424.
  25. ^ Pigott TA, Prakash A, Arnold LM, Aaronson ST, Mallinckrodt CH, Wohlreich MM (2007). “Duloxetine versus escitalopram and placebo: an 8-month, double-blind trial in patients with major depressive disorder”. Curr Med Res Opin 23 (6): 1303–18.doi:10.1185/030079907X188107PMID 17559729.
  26. ^ Davidson JR, Bose A, Wang Q (2005). “Safety and efficacy of escitalopram in the long-term treatment of generalized anxiety disorder”. J Clin Psychiatry 66 (11): 1441–6.doi:10.4088/JCP.v66n1115PMID 16420082.
  27. ^ Kasper S, Lemming OM, de Swart H (2006). “Escitalopram in the long-term treatment of major depressive disorder in elderly patients”. Neuropsychobiology 54 (3): 152–9. doi:10.1159/000098650PMID 17230032.
  28. ^ Guerdjikova, AI; McElroy SL, Kotwal R, et al. (January 2008). “High-dose escitalopram in the treatment of binge-eating disorder with obesity: a placebo-controlled monotherapy trial”. Human Psychopharmacology: Clinical and Experimental23 (1): 1–11. doi:10.1002/hup.899PMID 18058852.
  29. ^ Levenson M, Holland C. “Antidepressants and Suicidality in Adults: Statistical Evaluation. (Presentation at Psychopharmacologic Drugs Advisory Committee; December 13, 2006)”. Retrieved 2007-05-13.
  30. ^ Stone MB, Jones ML (2006-11-17). “Clinical Review: Relationship Between Antidepressant Drugs and Suicidality in Adults” (PDF). Overview for December 13 Meeting of Pharmacological Drugs Advisory Committee (PDAC). FDA. pp. 11–74. Retrieved 2007-09-22.
  31. ^ Levenson M; Holland C (2006-11-17). “Statistical Evaluation of Suicidality in Adults Treated with Antidepressants” (PDF). Overview for December 13 Meeting of Pharmacological Drugs Advisory Committee (PDAC). FDA. pp. 75–140. Retrieved 2007-09-22.
  32. ^ Gunnell D, Saperia J, Ashby D (2005). “Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company data from placebo controlled, randomized controlled trials submitted to the MHRA’s safety review”BMJ330 (7488): 385. doi:10.1136/bmj.330.7488.385PMC 549105PMID 15718537.
  33. ^ Khan A, Schwartz K (2007). “Suicide risk and symptom reduction in patients assigned to placebo in duloxetine and escitalopram clinical trials: analysis of the FDA summary basis of approval reports”. Ann Clin Psychiatry 19 (1): 31–6.doi:10.1080/10401230601163550PMID 17453659.
  34. ^ Budur, Kumar; Hutzler, Jeffrey (June 2004). “Severe suicidal ideation with escitalopram (Lexapro): a case report”. Primary Care Psychiatry 9 (2): 67–68.doi:10.1185/135525704125004222.
  35. ^ Karch, Amy (2006). 2006 Lippincott’s Nursing Drug Guide. Philadelphia, Baltimore, New York, London, Buenos Aires, Hong Kong, Sydney, Tokyo: Lippincott Williams & Wilkins. ISBN 1-58255-436-6.
  36. ^ Malling, D.; Poulsen, M.; Søgaard, B. (2005). “The effect of cimetidine or omeprazole on the pharmacokinetics of escitalopram in healthy subjects”British Journal of Clinical Pharmacology 60 (3): 287–290. doi:10.1111/j.1365-2125.2005.02423.x.PMC 1884771PMID 16120067edit
  37. ^ “Lexapro – Warnings”. RxList. 12/08/2004. Retrieved 2006-10-22.
  38. ^ Alwan S, Reefhuis J, Rasmussen SA, Olney RS, Friedman JM, for the National Birth Defects Prevention Study. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med 2007;356:2684–92.
  39. ^ van Gorp F, Whyte IM, Isbister GK. Clinical and ECG effects of escitalopram overdose. Ann. Emer. Med. 54: 404-408, 2009.
  40. ^ Haupt D. Determination of citalopram enantiomers in human plasma by liquid chromatographic separation on a Chiral-AGP column. J. Chrom. B 685: 299-305, 1996.
  41. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 552-553.
  42. ^ For an overview of supporting data, see Sánchez C, Bøgesø KP, Ebert B, Reines EH, Braestrup C (2004). “Escitalopram versus citalopram: the surprising role of the R-enantiomer”. Psychopharmacology (Berl.) 174 (2): 163–76. doi:10.1007/s00213-004-1865-zPMID 15160261.
  43. ^ Chen F, Larsen MB, Sánchez C, Wiborg O (2005). “The (S)-enantiomer of (R,S)-citalopram, increases inhibitor binding to the human serotonin transporter by an allosteric mechanism. Comparison with other serotonin transporter inhibitors”.European Neuropsychopharmacology 15 (2): 193–198.doi:10.1016/j.euroneuro.2004.08.008PMID 15695064.
  44. ^ Mansari ME, Wiborg O, Mnie-Filali O, Benturquia N, Sánchez C, Haddjeri N (2007). “Allosteric modulation of the effect of escitalopram, paroxetine and fluoxetine: in-vitro and in-vivo studies”. The International Journal of Neuropsychopharmacology 10 (1): 31–40. doi:10.1017/S1461145705006462PMID 16448580.
  45. ^ “2000 Annual Report. p 28 and 33” (PDF). Lundbeck. 2000. Retrieved 2007-04-07.
  46. ^ “”New drugs from old”. Presented at the Medical Journal Club, Morriston Hospital, by Scott Pegler, pharmacist at the National Health Service, UK, on November 20, 2006.” (PPT). Retrieved 2007-04-07.
  47. ^ “New drugs from old”Drug and Therapeutics Bulletin (BMJ Publishing Group Ltd.)44 (10): 73–77. 2006. doi:10.1136/dtb.2006.441073PMID 17067118.
  48. ^ Miranda Hitti. “FDA OKs Generic Depression Drug – Generic Version of Lexapro Gets Green Light”. WebMD. Retrieved 2007-10-10.
  49. ^ Marie-Eve Laforte (2006-07-14). “US court upholds Lexapro patent”. FirstWord. Retrieved 2007-10-10.
  50. ^ “Forest Laboratories Receives Patent Term Extension for Lexapro” (Press release). PRNewswire-FirstCall. 2006-03-02. Retrieved 2009-01-19.
  51. ^ Harris, “A Drug Maker’s Playbook Reveals a Marketing Strategy”
  52. ^ Lexapro Fiscal 2004 Marketing Plan
  53. ^ “Forest Laboratories: A Tale of Two Whistleblowers” article by Alison Frankel inThe American Lawyer February 27, 2009
  54. ^ United States of America v. Forest Laboratories Full text of the federal complaint filed in the US District Court for the district of Massachusetts
  55. ^ “Drug Maker Is Accused of Fraud” article by Barry Meier and Benedict Carey inThe New York Times February 25, 2009
  56. ^ “Forest Laboratories, Inc. Provides Statement in Response to Complaint Filed by U.S. Government” Forest press-release. February 26, 2009.

 

 

 

Full-size image (17 K)

http://www.sciencedirect.com/science/article/pii/S0040402011015249

 

http://www.sciencedirect.com/science/article/pii/S0040402011015249

 

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Turmeric Extract 100% Effective At Preventing Type 2 Diabetes, ADA Journal Study Finds

 diabetes  Comments Off on Turmeric Extract 100% Effective At Preventing Type 2 Diabetes, ADA Journal Study Finds
Aug 312013
 

A remarkable human clinical study published in the journal Diabetes Care, the journal of the American Diabetes Association, revealed that turmeric extract was 100% successful at preventing prediabetic patients from becoming diabetic over the course of a 9-month intervention.[1]

Performed by Thailand researchers, the study’s primary object was to assess the efficacy of curcumin, the primary polyphenol in turmeric which gives the spice its golden hue, in delaying the development of type 2 diabetes mellitus (T2DM) in a prediabetic population.http://www.greenmedinfo.com/blog/turmeric-extract-100-effective-preventing-type-2-diabetes-ada-journal-study-finds

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Experimental Drug Shows Promise for Rare Genetic Disorder

 Uncategorized  Comments Off on Experimental Drug Shows Promise for Rare Genetic Disorder
Aug 302013
 

Transthyretin, or TTR for amyloidosis

THURSDAY Aug. 29, 2013 — A new medication appears to be highly effective in combating a heredity-based form of the organ-damaging genetic disorder known as amyloidosis, according to researchers.

Amyloidosis refers to a family of more than a dozen diseases in which different types of abnormal proteins called amyloids lodge in major organs and nerves. These amyloids build up to the point that they cause damage and, ultimately, organ failure.

read all at

http://www.drugs.com/news/experimental-shows-promise-rare-genetic-disorder-47059.html

 

Transthyretin (TTR) is a serum and cerebrospinal fluid carrier of the thyroid hormone thyroxine (T4) and retinol-binding protein bound to retinol. This is how transthyretin gained its name, transports thyroxine and retinol. The liver secretes transthyretin into the blood, and the choroid plexus secretes TTR into thecerebrospinal fluid.

TTR was originally called prealbumin[1] (or thyroxine-binding prealbumin) because it ran faster than albumin on electrophoresis gels.

Binding affinities

It functions in concert with two other thyroid hormone-binding proteins in the serum:

Protein Binding strength Plasma concentration
thyroxine-binding globulin (TBG) highest lowest
transthyretin (TTR) lower higher
albumin poorest much higher

In cerebrospinal fluid TTR is the primary carrier of T4. TTR also acts as a carrier ofretinol (vitamin A) through its association with retinol-binding protein (RBP) in the blood and the CSF. Less than 1% of TTR’s T4 binding sites are occupied in blood, which is taken advantage of below to prevent TTRs dissociation, misfolding and aggregation which leads to the degeneration of post-mitotic tissue.

Numerous other small molecules are known to bind in the thyroxine binding sites, including many natural products (such as resveratrol), drugs (Tafamidis,[2] or Vyndaqel, diflunisal,[3][4][5] flufenamic acid),[6] and toxins (PCB[7]).

Structure

TTR is a 55kDa homotetramer with a dimer of dimers quaternary structure that is synthesized in the liverchoroid plexus and retinal pigment epithelium for secretion into the bloodstream, cerebrospinal fluid and the eye, respectively. Each monomer is a 127-residue polypeptide rich in beta sheet structure. Association of two monomers via their edge beta-strands forms an extended beta sandwich. Further association of two of these dimers in a face-to-face fashion produces the homotetrameric structure and creates the two thyroxine binding sites per tetramer. This dimer-dimer interface, comprising the two T4 binding sites, is the weaker dimer-dimer interface and is the one the comes apart first in the process of tetramer dissociation.[8]

  1.  Prealbumin at the US National Library of Medicine Medical Subject Headings (MeSH)
  2. a b Razavi H, Palaninathan SK, Powers ET, Wiseman RL, Purkey HE, Mohamedmohaideen NN, Deechongkit S, Chiang KP, Dendle MT, Sacchettini JC, Kelly JW (June 2003). “Benzoxazoles as transthyretin amyloid fibril inhibitors: synthesis, evaluation, and mechanism of action”. Angew. Chem. Int. Ed. Engl. 42 (24): 2758–61.doi:10.1002/anie.200351179PMID 12820260.
  3. ^ Sekijima Y, Dendle MA, Kelly JW (December 2006). “Orally administered diflunisal stabilizes transthyretin against dissociation required for amyloidogenesis”. Amyloid 13 (4): 236–49. doi:10.1080/13506120600960882.PMID 17107884.
  4. ^ Adamski-Werner SL, Palaninathan SK, Sacchettini JC, Kelly JW (January 2004). “Diflunisal analogues stabilize the native state of transthyretin. Potent inhibition of amyloidogenesis”. J. Med. Chem. 47 (2): 355–74. doi:10.1021/jm030347n.PMID 14711308.
  5. ^ Vilaro M, Arsequell G, Valencia G, Ballesteros A, Barluenga J, Nieto J, Planas A, Almeida R, Saraiva MJ (2007). “Reengineering TTR amyloid inhibition properties of diflunisal”. In Seldin DC, Skinner M, Berk JL, Connors LH. XIth International Symposium on Amyloidosis. Boca Raton: CRC.doi:10.1201/9781420043358.ch69ISBN 1-4200-4281-5.
  6. ^ Baures PW, Oza VB, Peterson SA, Kelly JW (July 1999). “Synthesis and evaluation of inhibitors of transthyretin amyloid formation based on the non-steroidal anti-inflammatory drug, flufenamic acid”. Bioorg. Med. Chem. 7 (7): 1339–47.doi:10.1016/S0968-0896(99)00066-8PMID 10465408.
  7. ^ Purkey HE, Palaninathan SK, Kent KC, Smith C, Safe SH, Sacchettini JC, Kelly JW (December 2004). “Hydroxylated polychlorinated biphenyls selectively bind transthyretin in blood and inhibit amyloidogenesis: rationalizing rodent PCB toxicity”.Chem. Biol. 11 (12): 1719–28.doi:10.1016/j.chembiol.2004.10.009PMID 15610856.
  8. ^ Foss TR, Wiseman RL, Kelly JW (November 2005). “The pathway by which the tetrameric protein transthyretin dissociates”. Biochemistry 44 (47): 15525–33.doi:10.1021/bi051608tPMID 16300401.

 

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Single molecule fights heart disease on two fronts

 Uncategorized  Comments Off on Single molecule fights heart disease on two fronts
Aug 212013
 

 

1-Fe
Could antioxidant that also inhibits cholesterol biosynthesis be more effective than statins?
Researchers in Israel have identified an antioxidant that can lower cholesterol levels as well as eliminating free radicals. This compound could be a promising alternative to statins, the most prescribed cholesterol-lowering drugs in the world.

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Indian U-turn on diabetes drug ban

 Uncategorized  Comments Off on Indian U-turn on diabetes drug ban
Aug 212013
 

pioglitazone

Pioglitazone increases the body’s sensitivity to insulin

Suspension of cheap and popular medicine reversed but will now come with new safety warnings

http://www.rsc.org/chemistryworld/2013/08/india-u-turn-diabetes-pioglitazone-drug-ban

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Roche’s new skin cancer drug now available in UK

 Uncategorized  Comments Off on Roche’s new skin cancer drug now available in UK
Aug 212013
 

AUGUST 20, 2013

Roche's new skin cancer drug now available in UK

UK patients with a certain type of skin cancer can now get access to Roche’s once-daily pill Erivedge following its launch in the country.

Erivedge(vismodegib)胶囊

Erivedge (vismodegib) is the first medicine available in the UK for the treatment of patients with symptomatic metastatic basal cell carcinoma (BCC) or locally advanced BCC that is unsuitable for surgery or radiotherapy.

http://www.pharmatimes.com/Article/13-08-20/Roche_s_new_skin_cancer_drug_now_available_in_UK.aspx

 

Erivedge(vismodegib)胶囊

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Brain Cancer Survival Improved Following FDA Approval of Bevacizumab, Mayo Study Finds

 Uncategorized  Comments Off on Brain Cancer Survival Improved Following FDA Approval of Bevacizumab, Mayo Study Finds
Aug 202013
 

 

ROCHESTER, Minn. — A new population-based study has found that patients with glioblastoma who died in 2010, after the Food and Drug Administration (FDA) approval of bevacizumab, had lived significantly longer than patients who died of the disease in 2008, prior to the conditional approval of the drug for the treatment of the deadly brain cancer. Bevacizumab is used to treat patients with certain cancers whose cancer has spread. The study appears in the journal Cancer

http://www.pharmalive.com/study-brain-cancer-survival-improved-following-fda-approval-of-avastin

STR REF –http://www.kidneycancerinstitute.com/Bevacizumab.html

IN CASE U NEED TO CONTACT ME THEN MAIL ME. amcrasto@gmail.com

Bevacizumab (trade name AvastinGenentech/Roche) is an angiogenesis inhibitor, a drug that slows the growth of new blood vessels. It is licensed to treat various cancers, including colorectal, lung, breast (outside the USA), glioblastoma (USA only), kidney and ovarian.

Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor A (VEGF-A). VEGF-A is a chemical signal that stimulates angiogenesis in a variety of diseases, especially in cancer. Bevacizumab was the first clinically availableangiogenesis inhibitor in the United States.


Bevacizumab was approved by the U.S. Food and Drug Administration (FDA) for certainmetastatic cancers. It received its first approval in 2004, for combination use with standardchemotherapy for metastatic colon cancer.It has since been approved for use in certain lung cancers, renal cancers, and glioblastoma multiforme of the brain.

At one point bevacizumab was approved for breast cancer by the FDA, but the approval was revoked on 18 November 2011. The approval for breast cancer was revoked because, although there was evidence that it slowed progression of metastatic breast cancer, there was no evidence that it extended life or improved quality of life, and it caused adverse effects including severe high blood pressure and hemorrhaging. In 2008, the FDA gave bevacizumab provisional approval for metastatic breast cancer, subject to further studies. The FDA’s advisory panel had recommended against approval. In July 2010, after new studies failed to show a significant benefit, the FDA’s advisory panel recommended against the indication for advanced breast cancer. Genentech requested a hearing, which was granted in June 2011. The FDA ruled to withdraw the breast cancer indication in November 2011. FDA approval is required for Genentech to market a drug for that indication. Doctors may sometimes prescribe it for that indication, although insurance companies are less likely to pay for it. The drug remains approved for breast cancer use in other countries including Australia.

Clinical trials are underway for many other indications including ovarian cancer, pediatric osteosarcoma, and certain non-malignant eye diseases. In the curative setting (adjuvant therapy), clinical studies are underway in breast cancer and lung cancer.

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